Q J Med 2001; 94: 187-193
© 2001 Association of Physicians
Why is there so much end-stage renal failure of undetermined cause in UK Indo-Asians?
From the Renal Unit and 1 Department of Histopathology, St Mary's Hospital, London, UK
Received 6 November 2000 and in revised form 20 February 2001
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Summary |
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There is a high incidence of end-stage renal failure (ESRF) of undetermined cause in the Indo-Asian population of the UK. We studied patients presenting from the district of Brent and Harrow, which has a large Indo-Asian community, and whose renal services are largely provided by our centre. The diagnosis and ethnicity of patients starting renal replacement therapy and/or undergoing renal biopsy were collated. The incidences of ESRF, rates of renal biopsy and underlying diagnoses were calculated for Indo-Asians and Caucasians. Requirement for renal replacement therapy in Indo-Asians presenting to our centre from Brent and Harrow was 221/106/year; no underlying diagnosis was identified in 77/106/year. Renal biopsy rate in these patients was 456/106/year, and the diagnostic categories significantly over-represented compared to Caucasians were: hypertension and ischaemia, focal segmental glomerulosclerosis (FSGS), idiopathic interstitial nephritis (IIN), diabetic nephropathy, minor glomerular abnormality, lupus nephritis and non-specific advanced chronic renal disease (p<0.001). The first three of these had a combined incidence of 135/106/year in Indo-Asians and 31/106/year in Caucasians. ESRF of undetermined cause is common in UK Indo-Asians, as is requirement for renal biopsy. Hypertension with ischaemia, FSGS and IIN are over-represented in the Indo-Asian population, and should be targeted for early diagnosis and treatment in this group.
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Introduction |
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There is a high incidence of ESRF in the Indo-Asian population resident in the UK.1 This is projected to increase in parallel with the ageing of a presently young population.2 The high incidence of ESRF is in part due to the prevalence of diabetes mellitus in Indo-Asians.3–6 Additionally, patients who present with ESRF, small kidneys, an unremarkable urinary sediment and no identifiable aetiology, are markedly over-represented in this population.6–8 These patients arguably constitute a significant opportunity for therapeutic intervention, since many are likely to benefit from established forms of treatment. This is exemplified by idiopathic interstitial nephritis (IIN), which is over-represented among Indo-Asians undergoing renal biopsy and is amenable to treatment if diagnosed promptly.9 IIN is characterized by presentation with chronic renal failure, small kidneys and an unremarkable urinary sediment. It may progress to ESRF, and patients with undiagnosed IIN are likely to contribute to the aforementioned cohort with ESRF of undetermined cause.9
There is relatively little information on the incidence of disease processes that might contribute to late-presenting ESRF in the Indo-Asian population. This study examines Brent and Harrow, a district with a sizeable Indo-Asian population, whose adult renal services are largely provided by one centre: St Mary's Hospital. We studied patients attending our centre, aged >18 years, in whom renal replacement therapy was instigated or renal biopsy undertaken. The requirement for ESRF therapy in Caucasians and Indo-Asians presenting to our centre from Brent and Harrow was determined, and the underlying diagnoses assessed. The rate of investigation by renal biopsy and the resulting diagnoses were similarly assessed. Diagnoses over-represented in Indo-Asians undergoing renal biopsy were identified, including putative contributors to ESRF of undetermined cause.
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Methods |
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Identification of cases
Patients requiring the initiation of renal replacement therapy for ESRF between 1 January 1994 and 31 December 1997 were identified at our centre. The Purchasing Authority and postal address were used to define those resident in Brent and Harrow. A similar process was applied to patients undergoing renal biopsy at our centre between 1 April 1993 and 31 March 1997. (These cohorts are offset by 9months due to peculiarities of the respective datasets interrogated to identify cases.)
Ethnicity was determined from the case-notes and computerized patient administration systems. Patients were categorized as Caucasian, Indo-Asian, African-Caribbean, or Other. The census categories Indian, Pakistani, and Bangladeshi were aggregated to form the Indo-Asian group, and Black Caribbeans, Black Africans, and Black Others were aggregated to form the African-Caribbean group. The denominators populations were derived from the 1991 census, made available by the Department of Health.
