Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide and a leading cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in young adults. It is characterized by mesangial deposition of IgA-containing immune complexes in the glomeruli, leading to progressive renal injury and fibrosis over time. The clinical course of IgAN is highly variable, ranging from a benign, slowly progressive disease to rapid deterioration of renal function culminating in ESRD within a few years of diagnosis (1,2). Despite advances in understanding its pathogenesis, predicting the progression of IgAN remains a major clinical challenge. Traditionally, baseline parameters such as proteinuria, hypertension, and renal function at presentation have been considered important predictors of outcome (3,4). However, even patients with apparently mild disease may experience gradual renal function decline, underscoring the need for more reliable prognostic models that incorporate clinical, biochemical, and histopathological factors (5). Recent multicenter studies have identified several independent risk factors—such as persistent proteinuria, reduced estimated glomerular filtration rate (eGFR), hypertension, and specific Oxford MEST-C histopathological scores—that contribute to disease progression (6,7). Models such as the International IgA Nephropathy Prediction Tool, developed using global cohorts, have improved the ability to estimate the risk of progression to ESRD (8). However, regional variations in genetics, environmental exposure, and treatment practices necessitate validation and potential recalibration of such models for different populations (9). In developing countries, including India, the disease is increasingly recognized as a significant cause of CKD, but data on long-term renal outcomes and locally applicable risk prediction models are limited (10). Understanding prognostic indicators in local populations can guide early therapeutic interventions and help stratify patients based on their risk of progression. Rationale of the Study Given the variability in clinical presentation and disease progression, there is a crucial need to evaluate renal outcomes in patients with primary IgA nephropathy in our population and to develop or validate a model for estimating the risk of progression. Such a model would be valuable in clinical decision-making and long-term patient management. Aim and Objectives Aim: To study renal outcomes in patients with primary IgA nephropathy and to develop a model for estimating the risk of disease progression. Objectives: To evaluate the clinical, biochemical, and histopathological parameters at baseline in patients diagnosed with primary IgA nephropathy. To assess renal function outcomes over follow-up, including decline in eGFR, proteinuria, and progression to ESRD. To identify independent predictors of renal disease progression. To develop and validate a risk prediction model for estimating progression in primary IgA nephropathy

Study Design and Setting This was a prospective observational cohort study conducted in the Department of Nephrology at a tertiary care teaching hospital in India over a period of five years (November 2017 to March 2023). The study was approved by the Institutional Ethics Committee, and written informed consent was obtained from all participants prior to enrolment. Study Population All adult patients (aged ≥18 years) with biopsy-proven primary IgA nephropathy were eligible for inclusion. The diagnosis of IgA nephropathy was established by renal biopsy demonstrating dominant or co-dominant mesangial deposition of IgA on immunofluorescence microscopy, in the absence of any systemic disease known to cause secondary IgA deposition (such as Henoch–Schönlein purpura, chronic liver disease, lupus nephritis, or infection-related glomerulonephritis). Inclusion Criteria Age 18 years or older. Histopathological confirmation of primary IgA nephropathy. Baseline renal function and proteinuria data available at diagnosis. Minimum follow-up period of 12 months. Exclusion Criteria Secondary IgA nephropathy (due to liver disease, autoimmune disease, or infection). Concomitant glomerular disease (membranous, focal segmental glomerulosclerosis, etc.). Incomplete follow-up data or loss to follow-up before one year. Prior renal transplantation. Baseline Clinical and Laboratory Assessment At presentation, demographic