Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments

The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome. Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain. The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN. Over a median follow-up of 4.7 years, 86% received renin–angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs. M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival. Their value was also assessed in patients not represented in the Oxford cohort. In individuals with eGFR less than 30ml/min per 1.73m2, the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2g/day or more. The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%). The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease. The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy. The Oxford Classification of IgA Nephropathy (IgAN) identified mesangial hypercellularity (M), endocapillary proliferation (E), segmental glomerulosclerosis (S), and tubular atrophy/interstitial fibrosis (T) as independent predictors of outcome. Whether it applies to individuals excluded from the original study and how therapy influences the predictive value of pathology remain uncertain. The VALIGA study examined 1147 patients from 13 European countries that encompassed the whole spectrum of IgAN. Over a median follow-up of 4.7 years, 86% received renin–angiotensin system blockade and 42% glucocorticoid/immunosuppressive drugs. M, S, and T lesions independently predicted the loss of estimated glomerular filtration rate (eGFR) and a lower renal survival. Their value was also assessed in patients not represented in the Oxford cohort. In individuals with eGFR less than 30ml/min per 1.73m2, the M and T lesions independently predicted a poor survival. In those with proteinuria under 0.5g/day, both M and E lesions were associated with a rise in proteinuria to 1 or 2g/day or more. The addition of M, S, and T lesions to clinical variables significantly enhanced the ability to predict progression only in those who did not receive immunosuppression (net reclassification index 11.5%). The VALIGA study provides a validation of the Oxford classification in a large European cohort of IgAN patients across the whole spectrum of the disease. The independent predictive value of pathology MEST score is reduced by glucocorticoid/immunosuppressive therapy. IgA nephropathy (IgAN) is the most common glomerulonephritis in the world, being particularly frequent in Asia, Australia, and Europe.1.D'Amico G. The commonest glomerulonephritis in the world: IgA nephropathy.Q J Med. 1987; 64: 709-727PubMed Google Scholar Although large multicenter cohorts of patients have been investigated in China,2.Zeng C.H. Le W. Ni Z. et al.A multicenter application and evaluation of the Oxford classification of IgA nephropathy in adult Chinese patients.Am J Kidney Dis. 2012; 60: 812-820Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar data from Europe have been mostly limited to single-center studies.3.Manno C. Strippoli G.F. D'Altri C. et al.A novel simpler histological classification for renal survival in IgA nephropathy: a retrospective study.Am J Kidney Dis. 2007; 49: 763-775Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 4.Berthoux F. Mohey H. Laurent B. et al.Predicting the risk for dialysis or death in IgA nephropathy.J Am Soc Nephrol. 2011; 22: 752-761Crossref PubMed Scopus (249) Google Scholar, 5.Maixnerova D. Bauerova L. Skibova J. et al.The retrospective analysis of 343 Czech patients with IgA nephropathy: one centre experience.Nephrol Dial Transplant. 2012; 27: 1492-1498Crossref PubMed Scopus (23) Google Scholar Therefore, this collaborative study aimed to create a large European database of patients with IgAN to include clinical, laboratory, and histological data followed over a prolonged time frame. The study was initially aimed to validate the Oxford Classification of IgAN in a European cohort (VALIGA). The Oxford Classification identified four pathological features (mesangial hypercellularity M, endocapillary hypercellularity E, segmental glomerulosclerosis S, and tubular atrophy/interstitial fibrosis T, resulting in a MEST score) that predicted renal outcome independently of clinical indicators at the time of renal biopsy and during follow-up.6.Cattran D.C. Coppo R. Cook H.T. et al.The Oxford classification of IgA nephropathy: