Gitelman syndrome

Most doctors qualify with a knowledge that the kidney is an important organ, that the diseases affecting it are complex, and that renal physiology is difficult to understand. Once in clinical practice confusion persists particularly over which patients should be referred and when and, for instance, over whether angiotensin converting enzyme inhibitors are uniquely effective at preventing progressive renal failure or contraindicated in renal failure. Much of this confusion is now unnecessary. Recent advances have clarified some aspects of renal physiology: now the teachers understand them there is more hope of explaining them to students. Knowledge of the various types of glomerulonephritis is not necessary in deciding when a patient should be referred: this decision is becoming increasingly important as the potential for prevention of progressive renal disease increases.

Methods

This is an unsystematic review of those areas of nephrology in which there have been recent advances, selected for a general readership. Space precludes coverage of advances in renal transplantation. I have relied on personal files, recent articles in the journals of international nephrology societies, Medline searches, and discussions with colleagues.

Renal physiology

Identification of the genetic basis of some rare conditions has led to increased understanding of normal renal physiology.

Water handling: aquaporins

Water reabsorption is stimulated by vasopressin, which is now known to act by causing insertion of a water channel, aquaporin-2, into the cell membrane of the collecting duct. Congenital nephrogenic diabetes insipidus is caused by mutations in the vasopressin receptor or the aquaporin-2 gene. Some forms of acquired nephrogenic diabetes insipidus are associated with decreased expression of aquaporin-2. Conversely, increased expression of aquaporin-2 results in increased water reabsorption. Measurement of urinary aquaporin-2 concentrations may prove useful in diagnosing disorders of sodium concentration, and drugs that interfere with the vasopressin-aquaporin-2 axis are likely to prove useful in the management of these disorders.[1]

Calcium handling: extracellular calcium receptors

Some rare genetic disorders of calcium homoeostasis illustrate the importance of the extracellular calcium receptor, which allows parathyroid and renal tubular cells, among others, to respond to changes in concentration of extracellular ionised calcium. An increase in serum calcium concentration inhibits parathyroid hormone secretion, 1-hydroxylation of vitamin D, and reabsorption of sodium, chloride, calcium, magnesium, and water.[2 3] Mutations that decrease the receptor's sensitivity cause familial benign hypercalcaemia with hypocalciuria; mutations that increase sensitivity cause hypocalcaemia with hypercalciuria. Drugs that stimulate the receptor are now under study for use in primary and secondary hyperparathyroidism.[4 5]

Sodium handling: monogenic causes of hypertension and salt wasting

Several genetic causes of severe hypertension have been identified, all of which affect renal sodium handling, supporting the concept that hypertension is frequently caused by impaired ability to excrete excess dietary sodium. Examples include Liddle's syndrome (increased activity of a sodium reabsorbing channel in the distal tubule and collecting duct); glucocorticoid remediable hypertension (causing stimulation of aldosterone production by adrenocorticotrophic hormone); and pseudohyperaldosteronism (genetic defect in 11-[Beta]-hydroxysteroid dehydrogenase, which normally prevents cortisol from having an aldosteronelike action in the kidney).[6 7] These diseases are rare, but such insights may lead to the identification of more common polymorphisms in genes controlling sodium excretion and enhance our understanding of "essential" hypertension.

Conversely, two diseases characterised by low blood pressure have been shown to be caused by mutations that decrease sodium reabsorption: Bartter's syndrome--caused either by impaired activity of the sodium-potassium-2-chloride cotransporter (the major target for loop diuretics) or by two related transporters; and Gitelman's syndrome--caused by impaired activity of the thiazide sensitive sodium chloride cotransporter.[8] The physiological abnormalities in these syndromes illustrate the effects of high dose permanent diuretic therapy.

Glomerulonephritis

Immunoglobulin A nephropathy is the commonest type of glomerulonephritis and an important cause of end stage renal failure. The primary abnormality seems to be the production of abnormally glycosylated IgA in the bone marrow, resulting in decreased hepatic clearance of [IgA.sub.1], mesangial deposition of IgA, and glomerular inflammation.[9 10] No specific treatment is yet available,[11] although a recent trial showed benefit from high dose steroids.[12] Patients with risk markers for progressive renal dysfunction (hypertension, proteinuria, increasing serum creatinine concentration) should be offered treatment based on existing trials or entered into a trial.

Uncertainty remains about how patients with microscopic or dipstick haematuria without any of the above risk markers should be investigated and managed once urological malignancy, stone disease, and crystalluria have been excluded. A major proportion of these patients have IgA nephropathy or another chronic glomerular disease that may be detected by biopsy, but they have a low relative risk of end stage renal disease,[13] and it is reasonable to defer biopsy if adequate (for example, annual) monitoring of risk markers for progressive disease can be ensured.

