Nephrology Dialysis Transplantation

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1 Nephrol Dial Transplant (993) Original Article Nephrology Dialysis Transplantation Chronic renal failure in India M. K. Mani Renal Unit, Apollo Hospital, Madras, India Abstract. In a series of 2028 patients with chronic renal failure, the diseases leading to renal failure, the presence or absence of reversible factors and their nature, and the rate of decline of renal function of the most common conditions have been described and analysed. Seven diseases: chronic interstitial nephritis (27.85%), diabetic nephropathy (26.76%), chronic glomerulonephritis (8.20%), benign nephrosclerosis (0.06%), chronic pyelonephritis (7.29%), focal glomerulosclerosis (3.20%), and autosomal dominant polycystic disease of the kidneys (2.07%), accounted for 95.43% of all the patients. These diseases were studied in greater detail and the results are presented here. It was found that there was a great variation in the rate of decline of renal function in the different groups, with chronic glomerulonephritis and focal glomerular sclerosis progressing most rapidly, diabetic nephropathy slightly slower, and the others at a less alarming pace. However, once serum creatinine had reached 77 umol/ there was an inexorable decline in renal function and the end stage was reached in almost all patients. Key words: chronic renal failure; causes; rate of decline in renal function; reversible deterioration of renal function Introduction Chronic renal failure causes significant morbidity and mortality in India. Treatment by dialysis and transplantation remains out of reach for the vast majority of Indian patients because of the high cost of renal replacement therapy. It is therefore well worthwhile to look at every possible means of preventing progression to the end stage. No large studies have been done of the causes and manifestations of chronic renal failure in this country. The renal unit of this hospital sees a large number of patients with chronic renal failure. This data forms the subject of this report. Correspondence and offprint requests to: M. K Maiu, Chief Nephrologist, Apollo Hospital, 2, Greams Lane, Madras , India Subjects and methods From January 984 to March 99, 2028 patients with chronic renal failure were seen in this unit. A tentative diagnosis was made in each patient, though it could not always be established firmly Chronic interstitial nephritis was diagnosed in patients who had an insidious onset of renal failure. Oedema occurred in these patients only at a late stage of renal failure, when they were on the verge of needing dialysis. The kidneys were usually contracted, but were of normal size in some, and in these patients renal biopsy was done and the diagnosis was established. Focal glomerular sclerosis was found in some, but these were labelled 'chronic interstitial nephritis' if the interstitial changes predominated Diabetic nephropathy was diagnosed when a long history of diabetes melhtus was obtained, and the patient had diabetic retinopathy and a classical history of slow progression with hypertension, albuminuna, and oedema preceding the onset of renal failure When diabetes melhtus had been present for less than 5 years, retinopathy was absent, or the presentation was not typical, renal biopsy was done. Chronic glomerulonephntis was diagnosed when there was a history of oedema in the distant past, with proteinuna many years before the development of renal failure. In many patients the diagnosis had been established by renal biopsy in the past. It is admitted that where biopsy was not available some patients with focal and segmental glomerular sclerosis would have been included in this category, and some patients with glomerulonephntis may have been wrongly classified as interstitial nephritis because they did not offer a history of oedema or proteinuna. A few patients labelled as chronic interstitial nephntis on clinical grounds have been found on biopsy to have predominant changes of glomerulonephritis. Chronic pyelonephritis was diagnosed when there was a clear history of episodes of acute pyelonephritis, or when vesicouretenc reflux or chronic unnary tract obstruction were present was diagnosed when there was a long-standing history of hypertension, and the fundus showed changes of hypertensive retinopathy. There should have been no evidence to support a positive diagnosis of one of the other renal diseases like glomerulonephntis. Renal biopsy was done whenever the renal size and cortical width permitted Hyaline deposits in the media and intima of artenoles and small artenes, reduplication of the elastica, and intimal thickening were the charactenstic vascular changes Glomeruli showed shrinkage of the tuft, going on to ischaemic obsolescence. Similar histological features were sometimes found in patients who had never been hypertensive, and they were included in this category Focal glomerulo- 993 European Dialysis and Transplant Association-European Renal Association