rationale, clinicopathological correlations, and classification.Kidney Int. 2009; 76: 534-545Abstract Full Text Full Text PDF PubMed Scopus (901) Google Scholar, 7.Roberts I.S. Cook H.T. Troyanov S. et al.The Oxford classification of IgA nephropathy: pathology definitions, correlations, and reproducibility.Kidney Int. 2009; 76: 546-556Abstract Full Text Full Text PDF PubMed Scopus (763) Google Scholar These findings were valid both in adults and children.8.Coppo R. Troyanov S. Camilla R. et al.The Oxford IgA nephropathy clinicopathological classification is valid for children as well as adults.Kidney Int. 2010; 77: 921-927Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar The limited number of patients (265 cases) and their heterogeneous origin (from 11 countries in four continents) indicated a need for validation in other cohorts. Several validation studies have addressed this (reviewed in Roberts9.Roberts I.S. Oxford classification of immunoglobulin A nephropathy: an update.Curr Opin Nephrol Hypertens. 2013; 22: 281-286Crossref PubMed Scopus (44) Google Scholar); however, most of the studies have serious limitations of either small cohort size or clinical features, which were likely to confound the results.10.Alamartine E. Sauron C. Laurent B. et al.The use of the Oxford classification of IgA nephropathy to predict renal survival.Clin J Am Soc Nephrol. 2011; 6: 2384-2388Crossref PubMed Scopus (107) Google Scholar, 11.Edstrom Halling S. 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Seo M.S. et al.Validation of the Oxford classification of IgA nephropathy: a single-center study in Korean adults.Korean J Intern Med. 2012; 27: 293-300Crossref PubMed Scopus (50) Google Scholar, 16.Moriyama T. Nakayama K. Iwasaki C. et al.Severity of nephrotic IgA nephropathy according to the Oxford classification.Int Urol Nephrol. 2012; 44: 1177-1184Crossref PubMed Scopus (35) Google Scholar, 17.Shi S.F. Wang S.X. Jiang L. et al.Pathologic predictors of renal outcome and therapeutic efficacy in IgA nephropathy: validation of the Oxford Classification.Clin J Am Soc Nephrol. 2011; 6: 2175-2184Crossref PubMed Scopus (132) Google Scholar, 18.Shima Y. Nakanishi K. Hama T. et al.Validity of the Oxford classification of IgA nephropathy in children.Pediatr Nephrol. 2012; 27: 783-792Crossref PubMed Scopus (77) Google Scholar, 19.Yau T. Korbet S.M. Schwartz M.M. et al.The Oxford classification of IgA nephropathy: a retrospective analysis.Am J Nephrol. 2011; 34: 435-444Crossref PubMed Scopus (41) Google Scholar The inclusion criteria of the Oxford study, ≥0.5g/day initial proteinuria, ≥30ml/min per 1.73m2 estimated glomerular filtration rate (eGFR) at renal biopsy, and ≥1 year available follow-up were chosen to ensure that a sufficient number of hard outcome events occurred within a limited follow-up. This enabled the independent value of pathology to be tested, avoiding overrepresentation of individuals with advanced scarring and excluding rare forms of IgAN with rapidly progressive course that might add excess heterogeneity. By design, the Oxford study did not include the whole spectrum of cases encountered in clinical practice. It could not address, for instance, the great proportion of the IgAN population presenting with normal renal function and minimal proteinuria, a common scenario where the need for renal biopsy is still debated. Similarly, the opposite end of the spectrum was not included—that is, patients with low GFR who may be expected to show irreversible scarring at renal biopsy, likely beyond response to immunosuppressive treatment, and at a point where evaluation of risks against benefits may cast doubts on renal biopsy need. Last, the diverse ethnic origin of the Oxford cohort made the impact of ethnicity difficult to assess. We therefore took advantage of the large European collaboration provided by the Immunonephrology Working Group of the ERA-EDTA to investigate whether the Oxford classification is valid and applies across the spectrum of IgAN disease presentation and diverse management. The VALIGA study includes 1147 patients from 13 European Countries with unrestricted criteria at entry, except biopsy-proven primary IgAN and adequate histology material available for review. This produced the largest single cohort reported in the worldwide literature of patients with IgAN. It was designed to address