doctors may have had more claims because they took on more difficult cases. Debate will continue on whether a small group of incompetent doctors produce much of the malpractice problem, but the Office of Technology Assessment has suggested that malpractice information should be collected and used for quality screening by hospitals, licensing boards, and others (perhaps even patients).6 Indeed, a national database of doctors who have lost malpractice suits went into operation on 1 September (22 September, p 569): hospitals are required to check the database before hiring doctors, but the data are not yet available to patients. The Florida researchers argue that this would be premature, but research in the epidemiology of
malpractice must continue so that we have data on which to base such proposals. RICHARD SMITH Senior Assistant Editor, BMJ I Harvard Medical Practice Study. Patients, doctors, and lauyers: medical injurv, malpractice litigation, and patient compensation in New York. Boston: Harvard Medical Practice Study, 1990. 2 Mills DH, ed. Medical insurance feasibility study. San Francisco: California Medical Association, 1977. 3 Buck N, Devlin HB, Lunn JN. The report of the confidential enquiry into perioperative deaths. London: Nuffield Provincial Hospitals Trust/King's Fund, 1987. 4 Sack K. Thousands of medical errors but few lawsuits, study shows. New York Times 1990 Jan 29:A15. 5 Sloan FA, Mergenhagen PM, Burfield B, Boviberg JD, Hassan M. Medical malpractice experience of physicians: predictable or haphazard?7AMA 1989;262:3291-7. 6 Office of Technology Assessment. The quality of medical care: information.for consumers. Washington DC: United States Office of Technology Assessment, 1988.
Regular Review
Interventions in chronic renal failure Treatment may slow progression in some cases Studies of chronic renal failure in a variety of animal models suggest that once the number of functioning nephrons is reduced to a critical proportion a self perpetuating and progressive deterioration in renal function develops, leading eventually to terminal uraemia. One of the main planks in this explanation is the hyperfiltration hypothesis. This hypothesis postulates that loss of nephrons owing to different causes leads to changes in glomerular haemodynamics in the remaining functioning nephrons with a rise in glomerular capillary pressure (glomerular hypertension) and an increase in filtration rates in the individual nephrons (hyperfiltration). These changes seem to produce increasing proteinuria and progressive glomerulosclerosis culminating in terminal uraemia due to a progressive reduction in the numbers of functioning residual nephrons. '5 It has proved possible in experiments in animals to delay or prevent the development of progressive glomerulosclerosis by ameliorating the haemodynamic changes-either by reducing protein intake -or by treatment with angiotensin converting enzyme inhibitors. The converse has also been shown: either a high protein diet or treatment with glucocorticoids increases both the glomerular hypertension and the degree of glomerulosclerosis. Some observations in these animal models do not, however, support a simple causal relation between the abnormal glomerular haemodynamic changes and progressive glomerulosclerosis. Other mechanisms have been suggested to account for the progressive nature of chronic renal failure. The precipitation-calcification hypothesis postulates that an excess of phosphate causes deposition of calcium phosphate and resultant interstitial and tubular damage.&8 Hyperlipidaemia may be another factor; accumulation of lipid within the mesangial cells may result in the development of focal glomerulosclerosis.9 10 Again in animals treatment of hyperlipidaemia has reduced the degree of albuminuria and the incidence of glomerulosclerosis."I It is a big step, however, to attempt to extrapolate the results of the mass of research work in animal models of chronic renal failure (mainly in the rat) to chronic renal failure in humans. Firstly, there is little evidence in humans that reduction of renal mass compromises the function of the remaining nephrons. Long term follow up of donors of kidneys for transplantation has shown only a slightly in622
creased incidence of mild hypertension and proteinuria."2 In follow up studies of more than 10 years the function of the remaining kidney has not deteriorated.'3 A long term follow up of 32 patients for a mean of 23 years after unilateral nephrectomy in childhood (for various reasons) showed no evidence of an increased incidence of renal impairment or
hypertension. 14
Clinical studies have confirmed that not all patients with chronic renal failure progress inexorably towards terminal uraemia. In a recent study progression of chronic renal failure was analysed in 108 patients by plotting the slope of the reciprocal of the plasma creatinine concentration against time.'5 Seventy patients showed a pattern of linear deterioration and 15 showed non-linear deterioration. In 23 patients, however, the chronic renal failure was stable. Progressive renal failure was usual in patients with chronic glomerulonephritis, diabetic nephropathy, reflux nephropathy, and polycystic kidney disease. By contrast, most of the patients with hypertensive nephrosclerosis, analgesic nephropathy, and renal impairment after acute renal failure were stable. Among patients with linear deterioration the rate was faster in those with chronic glomerulonephritis and diabetic nephropathy than in those with reflux nephropathy and polycystic kidney disease. The underlying renal disease seems, therefore, to be important in determining progression of chronic renal failure and also the rate at which this deterioration occurs. Clearly clinicians need accurate methods of measuring renal function in order to determine whether chronic renal failure is stable or is progressively deteriorating. Plots of the reciprocal of the serum creatinine concentration against time have frequently been used for this purpose.6 17 However, the validity of this method has been seriously questioned, as has the use of measurement of creatinine clearance.'8 19 Isotopic methods of determining the glomerular filtration rate are to be preferred. Deterioration in chronic renal failure may be due to continuing activity of the underlying renal disease-as in systemic lupus erythematosus. Several other factors that may result in acute deterioration in chronic renal failure need to be sought and excluded. Their prompt identification and correction may enable renal function to improve and even stabilise at the previous level. These factors include acute sodium and water depletion due to vomiting or diarrhoea, or BMJ VOLUME 301