data, clinical features, and laboratory findings were recorded. The following parameters were included: Age, sex, blood pressure, and body mass index (BMI) Serum creatinine and estimated glomerular filtration rate (eGFR) calculated using the CKD-EPI equation Urinary protein excretion quantified by 24-hour urine collection or spot urine protein-to-creatinine ratio (UPCR) Serum albumin, hemoglobin, and lipid profile Histopathological findings graded according to the Oxford MEST-C classification: Mesangial hypercellularity (M), Endocapillary hypercellularity (E), Segmental sclerosis (S), Tubular atrophy/interstitial fibrosis (T), and presence of Crescents (C). Follow-up and Outcome Measures Patients were followed at 3–6 month intervals for clinical assessment and laboratory testing. Blood pressure, serum creatinine, and proteinuria were measured at each visit. The primary outcome was progression of renal disease, defined as: ≥50% decline in eGFR from baseline, or Progression to end-stage renal disease (ESRD) (eGFR <15 mL/min/1.73 m² or need for dialysis/transplant).The secondary outcomes included changes in proteinuria, blood pressure control, and overall renal survival during follow-up. Treatment Protocol Patients were managed according to KDIGO 2021 Clinical Practice Guidelines. Those with proteinuria ≥1 g/day and preserved renal function received optimized supportive therapy, including renin-angiotensin system (RAS) blockade (ACE inhibitors or ARBs), strict blood pressure control, and dietary sodium restriction. Patients with persistent proteinuria ≥1 g/day despite ≥6 months of optimized therapy were considered for immunosuppressive therapy (oral corticosteroids ± azathioprine or mycophenolate mofetil), based on clinical judgment and biopsy findings. Statistical Analysis Data were analyzed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation (SD) or median (interquartile range, IQR) depending on distribution. Categorical variables were expressed as percentages. Renal survival was estimated using the Kaplan–Meier method, and differences between groups were compared using the log-rank test. Predictors of renal progression were identified using univariate and multivariate Cox proportional hazards regression analysis. Variables with p < 0.10 in univariate analysis were included in the multivariate model. A risk prediction model was developed using the regression coefficients (β) of significant variables from the multivariate model. The model’s discrimination was assessed using the area under the receiver operating characteristic (ROC) curve (AUC), and calibration was evaluated using the Hosmer–Lemeshow goodness-of-fit test. A p-value <0.05 was considered statistically significant.

Baseline Characteristics A total of 120 patients with biopsy-proven primary IgA nephropathy were included in the study. The mean age at diagnosis was 32.8 ± 10.4 years, and 72 (60%) were males. The median duration of follow-up was 56 months (IQR 36–72 months). At presentation, hypertension was present in 68 patients (56.7%), and the mean systolic and diastolic blood pressures were 138 ± 16 mm Hg and 86 ± 10 mm Hg, respectively. The mean baseline serum creatinine was 1.58 ± 0.62 mg/dL, and the mean eGFR was 68.4 ± 24.7 mL/min/1.73 m². Median proteinuria was 1.8 g/day (IQR 0.9–3.2 g/day). Histopathological evaluation according to the Oxford MEST-C classification revealed mesangial hypercellularity (M1) in 65 (54.2%), endocapillary hypercellularity (E1) in 28 (23.3%), segmental sclerosis (S1) in 58 (48.3%), tubular atrophy/interstitial fibrosis (T1/T2) in 36 (30%), and crescents (C1/C2) in 14 (11.7%) patients. Table 1 summarizes the baseline demographic, clinical, and histopathological features of the study population. Parameter Value Age (years, mean ± SD) 32.8 ± 10.4 Male, n (%) 72 (60) Hypertension, n (%) 68 (56.7) Baseline serum creatinine (mg/dL) 1.58 ± 0.62 Baseline eGFR (mL/min/1.73 m²) 68.4 ± 24.7 Proteinuria (g/day, median [IQR]) 1.8 (0.9–3.2) Serum albumin (g/dL) 3.6 ± 0.7 Hemoglobin (g/dL) 11.2 ± 1.8 Oxford MEST-C lesions, n (%) M1 65 (54.2) E1 28 (23.3) S1 58 (48.3) T1/T2 36 (30.0) C1/C2 14 (11.7) Follow-up and Treatment All patients received optimized supportive therapy including RAS blockade and blood pressure control. Immunosuppressive therapy was given to 42 patients (35%) who had persistent proteinuria ≥1 g/day after ≥6 months