Glomerular Density in Renal Biopsy Specimens Predicts the Long-Term Prognosis of IgA Nephropathy

Background and objectives: An early histopathologic predictor of the renal prognosis, before the occurrence of advanced glomerular sclerosis/interstitial fibrosis and/or apparent renal dysfunction, remains to be established in IgA nephropathy (IgAN). This study aimed to determine whether the glomerular density (GD; nonsclerotic glomerular number per renal cortical area) of biopsy specimens obtained at an early stage of IgAN could predict the long-term renal outcome.Design, setting, participants, & measurements: The predictive value of the factors at biopsy, including the GD, on the renal outcome was retrospectively analyzed for 98 patients who had IgAN with an estimated GFR of ≥60 ml/min per 1.73 m² at biopsy (87 ml/min per 1.73 m² on average).Results: The individual value of GD in biopsy ranged from 1.2 to 8.1/mm² (i.e., approximately a seven-fold variation), and the GD showed a close inverse correlation with mean glomerular volume. Among the various clinicopathologic factors involved, both a cellular/fibrocellular crescent and the GD were found to be significant predictors of progression in multivariate analyses. A low GD in the biopsy specimens was frequently associated with a steeper slope of the renal function and a synergistically enhanced risk for progression with the presence of cellular/fibrocellular crescent. The renal function, proteinuria, degrees of glomerulosclerosis, and interstitial fibrosis at biopsy were not independent predictors of the prognosis in these patients.Conclusions: A strong predictive relationship of low GD with progression observed in this study suggests that GD may serve as an early histopathologic marker of long-term renal prognosis in IgAN.The outcome of IgA nephropathy (IgAN) is highly variable among individuals (1–4). Some patients maintain only isolated urinary symptoms for many years, whereas other patients progress to ESRD. Previous studies have consistently identified various clinicopathologic parameters at the time of diagnosis, especially heavy proteinuria, reduced renal function, advanced glomerular sclerosis, or tubulointerstitial fibrosis, as independent risk factors for progression (4–7); however, these findings characterize already advanced renal injury rather than reflect the progression rate of renal diseases. The factors that may allow prediction of progression in early stage of IgAN remain to be fully elucidated.We recently performed a study using pairs of serial biopsy specimens from 18 patients with progressive IgAN (8). In these patients, renal biopsies were performed both before and after the establishment of impaired renal function. We found a low glomerular density (GD; the number of nonsclerotic glomeruli per renal cortical area) in the first biopsy to be associated with both the already enlarged glomeruli and an increased susceptibility to subsequent renal scarring and a more rapid progression. A high GD in the first biopsy was associated with a relatively slow progression despite a large increase in the glomerular size in the second biopsy. These results were consistent with the currently proposed concept that kidneys with a reduced nephron number, presumably having less of a functional reserve, may cause glomerular enlargement, thereby becoming more susceptible to subsequent renal injury and functional decline (9–11). We therefore hypothesized that the GD in the early stage of “potentially progressive” renal diseases, such as IgAN, can predict subsequent renal adaptation and/or scarring and thus serve as an early marker of renal prognosis.By analyzing a larger number of patients, this study aimed to clarify the relationship between GD and the long-term renal outcome of patients with IgAN and without any apparent renal dysfunction at the time of biopsy. In addition to the patients who showed a progressive loss of renal function, this study included patients whose renal function had been stable for a long time.