Analysis of ESRF
The causes of ESRF were determined from contemporary review of individual case notes. Incidences of the various aetiologies were calculated using cases presenting to St Mary's Hospital as the numerator and the relevant populations in Brent and Harrow as the denominator. This defines a lower limit for incidence, since approximately 1 in 3 cases of ESRF in Brent and Harrow are cared for elsewhere (v.i.). The relative risks of specific diagnoses in non-Caucasians were calculated using Caucasian as the index population. Uniform inter-centre ethnic distribution was assumed for this calculation. The 95% CIs for these relative risks are shown in parentheses in the text.10
Analysis of renal biopsy
The indications for renal biopsy were haematuria, proteinuria >0.5 g/day or undiagnosed renal impairment. All biopsies were examined in multiple sections at four levels and stained with haematoxylin and eosin, periodic acid Schiff, elastic van Gieson, Congo Red and Methyl Violet. Immunoperoxidase staining was performed on paraffin-embedded, formalin-fixed material, using an indirect immunoperoxidase technique and primary transmission. Antibodies to IgA, IgG, IgM, C1q, C3 and C4 were supplied by Dako. Transmission electron microscopy was performed routinely on gluteraldehyde fixed, resin embedded tissue, post-fixed in osmium tetroxide, and stained with uranyl acetate. Renal biopsy diagnoses were classified according to a modified WHO classification.11,12 If multiple pathologies were present on biopsy, the diagnosis most likely to have been the principle cause of renal impairment was used for this analysis.
The significance of the difference between ethnic groups in the frequency of each diagnosis, was assessed by the Mantel-Haenszel 
2 test. This calculation used the ethnic populations in Brent and Harrow as the relevant ‘totals’. In cases significantly over-represented, this was of a degree unlikely to have arisen as a consequence of the analysis of multiple categories, (p<0.001). The incidences of specific biopsy diagnoses were calculated for the different racial groups and the relative risks in non-Caucasians calculated as for ESRF. The 95%CIs for relative risks are shown in parentheses in the text and tables.10 Brent and Harrow purchasing authority provided data on the inter-centre distribution of prevalent ESRF.
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Results |
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The population of Brent and Harrow
The district of Brent and Harrow is located in London, UK. The population at the 1991 census was 443 214, with the following ethnic distribution: Caucasian 281 789 (63.6%), Indo-Asian 84 915 (19.2%), African-Caribbean 47 620 (10.7%), and Others 28 890 (6.5%). The census also showed the Indo-Asian population to be significantly younger than the Caucasian: 28.8% of Indo-Asians were aged >40 years compared to 48.0% of Caucasians.
The majority of adults from Brent and Harrow with renal disease are cared for by St Mary's Hospital, but a proportion attend other centres for reasons of geography and history. The incidence of ESRF and frequency of renal biopsy in the district were unavailable, but the centre-specific prevalence of renal replacement therapy for residents was known: 64.8% of adults are cared for by St Mary's Hospital, 16.0% at the Hammersmith Hospital, 8.5% at the Royal Free Hospital and 7.2% at UCL Hospitals. This distribution is likely to be similar to that for incident cases. The incidences given below are solely for presentation to St Mary's Hospital from Brent and Harrow.
End-stage renal failure in Brent and Harrow
During the 4-year period between 1/1/94 and 31/12/97, 181 individuals from Brent and Harrow began renal replacement therapy at our centre. The incidence of ESRF presenting to our centre from Brent and Harrow was therefore 102/106/year. The ethnic distribution of these cases is summarized in Table 1
. The unadjusted relative risk of ESRF in Indo-Asians was 3.8 (2.7–5.3) and the age-adjusted relative risk of ESRF was 6.6 (4.5–9.7).
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The causes of ESRF in the Indo-Asian and Caucasian populations are shown in Table 2
. There was a high incidence of ESRF secondary to diabetes mellitus in the Indo-Asian group: 82.4/106/year, giving an unadjusted relative risk of 6.2 (3.3–11.6). The incidence of ESRF of undetermined cause was similar: 76.6/106/year, giving an unadjusted relative risk of 7.8 (3.9–15.9). These findings accord with reports from across the UK.6–8 The group of patients with no underlying diagnosis included five in whom a renal biopsy showed only non-specific tubulointerstitial atrophy and fibrosis, but further investigation was considered inappropriate in the remaining 22, who presented with advanced renal impairment and small kidneys.
