Introduction

A number of disease states alter the renal handling of ions and water. This chapter covers the renal handling of ions (mainly sodium) and water in the following conditions:

  1. 1.

    Congestive heart failure

  2. 2.

    Shock

  3. 3.

    Hypertension

  4. 4.

    Liver disease

  5. 5.

    Nephrotic syndrome

In all except the last of these conditions (and possibly also in some forms of hypertension), altered renal function can be regarded as essentially a compensatory response, to maintain effective circulating volume. Before considering these disorders, it is necessary to consider the factors which can alter the balance between the formation and reabsorption of tissue fluid.

Oedema

Oedema is an increase in the interstitial fluid volume, so that swelling of the tissue results. There are many clinical states which lead to oedema, but the immediate cause is always a change in the rate of formation or reabsorption of tissue fluid, such that the rate of formation exceeds the rate of reabsorption. The formation of tissue fluid depends on Starling’s forces (Chap. 1), so that

$$\begin{array}{lclclclc}\text{Net}\;\text{formation}\;\text{of}\;\text{tissue}\;\text{fluid}\\ \alpha \;\text{forces}\;\text{favouring}\;\text{filtration}\;\text{out}\;\text{of}\;\text{capillary}\\ -\text{forces}\;\text{opposing}\;\text{filtration}\;\text{out}\;\text{of}\;\text{capillary} \\ \alpha \text({P}_{\text{cap}}+{\text{II}}_{\text{if}})-[{\text{II}}_{\text{cap}}+{P}_{\text{if}}]\end{array}]$$

(where P cap  =  capillary hydrostatic pressure; P if  =  interstitial fluid hydrostatic ­pressure; IIcap  =  capillary oncotic pressure; IIif  =  interstitial fluid oncotic pressure). A change in any of these four forces can lead to oedema.

The capillary hydrostatic pressure (P cap) is markedly influenced by alterations in venous pressure. The arterioles, which have a high resistance to flow, ensure that only a relatively small pressure is transmitted from the arteries to the capillaries and that changes in arterial pressure have little effect on capillary hydrostatic pressure. However, there are no high-resistance vessels between the capillaries and the venous side of the circulation and consequently changes in venous pressure can have a considerable effect on the capillary hydrostatic pressure

Increases in capillary hydrostatic pressure will occur, therefore, in any circumstances which increase the venous pressure, e.g. during volume expansion (when an increased intravascular volume increases venous pressure) or when venous return is inadequate (e.g. prolonged standing causes venous pooling in the legs and leads to oedema of the feet and ankles) or when the venous return is obstructed.

The plasma protein osmotic pressure (oncotic pressure, IIcap) opposes the capillary hydrostatic pressure and is responsible for the reabsorption of tissue fluid into the vascular system at the venous end of the capillaries. Volume expansion (e.g. by renal sodium retention), in addition to increasing the capillary hydrostatic pressure (see above), will also tend to dilute the plasma proteins, thereby reducing the force for tissue fluid reabsorption and exacerbating the oedema. IIcap can also be reduced by albumin loss in the urine or as a result of decreased plasma protein synthesis by the liver.

Interstitial fluid oncotic pressure (IIif) depends on the protein content of the interstitial fluid, and the capillaries have a very low permeability to plasma proteins. However, small quantities (mainly albumin) do seep across and, in some circumstances, proteins accumulate in the interstitial fluid and cause oedema. This occurs in conditions of: (a) increased capillary permeability; and (b) obstructed lymphatic drainage—the plasma proteins which leak out of the capillaries normally enter the lymphatic system and are eventually returned to the vascular system via the thoracic duct. Blockage of the lymphatics, e.g. by a tumour or by parasites (as in elephantiasis), increases the interstitial oncotic pressure and so causes oedema.

The interstitial fluid hydrostatic pressure (or “tissue turgor pressure”) is very difficult to measure accurately, but is close to 0 mmHg.

Local oedema can occur without an overall increase in body fluid content, but, in generalized oedema, body fluid volume is increased.

