Mechanism of glomerulotubular balance in the setting of heterogeneous glomerular injury. Preservation of a close functional linkage between individual nephrons and surrounding microvasculature.

Abstract

Autologous immune complex nephropathy (AICN), an experimental model for human membranous glomerulopathy, is characterized by marked heterogeneity in function from glomerulus to glomerulus. However, the fraction of the filtered load of fluid reabsorbed by the proximal tubule remains nearly constant from nephron to nephron, despite wide variation in single nephron glomerular filtration rate (SNGFR). To define the physiological mechanisms responsible for this marked variation in SNGFR values within a given kidney and for the remarkable preservation of glomerulotubular balance, the various determinants of fluid exchange across glomerular and peritubular capillary networks were evaluated in Munich-Wistar rats with AICN. For comparison, similar measurements were obtained in rats with the functionally more homogeneous lesion of heterologous immune complex nephropathy. In AICN rats studied approximately 5 mo after injection of renal tubule epithelial antigen (Fx1A), a high degree of glomerulus-proximal tubule balance was found, despite marked variations in SNGFR values within a single kidney. These changes were associated with marked heterogeneity in immunoglobulin and complement deposition within and among glomeruli. Although mean capillary hydraulic pressure and Bowman's space hydraulic pressure ranged widely from glomerulus to glomerulus, the mean glomerular transcapillary hydraulic pressure difference was remarkably uniform among these functionally diverse glomeruli and could not, therefore, be implicated as the cause of the dispersion in SNGFR values. The two remaining determinants of SNGFR, namely, glomerular plasma flow rate (Q(A)) and ultrafiltration coefficient (K(f)), varied markedly from glomerulus to glomerulus, but always in direct proportion to SNGFR, and proved to be responsible for the marked variation in SNGFR. The mean net peritubular capillary reabsorptive force ( P(r)) correlated closely with the absolute rate of fluid reabsorption in adjacent proximal tubules (APR) in AICN. Of the factors determining P(r), peritubular capillary hydraulic pressure was essentially constant in a given AICN kidney, whereas peritubular capillary plasma protein concentration and oncotic pressure varied directly with APR and largely accounted for the observed tight correlation between P(r) and APR. ON THE BASIS OF THESE OBSERVED CORRELATIONS, WE SUGGEST THAT THE CLOSE QUANTITATIVE COUPLING BETWEEN SNGFR AND APR IN INDIVIDUAL NEPHRONS IN AICN IS DUE TO THE FUNCTIONAL RESPONSE OF INDIVIDUAL GLOMERULI: those with the most pronounced declines in SNGFR are characterized by the most pronounced declines in Q(A) and K(f). The resultant low peritubular capillary oncotic pressure favors a decline in APR, thus favoring nearly perfect glomerulotubular balance. In glomeruli with higher SNGFR values, Q(A) and K(f) values are also higher. These changes in K(f) once again are capable of establishing the conditions in downstream peritubular capillaries, this time favoring augmented APR (i.e., high intracapillary oncotic pressure), again leading to nearly perfect glomerulotubular balance.