Primary IgA nephropathy in north India: is it different?
- 1Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
- 2Department of Nephrology, Postgraduate Institute of Medical Education & Research, Chandigarh, Chandigarh, India
- Correspondence to Professor Kusum Joshi, Department of Histopathology, Post-graduate Institute of Medical Education & Research, Chandigarh 160 012, India; kus_joshi{at}yahoo.com
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Contributors NM, KJ, SR, RN contributed equally to the analysis of the pathological findings; VS provided the clinical details; NM, KJ, SR contributed to the writing of the manuscript.
- Received 13 April 2011
- Accepted 1 October 2011
- Published Online First 3 November 2011
Abstract
Background Immunoglobulin A (IgA) nephropathy is the most common glomerulonephritis worldwide, but has a variable geographic distribution. The bulk of the disease burden is borne by Asian countries. However, its exact prevalence or clinicopathologic spectrum in India is not well documented.
Methods This cross sectional study analysed the renal biopsy findings and clinical features at presentation in 66 patients of primary IgA nephropathy diagnosed over a period of 2 years (2007–2008). The results were compared with studies from other centres in the country and elsewhere.
Results IgA nephropathy comprised 8.1% of all native kidney biopsies. The mean age of the patients was 29.9 years with a male:female ratio of 4.4:1. Most patients presented with renal failure and a significant percentage (23%) also had nephrotic range proteinuria. Renal biopsies were classified by the Haas classification and were further scored by the MEST scoring system of the Oxford classification. By Haas classification, 41 cases (62%) showed advanced sclerotic lesions of class V. Active crescents (cellular or fibrocellular) were seen in 42% of cases, and 26% of cases showed endocapillary proliferation. Serum creatinine values were highest in the presence of proliferative lesions. MEST scoring of the Oxford classification was not applicable in approximately 18% of cases because of the presence of advanced sclerotic lesions. On immunofluorescence, the majority of the cases showed both mesangial and membranous positivity for IgA antisera. Electron microscopy revealed para-mesangial location of immune complex deposition in the majority of the cases. It also showed glomerular basement membrane abnormalities in two cases.
Conclusion Comparison of clinical and pathological features revealed that this disease presents as an advanced disease in much younger individuals in this study compared to other studies. Elucidation of the underlying factors may have immense therapeutic implications.
- IgA nephropathy
- kidney biopsy
- advanced sclerosis
- Oxford classification
- Haas classification
- type III collagen
- collagenofibrotic glomerulopathy
- banded collagen
- nephrotic syndrome
- pathology
- histopathology
- nephrology
- oncology
Introduction
Immunoglobulin A (IgA) nephropathy was first described by Berger and Hinglais in 1968. Since then, studies worldwide have proved it to be the most common glomerulonephritis in the world.1–3 The bulk of the disease burden is borne by Asians and whites, as compared to blacks from the USA and South Africa.4 5 In addition, Polynesians from New Zealand6 have a low frequency of the condition, whereas native Americans from New Mexico7 and Australian aborigines8 have a high frequency. The incidence quoted in the literature in France,9 Germany,10 and Italy11 varies from 15 to 40 new cases per million population per year.
In Asia, Singapore,12 Japan,13 14 and China15 have a very high prevalence of IgA nephropathy. Studies from Japan recorded a prevalence of up to 50%. In a Japanese study by Okada et al,13 hypertension was found in 9.8% and focal glomerulosclerosis on morphology in 52.9% of their adult cohort. In a study from the North West Frontier province of Pakistan,16 the prevalence of the disease was 20.83% (25/120) of all renal biopsies, with only 4% of patients having nephrotic range proteinuria. Few studies17–24 have been published in the literature from the Indian subcontinent which quote a variable prevalence of 5.45–16% of all cases of glomerulonephritis from different regions. Moreover, many studies from Asia13 14 report pure mesangiopathy to be the most common lesion in IgA nephropathy. On the other hand, western literature quotes focal proliferative lesions to be the most common histological lesion.