Congestive Heart Failure

When the cardiovascular system is failing to provide normal perfusion of the tissues, renal functional adjustments occur which can be regarded as adaptations to increase the effective circulating volume. Such adjustments occur in congestive heart failure. In this condition, the reduction in cardiac output reduces renal perfusion and the effect to the kidney is as if there is hypovolemia. Here we see the reason for using the term “effective circulating volume” rather than just “circulating volume” or “vascular volume”. In chronic congestive heart failure, the vascular volume is normal (or may be elevated), but the effective circulating volume is reduced.

The diminished effective circulating volume has the same effect at the kidney as true hypovolemia—i.e. it promotes the renal retention of NaCl and water (for mechanism, see p. 109). The extent of this retention will depend on the severity of the heart failure, but if the failure is marked, the blood volume expands so much that the limit of venous distensibility is reached and venous pressure then increases. At the same time, the retention of NaCl and water dilutes the plasma proteins and hence reduces the plasma protein osmotic pressure. These two factors (increased venous pressure leading to increased capillary pressure, and decreased plasma protein osmotic pressure) give rise to oedema (see pp. 113 and 165 for mechanisms).

However, the oedema is essentially a side effect of a compensatory renal response, which increases effective circulating volume. The way in which the increased effective circulating volume is brought about is shown in Fig. 14.1 (Starling curves).

Fig. 14.1
figure 1

The way in which an increase in effective circulating volume is brought about by the kidney in congestive heart failure. An important determinant of cardiac output is the filling pressure (LVEDP, left-ventricular end-diastolic pressure). The normal relationship of LVEDP to stroke volume (SV) is shown by curve A. Point (a) on this line represents typical normal figures for LVEDP and SV, i.e. at the LVEDP of 9 mmHg, SV is 75 mL. In heart failure, the effectiveness of the cardiac contraction is reduced, and a new relationship between LVEDP and SV is established (curve B). If there is no change in the filling pressure, the stroke volume will be reduced to less than 50 mL (point b). This reduces cardiac output and decreases the effective circulating volume; the renal response to this is fluid and water retention, which increases the central venous pressure, which in turn increases the right ventricular filling pressure so that more blood is expelled by the right side of the heart, in turn increasing the LVEDP and so increasing the stroke volume to the value at point (c). (Similar curves can be drawn relating right-side SV and RVEDP (right-ventricular end-diastolic pressure), but normal RVEDP is approximately 5 mmHg less than LVEDP)

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It can be seen from the figure that expansion of the vascular volume restores tissue perfusion, by increasing the left-ventricular end-diastolic pressure (LVEDP). However, this may lead to a ‘side effect’ which outweighs the advantage of the restored tissue perfusion. This side effect is pulmonary oedema. If the LVEDP rises dramatically, there is transmission of this increased pressure back into the lungs—i.e. left atrial pressure is increased, as is pulmonary venous pressure, and the pulmonary capillary pressure, leading to pulmonary oedema. In the lungs, tissue fluid formation should not occur (otherwise the alveoli fill with fluid and become ineffective), so in health the forces for reabsorption of tissue fluid are greater than those for formation of tissue fluid, throughout the length of the pulmonary capillaries.

From the foregoing, it is apparent that the oedema of congestive heart failure occurs as a consequence of the renal retention of NaCl and water, to increase the effective circulating volume. This response of the kidney becomes counter-productive if pulmonary oedema occurs. Since it is the heart which is malfunctioning, treatment should logically be directed at the heart—i.e. treatment with digoxin or similar drugs—to restore a more normal cardiac output, although there is no doubt that diuretics do relieve the symptoms of congestive heart failure. However, it should be remembered that systemic oedema is of no danger to the patient and occurs as part of a compensatory mechanism. Only pulmonary oedema calls for urgent treatment with diuretics to reduce the body fluid volume. Diuretics are definitely advantageous when they reduce pulmonary congestion, but they also reduce the effective circulating volume.

The tissue anoxia resulting from circulatory inadequacy in congestive heart failure may cause potassium to leak out of cells and lead to a low total body potassium content before any drug therapy is started. Diuretics may then exacerbate potassium depletion. Furthermore, potassium depletion may occur without being apparent because the plasma potassium concentration can be normal (i.e. the loss is from the cells) and this is important because cellular potassium depletion increases the risk of digoxin-induced arrhythmias.

