Renal Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Syndrome of increased single-nephron glomerular filtration rateThere are certain renal diseases the courses of which are so severe and rapid as to completely destroy the structure and function of previously normal kidneys and to cause irreversible end-stage renal failure. Examples of such diseases are acute cortical necrosis, acute renal artery/vein thrombosis, rapidly progressive glomerulonephritis and bilateral ureteric obstruction. In these cases a ‘single hit’ is sufficient to cause total and permanent loss of renal function. On the other hand, the majority of progressive renal diseases encountered in clinical practice take on a less rapid course of progression, often after an insidious onset, making it difficult to define the nature of the initial insult to the kidney. Moreover, in many cases the presence of a specific condition (e.g. hypertension, diabetes mellitus) causes renal injury in some patients but not in others, suggesting that these potential renal insults interact with other factors in the pathogenesis of chronic renal disease.In the early 1980s Hostetter and coworkers demonstrated that substantial loss of nephrons in rats after surgical removal of 5/6 of renal mass led to a compensatory increase in the single-nephron glomerular filtration rate (SNGFR) in the remaining functioning nephrons, resulting from increases in glomerular plasma flow rate (QA) and glomerular capillary hydraulic pressure (PGC) [1••]. In the long term these mechanisms proved to be maladaptive by causing a self-perpetuating progressive renal injury, leading to end-stage renal failure. The most injurious of these maladaptive events was shown to be increased PGC by demonstrating the renal protective effects of angiotensin converting enzyme inhibitors, which reduce PGC but not SNGFR or QA[2••]. The implications of this hemodynamic theory were that any factor(s) which increased PGC would predispose the individual to chronic renal disease. While increased PGC occurs only after substantial reduction of nephron number, increased SNGFR and QA occur with milder deficits of nephrons. Even with normal PGC, increased SNGFR per se is a compensatory phenomenon, which involves exhaustion of the reserve filtration capacity. Therefore any event which increases SNGFR would also predispose the individual to renal disease by increasing the probability that a subsequent hit would completely exhaust the renal reserve (Fig. 1).Whole kidney GFR correlates with body weight during growth and in conditions of increased body mass such as obesity, pregnancy and acromegaly. Thus the number of functioning nephrons in relation to body mass appears to be the major determinant of SNGFR. Unfortunately, we do not yet have a reliable indirect method of estimating SNGFR in humans, and therefore cannot measure the number of functioning nephrons in such entities as renal dysplasias, essential hypertension, obesity, advanced age or any other state of absolute or relative reduction in nephron number. For this reason the state of reduced nephron number (oligonephronia) remains undiagnosable unless renal biopsy is performed. Nevertheless we can identify a group of risk factors predisposing to renal diseases (Table 1) and associated with renal hemodynamic adaptation. The common features which characterize these predispositions are increased SNGFR, glomerular permselectivity changes manifested by micro- or macroalbuminuria, systemic hypertension, increased prevalence of glomerular sclerosis (focal and segmental or diffuse and global), and insulin resistance or overt diabetes mellitus (Table 2).Congenital reduction of nephron numberOligomeganephroniaThe most severe and obvious form of congenital reduction in nephron number in humans is a rare disorder called oligomeganephronia.