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The intact nephron hypothesis as a model for renal drug handling

  • Sudeep Pradhan
  • Stephen B. Duffull
  • Robert J. Walker
  • Daniel F. B. Wright
Review

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.

Keywords

Intact nephron hypothesis Renal drug handling Renal dose adjustment Systematic review 

Notes

Acknowledgements

S.P. was supported by a University of Otago Doctoral Scholarship.

Author’s contributions

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.

Supplementary material

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References

  1. 1.
    Bricker NS, Morrin PA, Kime SW Jr (1960) The pathologic physiology of chronic Bright's disease. An exposition of the “intact nephron hypothesis”. Am J Med 28:77–98CrossRefGoogle Scholar
  2. 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
  3. 3.
    Kooman JP (2009) Estimation of renal function in patients with chronic kidney disease. J Magn Reson Imaging 30(6):1341–1346.  https://doi.org/10.1002/jmri.21970 CrossRefGoogle Scholar
  4. 4.
    Wright DFB, Duffull SB (2017) A general empirical model for renal drug handling in pharmacokinetic analyses. Br J Clin Pharmacol 83(9):1869–1872.  https://doi.org/10.1111/bcp.13306 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Putt TL, Duffull SB, Schollum JBW, Walker RJ (2014) GFR may not accurately predict aspects of proximal tubule drug handling. Eur J Clin Pharmacol 70(10):1221–1226.  https://doi.org/10.1007/s00228-014-1733-7 CrossRefPubMedGoogle Scholar
  6. 6.
    Gloff CA, Benet LZ (1989) Differential effects of the degree of renal damage on p-aminohippuric acid and inulin clearances in rats. J Pharmacokinet Biopharm 17(2):169–177CrossRefGoogle Scholar
  7. 7.
    Maiza A, Daley-Yates PT (1991) Prediction of the renal clearance of cimetidine using endogenous N-1-methylnicotinamide. J Pharmacokinet Biopharm 19(2):175–188CrossRefGoogle Scholar
  8. 8.
    Maiza A, Daley-Yates PT (1993) Variability in the renal clearance of cephalexin in experimental renal failure. J Pharmacokinet Biopharm 21(1):19–30CrossRefGoogle Scholar
  9. 9.
    Young S, Duffull SB (2011) A learning-based approach for performing an in-depth literature search using MEDLINE. J Clin Pharm Ther 36(4):504–512.  https://doi.org/10.1111/j.1365-2710.2010.01204.x CrossRefPubMedGoogle Scholar
  10. 10.
    Rohatgi A ([cited 2017 Dec 10].) WebPlotDigitizer. https://automeris.io/WebPlotDigitizer
  11. 11.
    Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16(1):31–41CrossRefGoogle Scholar
  12. 12.
    Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med 130(6):461–470CrossRefGoogle Scholar
  13. 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. 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. 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. 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. 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
  18. 18.
    Fu CJ, Melethil S, Mason WD (1991) The pharmacokinetics of aspirin in rats and the effect of buffer. J Pharmacokinet Biopharm 19(2):157–173CrossRefGoogle Scholar
  19. 19.
    Al-Sallami HS, Cheah SL, Han SY, Liew J, Lim J, Ng MA, Solanki H, Soo RJ, Tan V, Duffull SB (2014) Between-subject variability: should high be the new normal? Eur J Clin Pharmacol 70(11):1403–1404.  https://doi.org/10.1007/s00228-014-1740-8 CrossRefPubMedGoogle Scholar
  20. 20.
    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J, Ckd EPI (2009) A new equation to estimate glomerular filtration rate. Ann Intern Med 150(9):604–612CrossRefGoogle Scholar
  21. 21.
    Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group (2013) KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 3(1):1–150CrossRefGoogle Scholar
  22. 22.
    Barbour GL, Crumb CK, Boyd CM, Reeves RD, Rastogi SP, Patterson RM (1976) Comparison of inulin, iothalamate, and 99mTc-DTPA for measurement of glomerular filtration rate. J Nucl Med 17(4):317–320PubMedGoogle Scholar
  23. 23.
    Jobin J, Bonjour JP (1985) Measurement of glomerular filtration rate in conscious unrestrained rats with inulin infused by implanted osmotic pumps. Am J Phys 248(5 Pt 2):F734–F738.  https://doi.org/10.1152/ajprenal.1985.248.5.F734 CrossRefGoogle Scholar
  24. 24.
    Bricker NS, Klahr S, Rieselbach RE (1964) The functional adaptation of the diseased kidney. I. Glomerular filtration rate. J Clin Invest 43:1915–1921.  https://doi.org/10.1172/JCI105065 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wagnild JP, Gutmann FD, Rieselbach RE (1974) Functional characterization of chronic unilateral glomerulonephritis in the dog. Kidney Int 5(6):422–428CrossRefGoogle Scholar
  26. 26.
    Haberle D, Ober A, Ruhland G (1975) Influence of glomerular filtration rate on the rate of Para-aminohippurate secretion by the rat kidney: micropuncture and clearance studies. Kidney Int 7(6):385–396CrossRefGoogle Scholar
  27. 27.
    Haberle DA, Ruhland G, Lausser A, Moore L, Neiss A (1978) Influence of glomerular filtration rate on renal PAH secretion rate in the rat kidney. Dependency of PAH extraction on renal filtration fraction. Pflugers Arch 375(2):131–139CrossRefGoogle Scholar
