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

Abstract

Key Points The first study that estimated single-nephron GFR (SNGFR) in patients with membranous nephropathy (MN).Associations of SNGFR with MN staging by electron microscopy and clinicopathologic findings were cross-sectionally investigated.This study illustrates a role for disease-specific GBM structural lesions as determinants of SNGFR in patients with MN. Background 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. Methods 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 nonglobally 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. Results The study included 109 patients with MN (mean age 65 years; 73% male; eGFR 62 ml/min, 36% on renin-angiotensin-aldosterone system inhibitors prebiopsy). 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 56–42 nl/min and 5.1–3.8 µg/d, 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 prebiopsy use of renin-angiotensin-aldosterone system inhibitors. By contrast, EC stage was not associated with glomerular volume and SNUPE after multivariable adjustment. Conclusions 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 glomerular basement membrane structural lesions as determinants of SNGFR.