Small vessel vasculitis

Wegener's granulomatosis and microscopic polyangiitis --two major causes of pauci immune rapidly progressive glomerulonephritis--are now often suggested by positive tests for autoantibodies against enzymes present in the cytoplasm of human neutrophils (antineutrophil cytoplasmic antibodies), although false positives and false negatives still occur making biopsy confirmation of the diagnosis mandatory. Whether these antibodies are directly pathogenic remains uncertain.

Adult polycystic kidney disease

Adult polycystic kidney disease can be caused by mutation in one of several genes, two of which have been identified. Polycystin-1 is a large membrane bound protein, which probably regulates the interaction between the cell and extracellular matrix or other cells.[14] Polycystin-2 is probably a membrane bound ion channel. Only 1%-2% of tubules become cystic although all cells carry the mutation, suggesting that the cystic tubules are also affected by a second somatic mutation either in the polycystin-1 gene or in another gene encoding a protein that interacts with polycystin-1.[15] Patients are liable to progress more rapidly if they are male or have polycystin-1 mutations, early onset hypertension, episodes of gross haematuria,[16] or a family history of hypertension in the unaffected parent,[17] but these only account for a fraction of the variability of disease progression. Despite the association of hypertension with more rapid disease progression there is no convincing evidence that tighter blood pressure control retards progression,[18] Cyst decompression may help to relieve pain but does not alter the rate of progression. Indeed, there is currently no intervention that is known to alter the clinical course of polycystic kidney disease, although several agents are being tested in animal models.

Chronic renal failure

Patients who are referred for dialysis close to or at end stage renal failure have a much poorer prognosis than those managed for at least 3 months before needing dialysis or transplantation.[19 20] Possible reasons for this include a higher prevalence of comorbid illness in those referred late; suboptimal management of anaemia, phosphate retention, bone disease, acidosis, hypertension, dyslipidaemia, or nutritional state; and inadequate medical and psychological preparation for dialysis, for instance timely construction of arteriovenous fistulae. All patients with potentially progressive chronic renal failure should therefore be seen by a nephrologist unless the patient and doctor agree that dialysis would be pointless; but it should be borne in mind that many borderline patients who believe they are unsuitable for dialysis and who may have the most to gain from earlier referral often change their minds in extremis and end up being referred as a uraemic emergency.

Progression of diabetic and non-diabetic renal disease

Prevention of end stage renal failure is the main goal of nephrology owing to the high morbidity and mortality from dialysis and transplantation. For instance, 5 year survival rates for patients with type 1 diabetes on renal replacement therapy are around 50%, similar to the mortality from grade 2 stomach cancer. Although there are occasional opportunities for primary prevention, the greatest potential for prevention is in patients with slowly progressive renal disease--for example, due to diabetes or chronic glomerulonephritis. Numerous mechanisms play a part in the progressive destruction of glomeruli and tubules, some independent of the initiating disease process: these include glomerular hypertrophy, glomerular hypertension, and collagen deposition, all of which may be enhanced by angiotensin II. The DD genotype of angiotensin converting enzyme (the "D" allele conferring higher tissue and plasma angiotensin II concentrations) is probably not a risk factor for the development of diabetic nephropathy but may be associated with more rapid progression.[11 21]

In a wide variety of renal diseases hypertension and proteinuria are potent predictors not only of cardiovascular disease but also progressive deterioration in renal function. Proteinuria may be quantified by measuring the protein:creatinine concentration in a spot morning urine sample, and these measurements are as reliable as 24 hour urine collections in predicting progression.[22] For a given reduction in systemic blood pressure, angiotensin converting enzyme inhibitors reduce proteinuria to a greater extent than most other antihypertensives, whereas dihydropyridine calcium channel blockers may actually increase proteinuria despite a reduction in systemic blood pressure. Proteinuria itself may be pathogenic, and the extent of treatment induced reduction in proteinuria correlates with the subsequent reduction in rate of loss of glomerular filtration rate. A simplistic explanation for the antiproteinuric effect of angiotensin converting enzyme inhibitors is that their intrarenal actions reduce intraglomerular pressure thereby "protecting" the glomerulus from systemic hypertension. This effect is amplified by restriction of dietary sodium particularly in patients with the DD genotype.[23] The advantages of angiotensin converting enzyme inhibitors over other antihypertensives in slowing progression has been shown in several studies in diabetic and non-diabetic renal disease,[24-28] but this advantage may be lost if blood pressure is lowered far enough, independent of the agent used,[29 30] and is seen only in patients with significant proteinuria. Two large studies have shown a higher risk of cardiovascular events in patients with type 2 diabetes randomised to a dihydropyridine calcium channel blocker compared with those receiving an angiotensin converting enzyme inhibitor.[31 32] In the UK prospective diabetes trial the absence of any benefit from angiotensin converting enzyme inhibitors over [Beta] blockade may have been because of the extent to which blood pressure was lowered or to the comparative infrequency of proteinuric nephropathy in the study population.[33] Angiotensin converting enzyme inhibitors may also confer protection against progressive renal disease by non-haemodynamic actions, such as suppression of other effects of angiotensin II including glomerular hypertrophy (which may be maladaptive), glomerulosclerosis, and altered basement membrane permeability (fig 1).

