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.