Relaxin mechanistic effects on renal hemodynamics and natriuresis: a mathematical modeling approach

Abstract

Relaxin (RLX) is a hormone that stimulates renal vasodilation during early pregnancy. Recombinant RLX may have potential as a treatment for heart failure and chronic kidney disease, but its application has been limited in part due to uncertainties about its mechanism of action, and particularly its effect on glomerular capillary hydrostatic pressure (P gc ) and fluid status. The objective of this study was to couple mathematical modeling with experimental observations of the renal hemodynamic and natriuretic response to RLX, in order to quantitatively describe the mechanistic effects of relaxin on the kidney, and to predict its effect on clinically difficult-to-measure variables such as P gc . Utilizing a previously developed mathematical model of kidney function and hemodynamics, we began by hypothesizing a minimum set of RLX mechanisms (afferent/efferent vasodilation), fitting the available hemodynamic/natriuretic response in two previously published rat studies (GFR, renal plasma flow (RPF), mean arterial pressure (MAP), sodium and water excretion), and adding additional RLX mechanisms to the model only when the minimal set could not explain available data. We found that changes in renal vascular resistances alone were sufficient to reproduce observed changes in RPF, but insufficient to explain other data features. Experimental studies reported much larger increases in sodium excretion relative to water excretion with RLX, and this effect could only be reproduced if an effect of RLX on the osmotic setpoint for vasopressin release was included in the model – a mechanism that has previously been reported in ovariectomized rats treated with RLX. A small effect of RLX on heart rate was necessary to produce observed changes in MAP.In addition, the single experimental study in which P gc has been measured with RLX reported a rise in GFR but fall in P gc , and this difference could not be explained mathematically by relative afferent/efferent dilation or by downstream shifting of the filtration equilibrium with increased RPF; it could only be reproduced mathematically if RLX was assumed to large positive effect on glomerular membrane permeability. However, the magnitude of this effect is difficult to justify physiologically. Thus, while the model can be forced to fit this limited data, further study is needed to understand whether and how RLX might have such large permeability effects.The fitted model was then able to make predictions consistent with observed renal responses in human subjects, and these effects were better predicted when the RLX effect on permeability was excluded, further suggesting that this effect may not be real. In these simulations, RLX had no net effect on P gc . In conclusion, while some uncertainty remains, this analysis suggests that RLX acts primarily by dilating the afferent and efferent arterioles and shifting the osmotic setpoint for vasopressin release. AstraZeneca and Eli Lilly This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.