2 CRF in India 685 sclerosis was diagnosed in patients who had changes of focal glomerular sclerosis and hyahnosis on biopsy, with no evidence of a primary disease that could have caused hyperfiltration and secondary glomerulosclerosis. Some patients with this condition could have been missed because their kidneys were shrunken and biopsy could not be done, and it is likely that they were diagnosed as having chronic glomerulonephntis. The diagnosis of autosomal dominant polycystic disease was easily made on ultrasound examination. Obstructive nephropathy was diagnosed when long-standing, neglected obstruction was found. All these patients would have had chronic pyelonephritis too, but were classified under the head of obstruction only Hereditary nephropathy required a characteristic family history with classical clinical presentation. Histological studies with electron-microscopy were done in a few Systemic lupus erythematosus was diagnosed by the demonstration of antibodies to double-stranded native DNA at some time during the course of the illness Arterial obstruction was demonstrated in every case by artenography Amyloidosis was diagnosed by light-microscopy of the renal biopsy, and by the presence of birefringence on viewing Congo red stained slides under polarized light. Microscopic polyarteritis was diagnosed by the presence of ANCA, along with a suggestive histological and clinical picture Henoch-Schonlein purpura has a classical clinical history. One of the patients had a renal biopsy. The patient with primary hyperoxaluna had a classical family history and renal histology. Cortical necrosis, light-chain nephropathy, Wegener's granulomatosis, and haemolytic uraemic syndrome were all diagnosed on renal biopsy, and also had a typical clinical presentation Reversible factors were looked for in each case A detailed analysis was done of the seven more common conditions, chronic interstitial nephritis, diabetic nephropathy, chronic glomerulonephntis, benign nephrosclerosis, chronic pyelonephntis, focal and segmental glomerulosclerosis, and autosomal dominant polycystic disease, which constituted 95 43% of all the cases. The rate of decline in renal function was analysed. All the patients underwent biochemical examination of the Table I. Causes of renal failure Chronic interstitial Diabetic nephropathy Chronic glomerulonephntis Chronic pyelonephntis Focal sclerosis Polycystic kidneys Obstructive nephropathy Hereditary nephropathy Systemic lupus erythematosus Artenal obstruction Renal amyloid Microscopic polyartentis Henoch-Schonlein purpura Primary hyperoxaluna Cortical necrosis Light-chain nephropathy Haemolytic uraemic Wegener's granulomatosis Percent of total Percent male blood on first presentation, and at intervals thereafter. It was possible to follow 27 patients who presented with a serum creatinine between 2 and 5 mg/dl (77 and 442 umol/) until serum creatinine increased greater than 5 mg/dl (442 umol/), or for a period of at least 5 years with senal followup at least once a year. The reciprocal of the serum creatinine (in mg/dl) was calculated for all readings on all these patients, and the regression coefficient was calculated for each one. The mean and the standard deviations of all regression coeffiaents for each of the seven more common diseases (262 patients) were calculated. The coefficient of determination for each of these regressions was also calculated, and the mean was determined for each disease The statistical analyses on these figures were done on a microcomputer using Minitab statistical software, release 7. Results The causes of chronic renal failure are detailed in Table. With the exception of systemic lupus erythematosus, there was a marked male preponderance of 75.54%, but this did not differ significantly from the overall hospital attendance, which is around 70% male. (There were no males with Henoch-Schonlein purpura or Wegener's granulomatosis, but the numbers of patients with these two conditions were too small for the sex distribution to be of significance.) Among the common conditions, the age distribution of patients with diabetic nephropathy and benign nephrosclerosis was understandably significantly higher than that of other diseases. The diagnosis of chronic glomerulonephntis and benign nephrosclerosis was histologically established in almost half the patients (Table ). The histological variety of glomerulonephntis as made out by biopsy in this unit or elsewhere is listed in Table 2. Immunofluorescence was available only on the biopsies Mean age (SD) 40(4) 53(09) 35(3) 48(4) 39(8) 33 (5) 48 (0) 50(22) 20 (0) 32 (2) 6 (07) 49 (0) 46() 9(2) Proved by biopsy

