C14.Renal system

Renal disease and its ultimate consequence - renal failure - represent important issues in the

health debate. Although it is now technically feasible to relieve or reverse renal failure, limits to

what can be done in practice arise from ethical issues surrounding the allocation of healthcare

resources and the organization of organ donation, issues that are under constant debate.

Chronic renal failure is potentially fatal and may condemn a patient to years of dialysis with a substantially reduced quality of life. Successful renal transplantation provides an almost complete solution and now has an extremely good outcome; however, society has not yet fully adjusted to the implications of organ donation. Regular controversies on the persistent vegetative state and ‘brain death’ testify to this.

This chapter first reviews the normal function of the kidney. Subsequently, the consequences of impairment of these functions, i.e. homeostatic imbalances and renal failure, are explained. Finally, the common clinical conditions that cause these abnormalities are discussed.

Physiological principles of the renal system

The kidney is both structurally and function-

ally complex, and plays a central role in home-

ostasis.  Thus,  many  possible  forms  of  renal

malfunction can cause a wide range of clinical

conditions.  Manifestations  of  renal  disorder

include  fluid,  electrolyte  and  pH  imbalances,

haemodynamic imbalance, the accumulation of

drugs,  toxins  and  waste  metabolic  products,

loss  of  essential  metabolites,  and  endocrine

abnormalities  such  as  anaemia  and  bone

disease.

Pathological   processes   such   as   infection,

inflammation,  auto-immunity,  neoplasia  and toxins  can  cause  structural  damage  to  the

glomeruli,  the  tubules  or  the  urinary  tract. Systemic or local circulatory insufficiency can also seriously compromise renal function. The most   common   pathologies   are   glomerular inflammation, urinary-tract infection and drug-

induced   nephrotoxicity.   In   this   section   we review the physiological principles of normal renal function, so that abnormalities of the renal system may be better understood.

Anatomy

The gross anatomy of the renal system is shown

in Figure 14.1. It is important to distinguish

between  the  kidneys,  which  are  structurally

complex, and the urinary tract, the function of

which is essentially the storage and transport of

urine.  Three  main  regions  are  distinguished

within the kidney: the cortex, the medulla and

the pelvis. The cortex contains the glomeruli

and the proximal and distal tubules, and the

medulla contains the loops of Henle. Glomeruli

in different areas have different-length loops of

Henle to permit differential control over urine

concentration. The loops of the juxtamedullary

nephrons (nearest the medulla) extend almost to

the pelvis, the area into which the formed urine

drains from the collecting ducts. Throughout the

kidney   there   are   interstitial   cells,   probably

concerned with endocrine functions.

Although kidney disorders are almost always

serious,  disorders  in  the  lower  urinary  tract

are  seldom  serious  in  themselves  but  often

symptomatically troublesome. However, chronic

obstructive problems in the lower urinary tract

may eventually cause damage to the kidneys.

The importance of the kidneys may be judged

from the fact that although they together weigh

just 500 g (less than 1% of body weight) they

receive 25% of the cardiac output. Thus renal

blood flow is about 1.2 L/min. Like many other

organs, the kidneys are modular, each having

about    1   million   functional   subunits   or

nephrons, each of which performs all the major

renal functions and which together provide a

total  filtration  area  of 1 m2.  This  represents considerable  functional  over-capacity  because

life can continue quite normally with one-half of

a single functioning kidney, i.e. only 25% of

nephrons functioning. Thus when the kidneys

are diseased, serious symptoms do not appear

until there has been over 90% damage; more-

over, such damage is often irreversible, making

treatment difficult.

Summary of renal functions

The kidney is the body’s key organ of overall

homeostatic control and its functions may be

considered in three main groups (Table 14.1).

Elimination of waste is usually the main func-

tion associated with the kidney, but the regula-

tory functions are equally important, and the

kidneys  are  also  involved  in  several  major

endocrine systems.

Elimination

The potentially toxic by-products of metabolism

must be excreted, along with excess nutrients and

any exogenous toxins absorbed from the gut and

their subsequent metabolites. Generally, elimina-

tion is passive, although certain substances are

actively secreted.

Carbohydrate metabolism, the major energy

pathway of the body, produces carbon dioxide

and water. Most carbon dioxide is eliminated

passively by the lungs, but the kidneys have far

more control in secreting it, in small but crucial

amounts, as acid. Although much of the water

produced by metabolism, along with that taken

in the diet, is lost through sweating, respiration

and insensible losses, once again the kidney

exercises  selective  control  to  maintain  water

balance.

The predominant nitrogenous waste product

is urea from protein metabolism and its level in

the blood provides a useful approximate index of

renal function. Nucleic acid breakdown produces

urate, which is actively secreted, and muscle

metabolism produces creatinine, which is also

used  as  an  index  of  kidney  function.  Some

sulphate  and  phosphate  are  also  released  by

protein metabolism. Urea is not as harmful as is

commonly  believed,  guanidine,  amines  and

other metabolites (phenols, hydroxyacids, etc.)

being more toxic.

The kidney also has a role in the catabolism of peptides, notably insulin.

Fluid and electrolyte balance

The kidney plays a crucial, active role in main-

taining the correct ionic, osmotic, pH and fluid

balances throughout the body. It detects imbal-

ances, secretes local regulatory hormones, and

actively excretes or retains substances as neces-

sary. One of the drawbacks of its interaction with

so many different systems is that there may occa-

sionally be conflicting demands, which can be

resolved  only  by  compromises.  For  example,

chloride may be variously regarded as an anion,

an acid or simply an osmotically active particle,

depending on circumstances. Controlling chlor-

ide to preserve electrical neutrality or osmotic

balance may compromise pH balance.

Water balance

The body is normally in positive water balance,

the kidney adjusting for varying intakes and

losses by altering water clearance. Certain irre-

ducible constraints enforce a minimum average

daily  intake  of  about 1 L   (Table 14.2).  The

kidneys  require  at  least 500 mL  of  water  to

excrete the average daily load of osmotically

active   waste   products   at   maximal   urinary

concentration, i.e. under maximal ADH stimula-

tion. This is just about balanced by the water

produced from the metabolic oxidation of carbo-

hydrates.  Thus  the  minimum  dietary  intake

needed  is  that  which  will  replace  insensible

losses   in   breath,   faeces   and   perspiration

(excluding additional or exertional perspiration).

Fluid compartments

The main fluid compartments of the body are

given  in  Figure 14.2.  The  intravascular  and

extravascular  components  of  the  extracellular

fluid (ECF) are in equilibrium by free diffusion,

except  that  plasma  proteins  cannot  usually

leave the blood. Although water diffuses across

cell  walls  passively  under  osmotic  forces,

there  are  membrane  pumps  effecting  the

flow of most other substances to and from the

intracellular  fluid (ICF).  However,  the  activity

of  these  pumps  is  largely  dependent  on

concentration  gradients.  Thus  the  kidney,  by

controlling  ECF  composition,  influences  all

compartments.

There  is  a  complex  and  subtle  interplay

between the maintenance of ECF osmotic pres-

sure, mainly through control of sodium concen-

tration,  and  the  total  volume  and  relative

distribution of fluid between the compartments.

The kidney also controls the plasma potassium

level and thus total body potassium. By selec-

tively varying the secretion of hydrogen ions

and reabsorption or regeneration of bicarbonate

the kidney can significantly alter plasma pH, and

thus body pH.

Endocrine functions

The  kidney  is  involved  in  three  important

systemic hormonal systems.

Blood pressure

Renal  involvement  in  blood  pressure  control

operates  via  a  number  of  mechanisms (p.

880).  This  is  partly ‘enlightened  self-interest’

because  the  kidney  cannot  operate  without

an  adequate  perfusion  pressure,  but  it  also

contributes  to  the  systemic  blood  pressure

control mechanisms.

Calcium            •  Size-elective    but    otherwise    indiscrimi-

The kidney is vital to calcium and bone metabo-            nate   ultrafiltration   across   the   glomerular

lism. In addition to being a target organ for

vitamin  D  and  parathormone,  the  kidney  is

responsible for the final stage in the activation of

vitamin D by hydroxylating 25-hydroxychole-

calciferol to 1,25-dihydroxycholecalciferol. An

overview of vitamin D metabolism is given in

Chapter 3, p. 150.

Erythropoiesis

In response to hypoxaemia, the kidney secretes

erythropoietin, which promotes RBC production

in the bone marrow. Without erythropoietin,

erythropoiesis cannot proceed efficiently and Hb

levels   stay   below       6-8 g/100 mL,   producing

anaemia. In certain less common renal diseases,

e.g. polycystic kidney and renal tumour, there is

erythropoietin over-production, with consequent

polycythaemia.

It can now be appreciated why renal failure is

so  serious.  In  acute  renal  failure (ARF)  it  is

mainly elimination and fluid/electrolyte regula-

tion that are affected. The patient suffers partic-

ularly from retention of excess water, acid and

potassium. In chronic renal failure, endocrine

malfunction  adds  other  problems,  including

hypertension,  bone  disease  and  iron-resistant

anaemia.

Mechanisms of elimination

The kidney goes about elimination in a seem-

ingly perverse and inefficient manner. Instead of

selectively  excreting  unwanted  substances  it

filters almost everything, and then selectively

reabsorbs what needs to be conserved. About

10%   of   the   total   renal   blood   flow,   i.e.

120 mL/min, is filtered at the glomeruli, along

with most low-molecular weight constituents:

this is the glomerular filtration rate (GFR). Some

99% of this 180 L/day is then actively reab-

sorbed, leaving an average daily urine volume of

only about 1.5 L. (This system may be a relic of

the aquatic era of the evolution of life, when the

large amounts of fluid and sodium that were lost

could easily be replaced.)

There are three main phases of elimination

(Figure 14.3):

membrane  from  plasma  into  the  tubular lumen to produce filtrate.

•  Active  reabsorption  into  plasma  of  useful

            substances in bulk, mostly from the proximal

tubule.

•  Selective secretion from plasma or reabsorp-

            tion into plasma of certain critical substances

in small amounts to maintain the fluid and

electrolyte  balances,  mainly  in  the  distal tubule and collecting duct.

To understand how certain diseases affect renal function, the factors that affect filtration and

the  patterns  of  reabsorption  and  secretion

must  be  briefly  reviewed.  This  simple  discus-

sion  will not distinguish between the cortical and juxtamedullary nephrons; unless otherwise stated, the former are usually implied.

Filtration

During glomerular ultrafiltration blood cells and

colloidal macromolecules, i.e. plasma proteins,

are retained but smaller molecules (crystalloids)

are carried through the glomerular basement

membrane (GBM) under hydrostatic pressure by

solvent  drag (convection).  Substances  with  a

molecular weight ÷5000 Da pass freely. Passage

decreases with increasing molecular size, espe-

cially  above  about 25 kDa;  only 3%  of  Hb

(64 kDa) would pass if it were free in plasma, and

less than 1% of albumin (minimum size approx.

70 kDa)  passes.  Anions  pass  less  easily  than

cations because the GBM is negatively charged,

but again this effect is only significant for larger

molecules.

Factors affecting glomerular filtration rate

The GFR is the key index of renal function

because if there is no filtration then none of

the  regulatory  mechanisms  that  act  on  the filtrate can operate. Figure 14.3 is a functional diagram of a nephron, which identifies the sites where factors which influence the GFR operate. Table 14.3 summarizes the clinical conditions under which these factors can become altered. This usually happens due to changes in filtra-

tion  pressure (especially  the  systemic  arterial pressure).  The   integrity   of   the   basement membrane is another important factor.

Perfusion.   The  kidney  strives  to  maintain

systemic arterial blood pressure, but failing that,

filtration pressure at the glomerulus is defended

by intrarenal mechanisms. Probably the most

common cause of ARF is when such mechanisms

are overwhelmed by severe systemic hypoten-

sion,  e.g.  from  haemorrhagic  or  cardiogenic

shock. Long-term damage to renal arteries, e.g.

arteriosclerosis   and/or   atherosclerosis   from

untreated hypertension, can cause chronic renal failure.

Renal autoregulation maintains renal blood

flow, filtration pressure and GFR over wide vari-

ations in renal perfusion pressure, principally by

alterations in the calibre of afferent and efferent

glomerular arteries. The afferent arterioles are

dilated by intrarenal PGs, while the efferent ones

are constricted by intrarenal angiotensin. In this

way the transmembrane hydrostatic pressure,

and hence GFR, is defended. One input to this

system is tubulo-glomerular feedback. If the GFR is altered, the consequent changes in the solute load of the glomerular filtrate are detected in the distal tubule by the juxtaglomerular apparatus (p. 879),   which   is   involved   in   intrarenal hormone systems.

Another   important   intrarenal   regulatory

mechanism is the potentially confusingly named

glomerulotubular balance. This is a second line

of defence if GFR is compromised beyond the

ability  of  the  primary  compensatory  mecha-

nisms to cope. It serves to preserve excretion of

water, sodium and other solutes in the face of

reduced GFR. It thus provides one aspect of renal

reserve,  delaying  the  onset  of  symptomatic

uraemia if renal function declines chronically.

The operation of these control mechanisms is

illustrated  by  the  adverse  effect  of  ACEIs  in

patients with obstructive lesions in both renal

arteries (bilateral   renal   artery   stenosis),   or

patients in whom renal perfusion is otherwise

compromised   by   hypovolaemia (low   blood

volume) or cardiac failure. In such cases optimal

renal perfusion is being maintained partly by

raised  levels  of  angiotensin  originating  from

the   renal   response   to   the   hypoperfusion.

Angiotensin  maintains  renal  blood  flow  by

causing intrarenal efferent arteriolar constriction

and  also,  possibly,  by  elevating  systemic  BP.

ACEIs, by blocking this protective mechanism,

may precipitate renal failure by causing a signif-

icant reduction in renal perfusion. Similarly, PG inhibitors, e.g. NSAIDs, can have an adverse

effect on renal haemodynamics, causing renal impairment and fluid retention.

Glomerular basement membrane.   The GBM

is a sensitive structure that is exposed to high

flow rates and high concentrations of potential

toxins and mediators. It can be damaged by

numerous   pathological   processes,   and   this

underlies many chronic renal diseases. If the

GBM is damaged, its permeability to large parti-

cles, especially smaller colloids such as albumin,

may be increased, causing proteinuria. In more

severe cases there may also be, paradoxically,

retention of water and sodium owing to a degree

of renal impairment (reduced GFR).

Simple variations in pore size cannot account

for these changes; porosity may be partly related

to  a  loss  of  the  negative  membrane  charge,

which  normally  repels  the  similarly  charged

plasma   albumin.   Normally   some   proteins

smaller than about 60-100 kDa are filtered, but

almost all are completely reabsorbed. However,

the   reabsorptive   capacity   is   low   and   soon

exceeded if there is an increase in tubular protein

concentration. The catabolism of filtered protein

within  the  renal  tubules,  which  is  normally

minimal, may be increased in the presence of

proteinuria to compensate.

Glomerular number.   In chronic renal failure,

diminishing renal function is believed to result

from a reduced number of fully active nephrons

rather than to a general decline in the function

of all nephrons (the ‘intact nephron hypoth-

esis’). A progressive loss of functional nephrons

is the main reason why the elderly have reduced

renal   function -   a   process   that   continues

throughout adult life. Normally about half of the

nephrons are lost by the age of 80 years.

Tubular back pressure.   Obstruction anywhere

along the urinary tract will inhibit filtration by

increasing the pressure within the tubule, which

reduces the filtration pressure across the GBM.

Such obstruction can occur within the tubules

themselves if they are damaged; in the renal

pelvis (in  pyelonephritis  and  some  forms  of

nephrotoxicity); or in the lower urinary tract

(owing to the presence of a ureteral stone or

bladder outflow obstruction).

Reabsorption and secretion

Clinically, the important features here are the

consequences   of   the   interlinked   exchange mechanisms that the kidney employs.

Overall pattern through nephron

Proximal   tubule.   The   glomerular   filtrate

contains  essential  nutrients  as  well  as  waste

matter.  Most  of  the  former  are  returned  to

the circulation by reabsorption from the prox-

imal   tubule   into   the   peritubular   capillaries

(Figures 14.3 and 14.4). There are specific pumps

for most substances, such as sodium, potassium,

bicarbonate, amino acids, glucose, etc. Water

follows   osmotically   and   chloride   electro-

chemically.  These  pumps  have  a  maximum

transport capacity, and if the filtrate concentra-

tion of a substance exceeds the capacity of the

pump the substance appears in the urine. The

plasma concentration of the substance is then

said to exceed its renal threshold. The most

common   example   of   this   is   glycosuria   in

diabetes mellitus.

Most nutrients, and about 70% of the filtered

water  and  electrolytes,  are  reabsorbed  proxi-

mally. Reabsorption depends largely on uncon-

trolled   bulk   transport,   necessitated   by   the profligacy   of   glomerular   filtration.   Osmotic diuretics act in this region by increasing the

osmotic pressure of the filtrate, which inhibits water reabsorption.

Some substances, especially acids and bases, are actively secreted in the opposite direction, from the peritubular capillaries into the prox-

imal tubule, e.g. uric acid and many toxins and drugs. This increases the clearance of molecules that have escaped filtration.

Loop.   The main function of the loop of Henle

is not to reabsorb water and electrolytes but to

generate an osmotic gradient between the renal

cortex (hypotonic) and the medulla (hypertonic)

by a countercurrent mechanism. This enables

the collecting ducts, which pass through this

gradient, to adjust urine concentration under

the influence of ADH. No more than 10-15% of

sodium, chloride and water are reabsorbed here.

The powerful loop diuretics, e.g. furosemide, act

by inhibiting this mechanism, preventing subse-

quent   attempts   at   concentration   by   the

collecting ducts.

Distal tubule.   In the distal tubule, and to a

lesser extent in the collecting ducts, there is the

potential  for  fine  adjustments.  Although  the

total amounts of solutes reabsorbed are not great

- no more than the final 10% of sodium and

water - this is where the kidney exerts its main control  of  electrolyte  balance.  The  thiazide diuretics inhibit this mechanism.

Selective control in distal tubule

The distal tubule is crucial to the homeostasis

of several important systems. If body sodium,

blood  volume  or  blood  pressure  is  low,  the

distal reabsorption of sodium, with chloride or

bicarbonate and some water, can be increased

by the action of the mineralocorticoid aldo-

sterone. Here, sodium does not carry with it

an iso-osmotic load of water, so the immediate

effect  is  a  net  increase  in  plasma  osmotic

pressure.

Aldosterone  also  inhibits  the  secretion  of

potassium into the urine, in response to body

requirements,  reabsorbing  it  in  exchange  for

sodium. The aldosterone-antagonist (potassium

sparing) diuretics, e.g. spironolactone, act here.

Potassium secretion is closely linked to that of

acid (hydrogen ions) because the same transport mechanism is used for both. However, acid secre-

tion is under a different, and therefore poten-

tially conflicting, control mechanism. This is

triggered by variations in plasma pH, which

affects the activity of tubular carbonic anhy-

drase,  thereby  altering  acid  production  and secretion in the tubules (p. 881).

Total  body  water.   If  the  body  is  fluid-

depleted   or  relatively  hypertonic,  ADH  is

secreted.  This  hormone  permits  passive  diffu-

sion  of  water  from  the  glomerular  filtrate  in

the distal tubule and collecting duct back into

the  peritubular  capillaries.  This  is  possible

because the ducts pass through the hypertonic

region of the renal medulla. Conversely, when

the body is relatively hypotonic or fluid over-

loaded,  ADH  secretion  is  inhibited,  water  is

prevented from leaving the ducts and a dilute

urine  is  produced.  In  diabetes  insipidus  ADH

secretion   is   deficient,   resulting   in   severe

polyuria.

There   will   be   occasions   when   conflicting

demands on the kidney mean that one adjust-

ment needs to be compromised to allow another.

Usually the maintenance of osmotic pressure is

paramount,  but  in  severe  hypovolaemia  the

defence  of  blood  pressure  by  fluid  retention

takes  precedence.  Three  consequences  of  the

main exchange mechanisms need to be empha-

sized, because they have important implications

for electrolyte imbalance and its management

(Figure 14.5):

1. Sodium is reabsorbed with either chloride or

            bicarbonate (to preserve electrical neutrality).

2. Sodium   is   exchanged   for   either   acid

(hydrogen ions) or potassium in the distal

tubule (cation exchange to preserve electrical neutrality).

3. All  acid  secreted  results  in  an  equivalent

            amount  of  bicarbonate  being  reabsorbed

(equimolar amounts, generated by carbonic anhydrase).

Potassium and pH balance

The amount of potassium that can be reabsorbed

in the distal tubule, where fine control is exer-

cised, is related to the amount of acid secreted

(Figure 14.5 (2)). To secrete acid in exchange for

sodium, the tubule must forgo the secretion of

potassium because potassium and acid use the

same transport mechanism; at the same time the

tubule must also reabsorb bicarbonate (Figure

14.5 (3)). Thus, as far as the kidney is concerned, potassium moves with alkali (this is easy to

remember if one associates K with KOH). There-

fore, when the body requires alkali, in the form of bicarbonate, it tends to accumulate potassium and when it wants to eliminate excess alkali,

potassium tends also to be lost.

Ordinarily this causes no problems, but the

transport mechanism may become saturated if

the demand is excessive. Competition between

potassium and acid then forces a compromise to

be made so that dyskalaemias (potassium imbal-

ances) are frequently associated with pH imbal-

ances. Thus, for example, if hypokalaemia is not

corrected alkalosis will eventually occur as the

kidney attempts to retain potassium by using

this exchange pump and in doing so it secretes

acid. Conversely, acidosis is often complicated

by hyperkalaemia.

Chloride and pH balance

Because alkali conservation (bicarbonate reab-

sorption) is linked to chloride excretion, in effect chloride moves with acid. However, plasma pH is determined primarily by the carbon dioxide/

carbonic acid/bicarbonate equilibrium (p. 881), the only anion here being bicarbonate. Thus, if bicarbonate is displaced from the plasma by

another anion, such as chloride, the resulting

fall in bicarbonate will cause acidosis.

Similarly, if there is a high tubular load of chlo-

ride then it may be used non-specifically as the

anion to accompany the reabsorption of impor-

tant  cations,  which  compromises  bicarbonate

reabsorption and produces a loss of alkali (Figure

14.5 (1)). Hence the tendency to hyperchloraemic

acidosis when chloride intake is abnormally high.

This  has  important  implications  for  fluid

therapy  with 0.9%  sodium  chloride  solution

(physiological   saline).   Compare   its   ionic

composition with extracellular fluid, e.g. plasma:

•  Physiological saline:   Na,      150 mmol/L;  Cl,

150 mmol/L (approx.).

•  Extracellular fluid:      Na,      150 mmol/L;  Cl,

100 mmol/L (approx.).

Thus 0.9% NaCl is by no means ‘normal’, and the

term ‘normal saline’ is now outmoded. Although iso-osmotic,  it  is  relatively  chloride-rich  and Figure   14.6.  Note  that  aldosterone  controls

prolonged  IV  administration,  in  the  standard

3 L/day regimen, eventually produces hyperchlo-

raemic acidosis. Conversely, prolonged diuretic

therapy, by increasing chloride loss, may produce

hypochloraemic  alkalosis (in  addition  to  a

hypokalaemic alkalosis). Conversely, a benefit of

simple physiological saline infusion is that it will

correct mild metabolic alkalosis, so that acidic

solutions,  e.g.  ammonium  chloride,  are  rarely

needed.

