Remission of renal disease: recounting the challenge, acquiring the goal

Renal excretory function begins at the glomerular capillaries with the formation of a nearly ideal ultrafiltrate of plasma. The volume and composition of the ultrafiltrate undergo sequential change along the nephron, ultimately regulated to preserve near-constancy of mineral, electrolyte, and fluid balance. Modest derangement of these processes often escapes clinical or laboratory detection, because the myriad of unimpaired nephrons compensate more or less completely. Beyond a certain level of injury, however, compensatory adaptations no longer keep pace with nephron loss. As a result, glomerular filtration rate declines and organic nitrogenous wastes (e.g., creatinine, urea) accumulate in plasma and other body fluids. In acute renal failure, injury is usually transient, so that deterioration of function is short-lived and reversible. Not so, however, with the many forms of irreversible nephron damage, which typically progress over time, often eventuating in complete loss of renal function, systemic toxicity (uremia), and death unless the lost function is replaced by chronic dialysis and/or successful renal transplantation. Much of the effort in nephrology since the 1970s has been concerned with improving the effectiveness of these renal-replacement therapies. In the late 1960s, we fortuitously gained access to a unique strain of rats with many glomeruli that are situated on the renal cortical surface. For the first time, mammalian glomeruli were therefore accessible to direct study by new microtechniques developed in our laboratory. We therefore addressed the following questions: (a) What are the precise hemodynamic forces and biophysical properties that govern glomerular capillary function in health? (b) How are these elements modified during renal injury? (c) Do these modifications contribute to the relentless progression of renal disease? (d) If so, can they be reversed, so as to retard further deterioration of renal function and prevent end-stage renal disease (ESRD)?