3 686 Table 2. Histological types of glomerulonephntis 55 patients M K Mam Table 5. Prevalence of disease in upper and lower economic groups Membranoprohferative Extracapillary proliferative Mesangial proliferative Chronic prohferative Focal proliferative Membranous nephropathy IgA nephropathy Dense deposit disease Anti-GBM glomerulonephntis Number Percentage of chronic GN done in this hospital, so the prevalence of IgA nephropathy could well be an underestimate. The duration of known disease before the onset of renal failure is shown in Table 3. This was greatest in diabetic nephropathy and least in chronic interstitial nephritis. Analysis of variance yielded an F ratio of (/>< ). The proportion of patients who presented early (before the onset of renal failure), in moderate renal failure (serum creatinine between 33 and 442 umol/), and near the end stage (serum creatinine greater than 442 umol/) in the common diseases is shown in Table 4. This hospital is not a charitable institution, and 90% of the patients who attend have to pay for the cost of their treatment. The majority of the patients belong to Table 3. Known duration of disease before onset of renal failure Duration (years) SD Chronic interstitial nephritis 4 09 Focal glomerulosclerosis 5 8 Chronic glomerulonephntis Polycystic renal disease 7 46 Chronic pyelonephntis 7 82 Diabetic nephropathy 2 94 Analysis of variance F ratio 83 32, />< Table 4. Seventy of illness when renal involvement was discovered Chronic interstitial Focal glomerulosclerosis Chronic glomerulonephntis Polycystic renal disease Chronic pyelonephntis Diabetic nephropathy Percentages No renal failure Moderate No renal failure = serum creatinine < 33 umol/. Moderate renal failure = serum creatinine umol/. Near end-stage = serum creatinine >442 umol/. Endstage Diabetic ncphropathy Chronic interstitial nephntis Chronic glomerulonephntis Chrome pyelonephritis Focal glomerulosclerosis Polycystic disease Total Percentage prevalence in Upper income Economic data not available for 278 patients Chi-square test figure , P< Lower income the middle or upper economic class. However, 0% of patients are treated free of charge, and some of the lower income groups have their medical expenses met by their employers, and therefore 70.72% of the patients in this study were of upper economic status (e.g. landowners, businessmen, executives, doctors, and engineers) and 29.28% were of lower income (e.g. clerks, labourers, soldiers, and schoolteachers). The percentage prevalence of the different diseases in the upper and lower income groups is indicated in Table 5. The distribution of these diseases was compared by the chi-square test, and yielded a test figure of (P< ) This suggests that chronic interstitial nephritis and chronic glomerulonephntis are more common among lower income groups and diabetic nephropathy among the upper income groups. It was possible to achieve significant improvement in renal function in.9% of the patients. The causes of this reversible deterioration are listed in Table 6. The drugs which led to reversible deterioration in these cases are listed in Table 7. If the indication for the use Table 6. Causes of reversible detenoration in renal function (227 patients =.9% of total) Reversible factor Number Percentage of the 227 patients Dehydration Hypertension Cardiac failure Obstruction 25.0 Drugs Septicaemia Acute pyelonephntis Active glomerulonephntis 4.85 Postoperative Hypoalbuminaemia Unknown Active systemic lupus Uncontrolled diabetes mellitus Myocardial infarction 4 76 Vascuhtis 4 76 Ventncular tachycardia 3 32 Cerebrovascular accident 3 32 Pregnancy 0 44

4 CRFin India TaWe 7. Drugs causing reversible deterioration 22 patients Drug ACE inhibitors Diuretics Aminoglycosides NSAIDs Co-tnmoxazole Ampicillin Rifampicin Ayurvedic medicine Number affected Percentage of the 22 patients The period of follow-up varied from 0.28 to 7.20 years, with the mean period being 2.72 years. (95% confidence interval 2.52 to 2.9 years.) The mean of the coefficient of determination (R 2 ) of all these patients is also represented in this table. It can be seen that the coefficient was reasonably high, more than 60%, in all the diseases except chronic pyelonephritis and benign nephrosclerosis. Progression was fastest in the diseases affecting the glomerulus most: glomerulonephritis, primary focal glomerulosclerosis and, a little less rapid, in diabetic nephropathy. 687 of the drug could itself have led to deterioration in renal function, like septicaemia or acute pyelonephritis, the deterioration has been attributed to the disease and not to the drug, though this may be fallacious. Where the indication for which the drug was used could not itself have led to worsening renal function, the drug has been blamed. The rate of decline in renal function, based on the reciprocal of the serum creatinine, is depicted in Figure, and detailed in Table 8, for the 262 sufferers from these diseases who were available for follow-up. /creatlnln* Fig.. Decline in the reciprocal (/cr) of the serum creatinine (expressed in mg/dl) in different diseases CGN, chronic glomerulonephntis, CIN, chronic interstitial nephritis, CPN, chronic pyelonephritis; DN, diabetic nephropathy, FSGS, focal and segmental glomerulosclerosis, NEPHROSCL, benign