29 SEPTEMBER 1990
both; urinary tract infections; nephrotoxic drugs including tetracycline, non-steroidal anti-inflammatory drugs and aminoglycosides; and obstruction-for example, prostatic obstruction in elderly men, renal calculus disease, and papillary necrosis in patients with analgesic nephropathy. Overt sodium and water depletion is easily recognised. Some patients with chronic renal failure have a less obvious and insidious chronic urinary sodium losing tendency, however, which may result in progressive deterioration in residual renal function, which is all too easily attributed to progression of the underlying renal disease. The clinical clue in these patients is that they tend to have a normal blood pressure and to lose weight progressively. Correction of the chronic saline depletion-initially, if necessary, with intravenous saline and subsequently with an appropriate oral sodium supplementwill result in improvement and stabilisation of the chronic renal failure.20 Treatments to slow progression Recent research in connection with the hyperfiltration hypothesis has stimulated a resurgence of interest in possible interventions that may be of value in preventing or slowing the progression of chronic renal failure that occurs in many patients. One approach has been the use of low protein diets. These have been part of the treatment of symptoms of uraemia in patients with severe chronic renal failure for many years, but only relatively recently have they been used at an earlier stage to attempt to halt or slow down the progression of the disease.2' Clinical trials have suggested that dietary restriction of protein and phosphorus may be effective in these circumstances.2-25 Many of these trials, however, have been criticised on the grounds of poor experimental design. 8 9 The observation that more frequent clinical follow up (and presumably better control of blood pressure) retards the progression of chronic renal failure has important implications for the design of prospective randomised studies.26 So far only two prospective, randomised, controlled studies have been reported of low protein diets in patients with chronic renal failure. Rosman et al studied 228 patients and followed 149 for at least 18 months.27 Those with initial creatinine clearances of 10-30 ml/min/i 73 m2 were studied on a protein intake of 0 4 g protein/kg body weight a day while those with creatinine clearances of 31-60 ml/min/1-73 m2 received 0-6 g protein/kg/body weight a day. This trial has been criticised because of the use of plots of the reciprocals of serum creatinine concentrations against time to assess the progression of renal failure. Nevertheless, regression analysis indicated that the rate ofprogression was three to five times slower in patients whose protein was restricted than in controls. Ihle et al recently reported a prospective, randomised study of a low protein diet (0 4 g protein/kg body weight a day) in 64 patients with initial serum creatinine concentrations ranging from 350-1000 mmol/l.28 The study was for 18 months. End stage renal failure developed in nine of the 33 patients who were on their normal diet (27%) as compared with two of the 31 patients (6%) who were on the low protein diet. The mean glomerular filtration rate (measured isotopically) fell substantially in the control group but only very little in the group on the low protein diet. Protein state was checked during the study to see if there was any evidence of protein malnutrition. Serum albumin concentrations did not change, and there were no changes in certain anthropomorphic measurements. A note of caution was sounded, however, because total lymphocyte counts and serum transferrin concentrations both fell. No patient had an
opportunistic infection. A large multicentre cooperative study to define the influBMJ
VOLUME
301
29
SEPTEMBER
1990
ence of dietary restriction of protein and phosphorus and also blood pressure control on the progression of chronic renal disease is in progress. ' Low protein diets are also low in phosphorus. The relative importance of these two variables is not clear.8 One other aspect of low protein diets is the possible effect of the underlying renal disease and the haemodynamic response to the diet. El Nahas et al have reported maximal benefit in non-glomerular disorders and also that patients with a reactive renal vascular bed improved with a low protein diet while those with a fixed renal plasma flow progressed relentlessly.29
Control of hypertension Another important topic is the control of hypertension. Control of accelerated or malignant hypertension is known to be vital to patient survival.30 Such treatment is indicated whatever the level of renal function at presentation; deterioration of renal function does not necessarily occur. In those patients with severe impairment of renal function on presentation a period of dialysis may be necessary while the blood pressure is controlled. In some patients dialysis may be discontinued later-presumably the renal histopathological lesions of accelerated hypertension regress3' `-but in others the renal failure will not improve and permanent dialysis or renal transplantation will be necessary. The importance of less severe grades of hypertension in the progression of chronic renal failure, however, is not so easily shown. The kidney lesion may cause hypertension but the kidney may also suffer the effects of hypertension, which are termed nephrosclerosis. The mechanism of hypertensive nephrosclerosis is not clear. One explanation is that thickening of the arteriolar walls with narrowing