Sudeep Pradhan1, Stephen B Duffull1, Robert J Walker2, Daniel F B Wright3. 1. School of Pharmacy, University of Otago, PO Box 56, Dunedin, 9054, New Zealand. 2. Department of Medicine, University of Otago, Dunedin, New Zealand. 3. School of Pharmacy, University of Otago, PO Box 56, Dunedin, 9054, New Zealand. dan.wright@otago.ac.nz.
Abstract
PURPOSE: The intact nephron hypothesis (INH) states that impaired renal function results from a reduction in the number of complete (intact) nephrons. Under this model, renal drug clearance is assumed to be a linear function of glomerular filtration while tubular handling is ignored. The aims of this study were to systematically review published studies designed to test the INH and to assess the strength of the study designs used. METHODS: A systematic literature search was conducted in MEDLINE, EMBASE and Google Scholar. Studies specifically designed to understand the relationship between glomerular and tubular function across different levels of renal function were included. Studies that found a linear relationship between GFR and tubular clearance were deemed to support the INH while studies that found a non-linear relationship did not support the INH. Study design was accessed using a bespoke strength of evidence score. RESULTS: Thirty studies met the criteria for inclusion. Of these, 24 did not support the INH. Studies that did not support the INH used methods for measuring tubular clearance that were more robust and included subjects with a wider range of GFR values than studies that supported the INH. DISCUSSION: Our results suggest that the INH may not be a suitable general model for renal drug handling, particularly for drugs that are eliminated by tubular mechanisms. Further studies to assess the clinical importance of a non-linear relationship between drug clearance and GFR are warranted.
PURPOSE: The intact nephron hypothesis (INH) states that impaired renal function results from a reduction in the number of complete (intact) nephrons. Under this model, renal drug clearance is assumed to be a linear function of glomerular filtration while tubular handling is ignored. The aims of this study were to systematically review published studies designed to test the INH and to assess the strength of the study designs used. METHODS: A systematic literature search was conducted in MEDLINE, EMBASE and Google Scholar. Studies specifically designed to understand the relationship between glomerular and tubular function across different levels of renal function were included. Studies that found a linear relationship between GFR and tubular clearance were deemed to support the INH while studies that found a non-linear relationship did not support the INH. Study design was accessed using a bespoke strength of evidence score. RESULTS: Thirty studies met the criteria for inclusion. Of these, 24 did not support the INH. Studies that did not support the INH used methods for measuring tubular clearance that were more robust and included subjects with a wider range of GFR values than studies that supported the INH. DISCUSSION: Our results suggest that the INH may not be a suitable general model for renal drug handling, particularly for drugs that are eliminated by tubular mechanisms. Further studies to assess the clinical importance of a non-linear relationship between drug clearance and GFR are warranted.