Our current knowledge of IgA nephropathy in India is based on multiple small studies on native renal biopsies, the first one of which was by Bhuyan et al17 in 1992, which reported a prevalence of 7.24% in New Delhi. Three years later, Sehgal et al18 from northern India quoted a prevalence of 10.4%. Most of the other studies were from southern India,19–21 which has a demographic profile that is different from the northern part of the country. The largest of these was a 27 year (1986–2002) retrospective review of the pattern of IgA nephropathy at a single centre (Vellore).22 Of the 5415 native renal biopsies, 8.6% showed IgA nephropathy, which were further subclassified using the modified World Health Organization classification. Recent studies by Vanikar et al from western India23 and Chandrika et al from southern India24 recorded that 14% and 16% of their kidney biopsies, respectively, showed IgA nephropathy, which is much lower than the prevalence of 50% in Japan.13 14
The present study was conducted in a tertiary care centre in north India—a multi-specialty, 1700 bed teaching hospital with an active nephrology unit and a pathology department which performs histopathology, electron microscopy, and immunofluorescence on nearly 500 native kidney biopsies a year. Unlike corporate hospitals, a major proportion (80%) of patients visiting this hospital are of low socioeconomic status and consequently may present late in the course of the disease because of a lack of awareness about their health. All patients with glomerular haematuria, proteinuria or renal failure are biopsied, unless there are specific contraindications. However, we record that the clinicopathologic pattern of IgA nephropathy in the north of India is quite different from the rest of the world. In this study we analysed 66 cases of primary IgA nephropathy and examined correlation between biopsy findings and clinical features at presentation. The results obtained were compared with the studies from other centres (in India, other Asian countries, and western countries).
Patients and methods
Patients
All patients with native renal biopsies performed and evaluated at this centre, between December 2006 and November 2008, were included in this study. The criteria for case selection included:
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Availability of at least five glomeruli (light microscopy + immunofluorescence) for evaluation.
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Confirmation by immunofluorescence of at least moderate (2+) positivity for IgA antisera, with IgA being the dominant or the co-dominant immunoglobulin deposited.
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Exclusion of other systemic diseases which can affect/alter the morphology—for example, diabetes mellitus.
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Exclusion of secondary causes of IgA nephropathy, such as liver diseases or Henoch-Schonlein purpura.
Evaluation of biopsies
For each biopsy, one slide stained with haematoxylin and eosin and the other with periodic acid Schiff were used for histological grading. The biopsies were assigned identification numbers and the patients' identities were not used. The individual histological parameters were studied in detail, according to the guidelines of the Haas classification25 and also according to the Oxford 2009 consensus meeting,26 and recorded separately. These included the presence or absence of crescents and the type and number of crescents (in each slide of a given biopsy), the presence or absence of endocapillary proliferation, the fraction of globally and segmentally sclerosed glomeruli, the cortical area of the biopsy showing tubular atrophy, interstitial fibrosis and interstitial inflammation (each recorded as percentage of the total cortical area), the presence or absence of hypertensive changes and nodular hyalinosis on the biopsy, and, if present, the extent (mild, moderate, severe) of these changes. In addition, the presence or absence of granular casts, tubulitis, and glomerular capillary wall thickening were also estimated along with their semi-quantitative measurement. A comparison was made of each of the Haas classes with the MEST (Mesangial, Endocapillary cellularity, Sclerosis, Tubular atrophy) score of the Oxford guidelines26 (table 1).
Cross tabulation of the Haas classification and the Oxford classification system in 66 cases of IgA nephropathy
Clinical data
For each patient, basic epidemiological data which include age at the time of biopsy, sex, relevant renal function parameters (serum creatinine, urinary protein excretion at the time of biopsy, presence or absence of haematuria (gross/microscopic), presence or absence of hypertension (>130/85 mm Hg) or treatment with one or more antihypertensive drugs (before or at the time of biopsy)) were obtained from the files of the nephrology clinic.
Data analysis and statistics
Continuous variables were expressed as mean±SE and their distributions examined using the Shapiro-Wilk test. Independent sample t test or analysis of variance (ANOVA) was used to compare the normally distributed variables, while the Mann-Whitney test or the Wilcoxon test was used for the non-normally distributed data. Categorical variables were analysed using the Pearson χ2 test. Multivariate analysis was performed to assess the effect of the various histological variables on the value of serum creatinine at presentation. All tests were two sided and significance was assessed at p<0.05. Statistical analysis was performed using SPSS v.16 for Windows on a standard computer running Windows XP.
Results
IgA nephropathy comprised 72/892 (8.07%) of the native kidney biopsies (in which immunofluorescence was available) over a period of 2 years (December 2006 to November 2008). Of these 72 cases, six had secondary IgA and/or associated comorbidity and were excluded from this study, leaving 66 cases for final evaluation.
Clinical features
There was a distinct male preponderance with a male:female ratio of 4.4:1. The age range of the patients was 13–60 years with a mean age of 29.9 years. The majority of the patients presented with renal failure with a mean serum creatinine concentration of 3.1 mg/dl. Clinically detectable hypertension was present in 78.8% of the patients and 81% had either gross or microscopic haematuria at presentation. Nephrotic range proteinuria was seen in 23.1% of the patients.
