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