whether the Oxford pathology indicators continue to have independent predictive value, across the full clinical spectrum of IgAN disease and despite different therapeutic approaches. VALIGA reports data on 1147 patients with primary IgAN (Table 1) from 55 centers in 13 Countries (Supplementary Figure S1, Supplementary Figure S2). All patients were resident in Europe, and 97.5% were Caucasian. Patients’ mean age was 36±16 years, 174 (15%) were children, and 73% were male. At renal biopsy, the mean eGFR was 75±34ml/min per 1.73m2. Patients belonged mostly to stages 1, 2, and 3 chronic kidney disease (CKD; 33, 30 and 28% respectively), whereas 9% were in stage 4 or stage 5. Median proteinuria at renal biopsy was 1.3 (interquartile range, IQ 0.6–2.6) g/day; 20% of patients had mild proteinuria <0.5g/day, 20% had proteinuria ≥0.5 and <1g/day, 39% had proteinuria ≥1 and <3g/day, and 21% had proteinuria ≥3g/day. The mean arterial pressure (MAP) was 98±13mmHg, and 65% of the patients were hypertensive and/or receiving antihypertensive medications.Table 1Baseline characteristics of the study cohort of 1147 patients with IgA nephropathy (IgAN)Total number1147Age (years)36±16Pediatric subjects (% <18 years old)15Male (%)73Ethnicity (% Caucasian/African/Asian/other)97.5/0.5/0.5/1.5eGFR (ml/min per 1.73m2)73±30CKD stage 1 or 2*, 3, 4, 5 (%)60, 28, 7, 2MAP (mmHg)98±13SBP (mmHg)131±23DBP (mmHg)81±12Hypertensive subjects (%)65Proteinuria (g/day)1.3 (0.6–2.6)Proteinuria g/day (%)<0.5, ≥0.5 <1, ≥1 <3, ≥320, 20, 39, 21Before biopsy immunosuppressive treatments10Before biopsy nonimmunosuppressive treatments Prior tonsillectomy (%)4 Prior RASB (%)39Abbreviations: CKD, chronic kidney disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; MAP, mean arterial blood pressure; SBP, systolic blood pressure.Results are expressed as mean±s.d., median (interquartile range), or percent. Hypertensive patients and proteinuria units: see Materials and Methods and definitions. RASB: renin–angiotensin system blockade by angiotensin-converting enzyme inhibitors and/or angiotensin receptors blockers.CKD stages 1 and 2 were grouped in one only category owing to inaccuracy of MDRD measure of eGFR in stages 1 and 2. Open table in a new tab Download .pdf (.15 MB) Help with pdf files Supplementary Figure S1 Download .pdf (.09 MB) Help with pdf files Supplementary Figure S2 Abbreviations: CKD, chronic kidney disease; DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; MAP, mean arterial blood pressure; SBP, systolic blood pressure. Results are expressed as mean±s.d., median (interquartile range), or percent. Hypertensive patients and proteinuria units: see Materials and Methods and definitions. RASB: renin–angiotensin system blockade by angiotensin-converting enzyme inhibitors and/or angiotensin receptors blockers. CKD stages 1 and 2 were grouped in one only category owing to inaccuracy of MDRD measure of eGFR in stages 1 and 2. Before renal biopsy, 39% of VALIGA patients had received renin–angiotensin system blockade (RASB) and 10% glucocorticoids and/or other immunosuppressive drugs. Patients were followed up for a median of 4.7 (IQ, 2.4–7.9) years (Table 2). Time-average (TA) MAP was 96±9mmHg. The median number of antihypertensive medications received during follow-up was 1.0 (IQ 0.7–2.0); 86% of patients received RASB. TA proteinuria was 0.8 (IQ 0.4–1.6) g/day. During follow-up, 43% of patients received oral glucocorticoids, 16% received intravenous ‘pulse’ methylprednisolone, and 13% received fish oil; 4% of patients underwent tonsillectomy.Table 2Follow-up data and clinical outcome of IgAN patients enrolledFollow-up dataDuration of follow-up: median (IQ; years)4.7 (2.4–7.9)TA-MAP (mmHg)96±9TA-SBP (mmHg)129±14TA-DBP (mmHg)79±8Median number of antihypertensive drugs1.0 (0.8–2.0)TA proteinuria (g/day)0.8 (0.4–1.6)TA proteinuria <0.5, ≥0.5 <1, ≥1 <1.5, ≥1.5 <2, ≥2 (%)29, 28, 25, 9, 19Immunosuppression Oral corticosteroids (%)43 Intravenous ‘pulse’ methylprednisolone (%)16 Other immunosuppression (%)16 Any immunosuppression (%)46Nonimmunosuppressive treatments RASB (%)86 Fish oil (%)13 Tonsillectomy (%)5Clinical outcome data Rate of decline in renal function (ml/min per 1.73m2/year)-1.8±7.5 50% decrease in eGFR (%)14 ESRD (<15ml/min per 1.73m2) (%)12 50% decrease in eGFR or ESRD (%)16Abbreviations: DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; IgAN, IgA