nephrosclerosis, PCK, autosomal dominant polycystic disease of the kidneys Table 8. Progression of renal failure Chronic interstitial Diabetic nephropathy Chronic glomerulonephritis Chronic pyelonephritis Focal glomerulosclerosis Polycystic kidneys Number of patients Fall of /cr/yr 0 04(0.43) 0 6(0.35) 0.28(0 40) 0 06(0 8) 0 07(0 0) 0.24(0 2) 0 09(0 06) R mean(sd) 60 5(32.8) 64.34(35.06) 73.26(29 8) 53 80(34 87) 53 49(347) 63 47(29.48) 64 07(39.98) Discussion The causes of renal failure Should one assume a diagnosis when one cannot be sure of it? It has been customary to label patients as suffenng from end-stage renal disease whenever it was not possible to establish the diagnosis beyond reasonable doubt. I differ from this approach, and have made the most likely diagnosis in every patient. One must know the probable causes of renal failure in any community to have any prospect of preventing it. The clinical behaviour of patients differs to some extent according to the disease causing renal failure, and the findings in those in whom a presumptive diagnosis was made tally well with those in whom the disease was diagnosed on biopsy. The role of benign arteriolar nephrosclerosis in the causation of chronic renal failure is controversial. I quote from two authoritative text books of nephrology. 'In benign essential hypertension, (i.e. hypertension without a malignant phase or underlying primary renal disease) only rarely does death occur from renal failure. In contrast, malignant hypertension, if untreated, uniformly progresses to end-stage renal disease (ESRD).' [] 'Slowly progressive benign arteriolar nephrosclerosis is responsible for a far greater proportion of end-stage disease than is malignant arteriolar nephrosclerosis.' [2] It is well recognized that nephrosclerosis is a condition that may develop with advancing years, and is not necessarily associated with hypertension. Heptinstall says the change in the arterioles 'often referred to as arteriolosclerosis may occur in patients with normal blood pressure as well as in those with hypertension. It must be considered an aging process, but one that may be accentuated by hypertension or exaggerated by metabolic disorders such as diabetes.' [3] I accept this diagnosis as a cause of renal failure because of the number of patients in whom renal biopsy showed no other reason for renal failure, and in whom there was no history of hypertension, except isolated systolic hypertension. Heptinstall goes on to say '...the kidney of benign nephrosclerosis may become much reduced in size... Indeed, the reduction may be so great as to cause chronic renal failure.' [4] The arteriolar lesions may be the cause of hypertension and not just the effect, and some of these patients developed mild diastolic hypertension in addition to

5 688 the very high systolic pressures in the course of the disease. The US Renal Data System [5] accepts hypertension as the cause of 27.9% of end-stage renal disease. Chronic interstitial nephritis was the most common condition. Histological confirmation could only sometimes be obtained as the kidneys were often contracted. The onset was always insidious, and the absence of oedema till the late stages of the disease was characteristic. Significant proteinuna was hardly ever found. This condition is not usually diagnosed in the absence of a clear history of a drug responsible, like an analgesic; but analgesic abuse is not common in India, and no definite causative drug was identified in the majority of our patients, despite diligent efforts. Food additives are not effectively regulated in this country, and there is no control on the use of pesticides or the presence of pesticide residues on foodstuffs. I believe, admittedly without proof, that the culprit will be found among these. Meanwhile, it is important to be aware of the presence of a large number of patients who reach the end stage with no clear history of glomerular pathology, and whose clinical behaviour suggests interstitial disease. The clinical picture of the histologically proved cases and the clinically diagnosed ones is very similar, and warrants their being labelled together. It has been suggested that tuberculosis may be a cause of chronic interstitial nephritis. This possibility has not been directly addressed in this study, but it does not seem to be likely because tuberculosis is widely prevalent in the country, with an estimated 2497 patients per of the population [6]. Further, no less than 80% of males aged 25 and over, and 70% of females of 35 or more, react to tuberculin. An overwhelming majority of us have suffered from primary tuberculosis, and chronic interstitial nephritis is seen neither in the general population nor even among tuberculous patients to any significant extent. Further, we do not find a higher incidence of active tuberculosis among our patients with chronic interstitial disease than in the rest of the patients with chronic renal failure. However, this question deserves closer study. The prevalence of diabetic nephropathy is greater among the more affluent of our patients (Table 5). Perhaps the poor are more likely to succumb to other complications of the disease and do not survive until their kidneys are terminally affected. This has not, to my knowledge, been studied, and remains in the realm of conjecture. The age of the patients with diabetic nephropathy is lower than that at which Western patients usually present. This is only to be expected as NIDDM occurs at a younger age in India. 