Correlation of Oxford MEST-C Scores With Clinical Variables for IgA Nephropathy in South India

IgA nephropathy (IgAN) has been reported as the most common glomerulopathy worldwide.1D’Amico G. Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome.Semin Nephrol. 2004; 24: 179-196Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar Its presentation is varied, with symptoms ranging from microscopic to macroscopic hematuria; varying degrees of proteinuria including nephrotic syndrome; hypertension; and renal failure as part of chronic kidney disease or even acute renal insufficiency.2Wyatt R.J. Julian B.A. IgA nephropathy.N Engl J Med. 2013; 368: 2402-2414Crossref PubMed Scopus (754) Google Scholar The condition is also enigmatic in that in a proportion of patients, the course is benign, with intermittent episodes of hematuria, whereas in others it presents for the first time with advanced disease and renal failure. There are also those between these extremes,1D’Amico G. Natural history of idiopathic IgA nephropathy and factors predictive of disease outcome.Semin Nephrol. 2004; 24: 179-196Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar and the disease has a variable outcome across populations.3Lai K.N. Mac-Moune Lai F. Li P.K. et al.The clinicopathological characteristics of IgA nephropathy in Hong Kong.Pathology. 1988; 20: 15-19Abstract Full Text PDF PubMed Scopus (25) Google Scholar The prevalence of the disease in studies of renal biopsies across the world varies. Among 29 international centers surveyed by geographic region, the prevalence in biopsy series for IgAN varied from 6.1% in Latin America, to 11.8% in the US and Canada, 22.1% in Europe, and 39.5% in Asia.3Lai K.N. Mac-Moune Lai F. Li P.K. et al.The clinicopathological characteristics of IgA nephropathy in Hong Kong.Pathology. 1988; 20: 15-19Abstract Full Text PDF PubMed Scopus (25) Google Scholar, 4O'Shaughnessy M.M. Hogan S.L. Thompson B.D. et al.Glomerular disease frequencies by race, sex and region: results from the International Kidney Biopsy Survey.Nephrol Dial Transplant. 2018; 33: 661-669Crossref PubMed Scopus (73) Google Scholar, 5Koyama A. Igarashi M. Kobayashi M. Natural history and risk factors for immunoglobulin A nephropathy in Japan. Research Group on Progressive Renal Diseases.Am J Kidney Dis. 1997; 29: 526-532Abstract Full Text PDF PubMed Scopus (270) Google Scholar, 6Woo K.T. Chan C.M. Lim C. et al.Primary glomerulonephritis in Singapore over four decades.Clin Nephrol. 2019; 91: 155-161Crossref PubMed Scopus (3) Google Scholar Studies from Japan, Singapore, and China have also reported a high incidence. In the few studies that have been reported from India, this figure has varied from 7% to 16%.7Narasimhan B. Chacko B. John G.T. et al.Characterization of kidney lesions in Indian adults: towards a renal biopsy registry.J Nephrol. 2006; 19: 205-210PubMed Google Scholar, 8Bhuyan U.N. Dash S.C. Srivasthava R.N. et al.IgA associated glomerulonephritis.J Assoc Physicians India. 1992; 40: 310-313PubMed Google Scholar, 9Sehgal S. Datta B.N. Sakhuja V. et al.Primary IgA nephropathy: a preliminary report.Indian J Pathol Microbiol. 1995; 38: 233-237PubMed Google Scholar,S1,S2 The Oxford classification and scoring system, proposed by the working group of the International IgA Nephropathy Network and the Renal Pathology Society, identified 4 independent histologic variables in predicting renal outcome: the mesangial hypercellularity score (M); segmental glomerulosclerosis (S); endocapillary hypercellularity (E); and tubular atrophy/interstitial fibrosis (T).S3 Subsequently, the scoring of crescents (C) was also introduced as an Oxford score as a factor of predictive importance, creating the MEST-C score.S4 The classification has been evaluated in multiple population cohorts. The current study encompasses a large cohort of renal biopsies with a diagnosis of IgAN from a single geographic area of South India, from where there have been only a handful of reports. The Oxford classification has been used, according to strict criteria, and interobserver variation in the scoring has been analyzed. In total, there were 3345 cases of IgAN from a total of 25,277 biopsies, comprising 13.23% of the native renal biopsies. The proportion of IgAN in the 4 centers, varying from 10.4% in Hyderabad to 17.1% in Kochi, is depicted in Figure 1. The mean age in the entire cohort was 35.83 years, with ages ranging from 2 to 85 years. The male:female ratio was 2.4:1. The age distribution is depicted in Figure 2. The prevalence of hypertension, proteinuria (semiquantitative, urine protein:creatinine ratio, 24-hour proteinuria), hematuria, and mean serum creatinine in the 4 groups and in the entire cohort is depicted in Table 1.Figure 2Age distribution of cases.