nephropathy; MAP, mean arterial blood pressure; RASB, renin–angiotensin system blockade; SBP, systolic blood pressure; TA, time average (see text for definition).Results are expressed by mean±s.d., median (interquartile range), or percent as appropriate. Means and medians are time-averaged (see Materials and Methods). Open table in a new tab Abbreviations: DBP, diastolic blood pressure; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; IgAN, IgA nephropathy; MAP, mean arterial blood pressure; RASB, renin–angiotensin system blockade; SBP, systolic blood pressure; TA, time average (see text for definition). Results are expressed by mean±s.d., median (interquartile range), or percent as appropriate. Means and medians are time-averaged (see Materials and Methods). The rate of decline in renal function was 1.8±7.5ml/min per 1.73m2/year. End-stage renal disease (ESRD) developed in 135 patients (12%) (Table 2). The renal function survival from the combined end point of 50% reduction in eGFR or ESRD was 74% at 10 years and was significantly better in children than in adults (83% compared with 73%, P<0.001). A significant association was observed between data at renal biopsy (eGFR, MAP, proteinuria), during follow-up (TA-MAP and TA-proteinuria), and the outcomes (data not shown). Notably, in the VALIGA cohort, TA proteinuria <0.5g/day was a significant marker of better outcome than follow-up proteinuria between 0.5 and 1.0g/day (Figure 1). Twenty-eight percent of renal biopsies showed diffuse mesangial hypercellularity (M1), 11% showed endocapillary hypercellularity (E1), 70% showed segmental glomerulosclerosis (S1), and 21% showed tubular atrophy/interstitial fibrosis (T1 or T2). As T2 lesions were infrequent (3.6%), T2 and T1 lesions were combined to increase the statistical power. Arterial intimal thickening was detected in 28% of biopsies. Only 11% showed cellular/fibrocellular crescents and 7% showed necrosis, without a significant association between these two features. The frequency of MEST scores varied according to particular clinical settings at renal biopsy—for example, in patients with advanced CKD, and according to the level of baseline proteinuria (Figure 2). M, S, and T scores were strongly associated with proteinuria, MAP, and eGFR at the time of biopsy (Supplementary Table 1S online). E score was associated with proteinuria only (P<0.002). Download .doc (.11 MB) Help with doc files Supplementary Tables and Figure Legends Within the VALIGA cohort, the value of the MEST score to predict the rate of renal function decline, as well as survival without ESRD, or 50% reduction in initial GFR was verified (Table 3). The exception was the E lesion, which did not predict any of the outcomes when addressing the entire cohort. In particular, the E lesion was not predictive in the subgroup that did not receive immunosuppression, as it was in the original study. Table 3 shows the univariate and multivariate results for the M, S, and T lesions using either linear regression (rate of renal function decline) or Cox regression (survival from a combined event). All univariate and multivariate comparisons were significant, except for the multivariate value of S using linear regression (although significant using the survival model) and the multivariate value of M using survival (although significant using the linear model). The effect sizes of pathology findings were reduced after adjustment for clinical variables (for example, the hazard ratios (HRs) for the S and T lesions fell from 4.1 and 5.6 to 1.8 and 2.6, respectively).Table 3Correlations between pathological features and outcomesRate of renal function declineSurvival from renal failure or 50% drop in eGFRUnivariate (ml/min per 1.73m2/year)Multivariate ß (s.d.)aMultivariate models are adjusted for initial eGFR, follow-up blood pressure, and proteinuria.Univariate hazard ratio (95% CI)Multivariate hazard ratio (95% CI)aMultivariate models are adjusted for initial eGFR, follow-up blood pressure, and proteinuria.Mesangial proliferation M0-1.29±7.4911 M1-3.02±7.32-0.9 (0.5)2.3 (1.7–3.0)1.3 (0.9–1.7)P<0.001P=0.04P<0.001P=0.12Segmental glomerulosclerosis S0-1.15±5.4611 S1-2.03±8.18-0.1 (0.5)4.1 (2.6–6.5)1.8 (1.1–2.9)P=0.03P=0.85P<0.001P=0.02Tubular atrophy/interstitial fibrosis T0-1.36±7.2911 T1–2-3.28±7.97-1.4 (0.6)5.6 (4.2–7.5)2.6 (1.8–3.6)P<0.001P=0.01P<0.001<0.001Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate.Mesangial score >0.5 (M1), any endocapillary hypercellularity (E1), any segmental sclerosis (S1), tubular atrophy, and interstitial fibrosis (T1 and T2).a Multivariate models are adjusted for initial eGFR, follow-up blood pressure, and proteinuria. Open table in a new tab Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate. Mesangial score >0.5 (M1), any endocapillary hypercellularity (E1), any segmental sclerosis (S1), tubular atrophy, and interstitial fibrosis (T1 and T2). The VALIGA cohort included 219 patients with IgAN and initial proteinuria <0.5g/day, a subgroup not included in the original Oxford study (Supplementary Table 2S online). At the time of renal biopsy, the mean age of these patients was 32±17 years and 27% were children. Initial eGFR was 90±26ml/min per 1.73m2. All MEST lesions were significantly less frequent in this subgroup compared with the remaining cohort: M1 (15%), E1 (5%), S1 (50%), and T1/2 (6%; Figure 2). Initial and follow-up MAP values were lower than the whole group. Immunosuppression and RASB were given to 21 and 71% of these patients, respectively. Their rate of progression was -1.2±6.6ml/min per 1.73m2/year, and only 5% reached the combined outcome of 50% reduction in renal function and/or ESRD. The only significant MEST score predicting this outcome at univariate analysis was endocapillary proliferation (E1); P=0.04, HR 5.2 (1.1–25.9). No MEST score predicted renal outcome in multivariate analysis, even when age was included in the multivariate model. In this cohort of patients with initial low proteinuria, we calculated the risk of developing higher levels of proteinuria during the follow-up as a surrogate end point. Both M and E scores significantly influenced progression to levels of proteinuria ≥1 and ≥2g/day (Figure 3). Mesangial hypercellularity was significantly associated with the development of proteinuria ≥1g/day, P=0.012, HR 2.5 (1.2–5.1), and proteinuria ≥2g/day, P=0.01, HR 4.1 (1.4–12.0). Endocapillary hypercellularity was significantly associated with the development of proteinuria ≥1g/day, P=0.018, HR 2.8 (1.2–6.8), and proteinuria ≥2g/day, P=0.029, HR 4.2 (1.2–15.0). The HR of developing proteinuria ≥1 and ≥2g/day, with either M1 or E1, adjusted for MAP and RASB were 2.3 (1.3–4.0), P=0.004, and 3.5 (1.5–8.4), P=0.005, respectively. The VALIGA cohort included 99 patients who were not included in the original Oxford study because of a low initial eGFR (Supplementary Table 3S online). Their age at biopsy was 49±16 years, which was significantly higher than the cohort mean (P<0.001). They presented with a greater initial proteinuria (2.4g/day) and MAP (108±16mmHg) and displayed M1, S1, and T1-2 lesions more frequently compared with those with an initial eGFR ≥30ml/min per 1.73m2, being detected in 41, 92, and 77% of the cases, respectively (Figure 1). Only T1–2 correlated with proteinuria at renal biopsy in this group (P=0.04). These individuals had a higher blood pressure during follow-up despite receiving more antihypertensive drugs compared with the rest of the cohort (P<0.001). RASB was used in almost all patients (91%). Immunosuppressive drugs were also used more frequently (60% vs. 44%, P=0.004). The clinical outcome of patients with eGFR <30ml/min per 1.73m2 was significantly worse than in the remaining patients, with a survival from a combined event of only 50% at 5 years as opposed to 90% (P<0.001). M1 and T1–2 were associated with a lower survival from a combined event using univariate analysis. This significance was maintained in a multivariate model including five variables (S and E were excluded, as only eight patients presented with S0 and 11 with E1) and adjusted for initial eGFR, TA-MAP, and TA-proteinuria: M1 was associated with an HR of a combined event of 2.3 (1.2–4.2), P=0.009. Results did not change when age was included in the multivariate model. In the VALIGA cohort, 523 patients (46%) received glucocorticoid/immunosuppressive therapy and 622 (54%) did not. Those who received such treatment had a lower initial eGFR (70±32 vs. 76±29ml/min per 1.73m2, P=0.002) and higher initial proteinuria (1.9, IQ 1.0–3.5 vs. 0.9, IQ 0.4–1.9g/day, P<0.001). Otherwise, they had similar age, sex, ethnicity, and MAP (data not shown). However, individuals