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