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table 1Demographic, laboratory, and histologic data in the 4 centers and in the entire cohortCenterBangaloreChennaiHyderabadKochiTotalNo. of IgAN cases12298666336173345IgAN as a % of native biopsies14.212.510.417.113.23Mean age (yr)36.7833.8434.9237.6535.83Male:female ratio2.5:11.6:12.5:14.0:12.4:1HypertensionaThe denominator indicates the total number in which the value of this variable was recorded.647/1103445/828373/532397/6171862/3080ProteinuriaaThe denominator indicates the total number in which the value of this variable was recorded. Semiquantitative (≥3+)625/1218400/861343/627368/6141736/3320 Urine Pr:Cr ratio (≥1)393/420253/31864/78134/150844/966 Urine Pr:Cr ratio (≥3)202/420144/31830/7864/150440/966 24 h proteinuria (≥3 gm/d)123/3080102/26995/278320/855Hematuria (≥2/hpf)aThe denominator indicates the total number in which the value of this variable was recorded.720/961568/661422/528385/4692095/2619Mean serum creatinine3.92.83.33.13.27Histology-adequate biopsies4264162423611445M1149263179266857E119014095136561S1216254150252872T1766355104298T2171382361C1733587104299C26244028134C, crescents; Cr, creatinine; E, endocapillary hypercellularity; IgAN, IgA nephropathy; M, mesangial hypercellularity; Pr, protein; S, segmental glomerulosclerosis; T, tubular atrophy/interstitial fibrosis.a The denominator indicates the total number in which the value of this variable was recorded. Open table in a new tab C, crescents; Cr, creatinine; E, endocapillary hypercellularity; IgAN, IgA nephropathy; M, mesangial hypercellularity; Pr, protein; S, segmental glomerulosclerosis; T, tubular atrophy/interstitial fibrosis. A total of 1445 cases (43.2%) had more than 8 viable glomeruli, allowing the MEST-C scoring to be done. In the others, there were a smaller number of viable glomeruli or a greater number of sclerosed glomeruli, and these were excluded from the scores. The MEST-C scores in the 4 groups and in the entire cohort are listed in Table 1. In the 872 cases of segmental sclerosis, type of sclerosis was recorded in 255 and was of the not otherwise specified type in the majority. Instances of all MEST-C scores being 0 were seen in 199 of the biopsies with ≥8 viable glomeruli (13.8%). The mean age in this group was 33.76 years, with mean proteinuria of 3.6 gms/dl, and a mean serum creatinine level of 1.9 mg/dl. Chronic IgAN, defined as more than 50% sclerosed glomeruli and more than 50% tubular atrophy/interstitial fibrosis in biopsies with ≥8 glomeruli, was seen in 213 cases; the mean age in this group was 34.8 years; the male:female ratio was 3:1; the mean proteinuria was 4.2 gms/day, and the mean serum creatinine level was 5.3 mg/dl. The MEST-C scores were correlated with the serum creatinine level and degree of proteinuria and hematuria (Table 2). The correlation was statistically significant (P < 0.05) for the E-score for creatinine and hematuria, the T-score for creatinine, proteinuria, and hematuria, and the C-score for creatinine and hematuria. The values were highly significant (P < 0.0001) for the T- and C-scores for creatinine.Table 2MEST-C correlation with clinical variablesOxford scoresSerum creatinine (mg/dl);1445 casesProteinuria (gm/d);365 casesHematuria (number/hpf);903 casesMean ± SDP valueMean ± SDP valueMean ± SDP valueM score 02.39 ± 5.030.7763.57 ± 3.550.48120.04 ± 22.50.8 12.45 ± 2.316.32 ± 9.6921.08 ± 24.6E score 02.25 ± 3.940.0186.40 ± 3.630.44717.83 ± 19.870.012 12.71 ± 2.583.43 ± 2.8525.82 ± 28.95S score 02.32 ± 2.420.3663.49 ± 3.610.44622.01 ± 22.180.510 12.50 ± 4.016.43 ± 4.3520.4 ± 25.0T score 02.05 ± 3.660.000013.29 ± 3.190.04523.06 ± 26.250.018 13.07 ± 2.1715.44 ± 10.3123.06 ± 26.25 25.75 ± 3.394.59 ± 3.0115.80 ± 18.27C score 02.14 ± 3.660.000013.53 ± 3.640.21517.98 ± 20.170.002 12.41 ± 2.3311.50 ± 9.1322.66 ± 22.60 24.69 ± 3.523.99 ± 3.0930.22 ± 