Hypovolemia and Shock

Decreases in extracellular fluid volume produced by fluid loss lead to a reduction in cardiac output (due to reduced end-diastolic pressure, Fig. 14.1) and, consequently, tissue perfusion is also reduced. The distinction between hypovolemia and shock is essentially one of degree. Thus the donation of 500 mL of blood produces hypovolemia, but the loss of 1 L of blood (20% of the blood volume), in addition to hypovolemia, produces mild shock.

We can define shock as a life-threatening state with a marked reduction of cardiac output and inadequate perfusion of most organs. Hypovolemia and mild shock cause tiredness, thirst and dizziness. More severe falls in effective circulating ­volume are accompanied by signs of increased sympathetic activity (tachycardia, pallor, sweating) and impaired function of vital organs (confusion or coma due to cerebral ischemia, oliguria [low urine flow] or anuria [no urine flow] and acid–base disturbances due to impaired renal function). There are types of shock in which there is not a reduced blood volume, but all types of shock lead to a reduction in effective circulating volume.

The different mechanisms involved can be grouped into two types, hypovolemic and cardiogenic.

Hypovolemic Shock

In this type of shock, central venous pressure (CVP) decreases, venous return is reduced and hence cardiac output falls. There are three common causes of hypo­volemic shock:

  1. (a)

    Loss of blood—haemorrhage

  2. (b)

    Loss of plasma—burns

  3. (c)

    Loss of fluid—persistent vomiting, severe gastroenteritis, excessive sweating

Cardiogenic Shock

Sudden reductions in cardiac output, e.g. due to myocardial infarction, do not change the intravascular volume, but the venous pressure is increased. This change in venous pressure is in the same direction as occurs in the chronic condition of congestive heart failure. However, the increased CVP of cardiogenic shock is a direct consequence of the inability of the heart to pump blood adequately (so right-ventricular end-diastolic pressure is elevated), whereas in congestive heart failure the increased CVP is more likely to be a consequence of the renal response to inadequate perfusion.

In both types of shock, both the effective circulating volume and the blood pressure are reduced. In hypovolemic shock, the decreased effective circulating volume is due to a decreased ECF volume. In cardiogenic shock, the decreased effective circulating volume is due to inadequate circulation, although the intravascular volume is normal. Exactly what effects the reduction in blood pressure will have on renal function will depend on the magnitude of the reduction. When the effective circulating volume is reduced, blood pressure is maintained by increased sympathetic ­nervous activity (via baroreceptor reflexes), which causes vasoconstriction in most parts of the body (except the brain), including the kidney. Thus the increased activity in the sympathetic efferent nerves to the renal arterioles (primarily to afferent arterioles) reduces the renal blood flow. Vasoconstrictor stimuli to the kidney, however, lead to increased renal cortical synthesis of vasodilator prostaglandins (PGE2 and PGI2), so that, generally, the renal blood flow remains adequate (and in addition, efferent arteriolar vasoconstriction occurs to maintain filtration pressure) for glomerular filtration, unless the mean blood pressure falls below about 70 mmHg. (Non-steroidal anti-inflammatory drugs, which are the common “pain-killers”, inhibit the production of prostaglandins by blocking the cyclo-oxygenase enzyme which converts arachidonic acid to prostaglandins. Such drugs can therefore cause renal failure in patients whose renal function is being maintained by increased prostaglandin synthesis).

Below a mean blood pressure of 70 mmHg, the renal blood flow falls drastically, glomerular filtration decreases and renal function is impaired. Unless there is prompt restoration of the effective circulating volume, there is the danger of acute renal failure (see Box p. 175). Let us consider in detail the renal effects of shock, using hypovolemic shock caused by haemorrhage as an example.

Haemorrhage

Rapid loss of 20% of circulating blood volume produces compensated mild shock. If 30% of the blood volume is lost, there is moderately severe shock (systolic blood pressure below 90 mmHg, heart rate over 90 beats/min), 40% loss causes severe shock, fatal if untreated, and a loss of over 50% is rapidly fatal (Fig. 14.2).