Sodium, potassium and pH

In a similar way, sodium imbalance is also likely

to be associated with both pH imbalance and

dyskalaemia (Figure 14.5 (2)). The rationale for

these associations is left to the reader to eluci-

date, applying the same principles as used above.

Homeostasis

Total body water and osmotic pressure

Control

The mechanisms for the control of fluid volumes

and extracellular osmotic pressure are comple-

mentary and interdependent. The volume of

water in the body (total body water, TBW) is

determined by the total amount of osmotically

active substances. Normally, water clearance is

adjusted to maintain a uniform osmolar concen-

tration approximately equivalent to twice the

plasma   sodium   level.   Sodium   levels   are

controlled by the renal regulation of tubular

reabsorption. The distribution of water between

the intracellular and extracellular compartments

(plasma plus tissue fluid) is also primarily deter-

mined by osmotic forces, the osmotic pressure

within cells normally being about the same as

that of plasma.

Because TBW is usually distributed optimally,

it is only necessary for the body to monitor one

compartment for it to regulate all. Blood volume

is the most ‘accessible’ because this is reflected in

blood pressure. This is monitored in several ways

with  feedback  to  renal  control  mechanisms

(p. 880).

The inter-relationship between adjustments of

plasma osmolarity and body water is shown in

sodium reabsorption, but does not affect blood

pressure  directly.  Aldosterone  serves  only  to

change plasma osmotic pressure, because the

sodium reabsorption under aldosterone control

is not accompanied by an iso-osmotic amount of

water. The feedback loop is completed by ADH,

which adjusts water reabsorption as appropriate.

Thus  volume  imbalance  causes  changes  in electrolyte reabsorption via aldosterone, whereas osmotic imbalance causes changes in water reab-

sorption via ADH. This interdependence of the two systems permits very fine control.

Imbalance

The juxtaglomerular apparatus (JGA) is an area

of specialized tissue strategically located between

the afferent and efferent glomerular arterioles

and  beginning  of  the  distal  tubule  in  each

nephron, and in contact with all three (Figure

14.6). The JGA can thus detect changes in pres-

sure in the afferent arteriole (usually propor-

tional   to   systemic   arterial   pressure)   and

consequent changes in tubular filtrate flow and

concentration. It can then attempt to rectify any

fall in BP by the secretion of renin, which causes

the   activation   of   both   systemic       (plasma)

angiotensin  and  local  mechanisms  involving

intrarenal angiotensin and vasodilatory PG.

In order to see how this system functions,

consider the consequences of haemorrhage or

severe diarrhoea. The iso-osmotic volume loss

(hypovolaemia) causes a fall in BP. In response,

the  JGA  secretes  renin,  aldosterone  increases

sodium reabsorption, and plasma osmotic pres-

sure   rises.   This   promotes   ADH   secretion,

increasing   tubular   water   reabsorption   and

restoring TBW. Conversely, in hyponatraemia

the osmotic imbalance initially causes reduced

water reabsorption and increased urine volume

(via ADH), tending to normalize osmotic pres-

sure at the expense of TBW, blood volume and

BP. Subsequently the systems once again interact

gradually to restore all parameters.

Thirst  is  a  relatively  crude  mechanism  for

replenishing  both  electrolyte  and  fluid  loss,

because there is little control over the composi-

tion of intake. This loosely controlled process

requires the kidney to make the appropriate fine

adjustments.

Blood pressure control

The main ways in which the kidney is involved in maintaining BP are briefly summarized here and discussed fully in Chapter 4.

Simple pressure natriuresis

If BP changes, a complex interplay of autoregu-

latory   variations   in   glomerular   blood   flow

and/or  tubular  reabsorption  makes  compen-

satory changes in urine volume. Thus, a fall in

BP will cause an automatic fall in urine volume,

the fluid retained tending to restore BP. Gener-

ally the GFR is maintained constant so as not to

compromise excretory functions; the principal

mechanism  for  this  is  a  change  in  tubular

reabsorption.

Renin/angiotensin/aldosterone and the

osmoreceptor/antidiuretic hormone systems

These are discussed above.

Atrial natriuretic factor

Rises  in  blood  volume  can  be  detected  by

increased  pressure  in  the  atria  of  the  heart,

which secrete a peptide, atrial natriuretic peptide

(ANP) that acts in the kidney to promote water

loss (by preventing reabsorption). ANP seems to

play a role in unloading the heart in heart failure

(see Chapter 4).

Acid-base balance

Acid  generated  by  metabolism,  plus  dietary

intake, means that the body is in strongly posi-

tive acid balance. This presents three problems:

elimination  of  the  excess,  defence  of  pH  in

plasma and throughout body water, and the

ability to adjust for unexpected variations in acid

or alkali input or loss. The vast bulk of the excess

is eliminated by the lungs; blood buffers defend

pH; and the kidney adjusts for variations.

Respiratory compensation         index of carbon dioxide accumulation: the prin-

Most  of  the  carbon  dioxide  produced  by  the          cipal role of this mechanism is the maintenance

aerobic metabolism of carbohydrate is eliminated

routinely by the lungs (about 15 000 mmol of

acid  per  day; Figure 14.10).  Yet  despite  their

massive  capacity, the lungs can only be used

temporarily to adjust for unwanted changes in

acid level. If excess acid is produced, prolonged

fast breathing to eliminate it is exhausting, and

the extra energy used produces yet more carbon

dioxide. Conversly, to compensate for alkalosis

by  reducing  respiration  cannot  be  achieved

without causing hypoxaemia. Moreover, the net

effect of respiratory adjustments is to produce

absolute  increases  or  falls  in  blood  buffering

capacity. Nevertheless, the lungs provide impor-

tant  rapid  primary  respiratory  compensation.

This can be judged from the fact that, in the

absence of initial pH imbalance, if respiratory rate

were reduced to 25% of normal, blood pH would

soon fall to 7.0. Indeed, this is the pathogenesis of

respiratory acidosis, which occurs when a respira-

tory abnormality impairs elimination of carbon

dioxide.

Renal compensation

It is the kidney that makes the long-term adjust-

ment for abnormal changes in pH (assuming it is

not itself the primary cause of the problem) by

appropriate   changes   in   acid   secretion   and

complementary bicarbonate regeneration. The

kidneys  normally  secrete  only  a  small,  but

crucial,  amount  of  acid:  on  average  about

100 mmol per day. However, this can be varied

considerably to compensate for dietary or meta-

bolic imbalance or respiratory impairment. This

secondary renal compensation is delayed and

slow, but can work indefinitely. A consequence

is that in renal failure, metabolic acidosis is a

major problem.

Control of this important process is essentially

autonomous and passive. Carbonic anhydrase in

the tubular cells is simply responding to the law

of mass action: as the plasma level of carbon

dioxide rises, more is hydrolysed and conse-

quently more acid is secreted and bicarbonate

regenerated.  There  is  no  central  or  humoral

control but the proper functioning of the tubules

is of course essential. Respiratory function on the

other   hand   is   very   tightly   controlled   by

medullary receptors sensitive to pH. However,

pH is used by the respiratory centre merely as an

of blood oxygen level.

Plasma pH

Plasma pH is determined by the ratio of bicar-

bonate  to  total  carbon  dioxide (free  carbon dioxide plus carbonic acid):

[bicarbonate]

pH       ___________________          (14.1)

[carbon dioxide]

This ratio is determined by the equilibrium

position of the hydration of carbon dioxide,

which is catalysed by carbonic anhydrase in

kidney tubules and all body cells:

carbonic

anhydrase

CO2    H2O    H2CO3            HCO3  H

Although  other  ions,  e.g.  phosphate  and

ammonium,  are  involved,  this  hydration  is

essentially the process that occurs in the tubules

as acid is secreted and bicarbonate reabsorbed or,

more correctly, regenerated. Further, both fat

metabolism and the anaerobic metabolism of

carbohydrate  produce  ketoacids (acetoacetate,

lactate, etc.) and protein metabolism results in

the  production  of  sulphate  and  phosphate.

These non-volatile acids must also be eliminated

by the kidney.

Maintaining pH homeostasis

To maintain blood pH at 7.4 ± 0.05, the mecha-

nisms  described  above  work  in  concert,  as

follows:

•  Small natural changes (most commonly falls)

            are  initially  countered  by  the  blood  buffer

system.

•  If this is insufficient, the respiratory centre

            responds rapidly by altering respiratory rate

to increase the retention or elimination of

carbon dioxide, thereby adjusting the bicar-

bonate/acid   ratio   and   returning   pH   to

normal. This happens whether or not the

initial cause was actually a change in carbon

dioxide level.

•  Finally,   renal   compensation   will   slowly

            restore the absolute as well as the relative

            levels of acid and bicarbonate.

Clinical features and investigation of renal disease

The clinical features of renal dysfunction are

either changes in urine flow and composition, or

systemic features secondary to failure of renal

mechanisms. The spectrum of clinical features in

renal failure in particular are considered in detail

when this topic is covered below (p. 897).

Symptoms

Patients readily associate symptoms arising in the lower urinary tract as renal in origin. However, as a consequence of the imbalances caused by renal malfunction, symptoms may arise in any body system and may at first be obscure and seem

unrelated to the renal system.

Urinary symptoms

Some of the common urinary symptoms and

their possible clinical implications are summa-

rized in Table 14.4. While micturition abnormal-

ities usually result from the lower urinary tract,

persistent abnormalities of urine volume imply a

more serious aetiology. Oliguria is defined as less

than 500 mL of urine per day. This is because it

is the minimum volume required to carry the

average daily osmotic load of waste matter at

maximal urine concentration; any less implies a

degree  of  malfunction.  However,  the  precise

value  for  an  individual  will  vary  somewhat

depending on diet, body size and fluid intake.

Systemic features

Volaemic and osmotic imbalance

Fluid   and   electrolyte   imbalance   commonly result from renal impairment. Fluid imbalance generally has haemodynamic consequences with cardiovascular features such as changes in BP, oedema, shortness of breath, etc. Osmotic imbal-

ance usually results in neurological features, e.g. drowsiness, convulsions, because of changes in the intracranial pressure; (see below).

‘Uraemia’

This term, implying high levels of blood urea, is

a traditional synonym for renal failure; another

is azotaemia (high levels of nitrogenous prod-

ucts). Sometimes the former term is used more

specifically for the clinical picture and the latter

for the biochemical picture. These contribute to

the general malaise, lethargy, pruritus, cramps,

peripheral   tingling,   nausea,   vomiting   and

anorexia of which patients frequently complain.

However,  the  clinical  consequences  of  renal

failure extend far beyond the immediate effects

of high blood levels of urea or other nitrogenous

metabolic waste products. In addition, pH imbal-

ance and abnormalities of sodium, potassium

and other substances cause specific symptoms

that will be discussed in the appropriate sections

below.

Signs, examination and investigation

Urine

Much information on kidney function can be

inferred by looking for evidence of the conse-

quences of suspected malfunction. This is gener-

ally easier, less invasive and often more sensitive

and investigation of renal disease           883

measure of its efficiency. However, direct measure-

ment of this rate is difficult and so the concept of

clearance is utilized. Clearance is defined as a

hypothetical  volume  of  blood  from  which  a

substance would be completely removed by filtra-

tion in 1 min. It is calculated by measuring the

blood or plasma concentration of the substance,

urine flow rate (usually measured over 24 h to

minimize collection errors) and the urine concen-

tration of the substance. The clearance is given by:

Urine concentration       Urine

flow rate

than examination of the kidneys directly. Useful

qualitative and semi-quantitative information is

given by microscopic or chemical examination

of the urine. Simple biochemical urine tests,

valuable for preliminary screening, can nowa-

days be done using dipsticks, and should be part

of a routine clinical examination (Table 14.5).

Renal function

More accurate measurements are required for the

diagnosis,  staging  and  monitoring  of  serious

disease,  or  when  drug  dosage  adjustment  is

required.

Filtration and clearance

Because the principal function of the kidney is

filtration, the rate at which this occurs is a crucial

Clearance

Plasma concentration

We   know   that   approximately  120 mL   of

filtrate  is  normally  produced  each  minute.  If

a  substance  were  completely  filtered  at  the

glomerulus and subsequently neither reabsorbed

from the tubules nor secreted into them, then

the equivalent of 120 mL of blood would be

completely cleared of the substance each minute

and its clearance would be 120 mL/min. Inulin

fulfils these criteria, but it is usually more conve-

nient  to  exploit  creatinine,  a  natural  body

constituent,   which   very   closely   does   so.

Creatinine clearance is thus the usual index of

GFR. (Creatinine is actually secreted to a small

extent in the tubules, so its clearance gives a

slightly   high   estimate   of   GFR;   fortuitously

however,   current   laboratory   measurement 

slightly overestimates plasma creatinine, tending to cancel this out.)

Creatinine clearance measurement involves a

tedious and error-prone 24 h urine collection.

Hence, a single serum creatinine measurement

will often suffice because the serum creatinine

level depends on the balance between produc-

tion (which  is  dependent  on  muscle  mass,

gender and age and is normally constant for an

individual) and renal output (which is directly

proportional to filtration rate). Creatinine clear-

ance can be calculated from the serum creatinine

level alone by correcting for age, sex and weight

using tables or a simple formula:

Creatinine         (140     Age)    Weight

applicable to those under 18, obese, oedematous,

pregnant or with severly reduced muscle mass

(e.g.  undernourished  or  cachexic).  Creatinine

levels can also be affected by external factors

(Table 14.6) and there are also ethnic variations.

Other formulae have been devised to allow for

ethnicity or diet, avoiding using weight as a

parameter, e.g. the ‘modification of diet in renal

disease’ (MDRD) formulae, which gives a direct

estimate of GFR.

Unfortunately, serum creatinine does not start

to rise significantly until there is serious renal

impairment,  so  early  renal  disease  is  easily

missed if this method is relied upon. This is

because early renal damage is often compensated

by hypertrophy and hyperfiltration of remaining

clearance

K

            Serum creatinine

nephrons, which maintains clearance. Further-

more, the serum creatinine level is inversely

related to GFR, and the effect of this reciprocal

where age is in years, weight is ideal body weight

in kg, serum creatinine in micromol/L and the

correction factor K is 1.04 for females and 1.23

for  males.  This  is  the  Cockroft  and  Gault

formula. Creatinine clerance normally falls with

age as nephrons are lost, and it is lower in

females because of lower muscle mass. Thus, for

example, a normal value for a 75-year-old female

would be about 50 mL/min, whereas for a 25-

year-old  male  it  would  be 100-120 mL/min.

Because of the population sample from which

the formula was originally derived, it is not

relationship, illustrated in Figure 14.7, is that

quite large early falls in GFR will cause relatively

small absolute rises in creatinine. For example,

when the GFR has fallen to 50% of normal

(60 mL/min), creatinine level doubles to only

about 200 micromol/L,   not   far   outside   the

normal  range.  Subsequently  it  starts  to  rise

sharply, e.g. fourfold normal when GFR falls to

25% and 10-fold normal when GFR fall to 10%.

Thus serum creatinine cannot be relied upon

to detect moderate renal impairment. Its main

value in renal disease lies in monitoring the decline in renal function of a known sufferer

from chronic kidney disease, following a single

initial full creatinine clearance measurement to

establish the relationship to serum creatinine in

that particular patient. Progression can best be

followed by plotting the reciprocal of creatinine

clearance: the slope of the resulting straight line

indicates the rate of decline of renal function.

Any change in this slope requires investigation.

Furthermore, an extrapolation can be made to

indicate  the  time  when  GFR  will  fall  below

10 mL/min, and thus to predict when a patient will probably require some form of renal replace-

ment therapy (Figure 14.7).

Blood urea measurements suffer from similar

but more diverse limitations. Blood urea levels

are  affected  acutely  by  dietary  variations  in

protein intake, by skeletal muscle damage and by

catabolic states, e.g. fever or starvation. It is

therefore   less   reliable   than   creatinine   in

reflecting  GFR.  Nevertheless,  blood  urea  is  a

traditional general index and first approxima-

tion  of  renal  function  and  malfunction (the

routine ‘urea and electrolytes’ or ‘U and E’s’).

Other markers that are cleared without reab-

sorption or secretion (e.g. Iohexol, cystatin C)

are being investigated but are not yet in routine

use. Radioisotope clearance may also be used,

and investigation of renal disease           885

e.g. labelled EDTA. If precision is required, inulin

clearance can be determined by serial measure-

ment of the fall in plasma concentration at

timed intervals following a bolus injection; this

pharmacokinetic method avoids urine collection

errors.

Tubular function

Urine  concentrating  ability  can  be  tested  by

subjecting  the  patient  to  water  deprivation.

Inability to conserve water, manifested clinically

as polyuria, may be an early sign of chronic renal

disease. ADH can be used to establish whether it

is of pituitary origin, e.g. diabetes insipidus, or is

nephrogenic, e.g. tubular disease, nephrogenic

diabetes insipidus. Giving an acid or base load

can be used to test the kidney’s ability to secrete

or conserve acid, i.e. its urine acidifying ability.

General secretory function is tested with a

substance that is completely cleared in one pass through the nephron owing to maximal tubular secretion, e.g. para-amino hippuric acid (PAH). The secretion of specific metabolites can if neces-

sary be tested by giving known loadings. This might be helpful, e.g. in distinguishing diabetes mellitus from renal glycosuria, a rare condition of reduced glucose threshold.

Blood chemistry

The above tests can give precise measures of

discrete renal functions, but in practice it is the

consequences of impaired function that are clin-

ically important. The best indices are thus the

plasma  levels  of  the  metabolites  and  toxins

normally cleared renally. In addition to urea and

creatinine,   routine   measurement   of   plasma

sodium, potassium, bicarbonate, calcium, phos-

phate and pH is vital in estimating and moni-

toring renal function, although of course the

plasma levels of these substances may be altered

by other factors and disorders.

Imaging

Ultrasound will show the size and position of

the  kidneys  and  bladder;  this  technique  has

replaced plain abdominal X-ray and IV contrast

radiography (urography) as the first-line investi-

gation because it is cheaper and less invasive.

Enlargement of both kidneys suggests polycystic

disease,  while  unilateral  enlargement  implies

obstruction.  Shrunken  kidneys  imply,  non-

specifically,  advanced  chronic  renal  disease.

Calcified  deposits (stones)  in  the  kidney  or

ureters will also be visible. Doppler ultrasound

can  be  used  to  visualize  arterial  supply  and

intrarenal blood flow; this is less invasive than

the alternative, angiography, although the latter

gives much more reliable and complete infor-

mation. CT and MRI scanning are also used to

examine intrarenal structures.

An IV excretory urogram (IVU; formerly intra-

venous  pyelogram  or  IVP)  uses  an  X-ray

contrast medium to produce a series of images

which  will  show  any  inequality  of  perfusion

between  the  kidneys,  the  rate  and  extent  of

renal filling, internal renal structural abnormal-

ities, e.g. cysts, and the patency and complete-

ness  of  voiding  of  the  lower  urinary  tract.

However,  patients  may  react  badly  to  iodine-

containing  contrast  media.  Isotope  urography

yields similar information and is potentially less

toxic, although less readily available. In ante-

grade urography a needle is introduced into the

renal   pelvis     (nephrostomy)   and   contrast

medium injected, giving a picture of the whole

urinary outflow pathway.

The lower urinary tract can be visualized by

retrograde  urography  to  investigate  possible

obstruction; the contrast medium is adminis-

tered via a urethral catheter. There is a significant

risk of introducing infection, but the technique

may still be used if the patient cannot tolerate IV

contrast media. The lower urinary tract may also

be investigated with a fibre-optic cystoscope,

which also permits biopsy samples to be taken.

However, biopsies of the renal mass must be

taken   percutaneously.   They   are   particularly

useful in the differential diagnosis of nephritis

and in assessing transplant rejection.

Fluid and electrolyte imbalance

Only a general outline of the principles of this complex topic are given here. The References and further reading section lists some excellent specialist texts.

Volume and osmotic imbalance

Because control of total body water and plasma

osmolarity  are  closely  linked  there  are  often

coexisting imbalances. There is seldom a simple

loss or excess of either water or sodium, but if so

the  result  would  be  a  mixed  disorder,  e.g.

primary (pure)  water  depletion  would  cause

hypovolaemia with hypernatraemia. Moreover, a

patient’s observed biochemical status may be

due to the primary problem, to inadequate or

incomplete compensation, or to treatment. For

example, water and sodium loss from excessive

sweating, over-compensated by drinking hypo-

tonic fluid (e.g. pure water) will at some stage

cause both hypervolaemia and hyponatraemia.

Aetiology

Some of the possible combinations of volume

and   osmotic   imbalance   and   their   possible

primary causes are summarized in Table 14.7.

Water imbalance

Water depletion occurs either through excessive

losses or deficient intake. As water depletion

causes severe thirst, it will usually only become

serious  when  thirst  cannot  be  satisfied.  The

degree of associated hypernatraemia will depend on salt intake and the effectiveness of renal

compensation  by  fluid  retention.  The  main causes of water excess are renal, although excess fluid  intake  may  produce  a  hypervolaemic, hypo-osmolar state.

Sodium and osmotic imbalance

Sodium imbalance is rarely the direct result of

either excess or deficient sodium intake. More

usually it reflects either compensated primary

water imbalance or a renal sodium handling

defect.

Plasma sodium concentration gives a valuable

index of the relative excess or deficit of sodium

and water and thus of the underlying cause of

any fluid or electrolyte imbalance. However, the

plasma sodium level must always be interpreted

in association with the haemodynamic status and

haematological parameters. Thus hypovolaemia

from isotonic fluid loss (e.g. from burns) would

not cause a sodium imbalance, but would raise

packed cell volume, whereas predominant water

depletion  (e.g.  from  vomiting)  would  lead  to

hypernatraemia. Net sodium loss, e.g. dehydra-

tion and inappropriate (hypotonic) replacement,

would result in hyponatraemia.

Generally,   sodium   imbalance   implies   an

osmotic imbalance. However, in some circum-

stances other osmotically active substances can

first appear in the plasma in abnormal amounts

and  the  sodium  level  will  then  be  adjusted accordingly.  For  example,  in  diabetic  hyper-

glycaemia or severe uraemia, sodium will effec-

tively be displaced from the plasma by glucose

or  urea,  giving  a  secondary  or  appropriate

hyponatraemia. Thus, abnormal plasma sodium

measurements  may  reflect  neither  abnormal

sodium  balance  nor  true  plasma  osmolarity.

Further complications can arise in hyperlipid-

aemia or hyperproteinaemia when the aqueous

fraction of plasma is reduced. This is not taken

into account by the usual sodium measurement

techniques, and so the sodium level will appear

low  even  though  it  is  actually  in  isotonic

concentration in the plasma water; this is termed

‘pseudohyponatraemia’.

Pathophysiology

The consequences of fluid or osmotic imbalance are far-reaching, which is why the body defends normal balances so strongly. In general, fluid

imbalance   has   haemodynamic   consequences while  osmotic  imbalance  causes  neurological complications (Figure 14.8).