  28. 28.
    Rieselbach RE, Todd L, Rosenthal M, Bricker NS (1964) The functional adaptation of the diseased kidney. II Maximum Rate of Transport of Pah and the Influence of Acetate. J Lab Clin Med 64:724–730PubMedGoogle Scholar
  29. 29.
    Morrison AB, Howard RM (1966) The functional capacity of hypertrophied nephrons. Effect of partial nephrectomy on the clearance of inulin and PAH in the rat. J Exp Med 123(5):829–844CrossRefGoogle Scholar
  30. 30.
    Biber TU, Mylle M, Baines AD, Gottschalk CW, Oliver JR, MacDowell MC (1968) A study by micropuncture and microdissection of acute renal damage in rats. Am J Med 44(5):664–705CrossRefGoogle Scholar
  31. 31.
    Kramp RA, MacDowell M, Gottschalk CW, Oliver JR (1974) A study by microdissection and micropuncture of the structure and the function of the kidneys and the nephrons of rats with chronic renal damage. Kidney Int 5(2):147–176CrossRefGoogle Scholar
  32. 32.
    Olesen S, Madsen PO (1975) Compensatory renal hypertrophy. I Following unilateral nephrectomy An experimental study in dogs. Urol Res 3(4):169–175PubMedGoogle Scholar
  33. 33.
    Wagnild JP, Gutmann FD (1976) Functional adaptation of nephrons in dogs with acute progressing to chronic experimental glomerulonephritis. J Clin Invest 57(6):1575–1589.  https://doi.org/10.1172/JCI108428 CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Lin JH, Lin TH (1988) Renal handling of drugs in renal failure. I: differential effects of uranyl nitrate- and glycerol-induced acute renal failure on renal excretion of TEAB and PAH in rats. J Pharmacol Exp Ther 246(3):896–901PubMedGoogle Scholar
  35. 35.
    Maiza A, Daley-Yates PT (1990) Estimation of the renal clearance of drugs using endogenous N-1-methylnicotinamide. Toxicol Lett 53:231–235CrossRefGoogle Scholar
  36. 36.
    Nakamura T, Kokuryo T, Takano M, Inui K (1997) Renal excretion of vancomycin in rats with acute renal failure. J Pharm Pharmacol 49(2):154–157CrossRefGoogle Scholar
  37. 37.
    He YL, Kitada N, Yasuhara M, Hori R (2001) Quantitative estimation of renal clearance of N-acetylprocainamide in rats with various experimental acute renal failure. Eur J Pharm Sci 13(3):303–308.  https://doi.org/10.1016/s0928-0987(01)00117-8 CrossRefPubMedGoogle Scholar
  38. 38.
    Savant IA, Kalis M, Almoazen H, Ortiz SR, AbuTarif M, Taft DR (2001) Alternative high-performance liquid chromatographic assay for p-aminohippuric acid (PAH): effect of aging on PAH excretion in the isolated perfused rat kidney. J Pharm Biomed Anal 26(5–6):687–699CrossRefGoogle Scholar
  39. 39.
    Janku I, Zvara K (1993) Quantitative-analysis of drug handling by the kidney using a physiological model of renal drug clearance. Eur J Clin Pharmacol 44(6):521–524.  https://doi.org/10.1007/Bf02440851 CrossRefPubMedGoogle Scholar
  40. 40.
    Kampf D, Schurig R, Korsukewitz I, Bruckner O (1981) Cefoxitin pharmacokinetics: relation to three different renal clearance studies in patients with various degrees of renal insufficiency. Antimicrob Agents Chemother 20(6):741–746CrossRefGoogle Scholar
  41. 41.
    Lin JH, Chremos AN, Yeh KC, Antonello J, Hessey GA 2nd (1988) Effects of age and chronic renal failure on the urinary excretion kinetics of famotidine in man. Eur J Clin Pharmacol 34(1):41–46CrossRefGoogle Scholar
  42. 42.
    Paap CM, Nahata MC (1993) The relation between type of renal-disease and renal drug clearance in children. Eur J Clin Pharmacol 44(2):195–197.  https://doi.org/10.1007/Bf00315480 CrossRefPubMedGoogle Scholar
  43. 43.
    Rakhit A, Radensky P, Szerlip HM, Kochak GM, Audet PR, Hurley ME, Feldman GM (1988) Effect of renal impairment on disposition of pentopril and its active metabolite. Clin Pharmacol Ther 44(1):39–48CrossRefGoogle Scholar
  44. 44.
    Shi J, Ripley E, Gehr TW, Sica DA, Dandekar KA, Hinderling PH (1996) Pharmacokinetics of sematilide in renal failure. J Clin Pharmacol 36(2):131–143CrossRefGoogle Scholar
  45. 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
  46. 46.
    Dontas AS, Marketos SG, Papanayiotou P (1972) Mechanisms of renal tubular defects in old age. Postgrad Med J 48(559):295–303CrossRefGoogle Scholar
  47. 47.
    Ilic S, Vlajkovic M, Bogicevic M, Rajic M, Stefanovic V (2001) The significance of radiopharmaceutical choice on the estimation of the absolute renal function in different stages of renal failure. Med Princ Pract 10(1):29–33.  https://doi.org/10.1159/000050336 CrossRefGoogle Scholar
  48. 48.
    Janku I (1993) Physiological modelling of renal drug clearance. Eur J Clin Pharmacol 44(6):513–519CrossRefGoogle Scholar
  49. 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
  50. 50.
    Hsueh CH, Hsu V, Zhao P, Zhang L, Giacomini KM, Huang SM (2018) PBPK modeling of the effect of reduced kidney function on the pharmacokinetics of drugs excreted Renally by organic anion transporters. Clin Pharmacol Ther 103(3):485–492.  https://doi.org/10.1002/cpt.750 CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.School of PharmacyUniversity of OtagoDunedinNew Zealand
  2. 2.Department of MedicineUniversity of OtagoDunedinNew Zealand

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