39.50C, crescents; E, endocapillary hypercellularity; M, mesangial hypercellularity; S, segmental glomerulosclerosis; T, tubular atrophy/interstitial fibrosis.The figures in bold indicate the correlations that were significant (P < 0.05). Open table in a new tab C, crescents; E, endocapillary hypercellularity; M, mesangial hypercellularity; S, segmental glomerulosclerosis; T, tubular atrophy/interstitial fibrosis. The figures in bold indicate the correlations that were significant (P < 0.05). In the immunofluorescence study, in 2423 cases, a complete record of all 7 reagents including the intensity and pattern of deposits was available, and these were included. In the others, the records were incomplete. The results are depicted in Figure 3. C3c was seen accompanying IgA in up to 92% of the cases. The presence of lambda was of greater intensity by a factor of <2 in the majority of cases. The presence of lambda light chains to the exclusion of kappa light chains was seen in 12% of cases. For a measure of interobserver variability in MEST-scores, the alpha reliability estimates for the M-, E-, S-, T- and C-scores were 0.76, 0.851, 0.885, 0.844, and 0.891, respectively. Health care in India is not uniform. Government-run hospitals cater to lower socioeconomic groups, large private hospitals serve wealthier clients, and a range of smaller hospitals and nursing homes serve those in between. This study focuses on data collected from 4 renal pathology laboratories, one from each of the 4 states of South India. As renal biopsy reporting including immunofluorescence study is specialized, renal biopsies done in teaching hospitals, and in small and large private centers, are sent to these referral labs. The data presented are therefore a fair representation of the disease in South India. Although IgAN is purported to be the most common nephropathy worldwide, its prevalence in biopsy series across the world differs vastly, ranging from 2% to 50%.7Narasimhan B. Chacko B. John G.T. et al.Characterization of kidney lesions in Indian adults: towards a renal biopsy registry.J Nephrol. 2006; 19: 205-210PubMed Google Scholar Among 29 international centers surveyed by geographic region, involving over 41,000 biopsies, the prevalence of IgAN varied from 6.1% in Latin America, to 11.8% in the US/Canada, 22.8% in Europe, and 39.5% in Asia.4O'Shaughnessy M.M. Hogan S.L. Thompson B.D. et al.Glomerular disease frequencies by race, sex and region: results from the International Kidney Biopsy Survey.Nephrol Dial Transplant. 2018; 33: 661-669Crossref PubMed Scopus (73) Google Scholar Even within the same geographic area, figures vary, as in Croatia at 19.3%S7 compared with 34.5% in Czech Republic.S8 Studies from the Far East have reported a biopsy prevalence as high as 47.2%, in Japan,5Koyama A. Igarashi M. Kobayashi M. Natural history and risk factors for immunoglobulin A nephropathy in Japan. Research Group on Progressive Renal Diseases.Am J Kidney Dis. 1997; 29: 526-532Abstract Full Text PDF PubMed Scopus (270) Google Scholar and 40%, in Singapore.6Woo K.T. Chan C.M. Lim C. et al.Primary glomerulonephritis in Singapore over four decades.Clin Nephrol. 2019; 91: 155-161Crossref PubMed Scopus (3) Google Scholar In a large study in East China by Zhou et al.,S9 IgAN accounted for 50% of their biopsies.S9 In the present study, IgAN, comprising a total of 3345 cases, accounted for 13.23% of the cases, with a range from 10.4% in Hyderabad to 17.1% in Kochi. In other studies from India, the range has been similar, from 7% to 16% (Table 3), but the numbers in these studies are smaller, varying from as few as 11 to a high of 478 cases, with 2 of these studies coming from the same geographic area.7Narasimhan B. Chacko B. John G.T. et al.Characterization of kidney lesions in Indian adults: towards a renal biopsy registry.J Nephrol. 2006; 19: 205-210PubMed Google Scholar,S1Table 3IgA nephropathy studies in IndiaAuthorYearNo.Mean age (yr)Hypertension (%)Proteinuria nephrotic range (%)Hematuria (%)High serum creatinine (%)Bhuyan et al.8Bhuyan U.N. Dash S.C. Srivasthava R.N. et al.IgA associated glomerulonephritis.J Assoc Physicians India. 