Pathologic features
All cases were assessed by histology and immunofluorescence, while electron microscopy was performed on 32 cases. Histological parameters of all cases were viewed by the Haas classification and the MEST scores of the Oxford classification. The distribution of the cases according to the Haas classification as well as the Oxford system is shown in table 1. There were 2, 8, 14, 1, and 41 cases in Haas classes I, II, III, IV, and V, respectively. The MEST scoring system could not be applied to 12/66 (18.18%) cases satisfactorily due to the presence of extensive glomerulosclerosis (>50% globally sclerosed glomeruli). Among cases with advanced glomerulosclerosis (n=41, class V Haas), ‘M’ (mesangial) score could be applied to only 30/41 cases, while the ‘E’ (endocapillary cellularity) score and the ‘S’ (sclerosis) score could be applied to only 29/41 cases. Overall, M ≥0.5 was noted in 45/66 (68.18%), E=1 was noted in 16/66 (24.24%), and S=1 was noted in 32/66 (48.48%). ‘T’ (tubular atrophy)=1 was noted in 20/66 (30.30%), and T=2 was noted in 29/66 (43.93%) cases.
Among the individual histological features studied, glomerular sclerosis was striking with 47.6% mean globally sclerotic and 7.3% mean segmentally sclerotic glomeruli. However, proliferative lesions were also quite common. At least one glomerulus with a crescent (fibrous/fibrocellular/cellular) was seen in 36 (56%) cases, of which 27 (42.2%) had active crescents (fibrocellular and/or cellular). Approximately two-thirds (48 cases, 73.8%) had a variable degree of mesangial hypercellularity. Glomerular capillary wall thickening was an inconsistent finding seen in 21.5% of biopsies and, wherever present, was usually focal and mild. Among the tubulointerstitial changes, granular casts were noted in 30 (47%) cases and 20 cases (29.7%) had a variable degree of tubulitis. Applying the Haas classification, advanced sclerosis (class V Haas) was the dominant histological pattern (41/66 cases, 62.1%). This was followed by focal proliferative glomerulonephritis (class III Haas) in 14/66 (24.2%) cases and class II in 8/66 (12.1%) cases (figure 1).
Photomicrographs of light microscopic (A, B), immunofluorescence (C), and electron microscopic (D) examination of IgA nephropathy. (A) The glomerulus shows segmental sclerosis involving 33% of the tuft area, with mesangial prominence and mild focal hypercellularity in the preserved area of the tuft. No endocapillary proliferation is noted (period acid Schiff (PAS), 200×). (B) Advanced chronic glomerulonephritis (subclass V Haas). The glomerulus is globally sclerotic, shrunken, with a fibrous crescent. There is loss of Bowman's capsule at places. There was accompanying severe tubular atrophy and interstitial fibrosis, well exceeding the 40% level required to assign a biopsy to subclass V (PAS, 200×). (C) Immunofluorescence with antisera to IgA antibody shows marked positivity for the same in the mesangium as well as glomerular capillary wall. (D) Electron micrograph of one of the two cases with glomerular basement membrane abnormalities (18 000×). Note the rarefaction of lamina densa and uneven thickness of the glomerular basement membrane, sometimes referred to as ‘Alport's like changes’. An electron dense type of intramembranous immune complex deposit (arrow) along with podocyte foot process effacement is also noted.
Tubular atrophy was assessed semi-quantitatively by further dividing the atrophy into various subgroups based on the percentage of the cortical area affected. Eight cases (12.1%) had <10% tubular atrophy, 17 (25.8%) had 10–25%, 10 (15.1%) had 25–40%, and 31 (47.0%) had >40% tubular atrophy. Interstitial changes such as interstitial inflammation and fibrosis were proportionate with the tubular changes. Morphological evidence of hypertension was seen in 36 (54.5%) cases, which includes seven cases with changes of thrombotic microangiopathy along with severe arterionephrosclerosis. Diffuse peritubular capillary dilatation with leucocyte margination was noted in seven (10.6%) cases. This is a finding of undetermined significance.