Volume imbalance

Even small changes in the intravascular (blood)

volume can affect BP, cardiac performance and

tissue perfusion. In contrast, the intracellular

and the extracellular (extravascular tissue) spaces

can tolerate quite large changes. The tissues most

affected will be those under least external pres- sure opposing fluid redistribution. These include

soft tissues and areas where hydrostatic forces

increase diffusion from the capillaries into the

tissues, e.g. in dependent areas such as the ankles.

This is one mechanism of oedema formation.

Usually, oedema is without ill effect, except in

the lungs, where pulmonary oedema is always

dangerous.

Isotonic  changes  in  total  body  water  will

usually be restricted to the ECF, i.e. plasma and

tissue fluid, because sodium movement into cells

across cell membranes is restricted. Changes in

free water, e.g. excess of hypotonic fluid, or water

with a solute such as glucose which is normally

diffusible across cell membranes, will be distrib-

uted throughout all body fluid compartments.

Thus in either case, but especially in the latter, the

haemodynamic consequences will be buffered,

delayed  and  less  severe:  even  if  the  water  is

initially in the plasma (e.g. over-infusion, renal

retention) most of it will diffuse out into the

extravascular space. Moreover, most intravascular

water will be accommodated by the capacitance

vessels, i.e. the veins, so the effect on BP and

cardiac  loading  will  be  reduced (Chapter 4).

Nevertheless, hypervolaemia is a common cause

of cardiovascular problems, e.g. decompensated

heart failure.

Osmotic imbalance

If there is an acute osmotic imbalance between

the extracelular and intracellular compartments,

water will diffuse passively under osmotic forces.

Plasma and tissue fluid that is hypertonic rela-

tive to ICF will draw water from all body cells,

causing  intracellular  dehydration.  Conversely,

hypotonic ECF will overload cells with water.

Small changes in the intracellular volume of

most tissues are of little consequence, but the

brain  is  an  exception.  Because  the  brain  is

contained within the rigid skull, small changes

in volume will alter intracranial pressure, and

quite small alterations in this pressure can have

serious neurological effects, potentially resulting

in coma or death.

These effects only occur after acute changes;

compensatory mechanisms eventually tend to

correct the imbalance. Aldosterone and ADH will

restore   extracellular   osmotic   pressure   by

adjusting  sodium  clearance,  and  brain  cells

and investigation of renal disease           889

threatened with dehydration can manufacture

osmotically active substances intracellularly to retain water.

If plasma oncotic (colloid osmotic) pressure is

reduced owing to hypoproteinaemia, there will

be a disproportionate loss of water to the tissues.

Although the absolute osmotic differences are

relatively small the resultant oedema can some-

times   be   gross,   as   in   nephrotic   syndrome

(p. 939).

Clinical features

The  combination  of  signs  and  symptoms

presented by a patient will depend on the primary

cause,  the  main  volaemic (haemodynamic)

or  osmotic (neurological)  consequences  and

secondary effects or compensations. The acute

effects before compensation are summarized in

Table 14.8.

Management

Degree and speed of intervention

The first step is to ascertain the cause of osmotic

imbalance. If the situation is not critical, i.e.

there are no severe neurological problems or

pulmonary oedema, correction of the cause will

often be sufficient. If there is no underlying renal

disease the body is able to reverse most imbal-

ances eventually. Otherwise, minimal interven-

tion with the very simplest of corrections may

suffice. More specific measures usually need be

taken only when there is renal impairment.

Great care is needed, even with simple correc-

tion. All interventions, whether by the oral or

the  parenteral  route,  initially  alter  only  the

volume or concentration of the plasma. Equili-

bration between intravascular and extracellular

fluid occurs quite rapidly, but several hours are

needed for equilibration between the extracel-

lular and intracellular compartments. Thus, too

rapid a correction will cause a disproportionate,

potentially dangerous initial change in plasma

osmolarity or blood volume and result in an

overshoot, e.g. hyponatraemia treated too vigor-

ously  with  hypertonic  saline  may  cause  an

equally harmful hypernatraemia.

Conversely,   if   therapy   is   too   delayed,

compensation will have already been initiated - particularly in the brain - and correction may

then have an opposite effect. For example, if

plasma is hypertonic for too long, brain cells will also become hypertonic. At that stage, rapid

attempts  at  correction  with  hypotonic  fluids may then cause CNS over-hydration and raised intracranial pressure.

Fluid dose estimation and monitoring

Various formulae are available for calculating

fluid and electrolyte deficits and the amounts

needed for correction from electrolyte measure-

ments. However, these can only be used for

initial guidance. Subsequently, it is far more

important to observe the effect of initial therapy

and make appropriate adjustments according to

the patient’s physical signs and haemodynamic

and biochemical status.

The main measures used in monitoring water balance and general hydration, which must be considered together, are:

•  Sodium concentration.

•  Blood pressure (or preferably CVP). •  Packed cell volume.

Secondary considerations include:

•  Urine volume.

•  Possibility of pH imbalance.

Specific therapy

Dehydration and hypovolaemia.   Mild volume

deficit, especially of gastrointestinal origin, may

be corrected with glucose-electrolyte oral rehydra-

tion salt solutions if the patient is able to drink.

Severe volume depletion with circulatory insuffi-

ciency  requires  IV  therapy,  and  physiological

saline is usually satisfactory. Restoration of urine

output is the best index of success. Physiological

saline infusion should not be continued unneces-

sarily  because  it  can  lead  to  hyperchloraemic

acidosis (p. 878).

Hypernatraemia.   If neurological involvement

is threatened, the logical treatment would be a

sodium-reduced fluid. Sodium chloride 0.45% or

weaker solutions are available, but dextrose 5% is

probably better. This is isotonic on injection but

yields pure water once the dextrose is metabo-

lized. Dextrose 4% plus sodium chloride 0.18%

(‘dextrose saline’) is similar but provides some

sodium. Nevertheless, sodium chloride 0.9% is

often adequate if renal function is unimpaired.

Because  the  aim  is  a  gradual  reduction  of

osmotic   pressure,   the   small   diluting   effect

produced  is  temporarily  beneficial  until  the

kidneys can make the necessary compensation.

Hypervolaemia.   If mild, this can be treated by simple water restriction. In severe cases with pulmonary oedema or threatened cardiac failure, a diuretic is needed.

Hyponatraemia.   Mild hyponatraemia can be

treated orally with sodium chloride, but more

aggressive action is needed if cerebral oedema

develops.   Temporarily,   a   poorly   diffusing

osmotic  diuretic  such  as  mannitol  may  be

infused  to  elevate  plasma  osmotic  pressure.

Corticosteroids such as dexamethasone are also

advocated but neither the mechanism nor the

benefit is clear. Such cases may be treated - very

cautiously - with hypertonic sodium chloride,

with a concentration of up to 5% being used.

Inappropriate secretion of ADH can be treated with demeclocycline. The treatment of diabetes insipidus is not considered here.

Potassium imbalance

Pathophysiology

Distribution of body potassium

Most body potassium (K ) is either within the

cells or in bone (Figure 14.9). Extracellular fluid

K , as measured in the plasma, represents only a

very small proportion of total body load. Yet it is

that which has the greatest physiological impor-

tance,   being   involved   in   maintaining   the

membrane  potential  of  all  cells.  Changes  in

plasma K  of more than             2 mmol/L can have

serious effects on nerve and muscle function,

especially in the heart. The terms hypokalaemia

and investigation of renal disease           891

and hyperkalaemia refer specifically to plasma level abnormalities, and say little about total

body potassium balance.

Bone potassium is exchanged very slowly and

so plays little part in acute changes. The ICF acts

as a reservoir and buffers plasma potassium so

that considerable variations in total body potas-

sium can occur before the plasma level changes:

up to 200 mmol can be lost from the cells with no

appreciable change in plasma K . Despite plasma

level being a poor index of potassium status it is

the only easily accessible direct measure avail-

able.  Any  related  pH  imbalance  must  also  be

taken into account when interpreting plasma K

levels.

Homeostasis

Extracellular  K   is  in  equilibrium  with  the

ICF,  an  unequal  distribution  across  the  cell

membrane  being  maintained  by  the  sodium

(Na -K  exchange) pump. Cellular uptake of K

is promoted by an alkaline plasma (pH 7.4),

aldosterone, adrenaline (epinephrine) via beta-

receptors, and insulin.

A rise in plasma K   causes insulin release,

which promotes the uptake of glucose and K  by

cells. Whether this is a co-transport mechanism

or simply the supply of extra energy for the

pump itself is not known, but it provides a

useful  therapeutic  strategy  in  hyperkalaemia.

Conversely, acidic conditions, lack of insulin,

beta-blockers and the absence of aldosterone,

inhibit K  uptake and may cause hyperkalaemia.

These  factors  have  a  special  significance  in

renal tubular cells where they control not only

the  intracellular/extracellular  distribution  but

also  total  body  potassium.  When  the  filtrate

reaches the distal tubule almost all potassium

has been reabsorbed. If plasma K  is too high,

aldosterone  causes  the  distal  tubule  cells  to

remove K  from the plasma and secrete it into

the tubular fluid (urine), in exchange for Na .

Further,  as  has  been  shown  (p.  878),  because this  same  transport  mechanism  mediates  acid

secretion,  secondary  acid-base  imbalances  can

arise.

Aetiology

Gross abnormalities in total body potassium,

which may or may not be reflected in plasma

level changes, must be recognized in addition to

clinically  significant  hypokalaemia  or  hyper-

kalaemia. Because K  is not metabolized, total

body  imbalance  arises  from  abnormalities  in

either intake or loss (Table 14.9). Acute changes

will affect the plasma level, but more protracted

changes will at first be compensated by the intra-

cellular pool. Acute plasma potassium imbal-

ances may also arise from disturbed intracellular/

extracellular distribution, with no net change in

total body K .

Hypokalaemia

Normally  the  body  is  in  positive  potassium balance.  Daily  renal,  faecal  and  sweat  losses rarely  exceed 40 mmol,  and  a  healthy  diet

provides 50-100 mmol. However, a diet which is deficient in fresh fruit and vegetables can cause potassium deficiency.

Most  diuretics  cause  some  potassium  loss,

partly by presenting more filtered sodium to the

distal tubule. The kidney tries to compensate for

the enforced natriuresis by reabsorbing more

Na ,  and  in  doing  so  exchanges  it  for  K .

Although neither diet nor diuretics alone usually

cause  clinically  significant  hypokalaemia,  the

combination may be serious, especially in the

elderly.

Alkalosis affects the plasma potassium level in

two ways. It directly promotes cellular uptake of

K  and it causes the kidney to conserve acid by

reabsorbing it distally in preference to K . This

increases   K   loss   and   can   exacerbate   the

hypokalaemia.

Aldosteronism  (excess mineralocorticoid

activity)   can   present   in   various   ways,   e.g.

Cushing’s  disease,  Conn’s  syndrome,  cortico-

steroid   therapy,   heart   failure   or   hypopro-

teinaemia (e.g. from hepatic disease or nephrotic

syndrome). In the last two conditions, reduced

BP and/or circulating fluid volume activate the

RAAS, causing excess aldosterone secretion with

Na  retention and K  loss.

Gastrointestinal  secretions  contain  relatively

high levels of K , and laxative abuse is sometimes

a hidden  cause  of  hypokalaemia.  Liquorice,

which is sometimes used as a laxative, has an aldosterone-like action.

Hyperkalaemia

Potassium   excess        (hyperkalaemia)   is   less

common  than  hypokalaemia,  but  harder  to

treat. Renal failure is probably the most common

cause of hyperkalaemia, and this is one of the

main  problems  in  managing  renal  patients.

Dietary causes are rare, but over-zealous use of

potassium salts, e.g. potassium citrate mixture in

the self-treatment of cystitis, can be responsible.

Over-use of potassium supplements is only a

remote possibility, given patients’ well-known

lack of enthusiasm for the common slow-release

forms. More subtly, potassium-retaining diuretics,

e.g. amiloride and spironolactone, can lead to

excessive inhibition of K  secretion, especially in

combination with the ACEIs. This situation can

be exacerbated in the elderly, who usually have

impaired renal function.

Clinical features

Dyskalaemias disturb the transmembrane ionic balance and the membrane potential, so muscle and nerve cells are particularly susceptible.

Hypokalaemia, depending on its duration and

severity, can cause numbness, weakness, paral-

ysis, low cardiac output, tachyarrhythmias and

heart failure. The myocardial toxicity of digoxin

is  also  enhanced.  In  the  longer  term,  renal

damage can occur, while inhibition of gastro-

intestinal activity can lead to bowel obstruction.

Renal attempts at compensation with potassium

conservation   and   acid   loss   leads   to   meta-

bolic alkalosis, as occurs with long-term diuretic

overuse.   Chronic   severe   hypokalaemia   can

impair renal concentrating ability, leading to

ADH-resistant polyuria and polydipsia.

Hyperkalaemia,   although   more   dangerous, causes fewer symptoms and indeed may be silent until cardiac arrest occurs. A characteristic ECG change of a spiked T-wave may be observed. Acidosis is a further complication.

Management

Correction  of  abnormal  plasma  levels  is  the

immediate   therapeutic   target   in   potassium

and investigation of renal disease           893

imbalance. Oral therapy is adequate for mild

imbalances   but   severe   dyskalaemia (÷3   or

6 mmol/L) needs urgent attention, mainly to

protect the heart. However, the total body excess

or deficit will be many times larger than the

simple correction of plasma level would imply.

For example, a plasma level of 2.5 mmol/L

requires 2 mmol/L to restore a normal level of

4.5 mmol/L.   For   an   average   plasma   water

volume of 3 L this requires 3     2          6 mmol of K

(less than half a standard oral potassium tablet).

But most of the administered potassium will be

distributed extravascularly, diffusing rapidly into

the tissue fluid (9 L) and then more slowly, over

24 h, into the cells (30 L). The plasma will retain

less than one-fifteenth of the administered dose.

However, because of the time this takes to occur,

attempts at rapid correction with the calculated

total  body  deficit  (in  this  case,  6      15

90 mmol)  would  cause  acute  hyperkalaemia. Conversely,  too  rapid  a  reduction  in  raised plasma K  by dialysis will cause hypokalaemia. Gradual adjustment with frequent monitoring of plasma level is important.

Hypokalaemia

Generally speaking, it is easier to get potassium

into a deficient body than it is to extract an

excess.

Mild   hypokalaemia.   Dietary   correction   is preferred. The routine prescription of potassium supplements with diuretics is no longer thought necessary  and  should  preferably  only  follow plasma level measurement of K .

Most  potassium  salts  have  an  unpalatable, saline taste. Effervescent formulations disguise the taste, but they usually contain bicarbonate, which is often contra-indicated because of the associated alkalosis. Liquid preparations of the chloride are perhaps underused. Very large oral slow-release   forms   are   perhaps   the   least complied with of all medication, and there is

the   additional   possibility   of   gastrointestinal irritation, ulceration or obstruction.

Fixed-dose   combination   preparations,   e.g.

diuretic and potassium, used to be popular but

need particular care. In addition to the usual

problems    of    preformulated    combinations

(inflexibility of individual component dosage,

possible  confusion  over  adverse  effects,  etc.),

these preparations seem particularly likely to

cause severe gastrointestinal lesions. They have

now   been   superseded   by   potassium-sparing

diuretics.

Severe hypokalaemia.   This needs parenteral

potassium usually by IV infusion. Because of the

time needed for equilibration it must not be

injected too rapidly or in too high a concentra-

tion. Acceptable maxima are a 40 mmol/L solu-

tion given at no more than 20 mmol/h, with an

80 mmol daily maximum.

Hyperkalaemia

Mild hyperkalaemia.   It is possible to reduce

plasma potassium level slowly by binding it in the gut lumen with a cationic ion exchange resin such  as  polystyrene  sulphonate,  used  as  the calcium or sodium salt. This is unpalatable and it can be given rectally, but neither route is very efficient at potassium removal.

Severe hyperkalaemia.   The immediate need is

to correct the plasma level: the overall body excess

is less urgent. Calcium (10 mL of 10% calcium

gluconate)  is  injected  to  provide  a  temporary

physiological antidote to the cardiotoxic effect.

This is followed, in the absence of renal impair-

ment, by infusion of up to 200 mmol of sodium

bicarbonate (depending on the degree of acidosis),

insulin (20 units) and glucose (50 g). This stimu-

lates  potassium  uptake  into  all  body  cells,

reducing the plasma level, but of course does not

correct  the  total  body  excess.  In  non-diabetic

patients the insulin may not be needed because

the  glucose  will  stimulate  its  release.  Beta-

adrenergic agonists may also be used, e.g. nebu-

lized or injected salbutamol. The effect may be

additive to that of insulin and glucose.

Measures to reduce body potassium level then

follow.  An  ion  exchange  resin  treatment  is

started, but dialysis may be necessary if plasma

levels cannot be controlled satisfactorily. Other-

wise, renal compensation is given time to work.

Acid-base imbalance

This potentially confusing topic will be dealt

with here in a simplified way, to enable imbal-

ances and therapy to be understood in principle.

One common problem with the terminology can

be readily clarified. Any pH imbalance resulting

from respiratory disorder is termed ‘respiratory’

(either acidosis or alkalosis); all other forms are

‘metabolic’, whether or not they are caused by a

apparently genuine metabolic defect. Thus the

ingestion  of  battery  acid  is  as ‘metabolic’  as

lactic  acidosis,  although ‘non-respiratory’  is  a

preferable term.

Aetiology

Acid-base imbalance may be conveniently visu-

alized by considering the normal and possible

abnormal routes for the intake, production and

output of acid and bicarbonate in relation to the

equation that controls pH (Figure 14.10). Over-

activity or under-activity of any of these path-

ways can cause pH imbalance (Table 14.10).

Because the body is normally in positive acid

balance, acidosis is more common than alkalosis.

Respiratory   acidosis   is   usually   predictable

because of associated cardiorespiratory disease;

respiratory  alkalosis  is  rare.  Among  the  vast

number   of   possible   non-respiratory   distur-

bances, gastrointestinal causes are common and

acidosis is also a major problem in renal failure.

The  accumulation  in  the  blood  of  lactate,

ketoacids or acidic drug metabolites is another

major cause. Biguanide-induced lactic acidosis is

now rare.

Investigation and diagnosis

The first priority is to identify and correct the

underlying cause. Initially this involves measure-

ment of blood CO2, H2CO 3 and pH, and a

simplified guide is given in Figure 14.11. The

precise biochemical picture will depend on the

nature and degree of compensation. Complex

mixed disorders are possible, e.g. metabolic and

respiratory   acidosis   in   a   poorly   controlled

diabetic with COPD.

Anion gap

Normally total plasma cations (mainly Na  and

K ) exceed the measured anions (mainly Cl  and

HCO3  ) by about 15 mmol/L. The difference,

called the anion gap, is made up by phosphate, sulphate, protein and other organic acids:

Anion gap         ([Na ]   [K ]) - ([Cl ]     [HCO3  ])

In acidosis caused by the accumulation of

endogenous or exogenous toxic organic acids

(e.g. lactate, salicylate), these anions displace

bicarbonate  and  the  anion  gap  is  increased.

Conversely, in acidosis from simple acid accu-

mulation (e.g. renal failure) or bicarbonate loss

(e.g. diarrhoea), the bicarbonate is replaced by

chloride so the gap is normal. Lactic acidosis is

sometimes further subdivided into type A caused

by tissue hypoxia and type B caused by abnormal

production of acids, e.g. in uncontrolled diabetes

mellitus.

Clinical features

The effects of pH imbalance are profound but non-

specific, and diagnosis is usually made biochemi-

cally. Most systems in the body are affected (Table

14.11) but the main clinical problems are cardio-

vascular. Acidosis reduces cardiac contractility, an

effect potentiated by beta-blockers, and dilates

arteries  and  constricts  veins;  all  have  adverse

haemodynamic effects. Oxygen dissociation from

Hb  is  increased,  which  may  improve  tissue

oxygenation  but  impairs  pulmonary  oxygen

uptake.

The CNS is depressed by acidosis, but nerve and

muscle  excitability  are  increased  by  alkalosis,

leading to seizures and tetany. In non-respiratory

disorders  the  respiratory  rate  is  altered  to

compensate for this. Urinary acid secretion is

changed  appropriately,  with  consequences  for

potassium balance.

The distribution and clearance of acidic and

basic drugs is affected. This is the basis of forced

diuresis  for  treating  poisoning.  Alkali  loading

causes an alkaline urine which encourages the

clearance of acids such as salicylate. Conversely,

acid will encourage the clearance of bases, e.g.

many psychotropic agents, such as amphetamine.

Management

Unless the severity of the imbalance is causing

cardiovascular or CNS problems or the cause is

irreversible, e.g. chronic renal failure, the best

general strategy is simply to remove the cause and

allow the body to carry out normal correction at

its own pace.

Acidosis

Chronic moderate acidosis can be treated orally

with sodium bicarbonate. In acute severe meta-

bolic acidosis specific correction is avoided if the

patient  can  be  expected  to  recover  sponta-

neously. The use of bicarbonate infusion is easily

misjudged, causing an equally serious ‘alkaline

overshoot’.

Various strengths of bicarbonate injection are available. The preferred 1.26% preparation is isotonic (300 mmol/L) and provides about one-

sixth of a mmol/mL of bicarbonate. For urgent cases more concentrated solutions are available as  boluses,  but  these  must  be  injected  very slowly. An 8.4% solution provides 1 mmol/mL, which facilitates dose calculation but is very

hypertonic (six times physiological). Interme-

diate strengths are also available. Lactate is no longer used because it acts indirectly and some acidotic patients may not be able to metabolize it to its active form (bicarbonate).

The total dose needed is usually 100-200 mmol of bicarbonate. An estimate in mmol can be made empirically from the patient’s body weight (kg) and the measured plasma bicarbonate:

Bicarbonate dose          1⁄3 Body weight

(Normal plasma HCO3            Measured HCO3  ).

However, as with K imbalance, frequent moni-

toring and adjustment are better guides.

In  respiratory  acidosis  the  cause  must  be

treated  directly,  if  necessary  by  ventilation.

Simple bicarbonate correction is inappropriate.

Alkalosis

Metabolic alkalosis can usually be treated with simple infusions of 0.9% sodium chloride (p.

878). Sometimes, however, direct infusion of

acid  is  required.  Hydrochloric  acid  has  been used,  but  the  hydrochlorides  of  ammonium, lysine  or  arginine  are  preferred.  Ammonium chloride may be given orally.

Respiratory alkalosis is very rare and is almost

invariably a temporary self-correcting condition

(e.g. during childbirth). Rebreathing from a bag,

which limits carbon dioxide loss, may speed

recovery.

Renal failure

Renal failure denotes a global loss of renal func-

tion, but it occurs to different degrees. The body

can maintain normal homeostasis with renal

function reduced to about half the normal GFR,

particularly if the decline is slow, and even then

symptoms may not be seriously troublesome.

Different sources vary in their definitions of

degrees  of  renal  failure,  and  there  are  also

different systems depending on whether acute or

chronic  failure  is  being  discused.  A  generic

grading,  based  on  reduced  GFR,  assuming  a

normal GFR of 120 mL/min in a healthy young

male, would be:

•  Renal impairment: 100-60 mL/min

•  Mild renal failure: 60-30 mL/min

•  Moderate     to          severe  renal     failure:

30-10 mL/min

•  End-stage renal failure: ÷10 mL/min.