1992; 40: 310-313PubMed Google Scholar199283–3924–34Muthukumar et al.S2020029825.79.225.65.113.5Chacko et al.S2120054783258551660Chandrika et al.S12007227303536.718.95.7Mittal et al.S2220126629.978.823.181–Bhagchi et al.S23201610328.839.463.19116.5 Open table in a new tab The mean age in this study was 35.83 years, with the youngest aged 2 years and the oldest 85 years. This range is similar to that in other studies from across the world, in which the mean age has varied from 28 to 38 years (Table 4). It is possible that, in India, the disease is detected at a more advanced stage and hence the mean age is a little higher than that in other parts of the world. The male:female ratio in this study was 2.4:1, similar to the western data, whereas in Japan and China, the ratio is more on the order of 1:1.Table 4IgA nephropathy studies worldwideAuthor, countryYearNo.Mean age (yr)HTN (%)Proteinuria>3 gms/d (%)Hematuria (%)High serum creatinine (%)Nicolls et al.,S24 Australia1984244322363936D’Amico et al.,S25 Italy1986365293675524Droz et al.,S26 France1984280–61037–Bogenschutz et al.,S27 Germany1990239–19–2634Rekola et al.,S28 Sweden1990209251116416Alamartine et al.,S17 France19912822893392Katafuchi,S29 Japan19942253222162036Koyoma et al.,5Koyama A. Igarashi M. Kobayashi M. Natural history and risk factors for immunoglobulin A nephropathy in Japan. Research Group on Progressive Renal Diseases.Am J Kidney Dis. 1997; 29: 526-532Abstract Full Text PDF PubMed Scopus (270) Google Scholar Japan1997448–2932419Roberts et al.,S2 Oxford, multicentre200926530311.7 gms (mean)3426 (CKD ≥3)Zeng et al.,S30 China2011102634331.3 gms (mean)2724 (CKD ≥3)Katafuchi et al.,S15 Japan201170230UPCR 0.9 (mean)25 (CKD ≥3)VALIGA cohortS102014114736652137 (CKD ≥3)Present study2019334535.860.437.479.9 (≥2/hpf) 3.9 (plenty)78.9 (≥1 mg/dl)36.4 (≥3 mg/dl)CKD, chronic kidney disease; HTN, hypertension; UPCR, urine protein-to-creatinine ratio; VALIGA, Validation Study of the Oxford classification of IgAN. Open table in a new tab CKD, chronic kidney disease; HTN, hypertension; UPCR, urine protein-to-creatinine ratio; VALIGA, Validation Study of the Oxford classification of IgAN. There is no unifying factor in IgAN other than the mesangial deposits of IgA, and many believe that IgAN is not a single disease or even the same disease in different parts of the world.S9 Table 4 summarizes the clinical and laboratory data from studies with more than 200 cases of IgAN, and Table 3 summarizes the data from India where these results are available. Hypertension is variable across the studies, ranging from as low as 6% to as high as 65% in the VALIGA (Validation Study of the Oxford Classification of IgAN) cohort.S11 In the Indian studies, in all but one, hypertension is present in upwards of 35% of cases, approaching 60% in our group. In most of these studies, the details of when the hypertension was detected are not available. We presume that the IgAN would have been detected earlier, probably with less chronicity, had a complete evaluation for hypertension been done at the time of detection and the patient subjected to biopsies if urinary and/or renal functional abnormalities were detected at that time. The one finding that seems to be distinctive in IgAN in India, as compared with the rest of the world, is the degree of proteinuria. Nephrotic-range proteinuria is uncommon in IgAN in the western population and even in Japan.S12–S15 Table 4 shows a maximum of 16% in the Japanese group having significant proteinuria, whereas the prevalence of nephrotic-range proteinuria in all studies from India is high, with a minimum of 23% and a maximum of 63.1%.S16 In this study, a semiquantitative dipstick reading of proteinuria was what was available in all records, and a grade of ≥3 was present in 51%. Urine protein-to-creatinine ratios were available in 966 records (28.9% of cases); a value of ≥1 was seen in 87.4%, and ≥3 in 44.6%. A quantitative 24-hour proteinuria reading was available in 855 records (25.6% of cases); 86.3% of them had a proteinuria level of ≥1 gm/24 h, and 37.4% had a value of ≥3 gms/24 h. Macroscopic hematuria is not an uncommon finding in studies outside India (Table 4). The quantitative data on hematuria, whether microscopic or macroscopic, are not available in the Indian studies. The figure varies from 5.1% to 91% and could be ascribed to the rigor with which this test was done. In our study, microscopic hematuria, defined as red blood cell count ≥2/high-power field, was seen in 80% of cases. Macroscopic