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      Does Secretory Clearance Follow Glomerular Filtration Rate in Chronic Kidney Diseases? Reconsidering the Intact Nephron Hypothesis

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          Abstract

          Drug‐dose modification in chronic kidney disease (CKD) utilizes glomerular filtration rate (GFR) with the implicit assumption that multiple renal excretory processes decline in parallel as CKD progresses. We compiled published pharmacokinetic data to evaluate if GFR predicts renal clearance changes as a function of CKD severity. For each drug, we calculated ratio of renal clearance to filtration clearance (Rnf). Of 21 drugs with Rnf >0.74 in subjects with GFR >90 mL/min (implying filtration and secretion), 13 displayed significant change in Rnf vs. GFR (slope of linear regression statistically different from zero), which indicates failure of GFR to predict changes in secretory clearance. The dependence was positive ( n = 3; group A) or negative ( n = 10; group B). Eight drugs showed no correlation (group C). Investigated drugs were small molecules, mostly hydrophilic, and ionizable, with some characterized as renal transporter substrates. In conclusion, dosing adjustments in CKD require refinement; in addition to GFR, biomarkers of tubular function are needed for secreted drugs.

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          Metformin kinetics in healthy subjects and in patients with diabetes mellitus.

          H B Woods, John H Connor, Adrian Ward … (1981)
          Article 0 comments Cited 95 times – based on 0 reviews     Review now
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            Urinary biomarkers for sensitive and specific detection of acute kidney injury in humans.

            Vishal Vaidya, Sushrut S Waikar, Michael A H Ferguson … (2008)
            Acute kidney injury (AKI) is associated with high morbidity and mortality. The lack of sensitive and specific injury biomarkers has greatly impeded the development of therapeutic strategies to improve outcomes of AKI.The unique objective of this study was to evaluate the diagnostic performance of nine urinary biomarkers of AKI-kidney injury molecule-1 (KIM-1), neutrophil gelatinase associated lipocalin (NGAL), interleukin-18 (IL-18), hepatocyte growth factor (HGF), cystatin C (Cys), N-acetyl-beta-D-glucosaminidase (NAG), vascular endothelial growth factor (VEGF), chemokine interferon-inducible protein 10 (IP-10; CXCL10), and total protein-in a cross-sectional comparison of 204 patients with or without AKI.Median urinary concentrations of each biomarker were significantly higher in patients with AKI than in those without AKI (p 5.72 and HGF > 0.17) + 2.93*(PROTEIN > 0.22) -2*(KIM < 0.58)] was greater (0.94) than individual biomarker AUC-ROCs. Age-adjusted levels of urinary KIM-1, NAG, HGF, VEGF, and total protein were significantly higher in patients who died or required renal replacement therapy (RRT) when compared to those who survived and did not require RRT.Our results demonstrate the comparative value of multiple biomarkers in the diagnosis and prognosis of AKI.
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              Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802.

              C. Ward, G He, J Massarella (1999)
              Oseltamivir is an ethyl ester prodrug of Ro 64-0802, a selective inhibitor of influenza virus neuraminidase. Oral administration of oseltamivir delivers the active antiviral Ro 64-0802 to the bloodstream, and thus all sites of influenza infection (lung, nasal mucosa, middle ear) are accessible. The pharmacokinetic profile of oseltamivir is simple and predictable, and twice daily treatment results in effective antiviral plasma concentrations over the entire administration interval. After oral administration, oseltamivir is readily absorbed from the gastrointestinal tract and extensively converted to the active metabolite. The absolute bioavailability of the active metabolite from orally administered oseltamivir is 80%. The active metabolite is detectable in plasma within 30 minutes and reaches maximal concentrations after 3 to 4 hours. After peak plasma concentrations are attained, the concentration of the active metabolite declines with an apparent half-life of 6 to 10 hours. Oseltamivir is eliminated primarily by conversion to and renal excretion of the active metabolite. Renal clearance of both compounds exceeds glomerular filtration rate, indicating that renal tubular secretion contributes to their elimination via the anionic pathway. Neither compound interacts with cytochrome P450 mixed-function oxidases or glucuronosyltransferases. The pharmacokinetic profile of the active metabolite is linear and dose-proportional, with less than 2-fold accumulation over a dosage range of oseltamivir 50 to 500 mg twice daily. Steady-state plasma concentrations are achieved within 3 days of twice daily administration, and at a dosage of 75mg twice daily the steady-state plasma trough concentrations of active metabolite remain above the minimum inhibitory concentration for all influenza strains tested. Exposure to the active metabolite at steady state is approximately 25% higher in elderly compared with young individuals; however, no dosage adjustment is necessary. In patients with renal impairment, metabolite clearance decreases linearly with creatinine clearance. A dosage reduction to 75mg once daily is recommended for patients with creatinine clearance <30 ml/min (1.8 L/h). The pharmacokinetics in patients with influenza are qualitatively similar to those in healthy young adults. In vitro and in vivo studies indicate no clinically significant drug interactions. Neither paracetamol (acetaminophen) nor cimetidine altered the pharmacokinetics of Ro 64-0802. Coadministration of probenecid resulted in a 2.5-fold increase in exposure to Ro 64-0802; however, this competition is unlikely to result in clinically relevant effects. These properties make oseltamivir a suitable candidate for use in the prevention and treatment of influenza.
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                Author and article information

                Contributors
                CK Yeung: cathyy@uw.edu
                Journal
                Journal ID (nlm-ta): Clin Transl Sci
                Journal ID (iso-abbrev): Clin Transl Sci
                Journal ID (doi): 10.1111/(ISSN)1752-8062
                Journal ID (publisher-id): CTS
                Title: Clinical and Translational Science
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1752-8054
                ISSN (Electronic): 1752-8062
                Publication date (Electronic): 04 July 2017
                Publication date (Print): September 2017
                Volume: 10
                Issue: 5 ( doiID: 10.1111/cts.2017.10.issue-5 )
                Pages: 395-403
                Affiliations
                [ 1 ] Department of Pharmaceutics, School of Pharmacy University of Washington Seattle Washington USA
                [ 2 ] Kidney Research Institute, Division of Nephrology, Department of Medicine University of Washington Seattle Washington USA
                [ 3 ] Department of Pharmacy School of Pharmacy University of Washington Seattle Washington USA
                Author notes
                [*] [* ]Correspondence: CK Yeung ( cathyy@ 123456uw.edu )
                Article
                Publisher ID: CTS12481
                DOI: 10.1111/cts.12481
                PMC ID: 5593164
                PubMed ID: 28675584
                SO-VID: 9ac48990-25f9-4374-9692-ce9f7fd1391b
                Copyright © © 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics
                License:

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                Date received : 19 January 2017
                Date accepted : 21 May 2017
                Page count
                Figures: 1, Tables: 3, Pages: 9, Words: 7042
                Funding
                Funded by: National Institute of Health
                Award ID: TR000421
                Award ID: R01GM121354
                Categories
                Subject: Article
                Subject: Research
                Subject: Articles
                Custom metadata
                source-schema-version-number 2.0
                component-id cts12481
                cover-date September 2017
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.9 mode:remove_FC converted:11.09.2017

                ScienceOpen disciplines: Medicine
                Data availability:
                ScienceOpen disciplines: Medicine

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