The intact nephron hypothesis as a model for renal drug handling
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.
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.
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.
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.
KeywordsIntact nephron hypothesis Renal drug handling Renal dose adjustment Systematic review
S.P. was supported by a University of Otago Doctoral Scholarship.
D.F.B.W., S.B.D., R.J.W. and S.P. conceived and designed the study. S.P. performed the review with audit by D.F.B.W. S.P., D.F.B.W., S.B.D. and R.J.W. wrote and revised the manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
- 2.Food and Drug Administration, Center for Drug Evaluation and Research (CDER) (2010. [cited 2017 Dec 10]. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM204959.pdf) Guidance for industry: pharmacokinetics in patients with impaired renal function—study design, data analysis, and impact on dosing and labeling
- 10.Rohatgi A ([cited 2017 Dec 10].) WebPlotDigitizer. https://automeris.io/WebPlotDigitizer
- 13.Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, Kusek JW, Manzi J, Van Lente F, Zhang YL, Coresh J, Levey AS, Investigators C-E (2012) Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med 367(1):20–29. https://doi.org/10.1056/NEJMoa1114248 CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Sterner G, Frennby B, Mansson S, Nyman U, Van Westen D, Almen T (2008) Determining 'true' glomerular filtration rate in healthy adults using infusion of inulin and comparing it with values obtained using other clearance techniques or prediction equations. Scand J Urol Nephrol 42(3):278–285. https://doi.org/10.1080/00365590701701806 CrossRefPubMedGoogle Scholar
- 15.Rodriguez-Romero V, Gonzalez-Villalva KI, Reyes JL, Franco-Bourland RE, Guizar-Sahagun G, Castaneda-Hernandez G, Cruz-Antonio L (2015) A novel, simple and inexpensive procedure for the simultaneous determination of iopamidol and p-aminohippuric acid for renal function assessment from plasma samples in awake rats. J Pharm Biomed Anal 107:196–203. https://doi.org/10.1016/j.jpba.2014.12.009 CrossRefPubMedGoogle Scholar
- 16.European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP) (2016. [cited 2017 Dec 10]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2016/02/WC500200841.pdf ) Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with decreased renal function
- 17.Finco DR, Brown SA, Crowell WA, Barsanti JA (1991) Exogenous creatinine clearance as a measure of glomerular filtration rate in dogs with reduced renal mass. Am J Vet Res 52(7):1029–1032Google Scholar
- 45.Udy AA, Jarrett P, Stuart J, Lassig-Smith M, Starr T, Dunlop R, Wallis SC, Roberts JA, Lipman J (2014) Determining the mechanisms underlying augmented renal drug clearance in the critically ill: use of exogenous marker compounds. Crit Care 18(6):657. https://doi.org/10.1186/s13054-014-0657-z CrossRefPubMedPubMedCentralGoogle Scholar
- 49.Chapron A, Shen DD, Kestenbaum BR, Robinson-Cohen C, Himmelfarb J, Yeung CK (2017) Does secretory clearance follow glomerular filtration rate in chronic kidney diseases? Reconsidering the intact nephron hypothesis. Clin Transl Sci 10(5):395–403. https://doi.org/10.1111/cts.12481 CrossRefPubMedPubMedCentralGoogle Scholar