of the arteriolar lumen results in ischaemia of the glomerulus and glomerulosclerosis. Another explanation is that hypertension may damage the glomeruli more directly by increasing glomerular capillary pressure, which in turn results in glomerulosclerosis. Careful documentation of the effects of control of blood pressure on the progression of chronic renal failure in humans is limited.33 In one retrospective study there were no differences between patients who had developed significant loss of renal function and those who did not with respect to duration of hypertension, blood pressure during treatment, antihypertensive regimens, duration of follow up, or initial concentrations of serum creatinine.34 There was, however, an association between loss of renal function and race, with renal function decreasing in 23% of black patients but in only 1 1% of white patients. One explanation for these results is that the target level of good blood pressure control (< 140/90 mm Hg) needs lowering and may represent in fact inadequate control, particularly in black patients.33 Whether a further lowering of blood pressure could be achieved without unacceptable side effects remains to be determined. Another important aspect is the type of antihypertensive agent used to control the blood pressure. The introduction of angiotensin converting enzyme inhibitors has posed several important questions. These agents affect glomerular haemodynamics with preferential vasodilatation of the efferent arterioles. They would therefore be expected to reduce glomerular hypertension, and there is experimental evidence that they do this in animals with chronic renal failure. There is also evidence of beneficial effects on progression of chronic renal failure both in animals and in humans irrespective of blood pressure control. Angiotensin converting enzyme inhibitors may prove to be of value in progressive chronic renal failure not only as antihypertensive agents but also in the absence of hypertension. Prospective, randomised trials using 623
the inhibitors are currently in progress.35-37 Smith et al in a short rerm study of the effect of captopril on renal haemodynamics in chronic renal failure, however, concluded that the renal microvasculature in stable chronic renal failure was unresponsive to this inhibitor.38 Thee authors found no alteration in baseline glomerular filtration rate, effective renal plasma flow, or creatinine clearance with or without captopril. With the increasing use of angiotensin converting enzyme inhibitors in the treatment of hypertension and perhaps also chronic renal failure and diabetic nephropathy clinicians need to remember the possible side effects. Acute deterioration in renal function may occur in patients with bilateral renal artery stenosis or renal artery stenosis of a solitary kidney.3940 This complication is likely to be seen more commonly in elderly patients, with their relatively high incidence ofatherosclerosis and renovascular disease. The effect of angiotensin converting enzyme inhibitors on renal haemodynamics has been used as a test to detect renal artery stenosis. Calcium channel blocking agents have also been shown to protect against progression of chronic renal failure in animals.42 Whether these and angiotensin converting enzyme inhibitors have any advantage over more conventional antihypertensive agents remains to be determined. The hyperfiltration hypothesis may also be relevant in diabetes.43 Current approaches to the prevention and treat-
I Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N EnglJ Med 1982;307:652-9. 2 Dunn BR, Anderson S, Brenner BM. The hemodynamic basis of progressive renal disease. Semin Nephrol 1986;6:122-38. 3 Klahr S, Schreiner G, Ichikawa I. The progression of renal disease. N EnglJ Med 1988;318: 1657-66. 4 Anonymous. Progression of chronic renal failure [Editorial]. Lancet 1988;ii:374-5. 5 Fine LG. Preventing the progression of human renal disease: have rational therapeutic principles emerged? Kidney Int 1988;33:116-28 6 Ibels LS, Alfrey AC, Haut LL, Huffer WE. Preservation of function in experimental renal disease by dietary restriction of phosphate. N EnglJ7 Med 1978;298:122-6. 7 Ibels LS, Alfrey AC, Huffer WE, Craswell PW, Weil R. Calcification in end stage kidneys. AmJ Med 1981;71:33-9. 8 Lau K. Phosphate excess and progressive renal failure: the precipitation calcification hypothesis. Kidney Int 1989;36:918-37. 9 Moorhead JF, Chan MK, El Nahas M, Varghese Z. Lipid nephrotoxicity in chronic progressive glomerular and tubulointerstitial disease. Lancet 1982;ii: 1309-22. 10 Keane WF, Kasiske BL, O'Donnell MP. Hyperlipidemia and the progression of renal disease. AmJ Clin Nutr 1988;47:157-60. 11 Kasiske BL, O'Donnell MP, Garvis WJ, Keane WF. Pharmacologic treatment for hyperlipidemia reduces glomerular injury in rat 5/6 nephrectomy model of chronic renal failure. Circ Res 1988;62:367-74 12 Hakim RM, Goldszer RC, Brenner BM. Hypertension and proteinuria: long term sequelae of uninephrectomy in humans. Kidney Int 1984;25:930-6. 13 Miller IL, Suthanthiran MS, Riggio RR, et al. Impact of renal donation: long term clinical and biochemical follow up of living donors in a single center. AmJ Med 1986;79:201-8. 14 Robitaille P, Mongeau J, Lortie L, Sinnassamy P. Long term follow up of patients who underwent unilateral nephrectomy in childhood. Lancet 1985;ii: 1297-9. 15 Williams PS, Fass G, Bone JM. Renal pathology and proteinuria determine progression in untreated mild/ moderate chronic renal failure. QJ Med 1988;67:343-4. 16 Mitch WE, Walser M, Buffington GA, Lemann J Jr. A simple method of estimating progression of chronic renal failure. Lancet 1976;ii: 1326-8. 17 Rutherford WE, Blowdin J, Miller JP, Greenwalt AS, Vavra JD. Chronic progressive renal disease: rate of change of serum creatinine concentration. Kidney Int 1977;11:62-7. 18 El Nahas AM, Coles GA. Dietary treatment of chronic renal failure: ten unanswered questions. Lancet 1986;i:597-600. 19 Klahr S. The modification of diet in renal disease study. N EnglJ Med 1989;320:864-6. 20 Clarkson EM, Curtis JR, Jewkes RJ, et al. Slow sodium: an oral slowly released sodium chloride preparation. BrMedj 1971 ;iii:604-7. 21 Giovannetti S. Dietary treatment of chronic renal failure: Why is it not used more frequently? Nephron 1985;4:1-12. 22 Giordano C. Protein restriction in chronic renal failure. Kidney Int 1982;22:401-8. 23 Maschio G, Oldrizzi L, Tessitore N, et al. Effects of dietary protein and phosphate restriction on the progression of early renal failure. Kidney Int 1982;22:371-6. 24 Mitch WE, Walser M, Steinman TI, Hill S, Zeger S, Tungsanga K. The effect of a keto acid-amino acid supplement to a restricted diet on the progression of chronic renal failure. N Engl Med
