Tolvaptan, Kidney Function Decline, and Potential Confounding by Muscle Wasting

The vasopressin receptor 2 (V2R) antagonist tolvaptan is the only registered treatment to mitigate kidney function decline in patients with autosomal dominant polycystic kidney disease at high risk of progression. Recent work by Chebib et al. demonstrated that tolvaptan was associated with reduced annual decline in creatinine-based estimated glomerular filtration rate (eGFRcr) compared with standard-of-care in patients aged >55 years.1Chebib F.T. Zhou X. Garbinsky D. et al.Tolvaptan and Kidney Function Decline in Older Individuals With Autosomal Dominant Polycystic Kidney Disease: A Pooled Analysis of Randomized Clinical Trials and Observational Studies.Kidney Med. 2023; 5100639Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar However, the NKF and FDA only endorse use of eGFRcr-based endpoints if it has been demonstrated that an intervention does not impact muscle-derived creatinine generation.2Levey A.S. Inker L.A. Matsushita K. et al.GFR decline as an end point for clinical trials in CKD: A scientific workshop sponsored by the national kidney foundation and the US food and drug administration.Am J Kidney Dis. 2014; 64: 821-835Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar Chebib et al. do not mention studies demonstrating this, nor are we aware of such studies. Thus, the prerequisite exclusion of an impact on muscle-derived creatinine generation is not met in studies investigating effects of V2R antagonists on eGFRcr. Antagonizing V2R mimics nephrogenic diabetes insipidus, inducing polyuria up to >10 L/day (Figure 1),3Kramers B.J. van Gastel M.D.A. Boertien W.E. Meijer E. Gansevoort R.T. Determinants of Urine Volume in ADPKD Patients Using the Vasopressin V2 Receptor Antagonist Tolvaptan.Am J Kidney Dis. 2019; 73: 354-362Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar subsequent polydipsia, and high compensatory fluid consumption. Extraordinary fluid intake suppresses appetite—evidenced by a higher incidence of anorexia under tolvaptan treatment compared with placebo4Torres V.E. Chapman A.B. Devuyst O. et al.Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease.N Engl J Med. 2012; 367: 2407-2418Crossref PubMed Scopus (1083) Google Scholar—which may lead to malnutrition and, ultimately, sarcopenia, reducing creatinine generation.5Vandewoude M.F.J. Alish C.J. Sauer A.C. Hegazi R.A. Malnutrition-sarcopenia syndrome: Is this the future of nutrition screening and assessment for older adults?.J Aging Res. 2012; 2012 (Chebib et al declined to respond)651570Crossref PubMed Scopus (160) Google Scholar This line of reasoning suggests that the purported renoprotective effects of tolvaptan may, at least partially, be attributed to therapy-related muscle wasting, an argument that remains unchallenged as long-term effects of tolvaptan on kidney function decline have never been confirmed with clearance methods or muscle mass-insensitive markers of kidney function (e.g., cystatin C). In light of this evidential void, renoprotection by tolvaptan can only be fully substantiated with analyses based on these NKF and FDA endorsed alternatives.2Levey A.S. Inker L.A. Matsushita K. et al.GFR decline as an end point for clinical trials in CKD: A scientific workshop sponsored by the national kidney foundation and the US food and drug administration.Am J Kidney Dis. 2014; 64: 821-835Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar Financial Disclosure: The authors declare that they have no relevant financial interests. Peer Review: Received June 14, 2023. Accepted June 19, 2023 after editorial review by the Editor-in-Chief.