Clinico-pathological phenotypes of IgA nephropathy

Objective. The present study aimed to compare key demographic and clinical parameters with morphological features defined by the Oxford MEST-C classification, supplemented by additional quantitative assessment, in order to identify the principal clinico-morphological phenotypes of IgA nephropathy (IgAN).

Materials and Methods. This retrospective study included 2,679 patients with biopsy-proven IgAN. The mean age was 35.3±13 years. Clinical and laboratory variables (degree of hematuria, 24-hour proteinuria, and serum creatinine) were assessed at the time of biopsy. Morphological evaluation comprised Oxford MESTC scoring, quantitative assessment of of interstitial fibrosis/tubular atrophy (IFTA), global and segmental glomerulosclerosis, cellular/fibrocellular and fibrous crescents.

Results. At the time of biopsy, median proteinuria was 2.1 g/day (IQR: 0.75-3.0), estimated glomerular filtration rate (eGFR) was 60.4 mL/min (IQR: 33.3-84.16). Hematuria was detected in 88% of patients. The distribution of Oxford MEST-C lesions was as follows: M1, 37%; E1, 21%; S, 73%; T1, 37%; T2, 16%; C1, 16.5%; C2, 2.5%. The severity of proteinuria correlated with E and C lesions, as well as the extent of IFTA and both global and segmental glomerulosclerosis. Correlation coefficients were higher when lesions C and S were quantified (% involvement): 0.17 vs 0.24 and 0.07 vs 0.23, respectively. Decline in eGFR were associated with the degree of IFTA and the presence of crescents.

Based on clinicopathological correlations and morphological profiling, three distinct phenotypes of IgAN, likely reflecting different dominant mechanisms of disease progression, were identified:

Phenotype 1: (Typical): Defined by mesangial proliferation and segmental glomerulosclerosis. Clinically characterized by persistent microhematuria, gradually increasing proteinuria, and arterial hypertension.

Phenotype 2: (Aggressive): Defined by endocapillary hypercellularity with or without crescents. Clinically associated with acute nephritic syndrome, marked proteinuria – often at nephrotic range – and hematuria.

Phenotype 3: (Macrohematuric): Defined by focal necrosis of capillary loops and crescent formation in the absence of endocapillary hypercellularity. Clinically manifests with episodes of macroscopic hematuria; during remission, urinary abnormalities are typically absent and renal function remains preserved.

Conclusion. Identification of clinicopathological phenotypes in IgAN represents a promising strategy for personalizing therapy and refining prognostic assessment, thereby improving risk stratification for disease progression.

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