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Renal biopsy diagnosis
In the 4 years between 1/4/93 and 31/3/97, 405 individuals from Brent and Harrow underwent renal biopsy at our centre, giving an incidence of renal disease requiring investigation by biopsy of 228/106/year. The ethnic distribution is summarized in Table 3. The unadjusted relative risk of selection for renal biopsy in Indo-Asians was 3.2 (2.6–4.0) and the age-adjusted risk was 4.4 (3.4–5.5).
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Table 4
shows the distribution of specific diagnoses determined from renal biopsy in the Caucasian and Indo-Asian ethnic groups. The diagnoses are ordered according to the incidence calculated for the Indo-Asian group. There was a statistically significant over-representation of hypertension and ischaemia, diabetic nephropathy, focal segmental glomerulosclerosis, IIN, minor glomerular abnormality, SLE, and non-specific advanced chronic renal disease.
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In African-Caribbeans, small numbers limited the value of analysing separate diagnostic categories. Nevertheless the incidence s of focal segmental glomerulosclerosis (52.5/106/year), and of membranous nephropathy (32.5/106/year) were striking.
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Discussion |
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The predisposition of Indo-Asians to ESRF is well recognized,1,6 as is the importance of diabetes mellitus as a causal factor.3–6 The high level of ESRF of undetermined cause is similarly acknowledged to be a particular feature of this population,6–8 but there is little evidence pertaining to likely underlying causes. Restricted access to health services may be a contributing factor, but we hypothesize that late presentation is a consequence of the pattern of renal disease to which the Indo-Asian population is pre-disposed. In the absence of significant multi-system involvement, haematuria or proteinuria, late presentation is likely on clinical grounds alone. This featureless presentation is common in a native Indian population13 as well as the immigrant Indian population in the UK.8 It is typical of IIN, which was over-represented amongst Indo-Asians undergoing renal biopsy in a previous series from our centre.9 This report did not define the population from which the cases arose, precluding an estimation of the incidence of IIN and thereby assessment of its potential importance in relation to the occurrence of ESRF. Furthermore, this former study only had the power to detect diagnoses whose expression were disproportionate to any overall change in the frequency of renal biopsy in the Indo-Asian population. The current study calculates incidences of specific diagnoses made in patients at our centre in the Indo-Asian and Caucasian populations. The relative risks of specific renal biopsy diagnoses were calculated in Indo-Asians, indicating a trend toward over-representation in all but one category. In Indo-Asians the six most common diagnostic categories were significantly over-represented relative to Caucasians (p<0.001).
The diagnostic relationship between renal biopsy and ESRF is complex; many patients with diabetic nephropathy, for example, are never biopsied, nor many of those who develop ESRF. Nevertheless hypertension-ischaemia and IIN are evidently major contributors to renal pathology in the Indo-Asian population. Their clinical features are such that they may present or be referred late, both can cause ESRF, and both can benefit from treatment if diagnosed promptly.9,14 These are good candidates to account for ESRF of undetermined cause and early treatment may abrogate their progression.
Focal segmental glomerulosclerosis was also common in the Indo-Asian ethnic group, and although generally associated with proteinuria, this was frequently not nephrotic. Although this diagnostic category excluded cases in which there was evidence for a proliferative glomerulosnephritis or immune complex deposition, it did not discriminate on the basis of severity of proteinuria, and was consequently heterogeneous. In none was an underlying aetiology evident; there were no cases of vesico-ureteric reflux and in those in whom there was clinical suspicion, renovascular disease was excluded by conventional or magnetic resonance angiography. This included four Indo-Asians and three Caucasians. There were no cases of focal segmental glomerulosclerosis secondary to HIV, but two cases of an associated interstitial nephritis and one of proliferative glomerulonephritis. These are entered under the classification ‘Other’. Patients in whom focal segmental glomerulosclerosis is identified on renal biopsy without being nephrotic, may then contribute significantly to ESRF in Indo-Asians, and this could include those presenting late with no diagnosis.