Like heart failure, renal failure is not a specific disease but a complex syndrome with many

possible  causes  but  a  fairly  uniform  clinical presentation. In ARF the impairment of regula-

tory and excretory functions predominates: in the chronic form (chronic renal failure, CRF)

there is also an endocrine abnormality.

ARF  most  commonly  occurs  secondary  to

generalized  circulatory  failure.  The  condition

develops rapidly and has a high mortality but is

reversible if treatment is provided early enough:

if the patient survives there may be no perma-

nent sequelae. CRF by contrast has an insidious

onset and is usually caused by direct damage to

the renal tissue. The large natural renal reserve

and the slow progression of CRF mean that

considerable  irreversible  damage  has  usually

occurred by the time the patient reports symp-

toms.  There  is  then  an  inexorable  decline

towards end-stage renal failure, which is fatal

without renal replacement therapy, i.e. dialysis

or transplantation. However, the rate of decline

varies with the underlying cause, and can be

slowed by treatment.

Classification and aetiology

The many factors which can impair renal func-

tion   may   be   divided   into   three   groups, depending on whether the primary fault is in

renal  perfusion,  the  kidney  tissue  itself  or

urinary outflow (Table 14.12).

Pre-renal failure

The kidney relies on a continuous supply of

blood  at  sufficient  pressure  to  maintain  the

glomerular filtration, and endeavours to main-

tain systemic or intrarenal perfusion pressure by

numerous  homeostatic  feedback  mechanisms.

However, severe hypovolaemia and/or hypoten-

sion, owing usually to fluid depletion, cardiac

failure or other shock states, overwhelmingly

compromise this, and ARF commonly follows.

Intrinsic renal failure

The kidney is especially prone to immunological

or toxic damage. This is probably because in its

excretory  role  the  kidney  accumulates  high

concentrations of the products of the immune

system (e.g. immune complexes) and of metabo-

lism, and its high blood flow exposes the renal

tissues to potential toxins to a far greater extent

than most organs. Nephrotoxicity is a common

cause of renal failure, and a medication history is

essential in investigating any unexplained renal

impairment.

The glomeruli and the tubules and interstitial

tissues   may   be   affected   independently   by

different causes, although some conditions affect

both, e.g. ischaemia following circulatory failure.

Intrinsic damage is usually a chronic process but

toxic or ischaemic nephropathy can be acute.

Post-renal failure

Obstruction anywhere from the renal pelvis to the urethra is a less common and often reversible cause of renal failure. Back pressure is raised in the  tubules  and  this  reduces  the  glomerular filtration  pressure  and  hence  the  GFR.  The obstruction is usually within the urinary tract, but external pressure from an abdominal mass may also be responsible.

Post-renal failure is usually chronic. Occasion-

ally, acute forms may cause anuria. A common cause   of   this   in   elderly   men   is   prostatic hypertrophy obstructing bladder outflow.

Acute tubular nephropathy (ATN)

This  term  describes  acute  reversible  tubular

damage and is sometimes called, somewhat inac-

curately, ‘acute tubular necrosis’. It can be an

important consequence of acute pre-renal failure

following circulatory insufficiency that is not

rapidly reversed. Thus ARF and ATN frequently coexist and, confusingly, the terms are some-

times used synonymously. ATN may also be the result  of  renovascular,  glomerular  or  tubular disease or toxic damage.

What  difference  is  there,  for  the  kidney,

between renal ischaemia resulting from renovas-

cular obstruction, nominally ‘intrinsic ATN’, and

general systemic circulatory collapse (pre-renal)?

The conventional distinction, made on clinical

grounds,  is  that  pre-renal  failure  is  rapidly corrected by restoration of circulation whereas once ATN has supervened recovery is usually much slower.

The  precise  pathology  of  ATN  is  complex

and  incompletely  understood.  An  important

component is intense intrarenal vasoconstric-

tion, which inhibits filtration because of the

reduced afferent glomerular artery pressure. The nephrotoxicity of PG inhibitors, e.g. NSAIDs, is

due to a similar effect. The vasoconstriction may

simply be a response to injury, or it may be a

maladaptive attempt to maintain renal perfusion

pressure. In either case the subsequent ischaemic

damage is counterproductive. Moreover, it may be

perpetuated  even  after  perfusion  has  been

restored, owing to glomerular damage or tubular

obstruction with inflammatory or necrotic debris.

Pathophysiology

The loss of renal function has multiple complex

and serious consequences. One useful distinc-

tion,  which  helps  to  account  for  the  clinical

pictures found in different types and stages of

renal failure, is between glomerular and tubular

dysfunction. Although both structures may be

damaged, the trauma is often predominantly to

one or other, e.g. glomerulonephritis primarily

causes glomerular damage whereas aminoglycoside

nephrotoxicity  is  mainly  tubular.  In  pre-renal

failure both types occur at different stages.

Glomerular dysfunction

The  principal  causes  of  this  are  pre-renally

impaired perfusion, intrinsic glomerular inflam-

mation and post-renal obstruction. As the main

function of the glomeruli is filtration, there is a

fall in GFR with retention of those substances

usually  cleared  by  filtration,  including  water

(Table 14.13).

The consequent reduced volume of filtrate and

slower tubular flow permits increased proximal

tubular  reabsorption,  which  reinforces  these

effects. Furthermore, the reduced amounts of

sodium delivered to the tubules means that less

is available for the distal exchange mechanism

involved in acid and potassium secretion.

In some types of glomerular damage, despite a reduced GFR, there may be an apparently para-

doxical   increased   protein   loss (proteinuria; discussed below).

Tubular dysfunction

The main function of the tubules is the selective

reabsorption  of  water,  electrolytes  and  other  useful substances. Thus, the main consequence

of tubular failure is the voiding of large volumes

of dilute urine (polyuria) of low specific gravity,

along  with  electrolytes  and  nutrients (Table

14.14).

If  the  loop  of  Henle  fails  to  generate  an

adequate intrarenal concentration gradient in the

medulla,  urine  cannot  be  concentrated  and

passive  reabsorption  is  compromised  by  the

consequently increased tubular flow rate. Because

of the proximal tubular failure there is a vast

increase  in  potassium  loss,  which  completely

swamps  the  limited  potassium  retention  that

would  be  caused  by  the  impaired  distal

sodium-potassium-acid exchange pump. On the

other hand, the failure in distal acid secretion is

significant and acidosis results.

Summary

Predominant   glomerular   damage   results   in reduced urine volume, retention of water, acid and electrolyte, and possibly protein loss. This is the syndrome of oliguric renal failure. Tubular damage leads to acidosis, urine of low specific gravity and, if the GFR is adequate, to polyuria with fluid and electrolyte depletion.

Acute renal failure

Aetiology and prognosis

Although most of the conditions listed in Table

14.12 can cause ARF, pre-renal causes such as

hypovolaemia  or  shock  are  by  far  the  most

common  (75%  of  cases).  Less  common  are

intrinsic causes such as nephrotoxicity and acute

glomerulonephritis (20%). ARF as a result of

post-renal obstruction is uncommon (5%).

ARF is a serious medical emergency that can

develop very rapidly and has a high mortality. It

may be defined as a sudden fall in GFR to below

about 15 mL/min. Without treatment, survival is

less than 10%, which shows the crucial role of

correct  renal  function.  With  treatment  in  a

specialist unit, mortality can be reduced to below

50% but oliguric forms have a poorer prognosis.

These outcomes reflect the seriousness of the

conditions that precipitate ARF and the rapidly

progressive  nature  of  the  subsequent  multi-

organ failure caused, rather than inadequacy of

management. With the increased availability of

renal dialysis, the outlook for ARF has improved,

and death now rarely results from biochemical derangement.

Course

Whatever  the  primary  cause,  untreated  ARF

usually   follows   a   fairly   well-defined   and

predictable  course (Figure 14.12).  Onset  is

frequently   associated   with   oliguria,   which

continues  for  up  to  a  month  if  the  patient

survives. Urine flow then recovers and the patient

may become polyuric (up to 5 L per day) for

5-10  days.  During  the  final  recovery  phase,

which may last several months, urine flow and

renal function gradually return to normal.

A simplified explanation of these phases is as follows:

•  The early oliguric phase is caused by poor

            glomerular perfusion or tubular obstruction.

Both  result  in  a  predominant  pattern  of

glomerular dysfunction with reduced renal

clearance and fluid and electrolyte retention. Any tubular impairment is masked by the

reduced glomerular filtrate.

•  In   the   polyuric       (‘diuretic’)   phase   the

glomeruli have recovered somewhat and are

again producing filtrate, although the GFR

remains low. However, tubular dysfunction

persists, causing failure to concentrate and

loss  of  fluid  and  electrolytes.  The  initial

diuresis may be partly due to the accumulated

fluid and osmolar load, but this could not

alone  account  for  the  prolonged  pattern

sometimes seen.

•  In the recovery phase the tubule cells slowly

            regenerate.

After recovery there is usually no overt residual

renal damage. Although sensitive measures of

clearance  will  almost  certainly  detect  some

degree of permanent impairment, this is well within the renal reserve. The effect of a single episode of ARF resembles a small acceleration of renal ageing, with additional nephrons having been lost prematurely.

In pre-renal ARF, ischaemia rapidly produces

ATN. Intrinsic toxic tubular damage has the

same  effect.  ATN  is  a  serious  complication

which usually accounts for the oliguric phase,

but  may  be  avoided  if  the  circulation  is

promptly  restored  or  the  offending  toxin,

usually  a  drug,  is  withdrawn (Figure 14.12).

Similarly, early and aggressive immunosuppres-

sion can minimize the seriousness of some types

of acute glomerulonephritis.

Clinical features

In the more serious oliguric phase the clinical

problems are mainly of fluid and electrolyte over-

load and accumulation of metabolic by-products.

Secondary  or  indirect  complications  such  as

infection,  pericarditis  and  bleeding  may  also

occur. Other symptoms will depend on the initial

cause and the stage at which treatment is started.

For example, even though hypovolaemia may

have caused pre-renal failure it could be masked

by  subsequent  fluid  retention.  Table 14.15

summarizes  most  possible  features,  which  are

unlikely to occur simultaneously, along with a

brief outline of their conservative management.

In the polyuric phase, dehydration and elec-

trolyte depletion are possible, but are rare nowa-

days.   Modern   treatment   has   reduced   the frequency  with  which  ARF  occurs,  and  may prevent it entirely.

Management

There is no specific remedy for ARF. Management is aimed at eliminating the cause and keeping the patient alive until the kidney function recovers naturally. Thus the aims are to:

•  Discover and reverse or remove cause.

•  Correct fluid and electrolyte imbalances.

•  Minimize renal complications, i.e. ATN.

•  Support the patient through the acute oliguric

phase.

•  Avoid fluid and electrolyte depletion in the

            later phases.

•  Avoid nephrotoxic drugs

Many of these aims are met by renal dialysis, but conservative management may be adequate and is discussed first.

Discovering the cause

The cause of ARF, particularly if pre-renal, will

usually  be  evident  from  clinical  examination,

but  a  medication  history  should  always  be

sought. Nephrotoxicity is an increasing cause of

renal dmage, especially among the elderly. Table

14.16  summarizes  the  common  drugs  respon-

sible, with an indiction of how they damage the kidney.  Intrinsic  renal  damage  may  be  more obscure as may some indirect forms of obstruc-

tion.  A  plain  abdominal  X-ray  and  an  ultra-

sound  scan  are  usually  carried  out  if  there  is anuria.  If  the  failure  is  advanced,  supportive and symptomatic treatment are more important than immediate definitive diagnosis.

It is essential to ascertain if the episode is unique

or is possibly an acute exacerbation of a steadily

deteriorating  chronic  renal  failure,  so-called

‘acute-on-chronic’ failure. The patient’s history

and general clinical status should establish this

quite easily.

Restoration of function

In pre-renal failure, the first priority is prompt

fluid or blood replenishment and restoration of

the cardiovascular function, with monitoring of

CVP; this can prevent ATN from developing. If

sudden anuria suggests urinary tract obstruction

(e.g. cardiovascular function seems unimpaired)

the  patient  can  be  catheterized,  which  also

enables accurate assessment of urine output. A

number of techniques formerly used have been

invalidated by recent evidence: these include

osmotic or high-dose loop diuretics, bolus fluid

challenge and low-dose dopamine infusion.

Fluid and electrolytes

A careful balance must be struck between the

repletion of any volume deficit which might

have first caused the failure, and the prevention

of accumulation from subsequent oliguria. The

patient’s fluid balance and haemodynamic status

must be evaluated precisely before resorting to

diuretics,  which  might  cause  further  volume

depletion and exacerbate the condition. Simi-

larly, diuretics are inappropriate in obstruction,

e.g. in prostatic hypertrophy, and surgery or

cautious catheterization are more appropriate.

During the oliguric phase, sodium and fluid are

restricted and fluid balance is monitored closely

Renal failure      903

by   weighing   and   meticulous   charting   of intake/output.

The choice between crystalloid or colloidal

fluid replenishment (‘plasma expansion’) is still

debated. The theoretical advantage of the latter,

e.g. albumin, dextran, hydroxyethyl starch or

gelatin, is in preventing water loss from the

intravascular compartment to the tissue fluid

and  cells.  Crystalloid  solutions  risk  causing

pulmonary oedema and ascites with a reduced

gain   in   restoring   circulation.   However,   the

advantages of colloids have not been borne out

by careful trials and they are now not generally

recommended  except  where  specifically  indi-

cated by the nature of the loss that originally

precipitated the ARF, e.g. haemorrhage.

Hyperkalaemia is managed as usual (p. 894). Acidosis may be cautiously treated with sodium bicarbonate,  taking  care  to  avoid  fluid  and sodium overload.

Dialysis

If oliguria persists or ATN has supervened, or if

plasma urea, creatinine or potassium are rising

rapidly, patients are dialysed for short periods as

required. This solves most of the problems and

has the advantage of allowing a near-normal

diet. Continuous arteriovenous haemofiltration

is the preferred technique (p. 920), espeially in

haemodynamically   unstable   patients,   and

minimises  fluid  restriction.  Haemodialysis  or

peritoneal dialysis (PD) may also be used. Dial-

ysis facilitates parenteral nutrition if it is needed.

General measures and support

Some  protein  restriction  may  be  needed  if

gastrointestinal or cutaneous uraemic symptoms

are severe (Table 14.15). However, over-zealous

protein restriction is avoided as it can retard

recovery, especially as patients may be hyper-

catabolic, with increased protein breakdown and

weight loss. If protein is restricted, caloric intake

must be maintained by increasing carbohydrate

and fat intake. Parenteral feeding may be needed

in the early stages. Daily fluid intake is restricted

to the daily urine output plus 500 mL to replace

insensible losses (Table 14.2).

Infection   is   common.   All   drug   therapy,

including antibiotics, must be carefully evalu-

ated  to  avoid  toxic  accumulation  of  renally

cleared drugs or their sodium salts. Specialist

clinical pharmacists have an important role here.

Recovery

After the critical phase has passed, patients are

soon   discharged.   They   will   need   to   be

instructed about maintaining an adequate fluid

and  electrolyte  intake  and  keeping  a  fluid

balance chart.

For most patients the first episode of ARF will be  their  last.  Survivors  make  an  apparently complete recovery, but a few will develop CRF, the first attack representing an acute-on-chronic decompensation   against   a   background   of progressive renal disease.

Chronic renal failure (chronic kidney disease)

CRF presents a very different picture from ARF. It

usually has different causes, is insidious in onset,

follows a slowly progressive course and is irre-

versible. In addition to azotaemia and fluid and

electrolyte problems there are serious endocrine

abnormalities.  On  the  other  hand,  there  is

usually time to consider the best management

options  before  the  patient  reaches  end-stage

renal disease (ESRD) and the range of treatments

available  can  provide  the  vast  majority  of

patients with a reasonable quality of life.

Aetiology

It is difficult to quantify the relative frequencies

of  different  causes  of  CRF.  Patients  usually

present very late, with kidneys so shrunken and

fibrosed that retrospective diagnosis is impos-

sible. Table 14.17 gives one estimate of the distri-

bution of probable causes among Europeans, but

it is approximate, and there are geographical,

ethnic and racial variations. For example, hyper-

tensive nephropathy is more common among

Afro-Caribbeans,   and   diabetic   nephropathy

more common among South Asians, and this

accounts partly for higher ESRF rates among

these populations. In developing countries, as

usual infectious causes are far more prominent.

Generally CRF is due to intrinsic renal disease,

often glomerular in origin. Diabetes (the preva-

lence   of   which   is   rising)   is   an   increasing problem,  as  is  iatrogenic  disease,  especially among the elderly, and the various multisystem disorders  as  advances  in  treatment  prolong survival. Hypertension is now usually recognized earlier and treated better than previously. Renal neoplasms are uncommon.

Few preventative measures can generally be

recommended because the uncertain aetiologies

of the more common causes, such as glomeru-

lonephritis   and   pyelonephritis.   Nevertheless,

there is no excuse for the lack of vigilance that

permits most iatrogenic renal disease to occur,

especially in the elderly. Further, in diabetes,

improved control and the use of ACEIs slow the

rate of progression of CRF and reduce the preva-

lence of end-stage diabetic nephropathy. Fortu-

nately,  the  management  of  advanced  renal

failure is relatively uniform, regardless of the

aetiology.

Epidemiology

Because of national and regional differences in

diagnosing, reporting and treating ESRD, figures

for  incidence  and  prevalence  are  elusive  or

highly variable. Most available data derive from

analyses of patients considered for renal replace-

ment therapy and so are skewed by treatment

policies.  For  the  UK,  the  approximate  most

recently available data are given in Table 14.18.

The  significance  of  some  of  this  information will  become  clearer  when  discussing  renal replacement therapy.

There are national and racial differences in

incidence,  doubtless  reflecting  both  environ-

mental and genetic differences. While in the UK

the annual incidence is 100 per million popula-

tion (pmp), in Europe it is 135 pmp and in the

US 335 pmp. The US figure is made up of an inci-

dence among whites of 256 pmp and among

blacks of 980 pmp. In Australia figures are overall

much lower but show a similar racial disparity

(94 pmp vs 420 pmp).

Course

The slow decline in the number of functional

nephrons,  GFR  and  renal  reserve  may  take

decades  to  pass  from  normal  to  end-stage,

although the progression tends to accelerate as

end-stage is approached. Several staging systems

have been used to to chart this progress, and a

recent one is given in Table 14.19. Patients often

first present with a history of several months of

vague ill health, with tiredness, pruritus, sickness

and loss of appetite and weight. Hypertension is

often   found   and   patients   may   have   been

ignoring moderate urinary symptoms, usually polyuria,  for  some  time.  Another  common presentation is ARF following abnormal stress on the already impaired kidneys (acute-on-chronic renal failure).

Following  diagnosis,  declining  function  is monitored by regular serum creatinine measure-

ment,   which   correlates   inversely   with   GFR (Figure 14.7). Careful management during this stage  can  minimize  complications  and  may delay the onset of the end-stage decline. The

patient then has time to review and discuss with the physician the ultimate treatment options,

and to prepare psychologically.

Whatever form of renal replacement therapy patients  undergo,  there  is  a  reduced  life

expectancy.  The  greatest  mortality  is  from CVD, mainly IHD and heart failure. Following transplantation  there  may  be  complications resulting  from  long-term  immunosuppression, e.g. infection and neoplasia.

Pathology

In CRF there is usually a complete and perma-

nent failure of increasing numbers of nephrons.

This contrasts with ARF where there is usually a

uniform  reversible  partial  impairment  of  all

nephrons. Consequently, in CRF the residual

intact nephrons come under increased loading.

Changes  in  intrarenal  haemodynamics  cause

compensatory   glomerular   hypertension   and

temporary increases in filtration rates (hyper-

filtration).   However,   these   are   maladaptive,

Renal failure      907

eventually  causing  or  accelerating  glomerular

sclerosis and tubular atrophy, and the kidneys

gradually shrink. One important exception is

polycystic   disease,   where   gross   enlargement

occurs, although functional tissue is similarly

reduced.

Renal reserve consists of there being far more

nephrons than are needed to sustain life, but

numerous   adaptations   and   compensations

operate when the number is so reduced as to

threaten renal function. Adaptation to maintain

water, acid, sodium and potassium levels is good,

so serious hypervolaemia, acidosis and changes

in plasma electrolyte levels may be prevented

until the GFR falls below 5-10 mL/min, which

determines the onset of the end-stage. However,

both urate and phosphate will accumulate before

then. Urea and creatinine levels also rise, in

inverse proportion to the fall in GFR, because

there  are  no  compensation  mechanisms  for

these   molecules.   This   results   in   various

symptoms.

Before end-stage, the patients’ reduced renal

reserve makes them prone to decompensation if

additional demands are made on the kidneys.

These extra demands can produce an exacerba-

tion or an acute-on-chronic crisis that may be

the first indication of severe renal disease: they

include infection, surgery, fluid depletion (e.g.

severe diarrhoea or vomiting), trauma, certain

drugs (e.g. tetracyclines) and excess potassium

(e.g. potassium-retaining diuretics, foods with

high potassium content).

Pathophysiology and clinical features

A summary of the main clinical problems of CRF is given in Table 14.20, with their presumed

pathogenesis and the measures taken to retard progression or limit symptoms. When ESRD is reached, many of these features are mitigated or reversed by renal replacement therapy.

Fluid and electrolyte imbalance

Urine concentrating ability is often diminished in the early stages, causing dilute polyuria and the risk of dehydration and electrolyte deple-

tion, as in the polyuric phase of ARF. This is

partly the result of an osmotic diuresis induced by raised urea levels in the tubular filtrate of the remaining intact nephrons.

In the later stages urine volume falls and the

consequent retention of sodium and water is the

main cause of the hypertension usually found

in CRF patients. Other potential complications

of   hypervolaemia   are   oedema,   including

pulmonary oedema, and heart failure. At the

onset  of  end-stage  failure  the  patient  may

become anuric.

Uraemia

The major biochemical problems do not result from  the  accumulation  of  urea  itself  but  of various  electrolytes  and  miscellaneous  other mainly nitrogenous toxins. Nevertheless, urea can  cause  troublesome  gastrointestinal  symp-

toms and may be responsible for the capillary fragility and purpura (bruising) seen in renal

patients.   Uraemia   also   damages   platelets, increasing the bleeding tendency.

Although urate levels are raised, clinical gout

is   rare.   Various   other          ‘middle   molecules’

(500-5000 Da, nitrogenous and otherwise) may

contribute to the variety of non-specific symp-

toms. Continuous ambulatory peritoneal dialysis

(p. 920) is particularly efficient at clearing these

substances,   leading   to   an   improvement   in

well-being.

Potassium and acid

These are not retained in dangerous amounts

until end-stage. Before that, renal patients seem

to tolerate mild hyperkalaemia and acidosis, or

adapt to them. However, along with water reten-

tion these are the most serious acute problems at end-stage.

Metabolic features

There are several inter-related changes in lipid

and carbohydrate metabolism (Table 14.20). The

kidneys normally catabolize several hormones,

including about one-third of all natural insulin,

and this mechanism is diminished. Conversely,

glucose tolerance is reduced, so the effects are

unpredictable, especially in diabetics. Dyslipid-

aemia  results  in  a  raised,  atherogenic  lipid

profile.

