Chronic Renal Failure: A Disorder of Adaptation

CHRONIC RENAL FAILURE: A DISORDER OF ADAPTATION BARRY M. BRENNER* . . . I would emphasize particularly the contrast between a low glomerularfiltration rate due to conditions imposed upon a kidney ofnormal size, as in L·artfailure, and a low glomendarfiltration rate due to hss of nephrons. In thefirst instance the rate offiltration per glomerulus w low, and in the second instance . . . it is high. The total effective renal function is reduced owing to loss of tissue, but the work of each remaining unit is increased. Workers in thefield of applied renal physiology havefrequently overlooked this essential distinction, and at the risk of overemphasis I will illustrate it by a similefrom industry. The total production or output of a factory mayfallfor one of two reasons. The team of workers may become slack or may not have enough to do, like the nephrons in L·artfailure; or the team may have been seriously depleted in numbers owing to illness, thefew remaining workers actually putting in overtime in an unsuccessful attempt to compensatefor the absence of theirfellows. The latter is the state of affairs in experimental renalfailure , as our obliging rats have clearly demonstrated, and there is good reason to believe that it is the state ofaffairs aho in chronic renalfailure in the human subject. If we only study die total production of thefactory, without regard to tL· output per man, or in the case of the kidney to overallfunction without regard to structure, wefail to distinguish between these two causes of inadequacy, and since the behaviour of the tubule cells is in a large measure dependent upon the rate at which glomerularfiltrate is reaching them, the distinction is ofprimary importance in tL· interpretation of tL· phenomena of renal disease.—R. Platt [1] The principal pathophysiologic derangement in chronic renal disease is the permanent loss of nephron units. Structural and functional adaptations in surviving nephrons partially compensate for these unit losses in early stages, but as renal disease advances these adaptations eventually prove inadequate. Until the studies of Oliver [2-6], Piatt [1, *Director, Renal Division, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115, and Center for the Study of Kidney Disease, Harvard Medical School.© 1989 by The University of Chicago. AU rights reserved. 0031-5982/89/3203-0634101.00 434 I Barry M. Brenner ¦ Chronic Renal Failure 7], Bricker [8-10], and others [11-14], however, it was generally believed that the surviving nephrons in chronic Bright's disease underwent progressive structural deterioration, with a given nephron within a diseased kidney no longer looking like or functioning like any other. Jean Oliver was the first to take exception with the view that a highly chaotic architectural state exists in the chronically diseased kidney, arguing instead that some nephron units (glomeruli and associated tubules) bear the brunt of injury and involute or atrophy, whereas other units less affected by the primary disease process undergo structural hypertrophy [3, 5, 6]. Nephrons microdissected from single diseased kidneys confirmed this striking divergence in glomerular and tubule volumes and lengths [3, 13]. While the involution of nephron units can readily be understood as the end result of injury induced by the primary disease, the basis for the structural hypertrophy of less affected units presented more of an enigma. In fact, the possibility that hypertrophy of undamaged nephrons was largely a function of the animal's dietary protein intake was suggested as early as 1939 in an all-but-forgotten paper by Smadel and Farr [15], who showed that the marked structural heterogeneity of the chronically diseased kidney could be largely prevented by concomitant protein restriction. This important observation has recently been confirmed by others [16, 17]. Such adaptational conditioning is not limited to spontaneously occurring or experimentally induced chronic renal disease. Following partial nephrectomy in the rat, compensatory hypertrophy and nephron hyperfunction occur in the remnant kidney when the animal is fed a generous protein-containing diet, but this hypertrophic response is blunted by dietary protein restriction [17]. Although normal glomeruli (and tubules) possess a remarkable degree of hemodynamic reserve, a decrease in their number beyond a certain limit may lead to a functional overload of the surviving units irrespective of the nature of the renal...