Fig. 14.2
figure 2

The effects of losses of 10, 20, 40 and 50% of the circulating blood volume on systolic blood pressure (BP). Losses of up to 20% of the circulating blood volume have little effect on the blood pressure, although increased sympathetic nervous activity is necessary in order to maintain BP. A loss of 40% of the circulating blood volume lowers blood pressure dramatically, and although increased sympathetic activity can reduce the fall in BP, the degree of vasoconstriction necessary has serious consequences which may lead to death (see text). Larger haemorrhages (50% of circulating blood volume) are more rapidly fatal

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Initially, we will consider the ‘compensatory phase’ (i.e. where the loss is of less than 20% of the circulating blood volume and the systolic blood pressure remains above 90 mmHg). In such cases, there is increased sympathetic nervous activity, leading to tachycardia, increased myocardial contractility and peripheral vasoconstriction. These changes serve to maintain blood pressure, since\( \text{Blood}\;\text{pressure}=\text{Cardiac}\;\text{output}\times \text{peripheral}\;\text{resistance}\) and

$$ \text{Cardiac}\;\text{output}=\text{heart}\;\text{rate}\times \text{stroke}\;\text{volume}$$

(Stroke volume is determined by end-diastolic volume and contractility, so that increasing myocardial contractility will increase stroke volume even if end-diastolic volume is constant.)

These actions of the sympathetic nervous system, serving to maintain blood pressure, are beneficial in the short term, but can have deleterious effects if prolonged. This is because excessive tachycardia shortens diastolic filling time and impairs coronary blood flow (coronary blood flow is greater during diastole), and prolonged vasoconstriction has the following adverse consequences:

  1. 1.

    Increased aggregation of blood cells, and consequent increased viscosity and microembolization.

  2. 2.

    Hypoxia in the gastrointestinal tract leading to (a) increased fragility of lysosomes (and an increased concentration of lysosomal enzymes in the plasma), and (b) the production of a factor depressing the activity of the reticuloendothelial system, so that, within 2 h of haemorrhage, the body’s ability to destroy bacteria or to break down endotoxins is considerably reduced.

  3. 3.

    Hypoxia in the liver, leading to failure of glycogenesis and failure to convert protein metabolites into urea. Hypoglycemia, increased blood lactate levels and acidosis occur.

  4. 4.

    Hypoxia in muscle, leading to lactic acidemia and increased plasma potassium concentration, which has an adverse effect on cardiac performance.

  5. 5.

    Hypoxia in the heart, decreasing myocardial performance and exacerbating hypoxia in the rest of the body.

  6. 6.

    Modified renal function (see below).

Effect of Haemorrhage on Body Fluid Volume and Composition, and Renal Function

The problems associated with haemorrhage can be divided into two groups:

  1. 1.

    Those due to volume depletion leading to inadequate tissue perfusion

  2. 2.

    Those due to the electrolyte and acid–base disorders which can accompany volume depletion

In haemorrhage, the fluid (blood) which is lost is isotonic and thus there is no direct effect on the osmoreceptors. However, haemorrhage increases ADH release via the volume receptors so that water is retained (i.e. osmoregulation becomes subordinated to volume regulation, Chap. 9).

The main change in renal function after haemorrhage is increased sodium reabsorption. Indeed, increased sodium reabsorption (and hence decreased sodium excretion) is such a characteristic feature of hypovolemia that it can be used diagnostically. The mechanisms responsible for this decreased sodium excretion have been considered in Chap. 9, but will be briefly reiterated here. Haemorrhage reduces effective circulating volume which then reduces renal perfusion pressure. However, renal sodium conservation occurs before decreases in GFR can be observed, indicating changes in tubular reabsorption. GFR can be maintained in spite of some degree of afferent arteriolar constriction, if the efferent arterioles are also constricted (i.e. there is increased filtration fraction). The peritubular capillary hydrostatic pressure, however, will be reduced, favouring increased sodium reabsorption. In addition, the decreased renal perfusion pressure decreases afferent arteriolar wall tension and so stimulates the release of renin and the production of angiotensin II which increases adrenal aldosterone release to promote sodium retention. The intrarenal actions of angiotensin II also favour sodium reabsorption (Chap. 9).

