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

Abstract

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)?

Mechanisms and Treatment of CKD

“…4 The following years were devoted to investigating the pathogenic role of glomerular hypertension in the progression of renal disease and to assessing whether correction of this disordered adaptation -or maladaptation 5 -to nephron mass reduction is renoprotective. 6 three-quarters of the total renal mass in the rat, in addition to increase intraglomerular pressures, 1 led to abnormal glomerular permeability and proteinuria. At that time, proteinuria was considered a marker of the extent of glomerular damage, despite the fact that Franz Volhard and Theodor Fahr in 1914 8 and Wilhelm von Mollendorf and Philipp Stohr in 1924 9 had already found that exuberant protein excretion in the urine could per se promote renal injury.…”

Nephron Number, Hypertension, Renal Disease, and Renal Failure

“…Avoidance of infections and potentially harmful drugs is also wise. Finally, for those in whom elevated blood pressure or albuminuria has already appeared, multipronged therapy that includes renal protective drugs promises extension of life by many years (94).…”

Role of EGF Receptor Activation in Angiotensin II–Induced Renal Epithelial Cell Hypertrophy

“…This type of growth is known as compensatory renal hypertrophy and occurs after surgical renal ablation and in many chronic renal diseases (1)(2)(3). Although hypertrophic renal growth presumably augments functional capacity in compensation for nephron loss, excessive renal hypertrophy sometimes produces a maladaptive response and has been implicated in the development of further nephron damage, interstitial fibrosis, tubular atrophy, and a progressive decline in renal function, leading to ESRD, whereas attenuation of renal hypertrophy limits the progression of kidney damage (1)(2)(3)(4). Although all components of remaining nephrons are susceptible to varying degrees of hypertrophy, the proximal tubule is the nephron segment that consistently undergoes the most hypertrophy (4).…”