The intact nephron hypothesis as a model for renal drug handling

• Published in: European journal of clinical pharmacology Vol. 75; no. 2; pp. 147 - 156
• Main Authors: Pradhan, Sudeep, Duffull, Stephen B., Walker, Robert J., Wright, Daniel F. B.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.02.2019; Springer Nature B.V
• Subjects: Animals; Biological Transport - physiology; Biomedical and Life Sciences; Biomedicine; Drug administration; Glomerular Filtration Rate - physiology; Humans; Hypotheses; Kidney Diseases - metabolism; Kidney Function Tests - methods; Metabolic Clearance Rate - physiology; Nephrons; Nephrons - metabolism; Pharmaceutical Preparations - metabolism; Pharmacology/Toxicology; Renal function; Review; Studies; Intact nephron hypothesis; Systematic review; Renal drug handling; Renal dose adjustment
• ISSN: 0031-6970; 1432-1041; 1432-1041
• DOI: 10.1007/s00228-018-2572-8

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.