The increased ADH release brought about by the “volume” receptors in the atria and by the baroreceptors in the arteries leads to water retention; the patient will also feel thirsty and may drink if water is available. So the body fluid osmolality, including the plasma osmolality, decreases (Chap. 9), and since the main solute in the plasma is Na+, this decreased osmolality represents a decreased [Na+], which therefore acts as a direct stimulus in the adrenal cortex to increase aldosterone release. In addition, decreases in systemic blood pressure reflexly (via the baroreceptors) increase renal sympathetic nerve activity and this is an additional stimulus to renin release.

In concert, the above mechanisms can reduce the urinary sodium concentration to less than 1 mmol/L. Such effective sodium reabsorption can lead to disturbances of acid–base balance because the reabsorption and excretion of other ions are influenced by sodium reabsorption. The sodium concentration in the glomerular filtrate is 140 mM, whereas the filtrate Cl− concentration is only about 110 mM. Thus from each litre of glomerular filtrate, only 110 mmol Na+ can be reabsorbed with Cl− following to maintain electroneutrality. Any additional sodium reabsorption must involve other ways of maintaining electroneutrality, i.e. H+ and K+ secretion. Thus

$$ {\text{Na}}^{+}\;\text{reabsorption}={\text{Cl}}^{-}\;\text{reabsorption}+{\text{H}}^{+}\;\text{secretion}+{\text{K}}^{+}\;\text{secretion}$$

So, when sodium is being maximally conserved, K+ and H+ are lost from the body and the kidneys are tending to produce metabolic alkalosis.

However, since in hypovolemia or other forms of shock, other tissues are inadequately perfused and therefore are hypoxic, anaerobic metabolism leading to acid production may be occurring (i.e. metabolic acidosis), so that there may be little overall change in acid–base balance. This can change dramatically to severe metabolic acidosis when the kidneys can no longer maintain H+ secretion (intrinsic renal failure, see box and below).

Additional Problems of Severe Haemorrhage (Hypovolemic Shock)

As the degree of hypovolemia increases, there occurs a stage at which tissue perfusion becomes inadequate. When the perfusion of the kidneys is not sufficient for the maintenance of normal urine flow, H+ secretion can no longer occur at an adequate rate and metabolic acidosis can occur. This is exacerbated by inadequate blood flow to other tissues (e.g. muscle), so that tissue respiration becomes partially anaerobic and lactic acidosis occurs. Restoration of perfusion will correct such acidosis, but HCO −3 should be administered if arterial pH is below 7.2.

Measures to Prevent Irreversible Renal Damage

In severe volume depletion, the stimulus for renal vasoconstriction is so intense that the renal blood flow may not be restored by measures (e.g. blood transfusion) to restore the circulatory volume, and renal failure can occur due to anoxia and necrosis.

Hypertension

The kidneys contribute to the regulation of blood pressure by regulating the extracellular fluid volume and by releasing vasoactive substances (hormones) into the blood. In addition, as the renal blood supply is such a large fraction of the cardiac output and can be adjusted by the activity in the renal sympathetic nerves, the kidneys play a large role in regulating the blood pressure via the baroreceptor reflexes.

In Chap. 9, the renal regulation of ECF volume was discussed. The blood volume is determined by the ECF volume and, since blood volume influences cardiac output, which in turn influences blood pressure, it is clear that ECF volume is a potential determinant of blood pressure. However, changes in blood volume and the consequent changes in blood pressure are normally accompanied by compensatory changes in renal sodium and water excretion, so the persistence of a high blood pressure (i.e. hypertension) may indicate the presence of a disturbance in the kidneys’ response to the increased pressure.

In some types of hypertension (secondary hypertension), the causes of this abnormal responsiveness of the kidney are known. These include renal artery stenosis (renovascular hypertension), intrinsic renal disease (renal hypertension), primary hyperaldosteronism (leading to renal sodium retention) or excessive renin production (e.g. in some renal tumours).

Secondary Hypertension

Renovascular Hypertension

This is caused by the renal response to reduced renal perfusion (e.g. due to the stenosis of the renal artery or of one of the interlobar arteries). Reduced perfusion of the afferent arterioles stimulates renin release from the juxtaglomerular apparatus, increasing the production of angiotensin II and thereby causing increased blood pressure both directly (via the vasoconstrictor action of angiotensin II) and indirectly (via salt and water retention brought about by angiotensin and aldosterone).