1984;311:623-9. 25 Mitch WE. The influence of the diet on the progression of renal insufficiency. Annu Rev Med
1984;35:249-64. 26 Bergstrom J, Alvestrand A, Bucht H, Gutierrez A. Progression of chronic renal failure in man is retarded with more frequent clinical follow ups and better blood pressure control. Clin Nephrol 1986;25: 1-6. 27 Rosman JB, Ter Wee PM, Meijer S, Piers-Becht TPM, Sluiter WJ, Donker JM. Prospective
624
ment of diabetic nephropathy have been reviewed by Mogensen.i The three main lines include better metabolic control, effective antihypertensive treatment, and the use of moderately low protein diets. Patients with borderline hypertension- that is, a blood pressure of 140/90 mm Hg -should probably be treated with a lower target blood pressure of perhaps 135/85 mm Hg. Several accounts of the use of angiotensin converting enzyme inhibitors in diabetic nephropathy have reported improvement in microalbuminuria in incipient diabetic nephropathy and reduction in albuminuria in established diabetic nephropathy.4546 Microalbuminuria was also reduced in patients with incipient diabetic nephropathy, however, by conventional antihypertensive treatment.47 Some long term large scale double blind randomised trials of the inhibitors in patients with incipient diabetic nephropathy are in progress. Many questions regarding the progression of chronic renal failure remain unanswered. There are several other factors that may be important but require further research. These include the possible contributions of lead48; hyperuricaemia49; secondary oxalosis50; and atrial natriuretic peptide.5' J R CURTIS
Senior Lecturer in Medicine, Charing Cross Hospital, London W6 8RF
28 29 30 31 32
33 34 35 36 37 38 39 40 41 42
43 44 45 46 47
randomised trial of early dietary protein restriction in chronic renal failure. Lancet 1984;ii: 1291-6. Ihle BU, Becker GJ, Whitworth JA, Charlwood RA, Kincaid-Smith PS. The effect of protein restriction on the progression of renal insufficiency. N Englj Med 1989;321: 1773-7. El Nahas AM, Thomas AM, Brady SA, et al. Selective effect of low protein diets in chronic renal diseases. BrMedJ 1984;289:1337-41. Breckenridge A, Dollery CT, Parry EHO. Prognosis of treated hypertension: changes in life expectancy and causes of death between 1952 and 1967. QJ Med 1970;39:411-29. Woods JW, Blythe WB, Huffines WD. Management of malignant hypertension complicated by renal insufficiency. A follow up study. N Engl.jMed 1974;292:10-4. Cordingley FT, Jones NF, Wing AJ, Hilton PJ. Reversible renal failure in malignant hypertension. Clin Nephrol 1980;14:98-103. Klahr S. The kidney in hypertension-villain and victim. NEnglJMed 1989;320:731-3. Rostand SG, Brown G, Kirk KA, Rutsky EA, Dustan HP. Renal insufficiency in treated essential hypertension. N EnglJ7 Med 1989;320:684-8. Keane WF, Anderson S, Aurell M, de Zeeuw D, Narins RG, Povar G. Angiotensin converting enzyme inhibitors and progressive renal insufficiency. Ann Intern Med 1989;111:503-16. Feig PU, Rutan GH. Angiotensin converting enzyme inhibitors: the end of end stage renal disease? Ann Intern Med 1989;111:451-3. De Zeeuw D, Heeg JE, De Jong PE. Merits of ACE inhibitors in patients with renal insufficiency. In: Clement DL, ed. ACE inhibitors: past, present and beyond. London: Royal Society of Medicine, 1989:49-55. (Services International Congress and Symposium Series No 144.) Smith WGJ, Dharmasena AD, El Nahas AM, Thomas DM, Coles GA. Short term effect of captopril on renal haemodynamics in chronic renal failure. Nephrol Dial Transplant 1989;4: 696-700. Hricik DE, Browning PJ, Kopelman R, Goorno WE, Madias NE, Dzau VJ. Captopril induced functional renal insufficiency in patients with bilateral renal artery stenosis or renal artery stenosis in a solitary kidney. N EnglJ Med 1983;308:373-6. Jackson B, Matthews PG, McGrath BP, Johnson CI. Angiotensin converting enzyme inhibitors in renovascular hypertension: frequency of reversible renal failure. Lancet 1984;i:225-6. Maher ER, Othman S, Frankel AH, Sweny P, Moorhead JF, Hilson AJW. Captopril enhanced 99m Tc DTPA scintigraphy in the detection of renal artery stenosis. Nephrol Dial Transplant 1988;3:608-1 1. Harris DCH, Hammond WS, Burke TJ, Schrier RW. Verapamil protects against progression of experimental chronic renal failure. Kidney Int 1987;31:41-6. Hostetter TH, Troy JL, Brenner BM. Glomerular hemodynamics in experimental diabetes. Kidney Int 1981;19:410-5. Mogensen CE. Management of diabetic renal involvement and disease. Lancet 1988;i:867-70. Marre M, Leblanc H, Suarez L, Guyenne TT, Menard J, Passa P. Converting enzyme inhibitors and kidney function in normotensive diabetic patients with persistent microalbuminuria. BrMedJ7 1987;294:1448-52. Hommel E, Parving HH, Mathiesen E, Edsberg B, Damkiaer-Nielsen M, Giese J. Effect of captopril on kidney function in insulin dependent diabetic patients with nephropathy. Br MedJ 1986;293:467-70. Christensen CK, Mogensen CE. Antihypertensive treatment: long term reversal of progression of albuminuria in incipient diabetic nephropathy. A longitudinal study of renal function. Journal of
Diabetic Complications 1987;1:45-52. 48 Koster J, Erhardt A, Stoeppler M, Mohl C, Ritz E. Mobilizable lead in patients with chronic renal failure. EurJ Clin Invest 1989;19:228-33. 49 Scott JT. Asymptomatic hyperuricaemia. BrMedj 1987;294:987-8. 50 Thompson CS, Weinman EJ. The secondary oxalosis of renal failure. Seminars in Dialysis 1988;1:94-9. 51 Woolf AS. Atrial natriuretic peptide and renal disease. Nephrol Dial Transplant 1989;4: 1008-15.