Cardiovascular disease

Hypertension is almost universal and there is an

increased incidence of IHD and heart failure.

Numerous   factors   contribute.   Hypertension

results   from   fluid   retention   and   possibly

renin/angiotensin abnormalities. Dyslipidaemia

and   hypertension   accelerate   atherosclerosis,

which is a common feature. Heart failure is

multifactorial, involving hypervolaemia, hyper-

tension,  ischaemia  and  anaemia.  Cardiomy-

opathy is part of a generalized myopathy caused

by  calcium  and  phosphate  imbalance,  with

ectopic calcification (p. 910) in the heart as well

as the coronary arteries. Pericarditis sometimes

occurs.  CVD  accounts  for  almost  half  of  all

deaths in renal failure patients.

Anaemia

The major cause of anaemia in renal patients

is   marrow   hypoplasia   due   to   reduced   or

absent erythropoietin (see also Chapter 11). The

iron-resistant,   initially   normocytic,   normo-

chromic picture resembles that seen in many

chronic diseases (though for a different reason).

Hb levels rarely exceed about 8 g/dL (normal

12-18 g/dL).  Iron  and  folate  deficiencies  are

often superimposed owing to anorexia, dietary

restrictions, a bleeding tendency, and losses from

haemodialysis and frequent blood testing. There

are also gut losses due to stress ulceration. Thus

later iron deficiency may cause a microcytic,

hypochromic  picture.  Renal  anaemia  signifi-

cantly  reduces  the  quality  of  life  of  renal

patients, producing poor exercise tolerance and

increasing   the   risks   of   cardiac   failure   and

exposure to multiple transfusions.

Renal bone disease

The syndrome of renal osteodystrophy involves

complications secondary to vitamin D failure,

with consequent disturbed calcium and phos-

phate metabolism. Together they form perhaps

the most serious group of chronic clinical prob-

lems because of their prevalence, their wide-

spread, multisystem secondary effects and the

difficulty of treatment.

The pathophysiology of osteodystrophy in-

cludes  impaired  bone  mineralization (osteo-

malacia or ‘renal rickets’), bone demineralization (osteitis fibrosa) and extraskeletal deposition of calcium phosphate, especially in blood vessels, joints and muscle (metastatic or ectopic calcifi-

cation). Figure 14.13 shows a simplified account of the pathogenesis of these features in relation to normal calcium homeostasis.

The clinical consequences are fractures, bone pain, deformity, arthritis, (cardio)myopathy and arteriosclerosis with regional ischaemia (espe-

cially in coronary vessels). In addition, abnormal calcium and/or phosphate levels may contribute to pruritus, anaemia, anorexia, muscle cramps, tetany and peripheral neuropathy.

Other features

The immune system is compromised. Impaired

metabolism and/or urinary clearance of melanin

and other pigments often gives a characteristic brown  skin  pigmentation.  Abnormal  plasma

constituents may affect erythrocytes and coagu-

lation factors, causing haemolysis and a haemor-

rhagic tendency that results in bruising, nose

bleeds, gastrointestinal bleeding, etc. Some of

these problems are ascribed to the retention of

‘middle   molecules’.   Gastrointestinal   stress

ulceration is common.

Lethargy, fatigue and general malaise occur more in patients who are poorly managed or

who are less compliant with their treatment

regimens or fail to comprehend them.

Drug-related problems

The way in which renal impairment affects drug use is dealt with separately (p. 914).

Management

The general management strategy and conserva-

tive treatment of the patient before ESRD are

considered first. Renal replacement therapy is considered on pp. 916-929.

Aims and strategy

The aims in managing CRF are:

•  Early detection.

•  Identification and removal of cause.

•  Retard deterioration in renal function.

•  Identification and management of complica-

            tions.

•  Preparation of the patient for renal replace-

            ment therapy.

Early detection of CRF is unusual, and often a

primary cause cannot be identified because the

disease is advanced by the time it is detected.

However, certain groups of patients with partic-

ular susceptibility need special monitoring. This

includes patients with hypertension, diabetes, a

chance finding of proteinuria or a family history

of renal disease.

Once  CRF  has  been  diagnosed,  potential

aggravating factors such as untreated hyperten-

sion, urinary tract obstruction and the use of

nephrotoxic  drugs  must  first  be  eliminated.

‘Acute-on-chronic’ exacerbations in patients not

yet at end-stage, resulting from infection, fluid

depletion  or  overload,  etc.,  must  be  treated

promptly.  Complications  such  as  anaemia,

hyperphosphataemia  and  secondary  hyperten-

sion must be minimized; as well as their direct

problems,  they  contribute  to  progression  of

renal decline. Precise dietary recommendations

remain  controversial,  but  appropriate  dietary

control  may  also  slow  the  progression  of  the

renal damage.

Regular  measurements  of  serum  creatinine

provide a reliable index of the decline in func-

tion and enable the onset of end-stage to be

predicted.  The  rate  of  decline  varies  greatly

between patients but is generally constant for a

given patient. Patients must be encouraged to

come to terms psychologically with the fact that

they have an irreversible illness that eventually

will require artificial support or surgical inter-

vention. How this idea is introduced will depend

on the clinician’s assessment of the patient’s

resilience. The family should also be involved

and encouraged to be supportive.

As  patients  approach  end-stage  they  will, unless unsuitable, be tissue typed and entered on the transplantation register. Their home may be assessed for the suitability of home dialysis, and a SC arterio-venous fistula may be fashioned in preparation for haemodialysis.

The situation does not remain static once end-

stage has been reached: the treatment mode

needs regular re-assessment. Patients may need

Renal failure      911

to switch between different forms of dialysis, in and out of hospital, according to circumstances. Should a transplant prove unsuccessful, they

must return to dialysis.

Fluid and electrolytes

Daily fluid intake is restricted to urine output

plus 300-500 mL.   Such   restriction   can   be

extremely unpleasant in the later stages because

thirst is so troublesome. When there is severe

oliguria or complete anuria, a restriction of total

fluid intake to 500 mL including drinks, sauces,

fruit, cleaning teeth and liquid medication may

be  almost  impossible  to  maintain.  However,

the  swift  symptomatic  penalties  of  incipient

heart failure or pulmonary oedema are salutary

correctives.

Salt intake is restricted, with low-salt foods and

no added salt. High-potassium foods, such as

fresh fruit and vegetables, chocolate, etc. (the

very ones that non-renal patients on diuretics

are encouraged to seek) are avoided. As this

becomes   less   effective,   gastrointestinal   ion

exchange resins may be added to reduce potas-

sium absorption. Uncontrolled hyperkalaemia is

one of the prime indications for starting dialysis.

Acidosis can be managed with oral sodium

bicarbonate, but calcium carbonate is needed

when sodium restriction is critical; the calcium may also benefit bone disease. The usual care is needed if bicarbonate infusion is used to treat acidosis (p. 897), and persistent severe acidosis is another indication for dialysis.

Diet

Adequate nutrition with high-quality protein in reduced amounts (40-50 g/day) will prevent a negative nitrogen balance and protein malnutri-

tion, and may also slow the disease progression. However,  high-protein  diets  are  thought  to encourage   hyperfiltration,   thus   accelerating renal decline. Very low-protein diets in the early stages have their advocates.

When the GFR falls below about 50 mL/min

protein must be restricted to minimize uraemic

complications. Low protein diets have the bene-

ficial side-effect of reducing phosphate, potas-

sium and acid intake, and this might account in

part for their apparent effect in some trials of

reducing degeneration of renal function.

It is important, whatever course is adopted

with regard to protein, that patients have an

adeqauate caloric intake, because the nausea and

anorexia symptomatic of renal disease tend to

lead to poor nutrition. Adequate caloric intake is

provided by increasing carbohydrate and unsat-

urated  vegetable  fats  or  oils,  using  dietary

supplements. The lower the protein content of

the diet, the more important that it should be of

high biological value, so essential amino acid

(EAA) supplements may be needed. A further

way of minimizing nitrogen catabolism while

maintaining  protein  synthesis  is  to  include

ketoacid analogues of EAAs in the diet, as these

can be transaminated and thus provide EAAs

without additional nitrogen intake.

Vitamin   supplementation   should   not   be

needed, but many patients, even before dialysis,

are given water-soluble multivitamins and iron

to compensate for possibly poor nutrition and

the loss of blood in frequent blood tests. Dietary

compliance,  including  with  electrolytes  and

especially with fluid, tends to be poor and the

involvement  of  a  renal  dietician  is  highly

recommended. The summation of the different

restrictions  can  be  difficult  for  a  patient  to

comprehend, and malnutrition, anxiety or guilt

may occur. Dietary restriction may be partially

relaxed once the patient has started on dialysis.

Hypertension and other cardiovascular problems

Control of BP is a key factor in reducing the

progression of CRF. Careful attention to fluid

and sodium intake may at first be sufficient to

control  the  hypertension  that  most  patients

suffer. ACEIs are the drugs of choice because

they have the additional benefit of retarding

the  progression  of  CRF,  possibly  by  causing

intrarenal   vasodilatation   and   thus   reducing

glomerular hypertension. Of course, the poten-

tial nephrotoxicity of ACEIs in the presence of

renovascular  disease  must  not  be  forgotten.

ACEIs may be supplemented with diuretics while

the patient is still producing urine. A non-DHP

CCB, e.g. diltiazem, is the preferred additional

drug if BP is not adequately controlled with

ACEIs. Thereafter, any of the usual antihyperten-

sives  may  be  added.  ACEIs  are  particularly

beneficial   in   minimising   type             1   diabetic

nephropathy, but in type 2 diabetes ARAs are the drugs of choice.

Diuretics are needed for pulmonary oedema

and heart failure, and temporary dialysis may be

necessary if these are unsuccessful. If dietary

modification fails, hyperlipidaemia may require

HMG  CoA  reductase  inhibitors  (statins).  The

clearance  of  statins  is  less  affected  by  renal

impairment than other lipid-lowering agents.

Anaemia

Any iron or haematinic vitamin deficiency must

first be treated in the usual way (Chapter 11) but

this never restores the normal Hb level. Before

the availability of epoetin  the use of multiple

transfusions   was   the   only   recourse   in   the

anaemia of CRF. This could depress erythro-

poiesis and also cause iron overload. Moreover

the wide range of antibodies that the patient

raises against the pooled blood received in this

way throughout his or her illness could sensitize

them against a future transplant, although this

was minimized by using washed packed RBCs.

The advent of genetically engineered erythro-

poiesis-stimulation agents (ESAs) has solved this.

Epoetin and darbepoetin are recombinant forms of

human  erythropoietin,  the  natural  red  cell

growth factor secreted by the normal kidney and

acting on the bone marrow. The improved Hb

levels that can now be consistently achieved

significantly improve the quality of life of CRF

patients.

Epoetin  as   biosynthesised   occurs   in   two different levels of glycosylation, as alfa and beta forms, but these are clinically equivalent. Darbe-

poetin is even more glycosylated and this confers a significantly longer half-life. Numerous other ESAs are under development.

Indications and use.   ESA therapy is mainly

used in renal patients. Initially reserved for those

on haemodialysis, its indications have broad-

ened as the cost has reduced. PD patients, and

now increasingly pre-dialysis CRF patients, are

offered it if their Hb is sufficiently low and not

managed by haematinics. ESAs are also used for

anaemia following chemotherapy-induced bone

marrow depression and to facilitate the collec-

tion of autologous transfusion blood prior to

surgery. Care must be taken to follow the precise

dosage guidelines, which vary according to indi- cation and also specify titration and mainte-

nance protocols. Epoetin  is usually injected 3

times weeky; the longer half-life of darbepoetin

permits   once-weekly   dosing.   For   stabilized

patients  less  frequent  dosing  of  both  agents

appears to be adequate and is quite common.

The target Hb level for each patient needs

careful assessment, but a Hb no greater than

13 g/dL is usually aimed for, and about 12 g/dL

if the patient has any CVD. ESA therapy must

be  matched  by  appropriate  iron  intake,  and

iron supplementation is usually required. This is

usually given intravenously to accommodate the

increased  iron  requirement  generated  by  the

epoetin,  especially  in  haemodialysis  patients.

Moreover, careful optimization of iron status can

reduce the demand for epoetin, thus conferring

considerable economies.

Adverse   effects   and   cautions.   The   main

potential problem is potentiation of hyperten-

sion,   possibly   causing   encephalopathy   with

convulsions.  Also,  thromboses  may  obstruct

vascular   catheters   used   for   haemodialysis

access. The reason for the conservative Hb targets

is  that  if  complete  normalization  of  the  Hb

level were attempted, cardiovascular complica-

tions   could   arise   owing   to   the   resulting

polycythaemia (excessive RBC count) causing

increased  blood  viscosity,  blood  volume  and

blood pressure. A rare adverse effect of epoetin

alfa  is an immunologically-mediated pure red

cell aplasia, which if it occurs precludes furthur

use of any erythropoietin derivative, This effect

seems to be associated with SC use and so IV

administration only is currently recommended.

Renal bone disease

Osteodystrophy is difficult to manage because it

changes during the course of the illness and thus

requires different treatments at different times.

Renal bone disease is one of the complications

that is least improved by dialysis. The related

metastatic calcification of the aorta and coro-

nary arteries contribute significantly to CVD in

renal patients.

For hypocalcaemia in the absence of hyper-

phosphataemia, raising the plasma calcium level

will   improve   osteomalacia     (Figure             14.13).

Initially,  calcium  supplements  may  be  used,

calcium carbonate being the most suitable as it

Renal failure      913

will also counteract acidosis and complex some

phosphate in the gut. Later, vitamin D analogues

calcitriol  or alfacalcidol  are needed, neither of

which rely on renal hydroxylation for activation

(as does natural vitamin D, colecalciferol). They

tend to elevate the plasma calcium level, so close

monitoring of this is essential, otherwise this

could exacerbate metastatic calcification.

Hyperphosphataemia is treated initially with

phosphate restriction, but this is extremely diffi-

cult to achieve because phosphate occurs widely

in foods, e.g. dairy products, many fish, eggs,

liver, many vegetables, chocolate, nuts. Eventu-

ally,  oral  phosphate  binders  are  required,  to

prevent dietary phosphate and any phosphate in

gastrointestinal   secretions   being   absorbed.

Formerly, aluminium hydroxide was the standard

therapy: this forms insoluble aluminium phos-

phate in the gut, which is lost in the faeces.

Aluminium hydroxide is given in dry capsule

form,  e.g. ‘Alu-Cap’,  the  more  usual  antacid

mixture  being  unsuitable  for  fluid-restricted

patients. However, significant aluminium absorp-

tion occurs in renal patients who clear it ineffi-

ciently, and long-term use is associated with

dementia and anaemia; it will actually also cause

a form of osteodystrophy. This was exacerbated

in certain areas by exposure to aluminium in

dialysis  fluids  derived  from  the  local  water

supply.

Current  practice  favours  calcium  carbonate

tablets with the incidental benefits mentioned

above, though large doses are needed. Magne-

sium and lanthanum salts have also been used,

and  do  not  produce  hypercalcaemia  as  may

calcium carbonate. Close monitoring of plasma

phosphate and calcium are vital because doses

are easily misjudged and dietary mismanage-

ment by the patient may undo the most careful

adjustment.   The   newer   ion-exchange   resin

sevelamer offers advantages in reducing arterial

calcification but is expensive so currently is used

only in combination with oral calcium.

If secondary hyperparathyroidism is trouble-

some and refractory to medical management,

then partial or total parathyroidectomy may be indicated.   Calcimimetics,   e.g.   cinacalcet,   are currently   being   tested;   these   stimulate   the calcium  sensor  on  the  parathyroid,  thereby reducing PTH secretion.

Other problems

Some of the miscellaneous problems such as

neuropathy, gastrointestinal upset, pruritus, etc.

may resolve if the above methods are successful,

particularly protein restriction and calcium and

phosphate control. Others may need to await

dialysis,  which  almost  invariably  produces  a

notable improvement in general well-being.

Drug use in renal impairment

There  are  several  important  questions  to  be

asked when considering drug therapy in patients

with renal impairment. This applies to all drugs,

whether used for the renal disease itself or for a

co-morbidity.

•  Is the drug nephrotoxic? •  Is the drug essential?

•  What is degree of renal impairment?

•  What proportion of drug is cleared by kidney?

•  Does drug have narrow therapeutic index?

•  Is the drug’s action or toxicity altered in renal

impairment?

If a drug is potentially nephrotoxic, it should be

avoided if possible because these toxic effects,

even if only mild or rare, are likely to be of more

significance in the presence of renal impairment.

Is an alternative drug of comparable clinical

action  but  more  favourable  pharmacokinetic

profile available? If not, then the initial drug will

need to be used with care and following appro-

priate dosage adjustment. The degree of renal

impairment, measured quantitatively, will indi-

cate whether and to what extent the dose will

need to be reduced. This calculation will have to

be  further  refined  by  consideration  of  what

proportion of the drug dose is normally cleared

by the kidney; many drugs have more than one

route of clearance.

Another important point is the drug’s thera-

peutic index. If this is narrow, even small reduc-

tions in clearance, giving small rises in serum

level, could cause toxicity. We also need to know

if rapid achievement of therapeutic serum level

is important, because attainment of steady state

may  be  delayed  in  renal  impairment.  These

factors   will   be   discussed   briefly;   see   also References and further reading.

Nephrotoxicity

Adverse drug effects on the kidney are well docu-

mented by the BNF, in both Appendix 3 and

individual monographs. A summary was given in Table 14.16.

Renal clearance

In order to judge whether or not a drug will be

renally cleared, some general pharmacokinetic

principles need to be reviewed (see Chapter 1)

In   renal   impairment   we   are   primarily

concerned with drugs that are water soluble i.e.

polar  or  hydrophilic,  which  are  normally

predominately cleared by the kidney, e.g 98%

for  gentamicin.  We  are  less  concerned  about

hydrophobic drugs (i.e. lipid-like, non-polar or

fat-soluble), which rely on hepatic metabolism

for  clearance,  e.g.  theophylline,  phenytoin  or

warfarin.  Exceptions  are  when  the  hepatic

metabolite is renally cleared, clinically active or

more toxic that the original drug; in such cases

accumulation  in  renal  impairment  may  be

important, e.g codeine metabolised to morphine.

Other  drugs  are  cleared  partially  by  both

routes, e.g. digoxin (15% hepatic, 85% renal). It

is only the renal component that is altered in

renal  impairment;  usually  the  other  route  is

unaffected,  and  this  must  be  taken  into

account in dosage adjustment.

The change that occurs to the renal compo-

nent of clearance means that the drug is cleared

more slowly. The same dose will be retained

longer, i.e. the half-life will increase, and thus

with  regular  dosing  the  plasma  level  will  be

higher. These changes will be in proportion to

the fall in GFR or creatinine clearance. Consider,

for example, a patient who has a creatinine clear-

ance of 60 mL/min, taking a drug that is cleared

100% renally. Assuming the normal creatinine

clearance is 120 mL/min, the dosage reduction to

give normal plasma levels should be 50%. But if

the drug is only half cleared by the kidney, the

dose reduction would need to be only half that, i.e. 25%.

Therapeutic index

Even if a drug does accumulate to a limited

degree, this may be of little consequence if the

therapeutic effect, and especially the toxic effect,

are not closely related to the plasma level. Thus

some accumulation of most penicillins is usually

of little consequence and can be tolerated, so

dosage adjustment of oral penicillins is very

rarely necessary, even though most are cleared

mainly be the kidney.

Loading dose

Because  in  renal  impairment  half-lives  are

increased, it will take longer for a drug to achieve

its  steady  state  plasma  level.  Steady  state

following the regular dosing of any drug occurs

after about five half-lives, whatever the dose or

renal function. In some cases it may not be accept-

able to wait this long in a renally impaired patient,

e.g. with antibiotics or digoxin, especially if the

dose has been reduced because of the impair-

ment. In such cases, a loading dose may be given

to  achieve  therapeutic  concentrations  quickly.

Calculation of a loading dose is not dependent on

clearance (only on dose and volume of fluid in

the body) so the normal loading dose is given, or

possible higher if there is severe oedema, even if

subsequent dosage is to be reduced.

Drug handling

When the renal function is impaired there is

more  to  consider  than  reduced  clearance.  A number of consequences follow from the meta-

bolic and biochemical abnormalities secondary to the renal impairment, which could effect drug action or handling.

Oedema and volume of distribution

In   renal   impairment,   fluid   retention   with

oedema is usual, which would tend to increase

the volume of distribution of hydrophilic drugs.

Renal failure      915

Counteracting that however is the fact that the kidney will not be clearing hydrophilic drugs so efficiently.  Thus  the  net  effect  of  these  two opposing trends is difficult to predict and means that careful observation and/or therapeutic drug monitoring may be necessary.

Uraemia and drug binding

Some  of  the  metabolites  that  accumulate  in

uraemia, including urea, may displace a drug

from its plasma protein binding sites, raising the

plasma level, e.g. phenytoin, diazepam and theo-

phylline. By analogy with a drug interaction, this

is only likely to be of significance if the urea level

is high and the protein binding of the drug is

normally high ( 90%). Moreover, the rise in free

plasma level will increase the clearance of the

displaced drug (especially if it is usually cleared

hepatically),   reducing   adverse   consequences.

Furthermore,   renal   patients   tend   to   have

hypoproteinaemia owing to proteinuria, poor

diet   and   chronic   illness,   further   reducing

binding.

Reduced drug metabolism

Normally, insulin is partially metabolised in the

kidney; thus, renal impairment could alter the

control of diabetes. To avoid hypoglycaemia,

insulin dose may need to be reduced. We have

already   noted   that   metabolic   activation   of

vitamin D is reduced in renal impairment.

Pharmacodynamic changes

In addition to these pharmacokinetic effects,

there can also be pharmacodynamic changes in

the  actions  of  some  drugs.  The  blood-brain

barrier is less effective in renal failure patients, so

some centrally acting drugs such as benzodi-

azepines might have exaggerated effects. Renal

patients are more prone to upper gastrointestinal

bleeding   and   ulceration   and   so   are   more

sensitive to the gastro-erosive effects of NSAIDs.

Dosage adjustment

Considering all these possible influences on drug

action and clearance, drug selection and dosing in renal impairment is problematic. It requires

experience and judgement as well as access to

specialised formularies, such as that produced by

the UK Renal Pharmacists Group, giving the

changes in drug parameters such as half life or

proportion of renal clearance in different degrees

of  renal  impairment.  The  advice  of  a  renal

pharmacy specialist should always be sought.

Assuming it is essential to give a drug the clear-

ance of which will be affected by renal impair-

ment, pharmacokinetic calculations can be made

to show how clearance will be reduced. These can

be done effectively by programs on hand-held

computers. However, it still needs judgement to

decide how the dosage reduction will be imple-

mented. Suppose it is calculated that the clear-

ance is reduced by 50%. Does this require half the

normal dose at the same interval or the same dose

at  double  the  normal  interval?  Either  would

compensate for the reduced clearance.

It will depend, among other things, on the

plasma  level  profile  required.  If  a  roughly

constant  plasma  level  with  small  peaks  and

troughs is required (e.g. with anticonvulsants,

lithium), dose reduction is indicated; in such

cases, initialising therapy may need a loading

dose. If a pronounced peak or a definite trough

(to minimize toxicity) is required, e.g. as with

gentamicin,   an   increased   interval   will   be

preferred.