The importance of minor glomerular abnormalities to eventual ESRF is uncertain. There were only three Indo-Asians with minimal change nephropathy, and three Caucasians. In children, this is reportedly more common in Indo-Asians than in Caucasians.15 The natural history of the other cases of minor glomerular abnormality is unknown, but given its frequency in the Indo-Asian population, in which there is an abundance of ESRF, this finding should not be dismissed.
In accordance with previous reports, SLE was significantly more common in Indo-Asians.16 It is however unlikely to be a significant cause of ESRF of undetermined cause, since multi-system involvement will favour early presentation.
The over-representation of non-specific advanced chronic renal disease in Indo-Asians was expected. The frequent presentation of patients from this ethnic group with advanced chronic renal failure and small kidneys often causes difficulty in obtaining an adequate biopsy, and if this is successful, the appearances may only reveal non-specific tubular atrophy and interstitial fibrosis.
The increased risk of secondary interstitial nephritis in Indo-Asians did not reach statistical significance, but this heterogeneous group does require comment. An unexpectedly large number of Caucasians had lithium nephrotoxicity (6/9 compared to 1/7 Indo-Asians), while 4/7 Indo-Asians had sarcoidosis compared to 1/9 Caucasians.
A proportion of patients from Brent and Harrow attended other centres. The frequencies of different pathologies reported in this paper are therefore underestimates of true incidence. This does not detract from the high incidence of ESRF and of renal biopsy in the Indo-Asian population of Brent and Harrow evident in the data from our centre alone. Furthermore, if the inter-centre distribution of incident renal biopsy is similar to that of prevalent ESRF, in the extreme scenario that all Indo-Asians from the district attend St Mary's whilst other ethnic groups are distributed evenly between centres, over-representation of the aforementioned diagnostic categories remain significant, except for hypertension-ischaemia (p=0.08). This situation is in any case unlikely, particularly given data from the Hammersmith Hospital, where 31% of incident ESRF occurred in Indo-Asians.8
Other factors potentially confounding the analysis include a heightened awareness of the importance of renal disease in Indo-Asians following the influential paper of Roderick and colleagues.1 This could have provoked a coincident rise in referrals during the study period, but analysis of data from the 2 years preceding the study indicates no such change.9 Interpretation of the current data must also be cautioned by their retrospective acquisition. It is not possible to discount selection bias arising from an awareness of the frequent presentation of Indo-Asians with renal failure, small kidneys and an unremarkable urinary sediment. This could have lowered the threshold for biopsy in such patients, causing an over-representation of diagnoses that give this clinical picture. The degree of inter-ethnic variation observed is though, unlikely to have arisen solely as a consequence of such a bias.
These data indicate a current requirement for renal biopsy in the Indo-Asian population of approximately 1/2000 per year. This demand for renal biopsy, although considerable, is proportionate to the risk of ESRF in this ethnic group. In this Indo-Asian population, other than diabetic nephropathy, the three most common biopsy diagnoses were hypertension-ischaemia, IIN and focal segmental glomerulosclerosis. Their combined incidence at our centre of 135/106/year suggests that undetected cases could account for a significant part of the 77/106/year who present with ESRF of undetermined cause. This compares with the Caucasian population, in whom the combined incidence is 31/106/year and in whom undiagnosed ESRF occurs in 10/106/year.
As yet obscure pathologies may account for some instances of ESRF of undetermined cause, and plausible aetiologies not encompassed within a study of renal biopsy findings include renovascular disease and chronic pyelonephritis. Nevertheless, it is likely that many such cases do arise from the above diagnostic groups. The aforementioned three pathologies could be targeted for early detection and treatment in the Indo-Asian population, and hopefully such a strategy would offer an opportunity to retard the ‘epidemic’ of renal disease in this community and facilitate detailed investigation of its pathogenesis. This may require the development of new means of screening for renal diseases common in this ethnic group, for example the use of retinol-binding proteinuria in addition to albuminuria as a means of enhancing the detection of idiopathic interstitial nephritis.17 There is considerable evidence that early initiation of disease -pecific therapies and intensive control of hypertension can attenuate progressive renal impairment, while in those patients in whom ESRF does ensue, early preparation for renal replacement therapy and modification of cardiovascular risk factors is likely to improve long-term prognosis.