4.8% of NIDDM in Madras is found below the age of 25 (against 0.5% in London), 8.5% under 35, and 50% under the age of 45, whereas in Europe NIDDM is rarely diagnosed before the age of 40 [7]. The histological type of glomerulonephritis was available in about half the patients with chronic glomerulonephritis. This was based on reports of biopsies done in other institutions in many cases, and since immunofluorescence is available in only some centres M K Mani in the country, the diagnosis of IgA nephropathy may have been underestimated. All the patients of IgA nephropathy listed had their biopsies done in this hospital. As my impression is that most mesangial proliferative glomerulonephritis has a benign course, it is possible that some or all of the patients so listed had IgA disease. Focal glomerulosclerosis has been listed independently, and not under glomerulonephritis, because the aetiology is unknown, whereas that of the glomerulonephritides is clearly immunological. Tables 3 and 4 demonstrate that the onset of chronic interstitial nephritis is often insidious. The known duration of symptoms in this disease is less than with the others, and more patients presented in end-stage renal disease, which they had reached without being aware of the fact that they were ill. In contrast, patients with diabetes mellitus were often under medical supervision for years before the onset of renal failure. Urinary problems made the sufferer from chronic pyelonephritis aware of his illness early, and the size of the polycystic kidney drew attention to its presence before the patient had gone into renal failure. The use of the reciprocal of the serum creatinine to document the decline in renal function had its vogue, but has now been discredited. As this is a retrospective survey, we do not have radionuclide clearance studies, and have no choice but to use the serum creatinine levels. From the point of view of a clinician, serum creatinine is a good enough marker of renal function. The decline of the reciprocal of the serum creatinine was not always linear, but there was a high value of the coefficient of determination (R 2 ), making this a reliable index of the progression of these patients. The two diseases in which R 2 was lower than the others, chronic pyelonephritis and benign nephrosclerosis, are well known to show fluctuation in the course of the illness, related to active infection in pyelonephritis, and the blood pressure in nephrosclerosis. Even in these, R 2 was greater than 50%. It has not yet been established that vegetable protein has the same effects on glomerular hyperfiltration as meat protein, and perhaps it will not be necessary for us to restrict the intake of pulses and other nighprotein vegetable sources. This aspect has not been adequately studied as yet. Our patients were all prescribed restricted protein diets, even if they were vegetarian. Despite this, renal function declined inexorably in most of the patients once it had crossed a serum creatinine level of 77 umol/ (2 mg/dl), suggesting that there are limits to what can be achieved by diet. In summary, this study paints a rather gloomy picture of the prospects of a patient with chronic renal failure who has reached a serum creatinine level of 2 mg/dl (77 umol/), and stresses the importance of preventing patients from reaching this stage. The large number of patients with chronic interstitial nephritis calls for studies into the causes of this condition, which should be preventable by avoidance of exposure to the chemicals responsible.

6 CRF in India References. Nolan CR, Linas SL Accelerated and malignant hypertension In Schner RW, Gottschalk CW, ed. s of the Kidney, 4th edn. Vol II Little, Brown, Boston, Ives HE, Daniel TO. Vascular diseases of the kidney. In: Brenner BM, Rector FC, ed The Kidney, 4th edn Vol II WB Saunders, Philadelphia, Heptinstall RH. Pathology of the Kidney 3rd edn Vol. Little Brown, Boston, Heptinstall RH Pathology of the Kidney. 3rd edn Vol. 2. Little Brown, Boston, US Renal Data System, USRDS 990 Annual Data Report Causes of ESRD Am J Kidney Dis 990, [Suppl 2] Tuberculosis prevention trial, Madras. Trial of BCG vaccines in South India for tuberculosis prevention Indian J Med Res 980, [Suppl] Mohan V, Ramachandran A, Viswanathan M. Tropical diabetes, In Alberti K.GMM, Krall LP, ed. The Diabetes Annual 2. Elsevier Science Publishers, Amsterdam, Received for publication Accepted in revised form