BMJ VOLUME 301
29 SEPTEMBER 1990
malpractice must continue so that we have data on which to base such proposals. RICHARD SMITH Senior Assistant Editor, BMJ I Harvard Medical Practice Study. Patients, doctors, and lauyers: medical injurv, malpractice litigation, and patient compensation in New York. Boston: Harvard Medical Practice Study, 1990. 2 Mills DH, ed. Medical insurance feasibility study. San Francisco: California Medical Association, 1977. 3 Buck N, Devlin HB, Lunn JN. The report of the confidential enquiry into perioperative deaths. London: Nuffield Provincial Hospitals Trust/King's Fund, 1987. 4 Sack K. Thousands of medical errors but few lawsuits, study shows. New York Times 1990 Jan 29:A15. 5 Sloan FA, Mergenhagen PM, Burfield B, Boviberg JD, Hassan M. Medical malpractice experience of physicians: predictable or haphazard?7AMA 1989;262:3291-7. 6 Office of Technology Assessment. The quality of medical care: information.for consumers. Washington DC: United States Office of Technology Assessment, 1988.
Regular Review
Interventions in chronic renal failure Treatment may slow progression in some cases Studies of chronic renal failure in a variety of animal models suggest that once the number of functioning nephrons is reduced to a critical proportion a self perpetuating and progressive deterioration in renal function develops, leading eventually to terminal uraemia. One of the main planks in this explanation is the hyperfiltration hypothesis. This hypothesis postulates that loss of nephrons owing to different causes leads to changes in glomerular haemodynamics in the remaining functioning nephrons with a rise in glomerular capillary pressure (glomerular hypertension) and an increase in filtration rates in the individual nephrons (hyperfiltration). These changes seem to produce increasing proteinuria and progressive glomerulosclerosis culminating in terminal uraemia due to a progressive reduction in the numbers of functioning residual nephrons. '5 It has proved possible in experiments in animals to delay or prevent the development of progressive glomerulosclerosis by ameliorating the haemodynamic changes-either by reducing protein intake -or by treatment with angiotensin converting enzyme inhibitors. The converse has also been shown: either a high protein diet or treatment with glucocorticoids increases both the glomerular hypertension and the degree of glomerulosclerosis. Some observations in these animal models do not, however, support a simple causal relation between the abnormal glomerular haemodynamic changes and progressive glomerulosclerosis. Other mechanisms have been suggested to account for the progressive nature of chronic renal failure. The precipitation-calcification hypothesis postulates that an excess of phosphate causes deposition of calcium phosphate and resultant interstitial and tubular damage.&8 Hyperlipidaemia may be another factor; accumulation of lipid within the mesangial cells may result in the development of focal glomerulosclerosis.9 10 Again in animals treatment of hyperlipidaemia has reduced the degree of albuminuria and the incidence of glomerulosclerosis."I It is a big step, however, to attempt to extrapolate the results of the mass of research work in animal models of chronic renal failure (mainly in the rat) to chronic renal failure in humans. Firstly, there is little evidence in humans that reduction of renal mass compromises the function of the remaining nephrons. Long term follow up of donors of kidneys for transplantation has shown only a slightly in622
creased incidence of mild hypertension and proteinuria."2 In follow up studies of more than 10 years the function of the remaining kidney has not deteriorated.'3 A long term follow up of 32 patients for a mean of 23 years after unilateral nephrectomy in childhood (for various reasons) showed no evidence of an increased incidence of renal impairment or
hypertension. 14
Clinical studies have confirmed that not all patients with chronic renal failure progress inexorably towards terminal uraemia. In a recent study progression of chronic renal failure was analysed in 108 patients by plotting the slope of the reciprocal of the plasma creatinine concentration against time.'5 Seventy patients showed a pattern of linear deterioration and 15 showed non-linear deterioration. In 23 patients, however, the chronic renal failure was stable. Progressive renal failure was usual in patients with chronic glomerulonephritis, diabetic nephropathy, reflux nephropathy, and polycystic kidney disease. By contrast, most of the patients with hypertensive nephrosclerosis, analgesic nephropathy, and renal impairment after acute renal failure were stable. Among patients with linear deterioration the rate was faster in those with chronic glomerulonephritis and diabetic nephropathy than in those with reflux nephropathy and polycystic kidney disease. The underlying renal disease seems, therefore, to be important in determining progression of chronic renal failure and also the rate at which this deterioration occurs. Clearly clinicians need accurate methods of measuring renal function in order to determine whether chronic renal failure is stable or is progressively deteriorating. Plots of the reciprocal of the serum creatinine concentration against time have frequently been used for this purpose.6 17 However, the validity of this method has been seriously questioned, as has the use of measurement of creatinine clearance.'8 19 Isotopic methods of determining the glomerular filtration rate are to be preferred. Deterioration in chronic renal failure may be due to continuing activity of the underlying renal disease-as in systemic lupus erythematosus. Several other factors that may result in acute deterioration in chronic renal failure need to be sought and excluded. Their prompt identification and correction may enable renal function to improve and even stabilise at the previous level. These factors include acute sodium and water depletion due to vomiting or diarrhoea, or BMJ VOLUME 301