of supportive treatment. Corticosteroids alone were used in 26 cases (21.7%), and steroids with azathioprine or mycophenolate mofetil in 16 cases (13.3%). During follow-up, proteinuria remission (<0.5 g/day) was achieved in 44 patients (36.7%), partial remission (0.5–1 g/day) in 28 (23.3%), and persistent proteinuria >1 g/day was observed in 48 (40%). Renal Outcomes At the end of follow-up, 28 patients (23.3%) met the composite endpoint of disease progression, including: 18 (15%) with ≥50% decline in eGFR, and 10 (8.3%) who progressed to end-stage renal disease (ESRD) requiring dialysis or transplantation. The mean annual rate of eGFR decline among progressors was –5.6 ± 2.3 mL/min/1.73 m²/year, compared to –0.9 ± 1.8 mL/min/1.73 m²/year in non-progressors (p < 0.001). Renal survival at 3 and 5 years, estimated by the Kaplan–Meier method, was 92.3% and 79.6%, respectively. Predictors of Disease Progression Univariate Cox regression identified the following baseline factors significantly associated with disease progression: Proteinuria ≥1 g/day (HR 2.64; 95% CI 1.46–4.78; p = 0.001) Hypertension (HR 2.12; 95% CI 1.17–3.86; p = 0.013) Baseline eGFR < 60 mL/min/1.73 m² (HR 3.45; 95% CI 1.87–6.33; p < 0.001) T1/T2 lesions (HR 3.21; 95% CI 1.68–6.12; p < 0.001) S1 lesions (HR 1.94; 95% CI 1.01–3.72; p = 0.045) On multivariate Cox regression, independent predictors of progression were: Baseline eGFR < 60 mL/min/1.73 m² (adjusted HR 2.91; 95% CI 1.51–5.61; p = 0.001) Proteinuria ≥ 1 g/day (adjusted HR 2.37; 95% CI 1.21–4.62; p = 0.012) T1/T2 lesions (adjusted HR 2.76; 95% CI 1.36–5.59; p = 0.005) Development of Risk Prediction Model Based on multivariate analysis, a risk prediction score was constructed using regression coefficients (β) from the final Cox model. Each variable was assigned points proportional to its β coefficient (Table 2). Variable β Coefficient Adjusted HR (95% CI) p-value Score eGFR < 60 mL/min/1.73 m² 1.07 2.91 (1.51–5.61) 0.001 2 Proteinuria ≥ 1 g/day 0.86 2.37 (1.21–4.62) 0.012 1 T1/T2 lesion (Oxford) 1.01 2.76 (1.36–5.59) 0.005 2 Total risk score range: 0–5 points. Patients were stratified into three risk categories: Low risk (0–1 points): 3-year renal survival 97.1% Intermediate risk (2–3 points): 3-year renal survival 88.4% High risk (4–5 points): 3-year renal survival 68.5% (p < 0.001 by log-rank test). The model demonstrated good discrimination (AUC = 0.83; 95% CI 0.74–0.91) and acceptable calibration (Hosmer–Lemeshow p = 0.28).

In this prospective cohort of 120 patients with biopsy-proven primary IgA nephropathy, nearly one-fourth (23.3%) experienced significant renal disease progression over a median follow-up of 56 months. The independent predictors of renal progression identified in our study were baseline eGFR <60 mL/min/1.73 m², proteinuria ≥1 g/day, and tubulointerstitial fibrosis (T lesions) on renal biopsy. These findings are consistent with the established prognostic indicators described in prior international cohorts (11–13). Clinical and Pathological Predictors of Progression Baseline renal function has consistently emerged as one of the strongest predictors of long-term renal survival in IgA nephropathy. In our study, patients with baseline eGFR <60 mL/min/1.73 m² had nearly a threefold higher risk of progression, similar to previous studies where low eGFR was associated with rapid functional decline and progression to ESRD (14). Proteinuria, another key marker, was independently associated with adverse outcomes. Persistent proteinuria ≥1 g/day doubled the risk of progression, reinforcing earlier observations that time-averaged proteinuria is a critical modifiable determinant of prognosis (15,16). The role of histopathological features, particularly tubulointerstitial fibrosis and atrophy (T lesions), was also validated. The T score reflects chronic structural damage and correlates with irreversible nephron loss and long-term renal dysfunction (17,18). In our cohort, patients with T1/T2 lesions had an adjusted hazard ratio of 2.76 for disease progression. This finding aligns with the Oxford Classification updates (2016), which reaffirmed the prognostic significance of T lesions and highlighted their value in clinical decision-making (19). Comparison with International Studies The proportion of patients progressing to ESRD (8.3%) in our study is comparable to other regional studies from