In some cases, there may be an accessible clin-

ical parameter such as blood pressure, blood

glucose or clotting time, which will enable the

more pragmatic approach of therapeutic moni-

toring and dose titration without recourse to

frequent precise calculation and plasma level

monitoring.

The situation is different for patients on dial-

ysis, where clearance may be more difficult to estimate.  Once  again  the  advice  of  a  renal pharmacy specialist should be sought.

Renal replacement therapy

The  main  role  of  renal  replacement  therapy

(RRT) is in end-stage renal disease patients whose

GFR has fallen below 5-10 mL/min or in whom

other   complications   are   not   responding   to

conservative therapy. Renal replacement therapy

involves either the artificial techniques of dial-

ysis or natural replacement with a transplant.

Temporary dialysis may also be required in ARF

or poisoning.

Renal dialysis

Aim

Renal dialysis attempts to mimic the excretory

and to a lesser extent the homeostatic roles of

the  kidney.  Although  dialysis  cannot  restore

renal endocrine function, it ameliorates some of

the secondary effects of endocrine dysfunction

such as hypertension and hyperphosphataemia.

Anaemia may also be improved. Many patients

on dialysis lead near-normal lives and half of

them return to work. There is a reduced quality

of life compared with normal or after a trans-

plant,   but   there   are   far   fewer   restrictions

compared with conservative treatment in the

later stages of CRF.

When the GFR falls below about 10 mL/min,

toxic nitrogenous metabolites, potassium, acid

and   water   start   to   accumulate   to   a   life-

threatening degree. Serum creatinine at this stage

would probably be above 1000 lmol/L and blood

urea more than 30 mmol/L. If there are persistent

complications such as neuropathy, pericarditis or

refractory  hypertension,  intervention  is  made

even earlier.

Although there are nowadays few patients for whom   transplantation   is   absolutely   contra-

indicated, most will have to wait months or

years for an organ to become available, and dial-

ysis is essential to keep them alive until then.

Many  patients  have  been  successfully  main-

tained on dialysis for decades. Nevertheless, their poor general health results in a greater mortality than that of the general population.

Principles

Two general techniques are currently available,

namely   haemodialysis (HD)   and   peritoneal

dialysis (PD). Ideally these would perform the

same  functions  as  the  natural  kidney  where

ultrafiltration is followed by reabsorption.

In health filtration involves removal of water

and dissolved small molecules via a size-selective

semi-permeable membrane (the glomerular base-

ment membrane, GBM) driven by hydrostatic

pressure (arterial blood pressure). Reabsorption

involves  partially  selective,  sometimes  active

recouping of useful substances (in the tubules).

These processes cannot be mimicked exactly.

Almost all artificial kidneys utilize a membrane

analogous to the GBM, but with a different pore

size. In HD the membrane is artificial, while in

PD the patient’s own peritoneal membrane is

used. In PD the dialysis approaches equilibrium

before the dialysis fluid is changed, whereas in

HD fast cycling of fresh dialysis fluid speeds

diffusion by continually exposing the blood to

maximal concentration gradients. Thus HD is

more efficient.

In addition to its principal use in CRF, dialysis is also used in the oliguric phase of ARF and for drug overdose and poisoning. Some conserva-

tively managed early CRF patients may need

temporary   dialysis   during   acute-on-chronic exacerbations, after which they may stabilize

again and come off it.

Water removal

In both forms of dialysis, water removal is by ultrafiltration. In HD the driving force is hydro-

static, using negative pressure on the dialysate side; in PD water is removed osmotically.

Removal of waste solutes

Essentially  dialysis  means  solute  transfer  by

diffusion through a membrane down a concen-

tration gradient. In renal dialysis a system is set

up whereby blood on one side of a suitable

membrane is exposed to a dialysis solution on

the other. The dialysis solution may contain low

concentrations of the substances to be removed,

or none at all. Haemodialysis can generate urea

clearances of up to 100 mL/min. Yet because it

relies on diffusion, clearance is inversely propor-

tional to molecular weight, so that ‘middle mole-

cules’ are less efficiently removed than small

molecules such as urea and creatinine. With

high transmembrane flow rates and especially

with larger pores, larger solutes may also be

drawn across by solvent drag or convection.

Renal replacement therapy        917

Conservation of useful substances

There is no equivalent in dialysis to the subtle

processes   of   natural   tubular   reabsorption.

However, in practice significant electrolyte and

nutrient losses are uncommon. Two rather crude

substitutes may be used. There can be replace-

ment by dietary supplementation, e.g. of water-

soluble vitamins or amino acids; or else the

dialysis fluid can be loaded with the desired

substances  at  normal  plasma  concentrations,

thus inhibiting diffusion. The latter technique

may be extended by adding substances to the

dialysis fluid in excess, to promote net transfer to

the  patient’s  circulation,  e.g.  bicarbonate  to

combat acidosis, or insulin for diabetics on PD.

Haemodialysis

The early artificial kidneys were cumbersome

and inefficient devices the size of a suitcase,

which had to be painstakingly disassembled and

cleaned between treatments. Modern artificial

kidneys  are  disposable  and  little  larger  than

the organ they replace, though they have about

the same filtration area of 1 m2. In some there

are multiple thin cellophane films which sepa-

rate alternate layers of blood and dialysis fluid;

in others the blood is pumped through a parallel

array of multiple fine, hollow fibres, which are

surrounded by dialysis fluid. In each case the

dialysis fluids flows countercurrent to the blood.

Basic system and apparatus

A diagram of the basic HD system is given in Figure 14.14 and the apparatus is shown in use in Figure 14.15. The sequence is:

•  Arterial blood is directed outside the body and

            passed through the system by a peristaltic

pump

•  The blood is anticoagulated with heparin and

            circulated through the artificial kidney.

•  A countercurrent of haemodialysis fluid runs

against the blood.

•  A small negative pressure is applied to the

            blood.

•  Blood is returned to a vein and the dialysate is

            discarded.

Apart   from   the   artificial   kidney   itself,   the

function of most of the HD apparatus is the maintenance  of  a  safe  extracorporeal  blood

circulation and the preparation of a suitably

purified  dialysis  fluid.  The  blood  circuit  is

heparinized using an infusion pump at a rate

sufficient to prevent clotting within the appa-

ratus, but which ensures the heparin is inacti-

vated naturally by the time blood is returned

to the patient. Rarely, protamine may be needed

as an antidote, or epoprostenol may be used if

the   patient   has   bleeding   problems.   Up   to

500 mL/min of blood may be removed from the

patient and this must be returned free of air

bubbles and clots and at the correct pressure and

temperature.   Physiological   saline   is   flushed

through the blood circuit beforehand to prime it

and  afterwards  to  return  as  much  blood  as

possible to the patient. This also facilitates a top-

up infusion if an overshoot in ultrafiltration has

caused fluid depletion.

Vascular access

The patient is usually connected to the HD appa-

ratus via a SC arteriovenous fistula in the arm.

This is an artifical connection constructed surgi-

cally between an artery and a vein in the wrist

area (Figure 14.16(a)). After a few weeks, the

fistula is mature and the vein becomes ‘arterial-

ized’: it swells and its wall becomes thickened,

which  facilitates  repeated  puncture  for  both

access and return.

For  temporary  dialysis,  or  during  the  few weeks while a fistula matures, either a tempo-

rary IV line (jugular or subclavian catheter) or, less  comonly  nowadays,  an  external  shunt

(Figure 14.16(b)) is used. Fistulae last for several years  before  becoming  unusable,  when  a

different  site  needs  to  be  fashioned.  Shunts, although quick to set up, last less than a year

and are very inconvenient.

Dialysis fluid

The 100-200 L of dialysis fluid needed for each

treatment  are  prepared  automatically  in  the

proportionating unit using concentrated dialysis

solution. This is diluted as required with mains water that has been thoroughly purified. Ion

exchange or reverse osmosis remove potentially

dangerous cations. Aluminium and calcium are

the main problems long term: the former causes

encephalopathy             (‘dialysis           dementia’)    and

complicates osteodystrophy, while calcium can

cause acute neurological problems during dial-

ysis. Various environmental toxins and pyrogens

are adsorbed onto carbon, and ultaviolet radia-

tion is used as a microbicide. Flow rates of up to

800 mL/min mean that up to 150 L of water may

be needed for a single treatment. The blood

circuit has to be scrupulously sterile, and most of

it is disposable.

The ionic composition of the dialysis fluid is

adjusted   individually   to   normalize   each

patient’s  plasma,  i.e.  low  in  those  ions  to  be

removed, high in those to be taken up. Usually

it is equimolar in Na  and Mg2  , K  is between

0-3 mmol/L,  Ca2         is  variable  and  alkali  is

supplied  as  lactate  or  acetate,  bicarbonate

being  incompatible  with  Ca2  and  Mg2  .  For diabetics, glucose is sometimes added to prevent hypoglycaemia.

Routine therapy

Most patients need 3-6 h of HD two to three

times each week, depending on their fluid and

electrolyte retention between treatments, which

itself partly depends on residual urine output.

Dialysis requirement is usually monitored by

weight gain, and progress of HD is followed

measuring dialysate outflow. Ideally the patient

should not gain more than 1500 g between treat-

ments, i.e. 1.5 L of fluid, to avoid cardiovascular and pulmonary problems. Moreover, removing more than this in 4-6 h can cause temporary

fluid or electrolyte imbalance, the so-called ‘dis-

equilibrium   syndrome’ (involving   weakness, hypotension,   dizziness   or   cramps)   because plasma concentrations change far more rapidly than in extravascular sites.

Dialysis may be carried out overnight, thus

maximizing the utilization of dialysis facilities,

although in UK hospitals it is more usually done

during the day. Many patients continue full or

part-time work. Patients can also make tempo-

rary arrangements with dialysis units in holiday

areas. Once patients are stabilized, dialysis equip-

ment  may  be  set  up  in  their  homes.  This

depends on whether the patient and carers can

cope physically, intellectually and psychologi-

cally, and also on logistical factors, such as water

supply, whether there is a spare room (some

patients   have   Portakabins   erected   in   their

garden) and whether there is someone to help

them cope with any problems that may arise

while dialysing.

Most CRF dietary restrictions on potassium,

phosphate,  etc.  still  need  to  be  observed  by

patients on HD, and daily fluid intake must not

exceed 500 mL plus urine output. Advice and

counselling from a dietician is important. Anti-

hypertensive treatment is frequently continued,

although the hypertension may improve. Vita-

mins B complex and C are required to compen-

sate for losses of these water-soluble substances to

the dialysate, as are iron and folate for the blood

losses  incurred.  Epoetin  and  osteodystrophy

treatments need to be continued.

Problems

Acute  problems  include  fluid  or  electrolyte

imbalance  resulting  from  the  rapid  changes

causing cramps, hypotension, headaches, etc.

and ischaemia distal to the access site, e.g. in the

hand.   Immediately   after   treatment   some

patients need an oral sodium supplement for

cramps  caused  by  electrolyte  deficiency  The

main   chronic   problems   are   related   to   the

vascular access and include thrombosis, local or

systemic infection, haemorrhage, phlebitis and

haemolysis, etc.

Patients do very well on HD and feel better

than they did in the later stages of CRF before

starting dialysis, and it is used by about three

quarters of all dialysis patients. The quality of life

is reduced on account of regular disruption and

dependence on machinery, but some patients

still prefer this to the continuous commitment

of PD.

Haemofiltration

Drawbacks  to  the  conventional  HD  system

include complex apparatus and poor clearance

of ‘middle molecules’. The intermittent nature of

the treatment can impose high haemodynamic

stresses, especially in ARF. Several alternatives

have been developed that are particularly useful

for short-term dialysis, e.g. in ARF or cases of

poisoning.

In continuous arteriovenous haemofiltration

(CAVH) no dialysis fluid is used. The system

operates more like a plasma exchange, with large

quantities of fluid (up to 20 L per day) being

removed in an artificial kidney with a more

permeable  membrane.  Crystalloids  follow  by

convection,   rather   than   diffusion   as   in

haemodialysis. Fluid and electrolytes (without

unwanted toxins) are replaced continuously via

the return line, the volume replaced depending

on how much fluid needs to be lost. Where urea

levels are high, e.g. in the hypercatabolic states

of severe ARF, a blood pump and negative pres-

sure are used, which also improves the removal

of ‘middle molecules’. Alternatively, there may

be additional intermittent haemodialysis.

The newer technique of continuous arterio-

venous haemodiafiltration (CAV-HD) represents

a compromise. Dialysis fluid and a more porous

dialyser unit are used and a pump may not be

required. Fluid removal is controlled by the dial-

ysis fluid flow rate, which is generally much

slower than in normal HD. In haemoperfusion a

sterile activated charcoal column is put in the

blood circuit rather than an artificial kidney.

This is sometimes useful in poisoning treatment.

In  continuous  venovenous  haemofiltration  a

single dual-lumen IV catheter is used and a

pump added to the circuit.

Peritoneal dialysis

This process is far simpler mechanically. Up to

2.5 L of sterile dialysis fluid are run directly into the patient’s peritoneal cavity under gravity via

an indwelling silastic catheter, over about 10

min (Figure 14.17). Dialysis then takes place

between the blood in peritoneal capillaries and

the   dialysis   fluid   in   the   peritoneum.   The

dialysing interface is composed of the vascular

basement   membranes   and   the   peritoneal

membranes, both of which are semi-permeable.

The process is thus analogous to the formation

of tissue fluid or ascites. The entire fluid volume,

including excess water and dialysed substances,

is then drained out again under gravity, often by

simply putting the empty dialysis fluid bag on

the floor below the patient.

PD fluid comes ready-made and sterile, and is

similar in composition to diluted HD fluid but

with  little  potassium,  clearances  being  lower

than  in  HD.  Because  a  hydrostatic  pressure

gradient cannot be set up in the peritoneum to

promote water removal, different concentrations

of glucose are added (1.36-4%) to effect different

rates of removal osmotically. The system is rela-

tively cheap to set up and maintain and requires

far simpler equipment and fewer specialized staff

when used in hospital.

There are several different ways of organizing and scheduling PD.

Intermittent peritoneal dialysis

In  its  conventional  hospital-based  form  this

method  involves  multiple  hourly  fill-drain

cycles with short dwell times, repeated 24-48

times  over 1-2 days.  Because  the  rate  of

diffusion  of  molecules (equivalent  to  their

clearance)  declines  as  their  concentration  in

the  peritoneal  dialysate  increases,  a 30-min

contact   time   within   the   peritoneum   is

optimal.

Intermittent peritoneal dialysis (IPD) is only

about one-fifth as efficient as HD, with urea

clearance of about 20 mL/min. The cycle must

be repeated, two or three times weekly, using

50-100 L of PD fluid each time. Perhaps surpris-

ingly, it is not overly uncomfortable for most

patients, although they are physically restricted

for long periods. However, IPD is rarely used

nowadays  except  in  patients  awaiting  some

other management, in those for whom all other

methods have failed, and in those with some

residual renal function when the inefficiency of

IPD is less of a problem.

Continuous ambulatory peritoneal dialysis

Originally devised to exploit the simplicity of PD

but free the patient of its restrictions, continuous ambulatory peritoneal dialysis (CAPD) yielded unexpected additional benefits and is now the most popular form of dialysis in theUK(about 40-50% of cases). Instead of the frequent fluid changes  being  made  during  several  specified periods in the week, the patient carries the fluid in their abdomen continuously, day and night, while living an otherwise almost normal life.

The solution is changed two to five times daily, the longest dwell being overnight.

PD fluid is run in from a soft plastic bag, and

the line is then closed. After 4-6 h the dialysate

is  drained  out  and  fresh  fluid  run  in.  The

changeover takes 30-40 min, and the patient

needs  training  in  aseptic  technique.  CAPD  is

not suitable for all: some cannot cope emotion-

ally or intellectually, while others have manipu-

lative  difficulties,  e.g.  the  aged  or  arthritic;

others  do  not  appreciate  the  need  for  strict

asepsis. On the other hand, some patients are

even able to judge the right glucose concentra-

tion to use each time to extract more or less

fluid as required.

To   reduce   the   chances   of   infection   the

‘disconnect-flush before fill’ system is practised.

The  intraperitoneal  catheter  terminates  exter-

nally as a Y-tube, both arms of which can be

sealed. At changeover both an empty and the

new bag are connected. The dialysate is first

drained off, flushing away potential contamina-

tion from the connection procedure; new fluid is

then run in.

Successful patients achieve a steady contin-

uous clearance of water, electrolytes and uraemic

toxins  with  stable  if  somewhat  higher  than

normal blood levels, so the process resembles

normal renal function more closely than other

forms of dialysis. There is little of the peaking

and troughing of electrolyte levels characteristic

of both HD and IPD. In addition, the use of a

natural   membrane   and   longer   dwell   time

improves  the  removal  of ‘middle  molecules’.

Thus there is a more stable fluid and electrolyte

balance and consistently lower levels of toxins,

and consequently patients feel very much better.

Moreover, there are few dietary restrictions, the

main remaining modification being an increased

protein intake to compensate for losses across

the   peritoneum.   Water-soluble   vitamins   are

given as usual.

Automated peritoneal dialysis

This technique is increasingly used where CAPD

has   failed   to   provide   control   or   where   it

produces unacceptable daytime restrictions for

patients. Automated peritoneal dialysis (APD)

involves automation of intermittent PD, with a

machine to switch between bags and control the

tap. It can be used easily at home, and when run

overnight  causes  less  discomfort  because  the

patient is recumbent. The more rapid cycling

compared with CAPD means that night-time

exchanges may provide sufficient control and

obviate the necessity for the patient to dialyse

during  the  day,  or  else  only  require  a  few

daytime cycles. Thus, APD is preferred by many

patients and now is used by about one-quarter of

PD patients in theUK.

Problems

Contra-indications.   Patients   with   respira-

tory or abdominal disease present difficulties.

Diaphragm movement is impeded by the fluid-

filled abdomen, and this possibly impairs respi-

ration. Fistula formation might be encouraged in

IBD, with consequent peritonitis, and hernias

may be aggravated. Gut surgery can leave fibrous

adhesions which reduce the effective membrane

area.

Peritonitis.   Infections   from   contamination

during bag switching are unfortunately common:

a CAPD patient experiences one such episode on

average every 2-3 years. It is less frequent in

hospital-based PD. Usually, a commensal Gram-

positive  skin  organism (Staphylococcus  epider-

midis) is implicated, but enterococcal infection

(Streptococcus faecalis) suggestive of an intestinal

fistula may occur and is far more serious. Infec-

tion may be painless and is usually detected

when the dialysate becomes cloudy or takes far

longer than usual to drain. CAPD patients must

then report to the hospital immediately.

The dialysate should be sampled for culturing

and  sensitivity  testing  before  antibiotics  are

given,   but   blind   therapy   must   be   started

promptly  to  minimize  the  development  of

peritoneal fibrosis. Initial treatment is a cephalo-

sporin plus an aminoglycoside in the dialysis

fluid, with one or the other stopped according

to sensitivity data. A loading dose, possibly IV,

may be needed in severe cases: otherwise most  episodes are managed with the patient at home

or as an outpatient. Treatment should last 7-10

days,  during  which  normal  dialysis  may  be

continued, although at an increased frequency

because the inflamed membranes reduce urea

clearance.

A less invasive and far cheaper recommenda-

tion for mild peritonitis is to perform three rapid

exchanges at the first sign of infection and then

simply to stop PD for 2 days and allow for

natural resolution, though this requires careful

supervision  in  hospital.  Exit  site  or  catheter

tunnel infections are usually Gram-positive and

an antistaphylococcal agent such as vancomycin

is used.

Apart from the immediate problems of serious infection, each peritonitis episode causes scar-

ring and adhesions that gradually degrade the peritoneal surface area and reduce ultrafiltration efficiency.  This  may  be  exacerbated  by  the continuous exposure of the peritoneum to an

abnormal fluid volume.

Hyperglycaemia.   The glucose in the dialysis

fluid causes hyperglycaemia and obesity, espe-

cially  in  CAPD  because  there  is  significant

absorption during the long dwell times. This is a

particular problem with diabetics. The hyper-

lipidaemia which all renal patients suffer is exac-

erbated  in  PD  patients,  possibly  due  to  the

hyperglycaemia. Another consequence of glucose

absorption is a gradual reduction in the osmol-

arity of the in situ dialysis fluid, which reduces

ultrafiltration   as   each   exchange   proceeds.

Glucose polymers, e.g. icodextrin, which exert a

significant oncotic pressure in the dialysis fluid

but cannot be absorbed, minimise this.

Other problems include:

•  Loss of protein and amino acids.

•  Blockage of the catheter  (which otherwise

lasts many months, and is regularly cleared

with a heparin flush).

•  Local infection around catheter insertion site.

•  Sclerosing peritonitis, a rare, potentially fatal

complication, possibly associated with dial-

ysis  fluid  contaminants  or  additives,  e.g. chlorhexidine, acetate.

There is a high drop-out rate from CAPD, with

up to half of patients switching to some other

Renal replacement therapy        923

method within 3 years, and few lasting 10 years.

In theUKmany would regard CAPD as the treat-

ment of second choice (after transplantation) for

ESRD, and intensive efforts are being made into

improving its success rate because of the quality

of life it permits and its economic benefits. Up to

50% of dialysis patients are on CAPD and most

of the remainder on HD. However, the position

is different in the rest ofEurope; e.g. in Scandi-

navia, only 30-40% choose CAPD, the majority

preferring HD. There may be economic reasons

for this.

Drug therapy in PD

Many drugs can, like antibiotics, be given safely and effectively by the intraperitoneal route in

CAPD fluid. The most notable example is insulin for  diabetics  with  ESRD,  and  very  smooth diabetic control can be achieved in this way.

Further information may be obtained in the

References and further reading section.

Comparison of dialysis types

The 10-year survival rate for both methods is

about  75%,  with  CAPD  patients  achieving  a

slightly  better  rate.  Table 14.21  summarizes

important features of the two main types of dial-

ysis, and compares their relative advantages and

disadvantages.

Transplantation

For the vast majority of ESRD patients a renal

transplant  is  the  best  possible  treatment.  In

Europeas a whole about 30% of patients receive

replacement  kidneys,  but  there  are  regional

differences. TheUK, with 30 kidney donations

per million population annually, has the lowest

rate.

The  shortage  of  organs  is  still  the  major

impediment  to  improving  these  figures,  the

situation having been exacerbated by seat-belt

legislation which has reduced road traffic fatal-

ities. In addition, certain ethnic groups may

have cultural or religious objections. On the

other hand, as tissue matching and immuno-

suppressive   regimens   improve   and   surgical

experience grows, so the survival rate, especially

of   non-related   or   unmatched   living   grafts improves,   and   the   admission   criteria   to

transplant programmes have been relaxed.

Patients who formerly would not have been

grafted owing to age or an underlying disease that

predisposed them to renewed renal damage, e.g.

diabetes, hypertension, arterial disease, are now

considered. There remain few absolute contra-

indications; these include extensive neoplastic

disease, serious infection, and the inability to

withstand major surgery or immunosuppression,

e.g. otherwise immunocompromised patients.