Renal Hypertension

Impaired renal excretion leads to extracellular volume expansion, which can lead to hypertension. In addition, the kidney cortex and medulla synthesize vasodepressor prostaglandins and, although these are thought to have predominantly intrarenal functions, they may also have a systemic role in maintaining normotension, so that inadequate renal prostaglandin synthesis could lead to hypertension.

Primary Hyperaldosteronism

This is a rare condition, accounting for less than 1% of hypertension cases. Excessive aldosterone release by the adrenal cortex (usually as a result of an adrenal cortical adenoma) promotes distal nephron sodium reabsorption and potassium secretion. There is normally little or no volume expansion because of “escape” from the sodium-retaining actions of aldosterone (p. 108). However, there is continued potassium loss and most patients (90%) with primary hyperaldosteronism have hypokalemia (with plasma [K+] less than 3.5 mmol/L). Metabolic alkalosis ([HCO −3 ] greater than 30 mmol/L) may also be present, since H+ as well as K+ is lost from the distal nephron. It is not entirely clear why the condition produces hypertension; the degree of volume expansion is seldom large enough to account for the elevated blood pressure. The diagnosis of primary hyperaldosteronism is based on the observations of hypokalemia, a high rate of aldosterone excretion and low plasma renin activity.

Essential (Primary) Hypertension

In most hypertensive patients there is no obvious cause of hypertension and this condition is termed essential hypertension. Renal function is usually disturbed (i.e. the kidney is not responding to the hypertension with increased salt and water excretion), but it remains unclear whether the condition is caused by abnormal renal function or whether it causes abnormal renal function. Figure 14.3 is a scheme showing the interrelationship of renal function and blood pressure.

Fig. 14.3
figure 3

Renal involvement in the regulation of blood pressure. LVEDP. Alterations of blood pressure lead to changes in the release of renin, angiotensin, aldosterone, prostaglandins and kinins. Starling forces affecting tubular absorption are also changed. The modifications to renal function, to regulate the effective circulating volume, may then alter stroke volume, heart rate and peripheral resistance, which determine the blood pressure. Directional changes (i.e. increases or decreases) are not shown on the diagram, but will be clear from the text and from Chap. 9. Atrial natriuretic peptide is not shown, as its functional importance is still not clear

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About 90% of all hypertensive subjects have “benign essential hypertension”, so called because the condition worsens only gradually. The normal blood pressure is 120/80 mmHg. A pressure above 140/90 mmHg significantly increases the risk of strokes, heart failure, retinopathy and renal failure. Pathological changes in the kidney in this condition include hypertrophy of the tunica media of the renal afferent arterioles with consequent narrowing of the vascular lumen (arteriolar nephrosclerosis). Larger vessels (arteries) may also be affected (arteriosclerosis).

Treatment of Hypertension

The treatment of primary hypertension almost invariably involves drugs which have significant effects on renal function.

ACE Inhibitors/Angiotensin Receptor Blockers

As mentioned in Chap. 9, angiotensin II is a powerful vasoconstrictor, so angiotensin converting enzyme inhibitors (ACE inhibitors), which block the conversion of angiotensin I to angiotensin II, are widely used to treat hypertension. The names of ACE inhibitors end in “-pril”—and those commonly used include captopril, enalapril, ramipril and lisinopril. However, ACE also converts vasodilator kinins, including bradykinin, to inactive products and part of the antihypertensive action of ACE inhibitors may be due to this (this effect may also be responsible for the dry cough which is the main side effect of ACE inhibitors). Drugs such as Losartan and Valsartan, which block the Angiotensin II receptor (confusingly called the AT1 receptor), are an alternative to ACE inhibitors and generally do not produce cough.

In the kidneys, because angiotensin II preferentially constricts the renal efferent arterioles, blocking angiotensin II production or action may decrease GFR, and so both ACE inhibitors and angiotensin receptor blockers may have this effect.

Calcium Channel Blockers

Because most vasoconstrictor mechanisms in the circulation involve increased calcium entry into the arteriolar smooth muscle cells, calcium channel blockers are effective antihypertensive agents. Such drugs include nifedipine and amlodipine. They are often used in combination with thiazide diuretics (see below).

