● Introduction 273 ● Volume overload (salt and water excess) 273 ● Diuretics 274 ● SIADH: overhydration 276 ● Volume depletion 277 CHAPTER 36 NEPHROLOGICAL AND RELATED ASPECTS INTRODUCTION The ‘internal environment’ is tightly controlled so that plasma concentrations of electrolytes remain within narrow limits despite substantial variations in dietary intake, as a result of renal processes that ensure that the amounts excreted balance those taken in. Fluid and electrolyte disturbances are important in many diseases (e.g. heart failure, see Chapter 31). In the present chapter, we consider general aspects of their management. This usually involves dietary restriction and the use of drugs that act on the kidney – especially various diuretics. Additionally, we consider briefly drugs that act on the bladder and other components of the genito-urinary system. VOLUME OVERLOAD (SALT AND WATER EXCESS) Volume overload is usually caused by an excess of sodium chloride with accompanying water. Effective treatment is directed at the underlying cause (e.g. heart failure or renal failure), in addition to improving volume status per se by reducing salt intake and increasing its elimination by the use of diuretics. Limiting water intake is seldom useful in patients with volume overload, although modest limitation is of value in patients with ascites due to advanced liver disease and in other patients with hyponatraemia. Diuretics increase urine production and Na � excretion. They are of central importance in managing hypertension (Chapter 28), as well as the many diseases associated with oedema and volume overload, including heart failure, cirrhosis, renal failure and nephrotic syndrome, where it is important to assess the distribution of salt and water excess in different body compartments. Glomerular filtrate derives from plasma, so diuretic treatment acutely reduces plasma ● Disordered potassium ion balance 278 ● Drugs that alter urine pH 279 ● Drugs that affect the bladder and genito-urinary system 279 volume. It takes time for tissue fluid to re-equilibrate after an acute change in blood volume. Consequently, attempts to produce a vigorous diuresis are inappropriate in some oedematous states and may lead to cardiovascular collapse and ‘prerenal’ renal failure – i.e. caused by poor renal perfusion, often signalled by an increase in serum urea disproportionate to the creatinine concentration. The principles of using diuretics in the management of hypertension (Chapter 28) and heart failure (Chapter 31) are described elsewhere. Here, we describe briefly the management of hypoalbuminaemic states: nephrotic syndrome and cirrhosis. Hypoalbuminaemia affects the kinetics of several drugs through its effects on protein binding (Chapter 7) and causes an apparently inadequate intravascular volume in the face of fluid overload in the body as a whole. This results in an increased risk of nephrotoxicity from several common drugs, particularly non-steroidal antiinflammatory drugs (NSAIDs, Chapter 26). Particular caution is needed when prescribing and monitoring the effects of therapy for intercurrent problems in such patients. NEPHROTIC SYNDROME The primary problem in nephrotic syndrome is impairment of the barrier function of glomerular membranes with leakage of plasma albumin into the urine. Plasma albumin concentration falls together with its oncotic pressure and water passes from the circulation into the tissue spaces, producing oedema. The fall in effective blood volume stimulates the renin–angiotensin–aldosterone system, causing sodium retention. Depending on the nature of the glomerular pathology, it may be possible to reduce albumin loss with glucocorticosteroid or other immunosuppressive drugs (Chapter 50). However, treatment is often only symptomatic. Diuretics are of limited value, but diet is important. Adequate protein intake is needed to support hepatic synthesis of albumin. Salt intake should be restricted.
274 NEPHROLOGICAL AND RELATED ASPECTS CIRRHOSIS Fluid retention in cirrhosis usually takes the form of ascites, portal hypertension leading to loss of fluid into the peritoneal cavity, although dependent oedema also occurs. Other important factors are hypoalbuminaemia (caused by failure of synthesis by the diseased liver) and hyperaldosteronism (due to activation of volume receptors and reduced hepatic aldosterone catabolism). Transplantation may be appropriate in cases where the underlying pathology (e.g. alcoholism) is judged to have been cured or (as in some rare inherited metabolic disorders) will not recur in a donor liver. Nevertheless, symptomatic treatment is all that is available for most patients. Diet is important. Protein is restricted in the presence of hepatic encephalopathy, and should be of high quality to provide an adequate supply of essential amino acids. High energy intake from carbohydrate minimizes catabolism of body protein. Salt restriction is combined with moderate water restriction monitored by daily weighing. Excessive diuresis may precipitate renal failure: loss of approximately 0.5 kg body weight (as fluid) daily is ideal. Thiazides or loop diuretics exacerbate potassium depletion and alkalosis and can precipitate hepatic encephalopathy. Amiloride or spironolactone are used in this setting (see below), combined subsequently with loop diuretics if necessary. DIURETICS Many diuretics block sodium ion reabsorption from renal tubular fluid (Figure 36.1). This causes natriuresis (i.e. increased excretion of sodium ions), so diuretics are used to treat patients with volume overload. Some diuretics have additional distinct therapeutic roles because of additional effects on the kidney (e.g. the use of furosemide to treat hypercalcaemia or the use of Carbonic anhydrase inhibitors Na + (65–70%) NaHCO3 − Proximal convoluted tubule Cortex medulla H 2O Loop of Henle Glomerulus Filtration Distal convoluted tubule thick ascending limb of Loop of Henle − (~25%) 2CI – Na +K + Loop diuretics (~5%) Na +CI – − Thiazides H 20 thiazide diuretics to treat nephrogenic diabetes insipidus) or elsewhere in the body (e.g. mannitol for cerebral oedema). CARBONIC ANHYDRASE INHIBITORS Acetazolamide, a sulphonamide, is a non-competitive inhibitor of carbonic anhydrase. Carbonic anhydrase plays an important part in bicarbonate reabsorption from the proximal tubule (Figure 36.1). Consequently, acetazolamide inhibits reabsorption of sodium bicarbonate, resulting in an alkaline diuresis with loss of sodium and bicarbonate in the urine. Since chloride (rather than bicarbonate) is the preponderant anion in the plasma (and hence in glomerular filtrate), carbonic anhydrase inhibitors influence only a small fraction of sodium reabsorption and are thus weak diuretics. Uses More importantly than its diuretic effect, acetazolamide inhibits carbonic anhydrase in the eye and thereby decreases the rate of secretion of the aqueous humour and lowers intraocular pressure. Treatment of glaucoma is currently the major use of acetazolamide. Dorzolamide is a topical carbonic anhydrase inhibitor for use in glaucoma (Chapter 52). Carbonic anhydrase in the choroid plexus participates in the formation of cerebrospinal fluid and acetazolamide has been used in the management of benign intracranial hypertension. Acetazolamide is used in the prevention of mountain sickness, since it permits rapid acclimatization to altitude (which entails renal compensation for respiratory alkalosis caused by hyperventilation) by facilitating bicarbonate excretion. Urinary alkalinization with acetazolamide has been used in the treatment of children with cysteine stones due to cysteinuria, as cysteine is more soluble at alkaline than at acid pH. (Many of these uses are unlicensed.) Unwanted effects As a consequence of increased urinary elimination of bicarbonate during acetazolamide treatment, the plasma bicarbonate (1–2%) Na + K + H + − Urine excretion K + sparing diuretics Collecting duct Figure 36.1: Sites of action of different diuretics in the nephron.