[Figure 1 ILLUSTRATION OMITTED]

Ischaemic renal vascular disease

In most patients starting dialysis the only identifiable cause of renal failure is atherosclerotic renal artery disease.[34 35] Such patients frequently have widespread atherosclerosis and a poor prognosis on dialysis. Atherosclerotic renal artery stenosis, usually at the ostium or involving the proximal renal artery, can be shown by angiography in 30%-50% of patients undergoing peripheral or coronary angiography and in a similar proportion of patients with congestive cardiac failure. How to select patients for renal angiography with a view to revascularisation is therefore an important, and complicated, question. Not all patients with renal artery disease, even if bilateral, have a major reduction in renal function when treated with angiotensin converting enzyme inhibitors, and most die from cardiovascular disease not from or with end stage renal failure. Moreover, renal function does not always improve after revascularisation and may even deteriorate,[36] because renal dysfunction in renal artery disease may result from nephrosclerosis, atheromatous ("cholesterol") embolism (fig 2),[37 38] or coincident renal disease as well as from impaired renal perfusion.

[Figure 2 ILLUSTRATION OMITTED]

Indications for investigation with a view to revascularisation include spontaneous progressive loss of renal function in a patient with widespread atherosclerosis, a progressive increase in serum creatinine concentration after initiation or increase in dose of an angiotensin converting enzyme inhibitor, and recurrent pulmonary oedema despite good left ventricular function.[39] In all these situations bilateral renal involvement is likely and this selection policy does not therefore identify patients with unilateral disease, which may progress to complete occlusion if undetected. Hypertension is not always present and does not always improve after successful revascularisation.[40 41] Further clinical research is needed to refine these criteria, but indiscriminate angiography in other patients with atherosclerosis and renal impairment should be avoided. In most centres the utility of isotope renography, with or without angiotensin converting enzyme inhibitors or aspirin, in predicting success of revascularisation in preventing or reversing renal impairment is limited; these investigations are more useful in identifying patients with renovascular hypertension and comparatively well preserved renal function. For most patients with congestive cardiac failure the cardiac benefits from angiotensin converting enzyme inhibitors outweigh the renal risks[42] provided that there is adequate biochemical monitoring to detect progressive deterioration in renal function in patients with ischaemic renal disease, in whom continued use of angiotensin converting enzyme inhibitors is contraindicated.

The future

Given the costs of dialysis and transplantation, which may eventually use up 2% of the NHS budget, together with the high morbidity and mortality from end stage renal failure, there is a need for advances in prevention. Much could be achieved by applying existing knowledge, for instance in the use of angiotensin converting enzyme inhibitors and tight glycaemic control in diabetic nephropathy and in early identification and referral of patients with progressive renal disease. The recent discovery of the genetic basis for a rare form of congenital nephrotic syndrome[43] may lead to rapid advances in understanding of the control of glomerular permeability. Additionally, there are likely to be major advances in understanding of the pathogenesis of polycystic disease and glomerulonephritis, greater understanding of the molecular pathogenesis of progressive renal fibrosis and atrophy, and identification of new genetic markers for susceptibility to progressive renal disease, all of which may lead to effective treatments to prevent progressive renal failure.

Competing interests: CRVT has received honoraria or consultancy fees from Astra, Baxter, Bayer, Fujisawa, Janssen-Cilag, and Novartis.

Recent advances

Identification of the genetic basis for some rare disorders has led to increased understanding of normal renal physiology and opened up the possibility of new treatments for hyperparathyroidism and hyponatraemic states

Major advances have occurred in the understanding of the pathogenesis of IgA nephropathy and adult polycystic kidney disease, but as yet these have not led to breakthroughs in the treatment of these conditions

The reduction of proteinuria by antihypertensives slows the progression towards end stage renal failure of many types of renal disease--angiotensin converting enzyme inhibitors may have particular value in reducing proteinuria unless systemic blood pressure is lowered far enough

Although only a small proportion of affected patients benefit from renal revascularisation, the high frequency of renal artery stenosis in patients with atherosclerosis mandates regular monitoring of renal function if angiotensin converting enzyme inhibitors are used

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North Bristol NHS Trust, Richard Bright Renal Unit, Southmead Hospital, Westbury on Trym, Bristol BS10 5NB

C R V Tomson consultant renal physician

tomson_c@ southmead.swest. nhs.uk

BMJ 2000;320:98-101

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