Diuretics

The thiazide diuretics such as bendrofluazide are often used in combination with calcium channel blockers, and sometimes in combination with both calcium channel blockers and ACE inhibitors, to treat hypertension. The action of thiazides is considered in detail in Chap. 15. They increase sodium and water excretion and so reduce the vascular volume and the effective circulating volume.

Malignant Hypertension

In some patients, the hypertension becomes rapidly progressive (malignant hypertension), characterized by extremely high blood pressures (exceeding 230/130 mmHg), with spontaneous haemorrhages and impairment of the renal blood flow. There is fibrinoid necrosis of the arteriolar walls of many organs, including the kidneys.

Malignant hypertension is almost invariably associated with very high levels of plasma renin, but it is not clear at present whether this is a cause or simply a result of the hypertension and impaired renal blood flow. In benign essential hypertension (even in subjects who subsequently develop malignant hypertension), there are no consistent changes in plasma renin activity.

Recently, it has been suggested that changes in cell-membrane ion-transport processes could be associated with essential hypertension. Specifically, it has been proposed that if the cellular extrusion of Na+ were reduced, then because intracellular Na+ would increase, the gradient for Na+ entry would be reduced, and this would reduce Na+/Ca2+ exchange (counter-transport), resulting in an increased intracellular Ca. Such an increase occurring in blood vessels would increase vascular contractility. A related hypothesis is that the alteration of intracellular ion composition stems from a change in the composition of cell-membrane lipids, which alters ionic permeability.

In summary, if systemic arterial pressure is high, but natriuresis and diuresis are not occurring, then the normal relationship between afferent arteriolar pressure and natriuresis/diuresis does not apply. Has the altered pressure–natriuresis relationship caused hypertension, or occurred as a consequence of it? This question cannot be answered at present.

Liver Disease

It is a common clinical observation that patients exhibiting symptoms of liver disease—such as jaundice, ascites or portal venous hypertension—frequently develop oliguria (reduced urine flow), sodium retention or other symptoms of disordered renal function. How does liver disease lead to disorders of kidney function?

The accumulation of oedema fluid in the peritoneal cavity is termed ascites and frequently occurs when there is more general oedema (e.g. in heart failure), but it is a particular feature of abnormal liver function, as its usual cause is an increased hydrostatic pressure in the hepatic portal vein. The hydrostatic pressure in this vessel increases when there is an obstruction within the liver and the raised pressure forces fluid out of the intestinal capillaries into the peritoneal cavity. It is also possible for ascites fluid to form by transudation from the sinusoids within the liver if the hepatic vein is obstructed.

Renal Function in Pregnancy

GFR increases markedly (typically by about 50%) in the first trimester of pregnancy and remains elevated until the final month of gestation.

Renal blood flow also increases during the first two trimesters and can be 80% above the non-pregnant level. Near term, renal blood flow begins to decline, but remains well above the non-pregnant level.

The mechanisms responsible for the changes in renal haemodynamics in pregnancy are not clear. However, the changes have important consequences. Production of creatinine and other nitrogenous waste products is not greatly increased in pregnancy, so the increased GFR leads to reduced plasma concentrations of these substances. The increased filtered loads of glucose and amino acids can also lead to these being present in urine, as there is not a corresponding increase in tubular reabsorptive capacity to match the increased GFR. In fact, there are reports that tubular glucose reabsorptive capacity decreases.

Plasma osmolality decreases during the early months of pregnancy and reaches its lowest value (275 mOsm/kg H2O compared to the normal level of 285) in the third month. The decrease is primarily due to reduced plasma sodium concentration; the decrease does not suppress ADH release, i.e. the osmotic threshold for the regulation of ADH is altered.

The secretion of aldosterone into the plasma from the adrenal cortex is increased in pregnancy, but the effect of this is largely counterbalanced by progesterone, synthesized in increased amounts in pregnancy, which antagonizes the sodium-retaining effect of aldosterone.

A potentiating factor in the development of ascites in liver disease is decreased albumin synthesis (the liver is the source of plasma albumin), so that the plasma protein osmotic pressure decreases. The loss of part of the circulating volume by transudation from the capillaries into the peritoneal cavity decreases the effective circulating volume and leads to a renal compensatory response—increased NaCl and water reabsorption. A proportion of the fluid thus retained itself becomes ascites.

