Single-Nephron GFR in Different Glomerular Basement Membrane Stages of Membranous Nephropathy.

Abstract

Alterations in single-nephron dynamics have been demonstrated in animal models of membranous nephropathy (MN). This study applied a recently developed technique to estimate single-nephron parameters in human MN. Single-nephron GFR (SNGFR) and single-nephron urinary protein excretion (SNUPE) were calculated by dividing total GFR and UPE by the total estimated number of non-sclerotic glomeruli (NSG). The NSG number per kidney was estimated using cortical volume assessment and biopsy-based stereology. MN staging by electron microscopy was performed using Ehrenreich-Churg (EC) criteria. Single-nephron parameters were analyzed in relation to clinicopathological factors known to associate with disease outcomes. The study included 109 MN patients (mean age 65 years; 73% male; eGFR 62 mL/min, 36% on renin-angiotensin aldosterone system [RAAS] inhibitors pre-biopsy). EC stages were I, 19%;II, 49%; III, 26%; and IV, 6%. There was no difference in glomerular volume among EC stage groups. With advancing EC stage, SNGFR and SNUPE decreased from mean 56 to 42 nL/min and 5.1 to 3.8 μg/day, respectively. In multivariable models, EC stage was associated with SNGFR even after adjustment for key clinicopathological factors, such as reduced GFR, serum albumin, UPE, segmental glomerulosclerosis, chronic tubulointerstitial damage and pre-biopsy use of RAAS inhibitors. In contrast, EC stage was not associated with glomerular volume and SNUPE after multivariable adjustment. These results provide the first clinical evidence of alterations in single-nephron dynamics with advancing EC stage of human MN and support a role for disease-specific GBM structural lesions as determinants of SNGFR.