Pharmacologic manipulation of glomerular functionter

Abstract

Normally, the glomerular filtration rate (GFR) is kept nearly constant. This is achieved by the autoregulation of the renal blood flow and by the tubuloglomerular feedback mechanism [1, 2]. Renal blood flow is in part autoregulated by changes in afferent arteriolar resistance. Thus, increases in systemic blood pressure will result in a constriction of the afferent arteriole whereas reductions in systemic blood pressure will induce a dilation of the afferent arteriole, rendering glomerular blood flow nearly constant. Nitric oxide and prostaglandins play an important role in this pressure-induced autoregulation [3]. Likewise, the tubuloglomerular feedback mechanism affects afferent arteriolar, but also efferent arteriolar resistance: a fall in GFR will lead to a diminished flow in the distal tubule and a decreased sodium and chloride content at the macula densa. As a result afferent arteriolar vasodilation and efferent arteriolar vasoconstriction will occur in order to restore glomerular filtration. On the other hand, if sodium delivery at the macula densa enhances, afferent vasoconstriction will ensue. Thus, the autoregulation of the renal blood flow and the tubuloglomerular feedback mechanism aim to keep GFR constant. Glomerular ultrafiltration is determined by four factors [2, 4–6]: (1) the glomerular plasma flow (Q A ); (2) the transcapillary hydrostatic pressure difference (ΔP), which is the difference between the hydrostatic pressure in the glomerular capillary and the hydrostatic pressure in Bowman's space, that is, in the proximal tubule; (3) the oncotic pressure in the glomerular capillary (Π GC ), which is the opposite force of ΔP; (4) the ultrafiltration coefficient of the glomerular basement membrane (K f ), being the product of the surface area for filtration and the effective hydraulic permeability of the capillary wall. Whereas throughout the capillary loops ΔP remains relatively constant, Π GC rises progressively as a result of filtration of protein-free fluid. Experimental studies in rats and primates have revealed that Π GC counterbalances ΔP before the end of the glomerular capillary, by which so-called filtration equilibrium ensues. It has not been elucidated whether in humans a filtration equilibrium normally exists also. Micropuncture studies in rats have demonstrated that Q A is the most important determinant of the glomerular ultrafiltration both in states of filtration equilibrium and filtration disequilibrium [4, 7]. In case of filtration equilibrium, a rise in Q A is followed by a proportional rise in glomerular ultrafiltration until filtration disequilibrium is reached. In case of filtration disequilibrium, a rise in Q A will be followed by a proportionally lesser rise in glomerular ultrafiltration. As a result the filtration fraction (FF), defined as the glomerular filtration rate divided by the glomerular blood (plasma) flow, will fall. In case of filtration equilibrium increments in ΔP will not affect GFR. On the other hand, an elevation in ΔP will induce a rise in glomerular ultrafiltration in cases of filtration disequilibrium, which will be associated with a rise in FF. Whenever pharmacological agents affect GFR, they will do so by affecting one or more of the above-mentioned determinants of the glomerular ultrafiltration. In humans the renal effects of pharmacologic agents are usually evaluated indirectly by utilizing clearance techniques to determine GFR, effective renal plasma flow (ERPF) and FF. Subsequently, observed changes in renal hemodynamics and FF are frequently used to deduce alterations in the tone of the renal resistance vessels and the determinants of glomerular ultrafiltration. By means of mathematical modelling, Carmines et al [8] pointed out that proportionally similar reductions in afferent and efferent arteriolar resistances will result in a fall in FF. Thus, changes in FF alone cannot be used to deduce alterations in the tone of the afferent and efferent arterioles, or in the determinants of glomerular ultrafiltration. This is especially so when the assumption holds true that filtration equilibrium does not exist in humans, since filtration disequilibrium implies that a rise in ERPF always will result in a proportionally lesser increase in GFR, and thus in a fall of the FF. However, if a pharmacological intervention results in opposite effects on GFR and ERPF, it must be assumed that changes in ΔP and K f have occurred. Since such changes in ΔP and K f may have additional or opposing effects on GFR and FF, the interpretation of observed modifications in FF and renal hemodynamics may not suffice to extrapolate changes in the determinants of glomerular ultrafiltration with certitude. Additional information may be obtained by simultaneous investigation of the urinary protein loss and/or dextran clearances.