As the ascites develops, the intra-abdominal pressure rises and raises the venous pressure in the veins which pass through the abdomen. Thus, the venous drainage of the lower limbs becomes impaired and oedema of the lower extremities develops. Patients with ascites may also have arteriovenous fistulas within the liver, so that the effective circulating volume is further reduced (since blood passing directly from arteries to veins is not effectively perfusing the tissues).

The development of ascites in liver disease is shown in Fig. 14.4. The cautionary remarks concerning the use of diuretics in congestive heart failure also apply to their use in hepatic disease. There is no logical reason why ascites fluid needs to be rapidly removed. Its removal should be a gradual process, since part of the accumulation was in response to renal compensatory mechanisms maintaining effective circulating volume. The rapid removal of ascites fluid by a powerful diuretic could catastrophically decrease the effective circulating volume and in addition produce potassium loss. Electrolyte disturbances in the presence of liver disease can be serious and may lead to coma and death (hepatic coma), commonly due to excessively high levels of ammonia in the blood. The sequence of events is as follows: potassium loss from the body leads to hypokalemia, and the low extracellular fluid [K+] causes K+ to leave the cells and Na+ and H+ to move in. When this occurs at the renal tubule cells, the lowered cellular pH stimulates NH3 production from glutamine. Although much of the ammonia so formed enters the renal tubules and is excreted, some enters the blood and, if the liver is healthy, is converted into urea by the liver. In the presence of a diseased liver, the ammonia produced by the kidneys increases the blood ammonia concentration.

Fig. 14.4
figure 4

The development of ascites in liver disease

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Another way in which liver disease (e.g. cirrhosis) complicates renal function is due to the fact that the liver plays a considerable part in the inactivation of circulating ADH and aldosterone, and this inactivation is less effective in cirrhosis.

Nephrotic Syndrome

In this syndrome, the glomerular filtration barrier becomes permeable to plasma proteins and consequently there is proteinuria, with a progressive reduction in the plasma protein osmotic pressure (IIcap). Albumin is the smallest plasma protein and therefore is filtered most readily in the nephrotic syndrome, and it is also the protein which contributes most to the plasma protein osmotic pressure. Thus it is the fall in albumin concentration which is the main cause of the decreased plasma protein osmotic pressure. This in turn alters the “Starling forces” across the capillaries and causes oedema (Fig. 14.5). The reduced effective circulating volume leads to renal sodium and water retention by the same mechanisms as the ones which occur in congestive heart failure.

Fig. 14.5
figure 5

Oedema in the nephrotic syndrome

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Renal Failure

If renal glomerular filtration decreases from the normal 120 mL/min to levels of 30 mL/min or less, symptoms of renal failure become apparent, as a consequence of the retention of nitrogenous waste products (mainly urea and ammonia), and water and electrolyte retention. In fact, renal failure is generally defined as a fall in glomerular filtration leading to increased plasma urea levels. The condition may be chronic,with progressive loss of functioning nephrons leading to a gradual decline in renal function, or acute. Acute renal failure is usually due to renal ischaemia and hypoxia, or to toxic drugs or urinary obstruction.

Acute Renal Failure

The renal regulation of the internal environment depends on (a) ultrafiltration of the plasma, (b) the normal functioning of the tubules to selectively reabsorb and secrete and (c) the excretion of urine via the ureters, bladder and urethra. Disorders in these mechanisms can lead respectively to pre-renal failure (if the renal perfusion is inadequate), intrinsic renal failure if the kidneys are damaged or post-renal failure if there is an obstruction in the urinary tract.

Pre-renal Failure

Pre-renal failure is failure of the systemic circulation to supply the kidneys with an adequate blood flow to maintain GFR. It may be caused by congestive heart failure, or any of the other conditions associated with decreased effective circulating volume (see text). Essentially, renal function is appropriate in pre-renal failure (i.e. avid Na+ and water reabsorption occurs, as described in the text). Restoration of the effective circulating volume restores normal renal function and GFR.

Intrinsic Renal Failure

Intrinsic renal failure usually involves acute tubular necrosis. It can develop from pre-renal failure if the ischemia persists. Restoration of effective circulating volume does not restore normal GFR in intrinsic renal failure and the excretory function of the kidney is severely impaired.