On immunofluorescence, a combination of membranous and mesangial granular staining for IgA antisera (figure 1C), which was at least moderate (2+) in intensity, was the most common pattern (29 cases, 43.9%). Membranous staining had a positive correlation with the presence of proliferative lesions in the biopsy (p<0.05). Paramesangium (19/32 cases, 59.35%) followed by mesangium (17/32, 53.12%) were the preferred locations for immune complex type of electron dense deposits on transmission electron microscopy. Subendothelial deposits were also noted in 10/32 (31.25%) cases. In addition, 2/32 (6.25%) cases exhibited glomerular basement membrane abnormalities (figure 1D) in the form of glomerular basement membrane (GBM) splitting, rarefaction of the lamina densa, and areas of thinning and thickening.
In an evaluation of the various subclasses in the Haas classification system, the values of serum creatinine, tubular atrophy, interstitial inflammation, and presence or absence of crescents have shown statistically significant differences from one class to another (p<0.05) (tables 2 and 3). All the variables studied were subjected to a multivariate analysis to assess their impact on the serum creatinine values. Only the proliferative lesions seemed to affect the one-time serum creatinine values the most (p<0.05). Multivariate analysis was also performed on the MEST scores to assess the effect on one-time serum creatinine values, and revealed tubular atrophy alone to be significantly related to one-time serum creatinine values (p=0.001).
Clinical and histological findings in patients with IgA nephropathy according to various subclasses in Haas classification
A comparison of the clinicopathological characteristics of patients with IgA nephropathy according to their geographic location
Discussion
The prevalence of IgA nephropathy in our catchment area over a period of 2 years was 8.07% of the total number of native renal biopsies in which immunofluorescence was available. The fact that, in this centre, only symptomatic patients requiring hospitalisation are subjected to renal biopsy, and are hence diagnosed to have IgA nephropathy, may be the reason for a lower prevalence of this disease reported by us.
When comparing the clinical features of our cohort, the mean age of our patients is 29.9 years, which is at least a decade younger than the values quoted in the western literature.27–29 The majority of our patients presented with renal failure with a mean serum creatinine value (3.1 mg/dl) that was higher than creatinine values reported in many other previous studies.13 27 28 In a recently published hospital based study from Taiwan,30 20 out of 236 patients with biopsy proven IgA nephropathy had renal failure, whereas in our study more than two-thirds of patients presented with renal failure. Hypertension at presentation was also more frequent (81%) in our study compared to 24.2% in a study from Japan.13 On the other hand, the number of patients presenting with nephrotic range proteinuria were fewer (26.1% vs 36%) than the results obtained by Haas et al,27 but well within the range given in similar studies from Japan.13 14 Thus, our patients are younger and present clinically with a more advanced disease (tables 1 and 3). We acknowledge that our study is hospital based, which would have a selection bias towards more severe cases. However, our results have only been compared with other hospital based studies from different geographic areas.
As regards histological findings, studies from Japan,13 14 28 31 China,15 Singapore,12 32 Thailand33 and a single study from western India23 put pure mesangiopathy as the most common histological lesion. In a recently published Japanese study by Tsuboi et al,34 the finding of advanced glomerulosclerosis was seen in only 13.0±14.8% glomeruli at a mean age of 34 years. In our cohort, 41/66 (62.1%) had a pattern of advanced sclerosis, occurring at a mean age of 29.6 years with 47.6% globally sclerotic glomeruli, which has not been reported from any other part of the globe. Eleven of 41 (26.8%) cases of advanced glomerulosclerosis (class V of Haas classification) could not be scored according to the guidelines of the recent Oxford classification because of the presence of global glomerulosclerosis in >50% of the glomeruli. The western literature shows focal proliferation/sclerosis (class II/III Haas) as the dominant finding on histology, with endocapillary proliferation in 60% and segmentally sclerosed glomeruli in 20% of their cases,27 as compared to 26.2% with endocapillary proliferation and 7.7% of segmentally sclerosed glomeruli in our cases. The ratio reversed for extracapillary proliferation, which was present in over a half of the cases in our study, in comparison to only one-third in their cases.35 We attribute this difference to the observation that a significant amount of this extracapillary proliferation is contributed by the presence of fibrous (more commonly) and fibrocellular crescents in small globally sclerosed and shrunken glomeruli with absent/destroyed Bowman's capsule. However, the proliferative lesions were mainly focal, and diffuse proliferation (endo- and/or extracapillary) without sclerosis was distinctly uncommon in our study. There was also a propensity for segmental sclerosis to coexist with pure mesangial proliferation. This is unlike any other proliferative glomerulopathy—for example, lupus nephritis where segmental sclerosis usually goes hand-in-hand with segmental endo-/extracapillary proliferation. Moreover, this finding is the essence of the difference between the Haas classification (where focal sclerosis is coupled with pure mesangiopathy in class II) and the modified WHO classification for lupus nephritis, where segmental sclerosis goes hand-in-hand with segmental proliferative lesions in class III. Tubulointerstitial lesions closely followed the glomerular injury pattern. Granular casts were seen in 49.2% of cases and the biopsies with advanced sclerosis had the highest mean tubular atrophy (68.5%). Surprisingly, this finding does not agree with the findings of one of the recent studies from Taiwan,30 in which the biopsies have been divided according to severity of glomerular versus tubular injury. However, in our cases this kind of segregation is not possible as the cases with the highest global sclerosis were the ones with maximum tubulointerstitial scarring as well. Thus, in our population, the glomerular and tubulointerstitial injuries go hand-in-hand.
