MECHANISMS OF PROGRESSIVE GLOMERULAR INJURY IN MEMBRANOUS NEPHROPATHY

Glomerular function and structure were serially evaluated in 15 patien ts with membranous nephropathy who exhibited relapsing nephrosis and c hronic depression of GFR. GFR declined from 56 +/- 8 (mean +/- SEM) at onset to 31 +/- 3 ml/min per 1.73 m(2) after a 2- to 5-yr period of o bservation (P < 0.05). An analysis of filtration dynamics suggested pe rsistent elevation of net ultrafiltration pressure. To examine a possi ble role for declining intrinsic glomerular filtration capacity as the basis for the observed hypofiltration, glomeruli in the baseline and a repeat biopsy (performed after a median of 28 mo) were subjected to morphometric analysis and mathematical modeling. Analysis of the basel ine biopsy revealed a reduction in filtration slit frequency and thick ening of the glomerular basement membrane, lowering computed hydraulic permeability by 66% compared with normal kidney donors. In contrast, filtration surface area was increased by 37% as a result of glomerular hypertrophy. The repeat biopsy revealed persistent depression of hydr aulic permeability, primarily owing to foot process broadening. An add itional finding was a decrease in filtration surface area from baselin e in patent glomeruli, possibly due to encroachment on the capillary l umen of an increasingly widened basement membrane. Also, a striking in crease in the prevalence of global glomerulosclerosis from 7 +/- 2% to 23 +/- 4% was found between the two biopsies, suggesting a significan t loss of functioning nephrons. It is concluded that hypofiltration in membranous nephropathy is the consequence of a biphasic loss of glome rular ultrafiltration capacity, initially owing to impaired hydraulic permeability that is later exacerbated by a superimposed loss of funct ioning glomeruli and of filtration surface area.