29 SEPTEMBER 1990
both; urinary tract infections; nephrotoxic drugs including tetracycline, non-steroidal anti-inflammatory drugs and aminoglycosides; and obstruction-for example, prostatic obstruction in elderly men, renal calculus disease, and papillary necrosis in patients with analgesic nephropathy. Overt sodium and water depletion is easily recognised. Some patients with chronic renal failure have a less obvious and insidious chronic urinary sodium losing tendency, however, which may result in progressive deterioration in residual renal function, which is all too easily attributed to progression of the underlying renal disease. The clinical clue in these patients is that they tend to have a normal blood pressure and to lose weight progressively. Correction of the chronic saline depletion-initially, if necessary, with intravenous saline and subsequently with an appropriate oral sodium supplementwill result in improvement and stabilisation of the chronic renal failure.20 Treatments to slow progression Recent research in connection with the hyperfiltration hypothesis has stimulated a resurgence of interest in possible interventions that may be of value in preventing or slowing the progression of chronic renal failure that occurs in many patients. One approach has been the use of low protein diets. These have been part of the treatment of symptoms of uraemia in patients with severe chronic renal failure for many years, but only relatively recently have they been used at an earlier stage to attempt to halt or slow down the progression of the disease.2' Clinical trials have suggested that dietary restriction of protein and phosphorus may be effective in these circumstances.2-25 Many of these trials, however, have been criticised on the grounds of poor experimental design. 8 9 The observation that more frequent clinical follow up (and presumably better control of blood pressure) retards the progression of chronic renal failure has important implications for the design of prospective randomised studies.26 So far only two prospective, randomised, controlled studies have been reported of low protein diets in patients with chronic renal failure. Rosman et al studied 228 patients and followed 149 for at least 18 months.27 Those with initial creatinine clearances of 10-30 ml/min/i 73 m2 were studied on a protein intake of 0 4 g protein/kg body weight a day while those with creatinine clearances of 31-60 ml/min/1-73 m2 received 0-6 g protein/kg/body weight a day. This trial has been criticised because of the use of plots of the reciprocals of serum creatinine concentrations against time to assess the progression of renal failure. Nevertheless, regression analysis indicated that the rate ofprogression was three to five times slower in patients whose protein was restricted than in controls. Ihle et al recently reported a prospective, randomised study of a low protein diet (0 4 g protein/kg body weight a day) in 64 patients with initial serum creatinine concentrations ranging from 350-1000 mmol/l.28 The study was for 18 months. End stage renal failure developed in nine of the 33 patients who were on their normal diet (27%) as compared with two of the 31 patients (6%) who were on the low protein diet. The mean glomerular filtration rate (measured isotopically) fell substantially in the control group but only very little in the group on the low protein diet. Protein state was checked during the study to see if there was any evidence of protein malnutrition. Serum albumin concentrations did not change, and there were no changes in certain anthropomorphic measurements. A note of caution was sounded, however, because total lymphocyte counts and serum transferrin concentrations both fell. No patient had an
opportunistic infection. A large multicentre cooperative study to define the influBMJ
VOLUME
301
29
SEPTEMBER
1990
ence of dietary restriction of protein and phosphorus and also blood pressure control on the progression of chronic renal disease is in progress. ' Low protein diets are also low in phosphorus. The relative importance of these two variables is not clear.8 One other aspect of low protein diets is the possible effect of the underlying renal disease and the haemodynamic response to the diet. El Nahas et al have reported maximal benefit in non-glomerular disorders and also that patients with a reactive renal vascular bed improved with a low protein diet while those with a fixed renal plasma flow progressed relentlessly.29
Control of hypertension Another important topic is the control of hypertension. Control of accelerated or malignant hypertension is known to be vital to patient survival.30 Such treatment is indicated whatever the level of renal function at presentation; deterioration of renal function does not necessarily occur. In those patients with severe impairment of renal function on presentation a period of dialysis may be necessary while the blood pressure is controlled. In some patients dialysis may be discontinued later-presumably the renal histopathological lesions of accelerated hypertension regress3' `-but in others the renal failure will not improve and permanent dialysis or renal transplantation will be necessary. The importance of less severe grades of hypertension in the progression of chronic renal failure, however, is not so easily shown. The kidney lesion may cause hypertension but the kidney may also suffer the effects of hypertension, which are termed nephrosclerosis. The mechanism of hypertensive nephrosclerosis is not clear. One explanation is that thickening of the arteriolar walls with narrowing of the arteriolar lumen results in ischaemia of the glomerulus and glomerulosclerosis. Another explanation is that hypertension may damage the glomeruli more directly by increasing glomerular capillary pressure, which in turn results in glomerulosclerosis. Careful documentation of the effects of control of blood pressure on the progression of chronic renal failure in humans is limited.33 In one retrospective study there were no differences