A successful graft is an almost complete cure:

all fluid, electrolyte and toxaemic complications

are reversed, and in time the anaemia and even

the bone disease resolve. There may be some

residual hypertension but the only significant

disadvantage is the lifelong immunosuppression

that is needed, with its attendant risks, and the inconvenience of regular monitoring.

Organ donation

Live donors

Using  live  donors  is  convenient  and  allows

ample preoperative preparation. It also results in

improved graft survival because of the reduced

time that the organ spends disconnected from a

blood supply (cold ischaemic time). Donors are

carefully screened for renal disease or relevant

risk factors, e.g. hypertension, and for general

and psychological health. The loss of a kidney

does not adversely affect an otherwise healthy

person, and the operative risk is low (mortality

about 1/3000). Their remaining kidney hypertro-

phies, giving an eventual GFR of about two-

thirds the pre-donation level. Long-term follow-

up   of   donors   has   shown   no   significantly increased risk of renal disease or hypertension, nor any reduction of life expectancy.

Related donors are preferred. Obviously the

ideal of an identical twin is rarely achieved;

failing   that,   other   siblings   are   preferred.

However, genetically unrelated spouse donors

are  being  increasingly  used,  with  surprising

success. Anonymous organ donation for profit is

not permitted in most countries. In the future

there may be transplants from other species such

as pigs (xenotransplantation). One experimental

approach is to modify animals genetically to

make   their   tissues   immunologically   better

tolerated by the human immune system.

Increasingly,   diabetic   patients   are   being offered simultaneous renal and pancreatic trans-

plantation (see Chapter 9).

Cadaveric donation

About 75% of donations are cadaveric. The pref-

erence is for ‘beating heart’ donors, such as

brain-damaged  patients  taken  off  life-support

systems,  and  only 10%  of  cadaveric  kidneys

come from non-heart beating donors, e.g. road

traffic accidents. At 25%, theUKhas a relatively

low proportion of living donors to cadaveric, the

highest beingNorwaywith 45%. The criteria

applied in this controversial area are affected by

ethical, cultural, ethnic and religious considera-

tions that are outside the scope of this book.

However, it should be noted that rigorous rules

for determining brain death are now applied,

which effectively eliminate the risk of error.

Graft matching

All  ESRD  patients  approaching  end-stage  are

tissue-typed and registered centrally. When a

kidney   becomes   available,   several   closely

matched potential recipients are urgently called

to their local renal unit and a direct cross-match

is done. All other things being equal, the patient

with   the   best   match   is   then   immediately

prepared for surgery.

Histocompatibility

Two important immunological criteria affect the

risk of rejection. Blood group (ABO) compati-

Renal replacement therapy        925

bility operates as in blood transfusion, i.e. group O is a universal donor, etc. More complex is HLA compatibility (see Chapter 2). Class II HLA-D antigens  seem  to  be  the  more  important  in transplantation.

The intensity of an immune response and thus

the likelihood of rejection depends on the degree

of HLA similarity between donor and recipient;

e.g. they may have the same HLA-A and HLA-B

antigens (both Class I), but may differ in HLA-DR.

Children have a mixture of their parents’ HLA

genes. Identical (monozygotic) twins will have

identical genes, as occasionally may two siblings

by chance. The more distant the relationship, the

less compatibility there is likely to be.

In discussing the outcome of transplantation it

is usual to refer to graft survival, because if a graft

fails the patient is simply returned to the dialysis

programme.   Grafts   from   an   identical   twin

(isografts)  have  the  best  chance  of  survival.

Survival figures for grafts are better for live dona-

tions than from cadaveric (Table 14.18). The

longer a graft survives the lower the incidence of

rejection; at the best centres the 10-year graft

survival  rate  with  well-matched  kidneys  can

reach 70%, although the average is about 50%.

Immunosuppressant drugs can keep rejection

at bay at the cost of potential myelosuppression,

infection and other chronic iatrogenic complica-

tions. Improvements here have brought about

gradually   increasing   graft   survival.   Better

matching reduces not only the chance of rejec-

tion  but  also  the  immunosuppressant  doses

required, which itself improves patient survival.

Cross-matching

HLA-A, B, and C can be typed at any time using

specific antisera and the patient’s or donor’s

blood. For HLA-D, it is necessary to mix recipient

lymphocytes and potential donor serum directly,

from which donor lymphocytes must be deleted

by a cytotoxic drug so that only the recipient’s

lymphocytes  can  respond  to  any  incompati-

bility. Because typing takes 5 days, it is not prac-

ticable for cadaveric donors. The D subgroup

called   DR       (D-related),   currently   the   best

predictor of graft tolerance, is detectable serolog-

ically, providing faster, more accurate matching.

Nevertheless,   even   completely   HLA-mis-

matched grafts are sometimes successful and the

paramount  significance  of  HLA  matching  is

disputed.  Blood  group  compatibility,  general

health,   previous   transfusions   and   effective

immunosuppression seem to be equally impor-

tant in determining graft survival. Graft survival

rates from cadavers and living unrelated donors

are fast approaching those from living related

donors.

The ‘transfusion effect’ is an immune toler-

ance that seems to be induced in ESRD patients.

A wide variety of antigens are present in the

pooled  blood  of  the  numerous  transfusions

usually received by ESRD patients during the

course of their illness. Theoretically these would

be  expected  to  stimulate  the  production  of

multiple antibodies, some of which could - and

sometimes   do -   reject   a   subsequent   graft.

However, a significant overall graft-sparing effect

results from transfusions given in the months

before grafting.

A  final  direct  cross-matching  of  recipient serum and donor lymphocytes is performed just before surgery to check if there are any pre-

existing   cytotoxic   serum   antibodies   which would cause an immediate rejection. Such anti-

bodies could have arisen from previous blood transfusions, transplants or pregnancy.

Surgical procedure

The   operation   is   not   complex   surgically,

compared for example to heart transplanation

(Figure 14.18).  The  donor  organ  is  removed

along with lengths of renal artery, renal vein and

ureter. For living donors this can now be done

laparoscopically (‘keyhole surgery’) to minimize

trauma and improve post-operative recovery. It

is  placed  extraperitoneally  in  an  iliac  fossa,

where it can easily be felt and biopsied after

operation. This also preserves the peritoneum

should further dialysis be necessary. The graft’s

renal artery and vein are connected to major

local   abdominal   vessels   and   the   ureter   is

implanted  into  the  recipient’s  bladder.  The

bladder   connection   may   occasionally   cause

subsequent problems, but the operation has few

complications and a low risk.

The  original  kidneys  are  usually  conserved

even if the patient is anuric, unless there is

strong evidence of renal hypertension, stones (a

focus of infection) or a tumour. This preserves and utilizes any remaining function - especially important should the graft fail. Equally impor-

tant, it helps maintain the haematocrit as some erythropoietin is still secreted even when the

GFR is minimal. Bilateral nephrectomy intro-

duces further operative risk for no improvement in graft or patient survival.

Kidneys are implanted as soon as possible after

removal from the donor. This is easy to arrange

with a living donor using adjoining operating

theatres, and this contributes to the success of

this type of transplant. Cadaveric kidneys are

perfused with specially formulated organ preser-

vation solution at 5°C immediately after removal

to preserve their viability during transportation.

The   ischaemic   period   after   donor   organ

removal causes a variable degree of ATN that

may manifest as ARF in the recipient for up to

about 10 days after transplantation. During this

time the patient may need to continue on dial-

ysis, depending on their urine output and blood

chemistry. The sooner the organ is implanted

the less serious this episode is, and up to 75% of

recipients start producing urine within a few

days.

Rejection

A kidney graft may be rejected at any time,

although the longer it survives the less likely this

becomes. Moreover, most rejection episodes can

be controlled. About half of patients undergo at

least one epispode and a patient may undergo

several episodes yet still ultimately retain the

graft. However, if it cannot be saved the patient

is returned to dialysis and to the transplant

waiting  list.  The  failed  graft  neeed  not  be

removed unless it is a focus of infection or

chronic    inflammation;    otherwise,    further

surgery can be avoided by allowing it to become

fibrosed and eventually atrophy.

There are three main types of rejection:

Hyperacute or immediate rejection.   This is

caused by either pre-existing plasma antibodies

attaching to the graft and initiating an immune

response, or by ABO mismatch. It occurs within

days  or  even  hours,  as  soon  as  the  organ

becomes  adequately  perfused,  and  results  in renal vascular thrombosis and loss of the graft. Fortunately rare, this condition is untreatable

because  the  antibodies  are  already  formed, although plasmapheresis has been tried.

Acute  rejection.   This is the most common

form. It can occur at any time, but usually in the

first fortnight. It is a normal T cell-mediated

response  to  HLA  antigens  involving  primary

sensitization,   lymphocyte   proliferation   and

subsequent attack. The resulting vascular and

tubular  damage  initially  causes  non-specific

symptoms such as fever and tenderness over the

graft. If the organ has started functioning there

will be a decline in renal function, with oliguria

and a rise in serum creatinine.

There are problems in diagnosing acute rejec-

tion. If it occurs during the period of ATN that often follows cadaveric grafting, reduced renal

function cannot be identified. Furthermore, a

similar picture could be caused by a recurrence of

the primary disease, by post-operative infection

or obstruction, or by nephrotoxicity especially

from   ciclosporin.   Consequently,   most   such

episodes are treated by default as if they were

rejection while efforts are made to identify other

causes.

Chronic  rejection.   This  may  occur  at  any

time  after  the  first  few  months,  and  partly

involves  immune-complex  deposition  within

the  glomeruli  and  renal  vessels  resembling

chronic glomerulonephritis. Now referred to as

chronic  allograft  nephropathy,  it  is  relentless

and usually irreversible, resulting in loss of the

graft.

Prevention and treatment of rejection

Immunosuppressant therapy is started immedi-

ately before grafting, gradually reduced over 2-6

months to a maintenance dose and, except for

isografts (HLA-identical), is continued lifelong. If

there is an acute rejection episode it is increased

temporararily until the rejection is controlled or

the graft is lost. Treatment generally consists of

combination   therapy   with   drugs   acting   at

different sites in the immune process (Figure

14.19).   Combined   therapy   permits   lower individual doses, but monotherapy avoids the toxicity of some drugs completely.

Prevention

The range of drugs used includes:

Corticosteroids  (prednisolone),   which   non-

specifically inhibit the action of many immune cells, including lymphocytes and macrophages, partly by interfering with cytokine production. The main drawback is the well-known range of dose-related steroid side-effects.

Anti-proliferative agents (azathioprine, myco-

phenolate  mofetil,  sirolimus).  Azathioprine  non-

specifically   depresses   cellular   proliferation,

including immune cells; mycophenolate is more

specific for lymphocytes, more effective but also

more expensive. Sirolimus is also more specific

and is not nephrotoxic, making it a good substi-

tute if a calcineurin inhibitor is not tolerated.

The main adverse effect of all antiproliferatives is

some degree of bone marrow depression through

inhibition of haematological precursors.

Calcineurin inhibitors (ciclosporin, tacrolimus)

inhibit  activation  of  lymphocytes  targeted

against specific antigens, and thus do not depress

the bone marrow. They have potentially serious

long-term  adverse  effects,  including  hyper-

lipidaemia,   hepatotoxicity,   lymphoma   and,

unfortunately,  nephrotoxicity  that  results  in

hypertension. Tacrolimus is diabetogenic and can

cause cardiomyopathy, so monitoring is required.

Both have formulation dependant bioavailability

so  brand  and  formulation  changes  should  be

avoided. Toxicity is minimized by careful plasma

level monitoring. They are metabolized by the

cytochrome P450 (3A4) system so interact with

enzyme inducers and inhibitors.

Anti-lymphocyte antisera  (anti-lymphocyte

globulin, ALG; anti-thymocyte globulin, ATG),

are   raised   in   animal   hosts   against   human

lymphocytes and contain a wide range of anti-

bodies and so are polyclonal and non-specific.

OKT3 (anti-CD3) also targets lymphocytes but is

monoclonal.

Monoclonal  anti-interleukin  agents  (anti-

CD25 agents: basiliximab, daclizumab) block the interleukin-2 receptor (IL-2R), interfering with activated lymphocyte action. These agents are highly specific and appear to have few serious adverse effects. They are recommended by NICE for anti-rejection induction.

Treatment   regimens   vary   widely   between

centres. A typical combination used in the UK is:

•  Prednisolone, used high-dose for  ‘induction’

immediately before implantation (1 g methyl- prednisolone IV) and then at moderate doses

            following implantation (e.g. 20-30 mg pred-

            nisolone oral daily) for 1-3 months then tailed

            off to a maintenance level (5-10 mg daily).

•  Azathioprine,  initiated  post-operatively  at  a

maintenance dose.

•  Tacrolimus, also started post-operatively and

            carefully monitored.

Following a rejection episode the regimen would

be changed (rescue or salvage therapy), substi-

tuting  mycophenolate  and/or  siroliumus.  The

development of numerous alternatives has now

made it feasible to tailor regimens for particular

patients  or  situations,  which  can  improve

survival  or  minimize  adverse  effects,  or  both,

starting  with  the  most  suitable  drugs.  For

example, start with the second-line agents for a

high risk patient such as a re-transplant; avoid

nephrotoxic drugs following implantation with

an organ exposed to warm ischaemia; use steroids

and tacrolimus only with caution if latent diabetes

is suspected.

Management of rejection

The standard response to suspected rejection is

to increase the steroid dose substantially, e.g. IV

methylprednisolone 1 g daily for 3 days. There is

no point in raising antiproliferative dosage as

the cells doing the damage are already in the

blood,  and  calcineurin  inhibitors  cannot  be

increased because the dose being used was prob-

ably maximal before rejection, so that raising it

would cause unacceptable toxicity. The episode

will usually be aborted within a few days and

normal prophylactic doses can be resumed.

Should steroids fail other immunotherapeutic regimens are used, e.g ATG, ALG, OKT3.

Other post-transplant complications

Successfully transplanted patients are still not

entirely  problem-free,  owing  mainly  to  their

immunosuppressant therapy. They need regular

renal,  liver  and  blood  screening  and  must

be monitored for infective or haematological

complications throughout the rest of their lives.

Many patients still have hypertension: contrib-

utory factors may include iatrogenic disease (e.g.

steroid-induced  fluid  retention  or  ciclosporin

Important renal diseases            929

nephrotoxicity), an imperfectly functioning graft

and  the  influence  of  the  original,  diseased

kidneys. A slightly increased risk of malignancy

(lymphoma and skin) is associated with long-

term  cytotoxic  therapy.  Vascular  disease  is

common.  Dyslipidaemia  due  to  steroids  and

calcineurin inhibitors and hypertension lead to

atherosclerotic complications, mainly IHD and

stroke, which are a major cause of death. The

increased  incidence  of  peptic  ulcer  may  be

related  to  steroids,  as  may  osteoporosis  and

osteonecrosis. Hepatic disease may result from

treatment with both azathioprine and ciclosporin.

Immunosuppression  from  cytotoxic  drug-

induced   bone   marrow   suppression   and

steroids  predispose  to  infections,  especially

cytomegalovirus,  Pneumocystis,  reactivated  TB

and  bacterial  urinary-tract  infections.  Patients

are often put on a combination of antimicro-

bials   for   several   months   post-operatively,

including   antivirals   co-trimoxazole,  isoniazid,

and antifungal lozenges.

Important renal diseases

In this final section some of the more impor-

tant renal diseases, many of which may be the

underlying cause of ARF or CRF, are considered.

Obstructive uropathy

Obstruction can occur anywhere from the renal

pelvis to the urethra and may be either unilateral

or  bilateral (Figure  14.20).  Certain  forms  pro-

duce acute symptoms; bilateral obstruction, if

untreated, may lead to CRF. Drugs have little role

in the management of these conditions.

Pathology

The effect of obstruction depends on the site.

Obstruction in the ureter or above, e.g. a stone or

calculus, causes fluid accumulation in the renal

pelvis (hydronephrosis) and a rise in tubular

hydrostatic pressure. The increased tubular back

pressure reduces the GFR but filtrate continues to

be  produced  for  some  time,  even  following complete obstruction. The resulting increase in

intrarenal pressure causes dilatation and gross

damage owing to compression of renal tissue

within the tough renal capsule. The prolonged

urinary   stasis   which   follows   can   promote

secondary effects such as urinary-tract infection,

because organisms are not regularly flushed out;

stasis can also promote stone formation.

If the obstruction is relieved promptly, there

may be a complete restoration of renal function.

There usually follows a massive and prolonged

diuresis, which can be fatally dehydrating: a urine

output of up to 50 L in 24 h has been reported.

Such  losses  suggest  delayed  tubular  recovery

(compare this with the polyuric phase of ARF,

p. 901) in addition to the simple clearance of

accumulated fluid. Because post-renal failure is

potentially reversible, a patient presenting with

sudden oliguria or anuria must always be investi-

gated  for  possible  obstruction.  Although  a

comparatively rare cause of CRF, obstruction is

one of the few causes that are preventable.

Chronic partial obstruction leads to chronic

renal inflammation, scarring and possible infec-

tion.  Such  obstruction  is  often  a  result  of

congenital incompetence of the valve mecha-

nism between the ureter and the bladder (the

vesicoureteric   junction;   Figure 14.20),   Vesi-

coureteric reflux leading to reflux nephropathy usually starts in infancy, and may stabilize or

progress slowly to CRF in adulthood.

In bladder outflow obstruction, e.g. prostatic hypertrophy, urinary retention may be accom-

modated   by   bladder   distension,   with   little serious rise in intrarenal pressure.

Aetiology

The commonest causes of obstruction are listed

in Table 14.22. In the West, the most frequent

causes are gynaecological problems in women,

prostatic hypertrophy in men, and stones in

both.

Renal calculi (urolithiasis)

The lifetime prevalence of renal stones is about

10% in males and 5% in females, although not

all cases are symptomatic. The causes are poorly

understood. Calcium oxalate stones, the most

common type, may result from hypercalciuria

(high   urinary   calcium)   or   excessive   gastro-

intestinal absorption of oxalate (hyperoxaluria).

Stone formation is encouraged by an alkaline

urine,  e.g.  from  renal  tubular  acidosis,  and

hyperuricosuria, e.g. in hyperuricaemia or gout

(Chapter           12).      Conversely,    hyperuricaemia

together with an acid urine predisposes to urate

stones. In urinary infections caused by urease-

producing organisms, especially Proteus spp., the

urinary alkalinity and ammonium content cause

co-precipitation   of   mixed   phosphate   stones

(calcium,   magnesium   and   ammonium).   In

cystinuria, an inherited metabolic disorder, the

reduced tubular reabsorption of cystine results in

high urinary levels and cystine stone formation.

Clinical features and investigation

Symptoms  depend  on  whether  the  lesion  is

above or below the bladder outlet. In the latter

case,  dysuria,  hesitancy,  frequency,  terminal

dribbling or bladder distension and discomfort

occur. Above-bladder obstruction usually causes

renal   colic (sudden   severe   and   debilitating

unilateral loin pain due to ureteric spasm) often

associated   with   haematuria   and   complete

ureteric obstruction. Colic is also caused by the movement of stones in the ureter.

The urine flow disturbance will also depend on

the degree and site of obstruction and whether it

is bilateral. Paradoxically, polyuria may occur,

owing   to   tubular   damage.   Chronic   reflux

nephropathy, caused by bladder contents being

refluxed into the renal pelvis, may result in

hypertension   and   recurrent   renal   infection

(pyelonephritis).

Investigation ranges from simple examination and   analysis   of   the   urine   to   sophisticated imaging and biopsy.

Management

Whereas surgery used to be common in treating

obstruction, conservative management is increas-

ingly used, owing to the growing appreciation

that renal function may be preserved or restored,

and to the development of techniques of percuta-

neous  intrarenal  manipulation.  Surgical  repair

may be essential in some cases, e.g. a congenital

defect, but nephrectomy is now quite rare.

Small  stones  (especially  cystine)  may  be

passed in the urine if output is encouraged by

ample  fluid  intake (more  than 3L  daily),

especially  overnight.  Antispasmodics  such  as

propantheline    (contra-indicated   in   bladder

outflow obstruction) or catheterization may also

assist  the  passage  of  stones.  Penicillamine  will

help  to  dissolve  cystine  stones.  Reducing

urinary urate levels with allopurinol may help.

Alkalinization of the urine, e.g. with potassium

citrate mixture, will also reduce hypercalciuria

and in turn the formation of both urate and

cystine stones. Urinary acidification, e.g. with

ammonium  chloride,  will  minimize  phosphate

stone production.

For  oxalate  stones,  sodium  restriction  and thiazides are used both to reduce urinary calcium (thiazides   promote   tubular   reabsorption   of calcium) and to increase urine flow. It is impor-

tant not to reduce dietary calcium in an attempt to treat hypercalciuria, because, paradoxically, this tends to increase future stone formation and also cause loss of calcium from bones.

Nephrostomy may permit extraction of larger

pelvic stones and drainage in hydronephrosis.

Stones may be ultrasonically disrupted by extra-

corporeal shock-wave lithotripsy (ESWL) and the

fragments passed out in the urine. Fibre-optic

ureteroscopy, which requires general anaesthetic,

may be required. Open surgery is rarely necessary.

In reflux nephropathy prompt treatment of

infections and adequate control of hypertension are likely to prevent progression. Surgery is rarely indicated, except for reconstruction of a congen-

itally abnormal vesicoureteric junction.

Renal colic is treated with either pethidine or,

increasingly,   an   NSAID        (diclofenac),   which

reduces ureteric spasm in addition to its anal-

gesic effect. IV fluids are used to promote urine

flow, especially as the patient is likely to be

extremely nauseous.

In   all   methods   employing   treatments   to encourage urine flow, it is of course important to ensure  initially  that  there  is  not  complete

obstruction.

Infection

As with obstruction, there is a significant differ-

ence between infections of the lower and upper

renal systems. Lower urinary-tract infection (e.g.

urethritis, cystitis) causes discomfort, inconve-

nience and not a little pain, but is essentially

benign if restricted to a single attack at that site.

Conversely,   infection   of   the   kidney (upper

urinary-tract   infection   or   pyelonephritis)   is

always serious and has systemic complications. It

may   even   lead   to   CRF:   indeed,   chronic

pyelonephritis accounts for some 10% of all

ESRD.

However,    urinary-tract           infection            and

pyelonephritis are not completely distinct. Most

kidney infections are presumed to have ascended

from asymptomatic, untreated or inadequately

treated urinary-tract infection, and this retro-

grade infection is encouraged by the urinary

stasis,   which   can   result   from   obstruction.

Repeated or serious urinary-tract infection can

itself  lead  to  obstruction  by  causing  ureteric

fibrosis and stricture (narrowing). The patholog-

ical spectrum, from asymptomatic bacteriuria to

what is still termed chronic pyelonephritis, is

illustrated in Figure 14.21.

Because pyelonephritis causes inflammatory

damage there is also some pathological similarity

to such conditions as nephrotoxicity, analgesic

nephropathy, reflux nephropathy and the renal

manifestations  of  connective  tissue  disorders,

e.g. SLE. The generic term interstitial nephritis is

often preferred.