The age structure of the Indo-Asian population in the UK indicates that implementation of such strategies is likely to be particularly beneficial.2 Early diagnosis and intensive treatment in this predominantly young population has the potential to significantly blunt the anticipated rise in ESRF over coming decades.6
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Acknowledgments |
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We thank Brent and Harrow Health Authority for their co-operation, and acknowledge the advice of the Imperial College statistical service.
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Notes |
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Address correspondence to Dr S. Ball, Renal Unit, Mint Wing, St Mary's Hospital, Praed Street, London W2 1NY.
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References |
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1. Roderick PJ, Jones I, Raleigh VS, McGeown M, Mallick N. Population need for renal replacement therapy in Thames regions: ethnic dimension. Br Med J1994; 309:1111–14.
2. Roderick P, Clements S, Diamond I, Storkey M, Raleigh VS. Estimating the demand for renal replacement therapy in Greater London: the impact of demographc trends in ethnic minority populations. Health Trends1998; 30:46–50.
3. Mather HM, Keen H. The Southall Diabetes Survey: prevalence of known diabetes in Asians and Europeans. Br Med J (Clin Res Ed)1985; 291:1081–4.
4. Burden AC, McNally P, Feehally J, Walls J. Increased incidence of end stage renal failure secondary to diabetes mellitus in Asian ethnic groups in the United Kingdom. Diabet Med1992; 9:641–5.[Web of Science][Medline]
5. McGill MJ, Donnelly R, Molyneaux L, Yue DK. Ethnic differences in the prevalence of hypertension and proteinuria in NIDDM. Diabetes Res Clin Pract1996; 33:173–9.[Web of Science][Medline]
6.
Roderick PJ, Raleigh VS, Hallam L, Mallick NP. The need and demand for renal replacement therapy in ethnic minorities in England. J Epidemiol Community Health1996; 50:334–9.
7. Pazianas M, Eastwood JB, MacRae KD, Phillips ME. Racial origin and primary renal diagnosis in 771 patients with end-stage renal disease. Nephrol Dial Transplant1991; 6:931–5.
8. Lightstone L, Rees AJ, Tomson C, Walls J, Winearls CG, Feehally J. High incidence of end-stage renal disease in Indo-Asians in the UK [see comments]. Q J Med1995; 88:191–5.
9.
Ball S, Cook T, Hulme B, Palmer A, Taube D. The diagnosis and racial origin of 394 patients undergoing renal biopsy: an association between Indian race and interstitial nephritis. Nephrol Dial Transplant1997; 12:71–7.
10. Altman DG. Practical Statisitics for Medical Research, Chapman & Hall, 1991.
11. Churg J, Sobin L. Renal Disease Classification and Atlas of Glomerular Diseases, Tokyo, Igaku-Shoin, 1982.
12. Churg J. Renal Disease Classification and Atlas prepared by the World Health Organisation, Collaborating Centre for the Histological Classification of Renal Diseases. New York, Igaku-Shoin, 1987.
13.
Mani MK. Chronic renal failure in India. Nephrol Dial Transplant1993; 8:684–9.
14.
Kissmeyer L, Kong C, Cohen J, Unwin RJ, Woolfson RG, Neild GH. Community nephrology: audit of screening for renal insufficiency in a high risk population. Nephrol Dial Transplant1999; 14:2150–5.
15.
Feehally J, Kendell NP, Swift PG, Walls J. High incidence of minimal change nephrotic syndrome in Asians. Arch Dis Child1985; 60:1018–20.
16.
Samanta A, Roy S, Feehally J, Symmons DP. The prevalence of diagnosed systemic lupus erythematosus in whites and Indian Asian immigrants in Leicester city, UK. Br J Rheumatol1992; 31:679–82.
17. Ball S, Lapsley M, Norden A, Cairns T, Palmer A, Taube D. Retinol binding proteinuria identifies idiopathic interstitial nephritis in Indians. J Am Soc Nephrol1999; 10:A0351.
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