who received immunosuppression also had a greater prevalence of MEST lesions (M1, 32%; E1, 13%; S1, 78%, and T1/2, 25%) compared with untreated individuals (M1, 24%; E1, 9%; S1, 63%; and T1–2 18%, P<0.05 for all comparisons). The net reclassification index obtained by adding pathology to clinical variables was 11.5% (Table 4, P<0.001) in those who did not receive immunosuppression, whereas it was -0.9% (P=0.72) in those who did. To further address the impact of glucocorticoid/immunosuppressive therapy on the predictive value of pathology, we derived ROC curves using clinical, pathological, and clinicopathological models in treated and untreated individuals separately (Supplementary Figure 3S online). The areas under the curve in those without steroid/immunosuppressive therapy were 0.65, 0.72, and 0.75 with logistic models using pathology (M, S, T) or clinical (initial eGFR, TA-MAP, and TA proteinuria) variables, or both, respectively. In those who received immunosuppression, the areas under the curve were 0.57, 0.68, and 0.69, respectively. Hence, the added value of pathology was evident in those who did not receive glucocorticoid/immunosuppressive treatment, as the predictive value of pathology was reduced in those treated by immunosuppressive therapy.Table 4Net reclassification index using pathology in addition to clinical variables Download .jpg (.43 MB) Help with files Supplementary Figure S3 The VALIGA collaborative study has provided the largest reported cohort of patients with IgAN, unique in that the clinical and pathology data of the enrolled patients were categorized according to common criteria and centrally reviewed. The 1147 patients with IgAN represent the full spectrum of clinical presentations of this common but still challenging renal disease, encompassing, as in real clinical practice, its variety in age, histologic renal damage, renal function, proteinuria, blood pressure, and treatments. These patients were followed up for an average of 4.7 years, which is a reasonable duration, given their multicenter and international origin, thus providing a sufficient follow-up period to analyze renal functional decline and clinical outcomes. The VALIGA cohort does not depict the ‘natural history’ of IgAN, but rather the ‘nowadays history’ of this disease in Europe, as a large majority of patients were treated with RASB, and almost half of them were treated with steroid/immunosuppressive therapy. Moreover, almost 40% of patients had received RASB and 10% received corticosteroids before the renal biopsy. Early European randomized controlled trials in IgAN showed benefits of RASB,20.Praga M. Gutiérrez E. González E. et al.Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial.J Am Soc Nephrol. 2003; 14: 1578-1583Crossref PubMed Scopus (263) Google Scholar, 21.Coppo R. Peruzzi L. 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Rossini M. et al.Randomized controlled clinical trial of corticosteroids plus ACE-inhibitors with long-term follow-up in proteinuric IgA nephropathy.Nephrol Dial Transplant. 2009; 24: 3694-3701Crossref PubMed Scopus (203) Google Scholar and immunosuppressants,25.Ballardie F.W. Roberts I.S. Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy.J Am Soc Nephrol. 2002; 13: 142-148PubMed Google Scholar leading to the widespread use of these drugs in Europe, particularly in proteinuric cases, commonly considered at risk for progression.26.Reich H.N. Troyanov S. Scholey J.W. et al.Remission of proteinuria improves prognosis in IgA nephropathy.J Am Soc Nephrol. 2007; 18: 3177-3183Crossref PubMed Scopus (412) Google Scholar Even taking into account patient selection bias, it is clear that the functional decline in the VALIGA cohort is slower than that reported in previous European studies,27.Alamartine E. Sabatier J.C. Guerin C. et al.Prognostic factors in mesangial IgA glomerulonephritis: an extensive study with univariate and multivariate analyses.Am J Kidney Dis. 1991; 18: 12-19Abstract Full Text PDF PubMed Scopus (269) Google Scholar, 28.D'Amico G. Natural history of idiopathic IgA nephropathy: role of clinical and histological prognostic factors.Am J Kidney Dis. 2000; 36: 227-237Abstract Full Text Full Text PDF PubMed Scopus (447) Google Scholar presumably at least in part because most of those patients did not receive RASB or immunosuppressive treatments. The VALIGA