Urinary-tract infection

Because of the close pathogenetic links between

urinary-tract   infection,   reflux   nephropathy,

obstruction  and  pyelonephritis,  some  of  the

general features of urinary-tract infection are

discussed  here  so  as  to  present  a  complete

picture of renal system infections. Full details of

urinary-tract infections, especially their investi-

gation and management, are given in Chapter 8.

Aetiology and pathology

Urine is normally sterile. The faecal commensal

Escherichia coli is responsible for acute infection in

75% of those cases where a urinary organism is

identified.  Less  common  pathogens  include

staphylococci,  faecal  streptococci,  Proteus  and

Klebsiella.  Non-specific  urethritis        (i.e.  non-

gonococcal) is usually caused by Chlamydia spp.

Women.   Even   with   the   strictest   hygiene,

urinary-tract contamination with skin commen- sals or faecal organisms is difficult to avoid in

women. This is due to the anatomical proximity

of the urethral and anal openings, and the rela-

tively short urethra. Simple urinary-tract infec-

tion is far more common among women than

men.

The   route   of   infection   may   be   anus-

vagina-vulva-urethra. Vaginal secretions, urine

and the urinary tract all normally have protec-

tive antimicrobial properties, e.g. mucosal IgA,

locally acidic pH, frequent flow. Thus, recurrent

infection suggests a breakdown in these defence

mechanisms,  e.g.  obstruction,  or  a  protected

focus of infection, e.g. infected stones. Persisting

vaginal organisms may be introduced into the

urethra  mechanically,  especially  during  inter-

course -  hence  the  rather  quaint  but  now

distinctly   anachronistic   term   ‘honeymoon

cystitis’. Urinary-tract infection is more common

among postmenopausal women owing possibly

to a loss of protection afforded by oestrogens.

Although bacteriuria is found in about 5% of

adult women, few of these suffer symptoms.

Such asymptomatic or covert bacteriuria gener-

ally does not require treatment except during

pregnancy,  where  there  is  a 30%  chance  of

progression to acute pyelonephritis due to intra-

abdominal ureteric compression. On the other

hand, no organism can be found in up to 50% of

women who do have symptoms of cystitis; this is

known   as   abacterial   cystitis             (or        ‘urethral

syndrome’).

Men.   Infection in males is much rarer and

always  requires  investigation.  Sexually  trans-

mitted   non-specific   urethritis   is   the   most common cause in young men and chronic bac-

terial prostatitis in older men.

Both sexes.   In the elderly of either sex the

prevalence of urinary-tract infection may rise to 30% and this is a particular problem in institu-

tions. Catheterization alone carries a risk of infec-

tion variously estimated at between 2% and 20%. In diabetics, reduced host defence and glycosuria predispose to urinary bacterial growth.

Clinical features and course

The hallmark of acute urethritis/cystitis is an

intense burning sensation on micturition, to

which the simple term dysuria fails to do justice.

The condition may be exacerbated by a more

acid urine resulting from local bacterial metabo-

lism. Urinary frequency is common and there

may be suprapubic pain or discomfort. Pyuria,

purulent discharge or even haematuria may also

occur  but,  although  alarming  and  requiring

investigation, are not necessarily sinister. There

are no systemic signs. The elderly commonly

present with acute confusion, fever, malaise or

anorexia  but  few  specific  urinary  symptoms,

making it easy to miss during examination. It is

also difficult to spot in young children if not

suspected.

Urinary-tract infection is usually self-limiting within a few days, especially if fluid intake is promptly increased substantially. It may have no complications in the absence of any other renal abnormality. However, recurrence is common owing   either   to   infection   with   a   different organism, or to relapse or re-infection with the same organism. The latter situation suggests the presence   of   a   complicating   factor   that   is preventing complete eradication.

Investigation

Two  things  must  be  determined:  (i)  which

organism is responsible; and (ii) are there any

underlying causes or correctable complications?

The collection of urine samples and the indica-

tions for further investigation are discussed in

Chapter 8.

Management

In the management of urinary-tract infection

the aims are to:

•  reduce the risk of renal damage. •  provide symptomatic relief.

•  render the urine sterile.

•  provide prophylactic therapy.

The first of these is achieved by prompt atten-

tion and full investigation when appropriate.

General measures include increasing the fluid

intake substantially to promote urine flow, and

providing advice on hygiene. For women, advice

includes front-to-back wiping after defaecation

(although the role of this has been disputed),

and micturition before and after coitus. Frequent

recurrence or relapse in the absence of obstruc-

tive  or  other  correctable  complications  may

require prophylactic therapy. For details of treat-

ment, see Chapter 8.

Acute pyelonephritis

Like lower urinary-tract infection, most cases of acute pyelonephritis (APN) occur in women. E. coli  is the usual culprit, but Proteus, Staphylo-

coccus   and   Pseudomonas   are   found   more commonly than in simple urinary-tract infec-

tion. Tubular inflammation causes polyuria and a dilute urine but severe cases may progress to acute oliguric renal failure.

Clinical features

An acute onset of severe loin pain is accompa-

nied by systemic features such as fever, nausea

and vomiting. There may also be lower urinary-

tract   infection   symptoms   of   cystitis   and

urethritis (Figure 14.20). Rarely, if both kidneys

are affected, tubular oedema and inflammatory

exudate may cause intrarenal obstruction with

acute post-renal failure.

Management

Prompt appropriate oral antimicrobial therapy and an increased fluid intake are always indi-

cated. The same agents are used as in urinary-

tract  infection.  However,  close  attention  to microbiological results is vital because of the

greater likelihood of unusual or resistant organ-

isms and the importance of characterizing recur-

rence as either relapse, i.e. the same organism, or re-infection possibly with another.

Most  patients  have  a  single  attack  of  APN

and  recover  completely,  but  recurrent  attacks

or  persistent  asymptomatic  bacteriuria  require

further  investigation.  If  the  recurrence  is  a

relapse  with  the  same  organism,  either  the

antimicrobial   therapy   was   inadequate   or

there may be obstructive/reflux abnormalities.

Frequent re-infection with different organisms

or  strains  suggests  that  the  host  defences  are

defective,  and  that  prophylactic  antimicrobial

therapy  should  be  considered.  This  can  be

continuous  low-dose  therapy,  or  intermittent

5-day  full-dose  courses  at  the  onset  of  symp-

toms, which the patient can be instructed to

initiate.

Reflux nephropathy (chronic pyelonephritis)

Definition

The term chronic pyelonephritis has traditionally

been used to describe a condition diagnosed radi-

ologically where one or both kidneys appear irreg-

ular,  shrunken  and  scarred.  However,  because

evidence is accumulating of a strong association

with  reflux  or  infection,  the  term  reflux

nephropathy is now preferred. Although most

cases do not progress to renal failure, it can be

extremely difficult to treat, and renal scarring is

present in up to 20% of patients starting dialysis.

Pathogenesis

The relative contributions of chronic infection

and  sterile  reflux (causing  simple  pressure

damage) are still uncertain. Many patients have

neither bacteriuria nor a history of urinary-tract

infection, and although urinary-tract infection

and  APN  are  far  more  common  in  women,

reflux  nephropathy  shows  equal  sex  distribu-

tion. One form may result from vesicoureteric

reflux starting in the very young, and this has a

poorer  prognosis  because  it  may  be  silent  or

undiagnosed for long periods. In adults, recur-

rent  urinary-tract  infection  or  APN  may  be

responsible.

Bacterial   reflux   nephropathy   commonly

involves  more  virulent  Gram-negative  organ-

isms,  including  Pseudomonas,  and  persistent

infection with relapses is common. In contrast to

the urinary tract the renal pelvis seems to have

no natural antibacterial defences (presumably

evolution never anticipated organisms there).

There may even be factors that encourage the

microbial persistence, so complete eradication is

difficult.

Clinical features and investigation

The condition may be asymptomatic or may

present as proteinuria, hypertension or recurrent

urinary-tract infection. Rarely, the first indica-

tion may be symptoms of incipient renal failure

Important renal diseases            935

such as polyuria or nocturia, because the renal

damage is primarily tubular. Early reflux damage

may   initiate   the   hypertension-renal   failure

vicious cycle, and sometimes a history of related

childhood illnesses such as enuresis or cystitis

may  be  traced.  Diagnosis  and  investigation

involve urography, urine microbiology and renal

function tests.

Management

In the absence of renal impairment, all that may

be required is regular monitoring of blood pres-

sure,  urine  microbiology  and  renal  function.

Infective episodes must be treated promptly as

for APN, and appropriate antimicrobial prophy-

laxis may be indicated if bacteriuria cannot be

eliminated. In children, surgery to correct reflux

may be necessary.

Course and prognosis

Most patients have stable disease, especially if their BP and bacteriuria are managed success-

fully. Recurrent infective exacerbations carry a poorer prognosis, but only about 1% of patients progress to CRF.

Glomerular disease

Glomerular   disease   invariably   affects   both kidneys. Glomeruli seem especially sensitive to inflammatory immune damage, and most forms of  glomerular  disease  involve  immunological mechanisms.  Glomerulonephritis (GN)  is  the single most important cause of CRF.

Classification

For such a small and apparently simple structure

the glomerulus presents inordinate pathological

complexity. Descriptions of glomerular disease

have a long history in medicine, and under-

standing of the condition is confounded by the

numerous methods of classification. Moreover,

increasingly   sophisticated   microscopy   and

immunological techniques continue to identify

new criteria and subgroups. Thus, in addition to simple  clinical  and  aetiological  classes  there are histopathological and immunopathological groupings (Table 14.23).

There  is  no  consistent  correlation  between

these  different  methods  of  classification  and

much overlap. No single classification provides

an  unequivocal  guide  to  management,  and

usually each aspect needs to be specified when

considering   a   particular   patient.   Thus,   for

example,  diabetes  is  usually  associated  with

chronically progressive glomerulosclerosis and a

poor outcome. On the other hand, acute post-

infective nephritis showing diffuse proliferative

change has an excellent prognosis with minimal

treatment being required.

Presenting syndromes

The  histopathological  classification  is  becom-

ing   the   standard   among   nephrologists   but

glomerular disease remains perplexing for the

non-specialist. It is best tackled by first under-

standing that there are four main ways in which

it may present, ranging in severity from asymp-

tomatic proteinuria through nephritic syndrome

and nephrotic syndrome to irreversible renal

failure.   This   is   illustrated   in   Figure 14.22,

although this scheme must not be taken to

imply an inevitable or direct progression. Each

syndrome  can  have  various  aetiologies  and

outcomes, so the likely cause should be identi-

fied if possible and the pathology described. It is

then possible to decide treatment and judge

prognosis.

The clinical features and management options

for  these  syndromes  will  be  summarized  in

general terms, including a brief description of

the  main  varieties  of  nephritic  syndrome  as

commonly classified by prognostic categories.

The  syndrome  of  chronic  renal  failure  was

described above.

Asymptomatic proteinuria

Normal urine contains only trace amounts of

protein, usually less than 100 mg excreted over

24 h. Most plasma proteins are too large for

filtration; smaller ones such as microglobulin are

filtered to some extent, but most is reabsorbed in

the tubules. Proteinuria means the presence of

more than 500 mg protein in 24 h. If these are

smaller proteins it implies a tubular defect, i.e. a

failure of reabsorption (a ‘tubular pattern’).

Albumin is larger, and its presence in signifi-

cant amount suggests a ‘glomerular pattern’, i.e.

a failure of filtration. Thus it is more correctly

called albuminuria. Albumin is usually discov-

ered as an incidental finding during a general

medical examination or during investigation of

some other disease. Albumin loss below about

2 g/24 h may be benign, but such patients are

always investigated and regularly monitored for

the possible development of conditions such as

glomerulonephritis, diabetes and hypertension.

A medication history is also important. Intermit-

tent  proteinuria  is  quite  a  common  normal

finding after exercise or after prolonged standing

or walking.

Microalbuminuria (÷200 mg albumin per 24 h)

is a prognostic marker of the possible develop-

ment   of   nephropathy   in   diabetes.   Urine

dipsticks  can  currently  detect  this  level  of

proteinuria.  Microscopic  haematuria  may  be

benign. Even macroscopic haematuria need not

be a sinister sign although it is obviously very

alarming. Of course, both conditions also require

thorough investigation.

Nephritic syndrome

Definition

The hallmarks of nephritis are renal impairment

with   oliguria,   sodium   and   fluid   retention,

peripheral oedema, mild to moderate proteinuria

and possibly haematuria. Urinary RBC ‘casts’ are

diagnostic; these are clumps of cells that have

been shaped by the tubular lumen. Frequently

there are no further complications, but hyper-

tension,   hypertensive   encephalopathy   and

pulmonary oedema may occur. Serum creatinine

is moderately elevated, but only rarely does olig-

uric  ARF  supervene.  The  pathophysiological

basis of these features is illustrated in Figure

14.23.

Aetiology and pathogenesis

Acute nephritis following a non-renal strepto-

coccal infection, e.g. streptococcal sore throat, is the most common form although other infections may be responsible, e.g. malaria, bacterial endo-

carditis.  Drug  reactions  and  connective  tissue disorders, e.g. SLE and Wegener’s granulomatosis, are other possible causes.

Most cases are extra-renal in origin, involving

immune complex (IC) deposition on the GBM.

These complexes may be Ig plus, for example,

streptococcal  antigen  or  a  drug  acting  as  a

hapten.  In  connective  tissue  disorder,  anti-

nuclear antibodies may be involved. Why some

patients react in this way, and why the ICs are

deposited in the glomeruli rather than being

cleared  by  the  reticuloendothelial  system  as

usual, is not known. Low plasma complement

levels may be implicated, although this may be effect rather than cause, complement having

been precipitated on the GBM.

Course and prognosis

Usually nephritis runs an acute florid course

with excellent recovery, especially in children.

Some older patients may have benign persistent

or intermittent proteinuria for many months or

years. A significant number progress slowly to

CRF  and  a  few  follow  a  rapidly  progressive

decline.

Management

The aims of management are to:

•  identify any specific cause (e.g. infection) and

            treat that,

•  institute simple symptomatic and supportive

            measures until the patient recovers.

The   range   of   therapies   used   include   the

following (see Table 14.24), although the precise

combinations that are effective will depend on

precise histological assessment following biopsy.

Immunosuppression.   This can include corti-

costeroids, often in combination with antiprolif-

eratives such as cyclophosphamide, azathioprine,

mycophenolate  mofetil,  sirolimus  and  ciclosporin. Surprisingly, it is not universally effective.

Plasma exchange (plasmapheresis).   The aim

of this is to remove circulating auto-antibodies

and ICs from the blood. Whole blood is removed

and   centrifuged:   the   supernatant   plasma,

containing  the  harmful  immune  products,  is

discarded and the cellular components are then

re-injected.  Fluid,  electrolytes  and  albumin

must  also  be  administered  to  compensate  for

losses.

Renoprotection.   As   discussed   above   when

consdering CRF, protein restriction needs to be

used  with  caution,  for  fear  of  malnutrition.

ACEIs, possibly in combination with ARAs, offer

reduced progression and blood pressure control.

In  addition,  antihypertensive  agents,  anti-

microbials, diuretics, fluid restriction and dietary protein  manipulation  may  be  necessary,  as appropriate.

Common presentations

Acute glomerulonephritis.   This is the classic

post-streptococcal form usually seen in children

or young adults. A very abrupt and severe renal

inflammatory   response   might   develop   for

example a few weeks after a severe throat infec-

tion. Disease severity usually correlates with the

patient’s titre of ASO. In children particularly,

the prognosis is excellent with resolution in a

week or less, and only supportive therapy is

required. Anti-inflammatory therapy is usually

ineffective.

Rapidly  progressive  glomerulonephritis.   In

about 1% of patients who develop acute GN

there  is  rapid  progression  to  acute  oliguric

failure. If this occurs the outlook is poor, with

progression to ESRD within 2 years. Progressive

GN may be associated with the presence of anti-

GBM    auto-antibodies            (e.g.     Goodpasture’s

disease), or arise in association with vasculitic

connective   tissue   diseases (e.g.   polyarteritis

nodosa,  PAN).  The  renal  damage  caused  by

malignant hypertension usually presents as a

rapidly progressive GN although in this case the

damage is not immunological.

Treatment and prognosis depend on the aeti-

ology. For the connective tissue diseases early

aggressive  immunosuppressive  therapy  with

cytotoxic drugs and steroids may induce a remis-

sion or retard progression. In idiopathic forms or

in Goodpasture’s disease this is rarely successful,

but plasmapheresis may be helpful. Nevertheless,

eventual progression to CRF and renal replace-

ment therapy is common. Following transplanta-

tion a recurrence of the disease is still possible,

but  the  tendency  nowadays  is  to  transplant

anyway.

Chronic glomerulonephritis.   About 10% of

GN patients, usually adults, progress to chronic

illness.   It   is   this   slowly   progressive,   late-

presenting form of GN that is the most common

cause of CRF. Invariably there are co-existent

hypertension  and  proteinuria.  The  cause  of

chronic   GN   is   usually   unknown.   Diabetic

nephropathy could be considered to be one form

of the condition, although strictly speaking this

is glomerular sclerosis rather than inflammation,

and nephrotic syndrome is a more common

presentation.

Specific treatment is rarely possible and the

patient   must   enter   a   renal   replacement

programme. Certain forms of chronic GN with

less  glomerular  damage (‘membranous’  and

‘minimal change’ GN) may respond to immuno-

suppressant therapy, but this is still controversial.

Nephrotic syndrome

The nephrotic syndrome can occur in associa-

tion with many forms of nephritis or may arise

independently. It is defined by the symptom

triad:

•  Heavy proteinuria.

•  Hypoalbuminaemia.

•  Gross pitting oedema.

The hallmark of nephrotic syndrome is extensive

urinary protein loss associated with hypopro-

teinaemia sufficient to cause severe generalized

oedema. The liver can synthesize albumin up to

a maximum of about 15 g/24 h in an attempt to

maintain plasma albumin levels, but paradoxi-

cally proteinuria no greater than 4-6 g/24 h may

be sufficient to cause nephrotic syndrome. Thus

there is probably another avenue of protein loss

involved. This is may be an increase in the renal

tubular   catabolism   of   albumin,   such   that

measurement of urinary protein loss underesti-

mates the total deficit. These combined losses

exceed hepatic capacity to synthesize protein

and   lead   to   progressive   hypoproteinaemia,

regardless   of   dietary   protein   intake (Figure

14.24).

Aetiology

The nephrotic syndrome may be a complication

or progression of GN or it may present de novo.

Specific aetiologies include diabetes, drugs (e.g.

penicillamine,   captopril,   heavy   metals)   and infections (e.g. malaria, endocarditis).

Pathophysiology

The  apparently  paradoxical  combination  of  a

reduced  GFR  with  a  ‘leak’  sufficient  to  pass

albumin molecules of molecular weight   60 kDa

may arise because the reduced plasma volume

causes a mild pre-renal impairment of filtration,

while changes in the GBM electrostatic charge

allow smaller proteins, that are normally repelled,

to pass through. In mixed nephritic-nephrotic

syndromes there is also some glomerular obstruc-

tion. The phenomenon of proteinuria is still not

understood.

The oedema forms by a quite different mecha-

nism to that of simple nephritis or heart failure.

In the latter cases there is redistribution of the

raised total body water with increased volumes

in  all  compartments,  plasma  hypervolaemia

causing hypertension and tissue hypervolaemia

causing the oedema. By contrast, in nephrotic

syndrome there is a reduced plasma volume and

often  hypotension.  The  hypovolaemia  results

from  the  reduced  plasma  oncotic  pressure

brought about by the hypoproteinaemia, which

permits a loss of plasma water to the extravascular

compartment (Figure 14.23).

In  nephrotic  syndrome  the  RAAS  acts  to

restore BP by increasing renal sodium and water

reabsorption. However, blood volume cannot be

expanded while plasma protein is low because

the   resultant   low   plasma   oncotic   pressure

permits renally retained fluid to pass straight to

the  tissue.  This  exacerbates  the  oedema  and

causes further fluid and electrolyte retention.

This vicious cycle may result in gross oedema,

and the presence of over 20 L of oedema fluid

has been reported. Nevertheless, many patients

are not overtly hypotensive, possibly owing to

the direct vasoconstrictor action of persistently

raised angiotensin levels. Postural hypotension

is usual, however. This classical account of the

pathophysiology   of   oedema   in   nephrotic

syndrome has been challenged and may not

represent the whole picture.

Course and prognosis

The prognosis will depend on the age of the

patient and the underlying lesion. In children

the cause is usually acute GN and the outlook is good, with an 80% remission rate. In adults the underlying pathology is more likely to be a

chronic  progressive  disease  and  the  average remission rate is nearer 20-30%.

Clinical features

The clinical picture is usually very distinctive.

Nephrotic  syndrome  may  have  an  acute  or

insidious onset and resembles acute GN, except

that the oedema is usually greater, including

pulmonary oedema and ascites, and the patient

Important renal diseases            941

is not hypertensive and may be hypotensive. The

patient is usually very ill, weak, anorexic and

oliguric.  A  common  unexplained  finding  is

hyperlipidaemia, possibly related to disordered

protein metabolism (an attempt to synthesize

new amino acids). High aldosterone levels often

cause hypokalaemia.

Management

The aims of management are:

•  To investigate and treat the cause (e.g. an

            underlying disease).

•  To  correct  haemodynamic  and  metabolic

            abnormalities.

•  To reduce glomerular inflammation.

Table 14.25 summarizes the treatment options.

The  effectiveness  of  immunosuppressant  ther-

apy, initially high-dose steroids, will depend on

the  cause,  but  in  general  steroid  therapy  is

more  beneficial  than  in  simple  GN.  Patients

who  relapse  after  steroid  withdrawal,  i.e.  are

steroid-dependent, may benefit from cytotoxic

drugs.

Reversal   of   the   hypoproteinaemia   must

usually   await   resolution   of   the   glomerular

damage, but high-protein diets are traditional.

The principal clinical problems are oedema and

sodium  and  fluid  retention.  Salt  and  water

restriction and loop diuretics are used and high

doses may be needed, e.g. 50 mg furosemide. Care

must be taken not to exacerbate hypovolaemia

and precipitate pre-renal failure by too rapid a

diuresis; thus the use of diuretics may be delayed

until there is a recovery in urine output. This

can be prevented by subsequent infusion of a

plasma  expander  such  as  salt-free  albumin.

Hypokalaemia, which would be exacerbated by

loop diuretics, can be treated with high-dose

spironolactone and potassium supplements.

Polycystic disease

Adult polycystic disease is the most common

inherited renal disease. Both kidneys become

enlarged up to two or three times normal size,

owing to the development of many fluid-filled,

inert cysts. These gradually crush adjacent renal

structures.

The more common autosomal dominant form

has a prevalence of 1/1000. The age of onset

and progression are highly variable. Progression

to end-stage renal failure usually occurs within

10-20 years of diagnosis, so patients who first

present late in life may avoid this. Nevertheless,

10% of ESRD patients have polycystic disease.

In  the  rarer  recessive  form,  onset  and  rapid

progression to renal failure occur in childhood.

Clinical features are similar to those of other

forms of RF. Hypertension is common, there

may be loin or lumbar pain, and haematuria if a

cyst ruptures. Diagnosis is based on ultrasound

imaging.

There is no specific treatment beyond the stan-

dard procedures for CRF; control of BP will slow progress.   Regular   screening   of   siblings   and offspring is important.