The intact nephron hypothesis in reverse: an argument to support incremental dialysis.

In this issue of NDT, Wong and associates define, describe and argue on behalf of the strategy of initiating hemodialysis in an incremental fashion [2]. They depict the history of this approach, which we have been advocating now for several decades for all dialysis modalities, including conventional in-center hemodialysis [3, 4]. Within the Wong et al. [2] review are observational data that, in the least, suggest an effect of residual kidney function preservation with incremental dialysis [5, 6], such that a call for a randomized trial has been proposed [7]. While we generally agree with these ideas, there are several more aspects to the importance of studying incremental dialysis and that is the purpose of this editorial. First, we expand on the hypothesis that an incremental approach to the initiation of dialysis might help preserve residual kidney function. Bricker’s original exposition of what he called the ‘intact nephron hypothesis’ [8] was an expansion on the earlier work of Hayman et al. [9] and Robert Platt [10, 11], and is really best understood from the Bricker et al. chapter in the First Edition of Brenner and Rector The Kidney [1]. Bricker and his colleagues laid out the evidence that as kidney diseases progress, the nephrons that remain increase their excretory rates to compensate for the damaged nephrons. Furthermore, ‘the surviving nephrons of the diseased kidney largely retain their essential functional integrity’ [8], which essentially means they act as a functioning unit with tubuloglomerular feedback. The surviving nephrons act as ‘super’ nephrons in many of their functions in what they called a ‘magnification phenomena’. This process of becoming ‘super’ nephrons is slow and adaptive. It probably differs by disease states as well as directed for specific solutes or other retained substances as kidney function deteriorates. For some substances there may be ‘no regulation’, versus ‘regulation with limitation’ versus ‘complete regulation’. The adaptations are designed to ‘deactivate’ the stimulus. Many of these adaptations are understood within the basic functioning of the kidney, such as an increase in single nephron glomerular filtration rate, decreased tubular reabsorption, or increased tubular secretion. Such adaptations require control systems. Renal physiologists have been studying these systems ever since. A decade later, Bricker expanded on the ‘intact nephron hypothesis’ in his exposition of the ‘trade-off hypothesis’ in which he described some of the adaptations in detail and wherein he noted that some adaptations actually carry consequences on other systems that may not be advantageous [12]. In other words short term adaptations to accommodate a dysfunction (e.g. decreased phosphate excretion) result in adverse effects later (e.g. hyperparathyroidism). A popular area of contemporary research that points out the importance of this hypothesis is the role of the phosphatonin fibroblast growth factor 23, which may have both short term beneficial and longer term adverse effects as its activity increases during progressive kidney failure [13, 14]. We believe that the body of evidence supports both the ‘intact nephron’ and ‘trade-off’ hypotheses. If the progressive nature of loss of renal function activates compensatory adaptations, then it follows that the initiation of dialysis may lead to the ‘deactivation’ of stimuli for certain adaptations and consequently the adaptive and maladaptive changes that result from these stimuli. In other words, the diseased kidney’s adaptation to nephron loss is potentially compromised. Volume expansionmay be one such stimulus and its loss by dialysis may play a role in renal functional decline, as discussed by Davenport [15]. The diseased kidney’s adaptation, so long in its development, may actually remain stimulated when dialysis is gently and incrementally introduced. This might occur in contradistinction to that seen in aggressive salvage dialysis, which may entirely ablate the stimuli for adaptations. In this manner, we can hypothesize the possible mechanism(s) by which incremental dialysis may help preserve residual kidney IN F O C U S