Rethinking Histological Assessment of IgAN

Treatment options for immunoglobulin A nephropathy (IgAN) have progressed substantially in recent years. However, since the Oxford Classification of IgAN was developed in 2009, the histologic stratification of patients with IgAN has failed to evolve. There is a need to better individualize prognosis and guide therapy utilizing factors other than proteinuria and renal function.

Bogdan Obrișcă, MD, and colleagues investigated the clinical significance of the light microscopy (LM) pattern of glomerular injury and intensity of mesangial C3 staining in IgAN to enhance histological assessment. The findings of their retrospective, observational study appeared in BMC Nephrology.

The study’s primary composite end point was doubling of serum creatinine or end-stage renal disease (ESRD; dialysis, renal transplant, or estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m²). The secondary end point was annual eGFR decline. The researchers reassessed the LM pattern of glomerular injury based on a modified Haas Classification. Mesangial C3 deposition by immunofluorescence (IF) staining was scored semiquantitatively.

The 214 adult patients included all had biopsy-proven primary IgAN with a minimum of 12 months of follow-up; 66.4% were male. Mean patient age was 41.4 ± 12.6 years, mean eGFR was 55.2 ± 31.5 mL/min/1.73 m², and median 24-hour proteinuria was 1.5 g/day (interquartile range [IQR], 0.80-3.25). The most frequent LM pattern was the mesangioproliferative (37.4%), followed by sclerotic (22.5%) and proliferative/necrotizing (21.4%).

Median follow-up was 49.1 months (IQR, 17.3-86.1), during which 29.0% of participants reached one of the events of the primary composite end­ point; 24.8% ultimately progressed to ESRD. Patients who progressed had worse renal function, higher proteinuria, higher mean arterial pressure at baseline, and lower serum C3 levels versus patients who did not reach the composite end point.

Mild-moderate and intense mesangial C3 staining was observed in 30.6% and 61.1% of patients, respectively. Patients with sclerosing and crescentic patterns had the worst renal survival, with 5-year renal survival of 48.8% and 42.9%, respectively. These patients also had the highest rate of eGFR change per year (−2.32 mL/min/1.73 m²/year and −2.16 mL/min/1.73 m²/year, respectively) versus those with other glomerular patterns of injury.

Patients with intense C3 staining reached the primary composite end point more often versus patients without intense C3 staining (35.5% vs 21.4%; P=.04). After multivariate adjustment, patients with crescentic and sclerosing patterns had a 3.6-fold and 2.1-fold higher risk, respectively, of reaching the composite end point compared with patients with mesangioproliferative pattern. Intense mesangial C3 deposition was associated with worse renal outcomes (hazard ratio, 3.33; 95% CI, 1.21-9.20).

Limitations of the study include its single center, retrospective nature; the inability to determine whether the activation of predominantly alternative or lectin pathway is related to renal outcome; and the inability to account for the impact of immunosuppressive therapy on renal outcomes due to the heterogeneity in terms of treatment interventions.

“In conclusion,” the study authors wrote, “there is a need to refine the histological assessment of IgAN, taking into account variables not included in the Oxford Classification, which could possibly suggest a different treatment approach. Accordingly, we have shown that the LM pattern of glomerular injury and the intensity of mesangial C3 deposition might stratify more accurately the renal outcome in patients with IgAN.”

Source: BMC Nephrology