between patients who had developed significant loss of renal function and those who did not with respect to duration of hypertension, blood pressure during treatment, antihypertensive regimens, duration of follow up, or initial concentrations of serum creatinine.34 There was, however, an association between loss of renal function and race, with renal function decreasing in 23% of black patients but in only 1 1% of white patients. One explanation for these results is that the target level of good blood pressure control (< 140/90 mm Hg) needs lowering and may represent in fact inadequate control, particularly in black patients.33 Whether a further lowering of blood pressure could be achieved without unacceptable side effects remains to be determined. Another important aspect is the type of antihypertensive agent used to control the blood pressure. The introduction of angiotensin converting enzyme inhibitors has posed several important questions. These agents affect glomerular haemodynamics with preferential vasodilatation of the efferent arterioles. They would therefore be expected to reduce glomerular hypertension, and there is experimental evidence that they do this in animals with chronic renal failure. There is also evidence of beneficial effects on progression of chronic renal failure both in animals and in humans irrespective of blood pressure control. Angiotensin converting enzyme inhibitors may prove to be of value in progressive chronic renal failure not only as antihypertensive agents but also in the absence of hypertension. Prospective, randomised trials using 623
the inhibitors are currently in progress.35-37 Smith et al in a short rerm study of the effect of captopril on renal haemodynamics in chronic renal failure, however, concluded that the renal microvasculature in stable chronic renal failure was unresponsive to this inhibitor.38 Thee authors found no alteration in baseline glomerular filtration rate, effective renal plasma flow, or creatinine clearance with or without captopril. With the increasing use of angiotensin converting enzyme inhibitors in the treatment of hypertension and perhaps also chronic renal failure and diabetic nephropathy clinicians need to remember the possible side effects. Acute deterioration in renal function may occur in patients with bilateral renal artery stenosis or renal artery stenosis of a solitary kidney.3940 This complication is likely to be seen more commonly in elderly patients, with their relatively high incidence ofatherosclerosis and renovascular disease. The effect of angiotensin converting enzyme inhibitors on renal haemodynamics has been used as a test to detect renal artery stenosis. Calcium channel blocking agents have also been shown to protect against progression of chronic renal failure in animals.42 Whether these and angiotensin converting enzyme inhibitors have any advantage over more conventional antihypertensive agents remains to be determined. The hyperfiltration hypothesis may also be relevant in diabetes.43 Current approaches to the prevention and treat-
I Brenner BM, Meyer TW, Hostetter TH. Dietary protein intake and the progressive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation, and intrinsic renal disease. N EnglJ Med 1982;307:652-9. 2 Dunn BR, Anderson S, Brenner BM. The hemodynamic basis of progressive renal disease. Semin Nephrol 1986;6:122-38. 3 Klahr S, Schreiner G, Ichikawa I. The progression of renal disease. N EnglJ Med 1988;318: 1657-66. 4 Anonymous. Progression of chronic renal failure [Editorial]. Lancet 1988;ii:374-5. 5 Fine LG. Preventing the progression of human renal disease: have rational therapeutic principles emerged? Kidney Int 1988;33:116-28 6 Ibels LS, Alfrey AC, Haut LL, Huffer WE. Preservation of function in experimental renal disease by dietary restriction of phosphate. N EnglJ7 Med 1978;298:122-6. 7 Ibels LS, Alfrey AC, Huffer WE, Craswell PW, Weil R. Calcification in end stage kidneys. AmJ Med 1981;71:33-9. 8 Lau K. Phosphate excess and progressive renal failure: the precipitation calcification hypothesis. Kidney Int 1989;36:918-37. 9 Moorhead JF, Chan MK, El Nahas M, Varghese Z. Lipid nephrotoxicity in chronic progressive glomerular and tubulointerstitial disease. Lancet 1982;ii: 1309-22. 10 Keane WF, Kasiske BL, O'Donnell MP. Hyperlipidemia and the progression of renal disease. AmJ Clin Nutr 1988;47:157-60. 11 Kasiske BL, O'Donnell MP, Garvis WJ, Keane WF. Pharmacologic treatment for hyperlipidemia reduces glomerular injury in rat 5/6 nephrectomy model of chronic renal failure. Circ Res 1988;62:367-74 12 Hakim RM, Goldszer RC, Brenner BM. Hypertension and proteinuria: long term sequelae of uninephrectomy in humans. Kidney Int 1984;25:930-6. 13 Miller IL, Suthanthiran MS, Riggio RR, et al. Impact of renal donation: long term clinical and biochemical follow up of living donors in a single center. AmJ Med 1986;79:201-8. 14 Robitaille P, Mongeau J, Lortie L, Sinnassamy P. Long term follow up of patients who underwent unilateral nephrectomy in childhood. Lancet 1985;ii: 1297-9. 15 Williams PS, Fass G, Bone JM. Renal pathology and proteinuria determine progression in untreated mild/ moderate chronic renal failure. QJ Med 1988;67:343-4. 16 Mitch WE, Walser M, Buffington GA, Lemann J Jr. A simple method of estimating progression of chronic renal failure. Lancet 1976;ii: 1326-8. 17 Rutherford WE, Blowdin J, Miller JP, Greenwalt AS, Vavra JD. Chronic progressive renal disease: rate of change of serum creatinine concentration. Kidney Int 1977;11:62-7. 18 El Nahas AM, Coles GA. Dietary treatment of chronic renal failure: ten unanswered questions. Lancet 1986;i:597-600. 19 Klahr S. The modification of diet in renal disease study. N EnglJ Med 1989;320:864-6. 20 Clarkson EM, Curtis JR, Jewkes RJ, et al. Slow sodium: an oral slowly released sodium chloride preparation. BrMedj 1971 ;iii:604-7. 21 Giovannetti S. Dietary treatment of chronic renal failure: Why is it not used more frequently? Nephron 1985;4:1-12. 22 Giordano C. Protein restriction in chronic renal failure. Kidney Int 1982;22:401-8. 23 Maschio G, Oldrizzi L, Tessitore N, et al. Effects of dietary protein and phosphate restriction on the progression of early renal failure. Kidney Int 1982;22:371-6. 24 Mitch WE, Walser M, Steinman TI, Hill S, Zeger S, Tungsanga K. The effect of a keto acid-amino acid supplement to a restricted diet on the progression of chronic renal failure. N Engl Med