Coexistent membranous nephropathy36 and Alport's like changes37 are well known additional electron microscopic findings in this disease, with frequencies of up to 19% and 15%, respectively. None of our cases showed diffuse subepithelial deposits which could suggest coexistent membranous glomerulopathy. On the other hand, Alport's like changes were seen in only two (7%) of our cases.
Statistical analysis using the ANOVA test showed that the values of tubular atrophy, serum creatinine, presence or absence of crescents, interstitial inflammation, and fibrosis showed statistically significant differences from one class to another (p<0.05). A multivariate analysis showed that proliferative lesions scored above others in significantly affecting the one-time serum creatinine values, similar to the study by Tsuboi et al.34
Overall, we believe that the above findings hint at a more severe phenotypic expression of IgA nephropathy in our population. The advanced stage of the disease occurring in much younger patients at first presentation in our cohort is the rationale behind this interpretation. What underlies this remarkable degree of phenotypic variation? Is it the heterogeneity of aetiology or pathogenesis, or both, remains to be explored. The recent studies38 using immortalised B cells from subjects with IgA nephropathy and normal controls have shown that ‘molecular mimicry’ from environmental agents (such as ubiquitous bacterial and viral envelope proteins) may be involved in the autoantibody response to the cryptic, neo-antigenic GalNac sites on the aberrant IgA1, leading to the production of autoantibodies to GalNac. The idea that a high prevalence of infections in developing countries like ours may thus play an important role in the pathogenesis and progression of this disease opens up new frontiers for research. However, we have no longitudinal follow-up or any information on past infections to corroborate this hypothesis.
To summarise, while the rest of the world sees IgA nephropathy as a disease of men in their mid 30s, which has a nephritic–nephrotic presentation and is morphologically a proliferative glomerulopathy, in this part of India we see it a decade earlier, presenting as acute on chronic renal failure and on morphology showing a burnt out disease with a pattern of advanced sclerosis which may or may not be accompanied by proliferative lesions. This is a finding of the utmost importance as a direct implication is that our patients are barely amenable to any form of therapy when they reach the hospital. This calls for early intervention strategies as well as screening programmes, not only to identify and treat the patients, but also for a better understanding of the factors which lead to this rapid and early progression.
Main messages
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IgA nephropathy is a more aggressive disease in the north Indian population, presenting more frequently as advanced glomerulosclerosis at an early age.
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MEST scoring of the Oxford classification system could not be applied to a significant proportion of the IgA nephropathy cases in our cohort because of the initial presentation with advanced sclerotic lesions.
Current research questions
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Is the low socioeconomic status and/or the high incidence of infections within our study population responsible for the advanced disease presentation at an early age?
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Are there any genetic predispositions/polymorphisms in our study population, which affect the rate of progression of IgA nephropathy?
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Will the introduction of screening programmes have any benefit in view of the rapid course of this disease?
Key references
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Levy M, Berger J. Worldwide perspective of IgA nephropathy. Am J Kidney Dis 1988;12:340–7.
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Haas M. Histologic subclassification of IgA nephropathy: a clinicopathologic study of 244 cases. Am J Kidney Dis 1997;29:829–1142.
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Cattran DC, Coppo R, Cook HT, et al. The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification. Kidney Int 2009;76:534–45.
Footnotes
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Competing interests None to declare.
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Patient consent In this study, kidney biopsies were done on patients (with informed consent) for the purpose of providing a diagnosis. These biopsies were analysed in a retrospective manner, along with the relevant clinical features, maintaining patient confidentiality.
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Ethics approval Institutional Ethics Committee of Postgraduate Institute of Medical Education and Research, Chandigarh.
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Provenance and peer review Not commissioned; externally peer reviewed.