hematuria, defined as “plenty” of red blood cells or >100/high-power field of microscopy, was seen in only 3.9% of our cases. IgAN is a disease with varying degrees of progression and varying presentation, and the reasons for this, be they genetic, racial, and/or environmental, are not clear. In a Canadian-based study of a large multiracial cohort of IgAN with over 600 patients, it was observed that individuals of Pacific-Asian origin had a higher risk of progression to end-stage renal disease.S17 The studies differ in their definition of a high level of serum creatinine and hence cannot be compared directly. However, “raised” levels of serum creatinine have varied from as low as 2%, in the study by Alamartine et al.,S18 to as high as 36% in the report from Japan by Katafuchi et al.S16 The studies from India, however, have reported high creatinine levels in as low as 5.6% of casesS11 to as high as 60%.S18 A serum creatinine level of >1 mg/dl was seen in 78.9% of our cases, and of >3 mg/dl in 36.4%. IgAN in South India is being detected at a more advanced stage than it is in other parts of the world. The Oxford MEST-C scores proposed by the International IgA Nephropathy Network and the Renal Pathology Society proposed 4 scores—mesangial hypercellularity (M), endocapillary hypercellularity (E), segmental sclerosis (S), and tubular atrophy/interstitial fibrosis (T), all of which had good interobserver correlation—to be independently associated with renal outcome in renal biopsies of IgAN with >8 glomeruli.S3 Subsequently, the crescent (C) score was added as an independent predictive factor.S4 In a systematic meta-analysis of 16 studies with 3893 cases of IgAN,S19 the M-, S-, T- and C-scores were strongly associated with progression to renal failure, with hazard ratios of 0.6, and of in were not associated with renal failure in this with a hazard ratio of and with of lesions have been proposed as a for but this was in only small in this In our study, a correlation of the scores with serum creatinine, proteinuria, and hematuria blood at the time of biopsy (Table 2). The mean serum creatinine level in all groups was higher in score compared with score 0 but (P < 0.05) in only the The mean proteinuria level was higher in score in the M, S, and with a statistically significant value in the as was higher in the and groups, compared with the 0 and was higher in the group compared with the group. As IgAN in South India is being detected at an advanced a correlation of the scores with creatinine level is not The T-score seems to be the most predictive of renal failure at the time of Even in the small cohort in this study of 199 cases of biopsies, where all scores were the mean proteinuria level was 3.6 and the serum creatinine level was 1.9 mg/dl. The group with IgAN, defined as sclerosed glomeruli and tubular atrophy/interstitial fibrosis had a mean proteinuria of 4.2 gms/d and a serum creatinine level of 5.3 mg/dl. 2 groups similar in degree of proteinuria, a that could be if IgAN is a disease within the renal This the of whether a number of viable glomeruli is for a scoring There has been over the interobserver in the scoring system, the study at the 4 scores and also the scores. In the group has an of each histologic that is to in of the VALIGA however, has in the and As a part of this study, of with all from a total of cases, from each were and interobserver on the M, E, S, T, and C, was The alpha reliability in each of the variable scores of the MEST-C was good interobserver The data be The correlation also have been to the that in all 4 centers, the were in renal with a minimum of and were strict for the scores. It would be to study whether similar is with less in renal biopsy This study the cohort of IgA patients, have a greater prevalence of hypertension, significant proteinuria, and higher of chronic kidney disease at presentation compared with the The MEST-C scores an with clinical hypertension with the serum creatinine level and degree of hematuria with the E-, and and proteinuria with the but their in and is not clear. The therefore to be on to the disease at an stage and to its the no The of for the A part of the study was presented as a at the of the Indian Society of Renal and Pathology at India, in Download with

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