1984;311:623-9. 25 Mitch WE. The influence of the diet on the progression of renal insufficiency. Annu Rev Med
1984;35:249-64. 26 Bergstrom J, Alvestrand A, Bucht H, Gutierrez A. Progression of chronic renal failure in man is retarded with more frequent clinical follow ups and better blood pressure control. Clin Nephrol 1986;25: 1-6. 27 Rosman JB, Ter Wee PM, Meijer S, Piers-Becht TPM, Sluiter WJ, Donker JM. Prospective
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ment of diabetic nephropathy have been reviewed by Mogensen.i The three main lines include better metabolic control, effective antihypertensive treatment, and the use of moderately low protein diets. Patients with borderline hypertension- that is, a blood pressure of 140/90 mm Hg -should probably be treated with a lower target blood pressure of perhaps 135/85 mm Hg. Several accounts of the use of angiotensin converting enzyme inhibitors in diabetic nephropathy have reported improvement in microalbuminuria in incipient diabetic nephropathy and reduction in albuminuria in established diabetic nephropathy.4546 Microalbuminuria was also reduced in patients with incipient diabetic nephropathy, however, by conventional antihypertensive treatment.47 Some long term large scale double blind randomised trials of the inhibitors in patients with incipient diabetic nephropathy are in progress. Many questions regarding the progression of chronic renal failure remain unanswered. There are several other factors that may be important but require further research. These include the possible contributions of lead48; hyperuricaemia49; secondary oxalosis50; and atrial natriuretic peptide.5' J R CURTIS
Senior Lecturer in Medicine, Charing Cross Hospital, London W6 8RF
28 29 30 31 32
33 34 35 36 37 38 39 40 41 42
43 44 45 46 47
randomised trial of early dietary protein restriction in chronic renal failure. Lancet 1984;ii: 1291-6. Ihle BU, Becker GJ, Whitworth JA, Charlwood RA, Kincaid-Smith PS. The effect of protein restriction on the progression of renal insufficiency. N Englj Med 1989;321: 1773-7. El Nahas AM, Thomas AM, Brady SA, et al. Selective effect of low protein diets in chronic renal diseases. BrMedJ 1984;289:1337-41. Breckenridge A, Dollery CT, Parry EHO. Prognosis of treated hypertension: changes in life expectancy and causes of death between 1952 and 1967. QJ Med 1970;39:411-29. Woods JW, Blythe WB, Huffines WD. Management of malignant hypertension complicated by renal insufficiency. A follow up study. N Engl.jMed 1974;292:10-4. Cordingley FT, Jones NF, Wing AJ, Hilton PJ. Reversible renal failure in malignant hypertension. Clin Nephrol 1980;14:98-103. Klahr S. The kidney in hypertension-villain and victim. NEnglJMed 1989;320:731-3. Rostand SG, Brown G, Kirk KA, Rutsky EA, Dustan HP. Renal insufficiency in treated essential hypertension. N EnglJ7 Med 1989;320:684-8. Keane WF, Anderson S, Aurell M, de Zeeuw D, Narins RG, Povar G. Angiotensin converting enzyme inhibitors and progressive renal insufficiency. Ann Intern Med 1989;111:503-16. Feig PU, Rutan GH. Angiotensin converting enzyme inhibitors: the end of end stage renal disease? Ann Intern Med 1989;111:451-3. De Zeeuw D, Heeg JE, De Jong PE. Merits of ACE inhibitors in patients with renal insufficiency. In: Clement DL, ed. ACE inhibitors: past, present and beyond. London: Royal Society of Medicine, 1989:49-55. (Services International Congress and Symposium Series No 144.) Smith WGJ, Dharmasena AD, El Nahas AM, Thomas DM, Coles GA. Short term effect of captopril on renal haemodynamics in chronic renal failure. Nephrol Dial Transplant 1989;4: 696-700. Hricik DE, Browning PJ, Kopelman R, Goorno WE, Madias NE, Dzau VJ. Captopril induced functional renal insufficiency in patients with bilateral renal artery stenosis or renal artery stenosis in a solitary kidney. N EnglJ Med 1983;308:373-6. Jackson B, Matthews PG, McGrath BP, Johnson CI. Angiotensin converting enzyme inhibitors in renovascular hypertension: frequency of reversible renal failure. Lancet 1984;i:225-6. Maher ER, Othman S, Frankel AH, Sweny P, Moorhead JF, Hilson AJW. Captopril enhanced 99m Tc DTPA scintigraphy in the detection of renal artery stenosis. Nephrol Dial Transplant 1988;3:608-1 1. Harris DCH, Hammond WS, Burke TJ, Schrier RW. Verapamil protects against progression of experimental chronic renal failure. Kidney Int 1987;31:41-6. Hostetter TH, Troy JL, Brenner BM. Glomerular hemodynamics in experimental diabetes. Kidney Int 1981;19:410-5. Mogensen CE. Management of diabetic renal involvement and disease. Lancet 1988;i:867-70. Marre M, Leblanc H, Suarez L, Guyenne TT, Menard J, Passa P. Converting enzyme inhibitors and kidney function in normotensive diabetic patients with persistent microalbuminuria. BrMedJ7 1987;294:1448-52. Hommel E, Parving HH, Mathiesen E, Edsberg B, Damkiaer-Nielsen M, Giese J. Effect of captopril on kidney function in insulin dependent diabetic patients with nephropathy. Br MedJ 1986;293:467-70. Christensen CK, Mogensen CE. Antihypertensive treatment: long term reversal of progression of albuminuria in incipient diabetic nephropathy. A longitudinal study of renal function. Journal of
Diabetic Complications 1987;1:45-52. 48 Koster J, Erhardt A, Stoeppler M, Mohl C, Ritz E. Mobilizable lead in patients with chronic renal failure. EurJ Clin Invest 1989;19:228-33. 49 Scott JT. Asymptomatic hyperuricaemia. BrMedj 1987;294:987-8. 50 Thompson CS, Weinman EJ. The secondary oxalosis of renal failure. Seminars in Dialysis 1988;1:94-9. 51 Woolf AS. Atrial natriuretic peptide and renal disease. Nephrol Dial Transplant 1989;4: 1008-15.
BMJ VOLUME 301
29 SEPTEMBER 1990