Asia. In a large Chinese cohort, Zhang et al. reported a 10-year ESRD incidence of 9.8%, whereas Barbour et al. in a multiethnic international cohort found ESRD progression in 14% of patients over a median follow-up of 6.4 years (20,21). Differences in treatment practices, genetic susceptibility, and environmental factors may explain the variations across populations. Our renal survival rates—92.3% at 3 years and 79.6% at 5 years—are similar to survival estimates in other South Asian series (22,23). However, delayed diagnosis and limited access to early nephrology care in resource-limited settings may contribute to worse long-term outcomes. Risk Prediction and Model Development A major objective of the present study was to develop a risk prediction model for estimating disease progression. Using multivariate Cox regression, we derived a simple scoring system incorporating three readily available baseline parameters: eGFR, proteinuria, and T lesions. This model demonstrated good discrimination (AUC = 0.83) and calibration. Our model parallels the structure of the International IgA Nephropathy Prediction Tool, which includes clinical and histopathologic variables to predict the 5-year risk of a 50% decline in eGFR or ESRD (24). However, as suggested by Barbour et al., regional calibration is crucial, since risk estimates may vary by ethnicity and treatment exposure (25). The locally derived model in our cohort offers a more population-specific approach for risk stratification in Indian patients. Impact of Treatment Approximately one-third of our patients received corticosteroid-based immunosuppression, consistent with KDIGO 2021 recommendations for persistent proteinuria despite supportive therapy (26). Notably, patients achieving proteinuria remission (<0.5 g/day) demonstrated significantly better renal outcomes, confirming that proteinuria control remains a key therapeutic target. Similar outcomes were observed in studies by Reich et al. and Coppo et al., emphasizing the importance of remission in modifying disease trajectory (27,28). Pathophysiological Correlation The pathogenic link between persistent proteinuria, tubular injury, and fibrosis underscores the interplay between hemodynamic and inflammatory mechanisms in IgA nephropathy (29). Chronic glomerular leakage of protein contributes to tubular activation, cytokine release, and interstitial fibrosis, which ultimately determine renal outcome. The strong association of T lesions in our model highlights the significance of early intervention before irreversible damage ensues. Strengths and Limitations The strengths of this study include its prospective design, uniform histopathological assessment using the Oxford MEST-C classification, and adequate follow-up duration for outcome evaluation. The study also provides locally relevant data on long-term renal outcomes in Indian patients with IgA nephropathy, a group underrepresented in global prediction tools. However, several limitations must be acknowledged. The study was conducted at a single tertiary center with a moderate sample size, which may limit the generalizability of findings. Additionally, treatment heterogeneity and absence of time-averaged proteinuria analysis could have influenced outcome estimates. Future multicentric studies with external validation are warranted to refine and calibrate the proposed risk model. Clinical Implications The results reinforce that baseline eGFR, proteinuria, and tubulointerstitial fibrosis are key determinants of progression in IgA nephropathy. The risk model derived here provides a simple, clinically applicable tool to identify high-risk patients who may benefit from closer follow-up and early therapeutic intervention. Integration of such models into clinical practice can improve individualized patient care and optimize resource utilization.

Primary IgA nephropathy demonstrates a variable clinical course, with approximately one-fourth of patients showing progressive renal dysfunction over 5 years. Low baseline eGFR, persistent proteinuria, and tubulointerstitial fibrosis were the most significant predictors of poor renal outcome. The proposed risk prediction model, based on these variables, effectively stratifies patients by progression risk and can assist clinicians in prognostication and treatment planning. Further validation in larger, multicentric cohorts is recommended.

1.Wyatt RJ, Julian BA. IgA nephropathy. N Engl J Med. 2013;368(25):2402–14. 2.D’Amico G. Natural history of idiopathic IgA nephropathy: Role of clinical and histological prognostic factors. Am J Kidney Dis. 2000;36(2):227–37. 3.Bartosik LP, Lajoie G, Sugar L, Cattran DC. Predicting progression in IgA nephropathy. Am J Kidney Dis. 2001;38(4):728–35. 4.Reich HN, Troyanov S, Scholey JW, Cattran DC. Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol. 2007;18(12):3177–83. 5.Coppo R, Troyanov S, Bellur S, Cattran D, Cook HT, Feehally J, et al. Validation of the Oxford classification of IgA nephropathy. Kidney Int. 2014;86(4):828–36. 6.Trimarchi H, Barratt J, Cattran DC, Cook HT, Coppo R, Haas M, et al. Oxford classification of IgA nephropathy 2016: An update from the IgA Nephropathy Classification Working Group. Kidney Int. 2017;91(5):1014–21. 7.Goto M, Wakai K, Kawamura T, Ando M, Endoh M, Tomino Y. Risk stratification for progression of IgA nephropathy using a decision tree induction algorithm. Nephrol Dial Transplant. 2009;24(4):1242–7. 8.Barbour SJ, Coppo R, Zhang H, Liu ZH, Suzuki Y, Matsuzaki K, et al. Evaluating a new international risk-prediction tool in IgA nephropathy. JAMA Netw Open. 2021;4(7):e2117353. 9.Knoop T, Vikse BE, Svarstad E, Leh S, Bjørneklett R. Mortality in patients with IgA nephropathy. Am J Kidney Dis. 2013;62(5):883–90. 10.Chacko B, John GT, Neelakantan N, Korula A, Kirubakaran MG, Jacob CK. Primary IgA nephropathy: A ten-year analysis on the renal outcome. Indian J Nephrol. 2004;14(2):64–71. 11.Le W, Zeng CH, Liu Z, et al. Clinical and pathological features of IgA nephropathy with mild proteinuria. Kidney Int. 2012;81(7):790–7. 12.Lv J, Zhang H, Zhou Y, et al. Natural history of IgA nephropathy and predictive factors of prognosis: a long-term follow-up study. Am J Kidney Dis. 2013;62(6):891–9. 13.Berthoux FC, Mohey H, Afiani A. Natural history of primary IgA nephropathy. Semin Nephrol. 2008;28(1):4–9. 14.Tanaka S, Ninomiya T, Katafuchi R, et al. Development and validation of a prediction rule using the Oxford classification in IgA nephropathy. Clin J Am Soc Nephrol. 2013;8(12):2082–90. 15.Reich HN, Troyanov S, Scholey JW, Cattran DC. Remission of proteinuria improves prognosis in IgA nephropathy. J Am Soc Nephrol. 2007;18(12):3177–83 16.Feehally J, Coppo R, Troyanov S, et al. The Oxford classification of IgA nephropathy: an update from the IgA Nephropathy Classification Working Group. Kidney Int. 2016;89(4):738–53. 17.Trimarchi H, Barratt J, Cattran DC, et al. Oxford classification of IgA nephropathy 2016: an update. Kidney Int. 2017;91(5):1014–21. 18.Coppo R, D’Amico G. Factors predicting progression of IgA nephropathies. J Nephrol. 2005;18(5):503–12. 19.Katafuchi R, Joh K, Hori K, et al. Validation of the Oxford classification in a Japanese cohort with IgA nephropathy. Am J Kidney Dis. 2011;58(5):829–36. 20.Zhang H, Chen W, Huang F, et al. A long-term cohort study of IgA nephropathy in Chinese adults. Nephrol Dial Transplant. 2014;29(9):1737–42. 21.Barbour SJ, Coppo R, Zhang H, et al. Evaluating a new international risk-prediction tool in IgA nephropathy. JAMA Netw Open. 2021;4(7):e2117353. 22.Chacko B, John GT, Neelakantan N, et al. Primary IgA nephropathy: a ten-year analysis on the renal outcome. Indian J Nephrol. 2004;14(2):64–71. 23.Abraham G, Reddy Y, Amalorpavanathan J, et al. IgA nephropathy: clinical profile and natural course in Indian patients. Ren Fail. 2008;30(1):55–60. 24.Barbour SJ, Reich HN, Cattran DC. The Oxford classification of IgA nephropathy: rationale, findings, and implications. Curr Opin Nephrol Hypertens. 2018;27(3):168–76 25.Coppo R, Durlik M, Bellur S, et al. Validation of the Oxford classification in cohorts with different ethnic origins. Nephrol Dial Transplant. 2014;29(9):1715–24 26.KDIGO Clinical Practice Guideline for Glomerular Diseases. Kidney Int Suppl. 2021;100(4S):S1–S150. 27.Reich HN, Troyanov S, Scholey JW, et al. Remission of proteinuria as a therapeutic target in IgA nephropathy. Kidney Int. 2013;84(6):1128–35. 28.Coppo R, Troyanov S, Bellur S, et al. The role of immunosuppression in IgA nephropathy: insights from the VALIGA study. J Am Soc Nephrol. 2017;28(8):2247–58. 29.Suzuki H, Kiryluk K, Novak J, et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol. 2011;22(10):1795–803.