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Randomized Controlled Trial
. 2023 Jun 25;44(24):2202-2212.
doi: 10.1093/eurheartj/ehad210.

Importance of cystatin C in estimating glomerular filtration rate: the PARADIGM-HF trial

Paolo Tolomeo  1   2 , Jawad H Butt  1   3 , Toru Kondo  1   4 , Gianluca Campo  2 , Akshay S Desai  5 , Pardeep S Jhund  1 , Lars Køber  3 , Martin P Lefkowitz  6 , Jean L Rouleau  7 , Scott D Solomon  5 , Karl Swedberg  8 , Muthiah Vaduganathan  5 , Michael R Zile  9 , Milton Packer  10 , John J V McMurray  1
Affiliations
Randomized Controlled Trial

Importance of cystatin C in estimating glomerular filtration rate: the PARADIGM-HF trial

Paolo Tolomeo et al. Eur Heart J. .

Abstract

Aims: The 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation combining creatinine and cystatin C provides a better estimation of glomerular filtration rate (GFR) compared to the creatinine-only equation.

Methods and results: CKD-EPI creatinine-cystatin C equation (creatinine-cystatin) was compared to creatinine-only (creatinine) equation in a subpopulation of Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF). Patients were categorized according to difference in eGFR using the two equations: Group 1 (<-10 mL/min/1.73 m2, i.e. creatinine-cystatin more than 10 mL/min lower than creatinine), Group 2 (>-10 and <10 mL/min/1.73 m2), and Group 3 (>10 mL/min/1.73 m2, i.e. creatinine-cystatin more than 10 mL/min higher than creatinine). Cystatin C and creatinine were available in 1966 patients at randomization. Median (interquartile range) eGFR difference was -0.7 (-6.4-4.8) mL/min/1.73 m2. Compared to creatinine, creatinine-cystatin led to a substantial reclassification of chronic kidney disease stages. Overall, 212 (11%) and 355 (18%) patients were reallocated to a better and worse eGFR category, respectively. Compared to patients in Group 2, those in Group 1 (lower eGFR with creatinine-cystatin) had higher mortality and those in Group 3 (higher eGFR with creatinine-cystatin) had lower mortality. Increasing difference in eGFR (due to lower eGFR with creatinine-cystatin compared to creatinine) was associated with increasing elevation of biomarkers (including N-terminal pro-B-type natriuretic peptide and troponin) and worsening Kansas City Cardiomyopathy Questionnaire clinical summary score. The reason why the equations diverged with increasing severity of heart failure was that creatinine did not rise as steeply as cystatin C.

Conclusion: The CKD-EPI creatinine-only equation may overestimate GFR in sicker patients.

Clinical trial registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT01035255.

Keywords: Albuminuria; CKD; Cystatin C; HFrEF; NT-proBNP; eGFR.

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Conflict of interest statement

Conflict of interest J.H.B. reports advisory board honoraria from Bayer. A.S.D. reported receiving personal fees from Abbott, Biofourmis, Boston Scientific, Boehringer Ingelheim, Merck, Regeneron, and Relypsa and grants and personal fees from AstraZeneca, Alnylam, and Novartis outside the submitted work. L.K. reports personal fees from speaker honoraria from Novartis, AstraZeneca, Novo Nordisk, and Boehringer Ingelheim. M.P.L. is an employee of Novartis. J.L.R. has received grants and consulting fees from Novartis and consulting fees from Abbott, AstraZeneca, MyoKardia, and Sanofi. S.D.S. has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Lone Star Heart, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, and Theracos and has consulted for Abbott, Action Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, Gilead, GSK, Ironwood, Lilly, Merck, Myokardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, Cardurion, AoBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent. M.R.Z. has received research funding from Novartis and has been a consultant for Novartis, Abbott, Boston Scientific, CVRx, EBR, Endotronics, Ironwood, Merck, Medtronic, and Myokardia V Wave. M.P. has received consulting fees from AbbVie, Akcea, Actavis, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Gilead, Johnson & Johnson, Novo Nordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance. K.S. reports honoraria from Astrazeneca, Boerhinger-Mannheim, and Novartis. M.V. has received research grant support from or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi; has had speaker engagements with Novartis and Roche Diagnostics; and participates on clinical trial committees for studies sponsored by Bayer AG, Galmed, Occlutech, Novartis, and Impulse Dynamics. P.S.J. has received consulting fees, advisory board fees, and lecture fees from Novartis; advisory board fees from Cytokinetics; and grant support from Boehringer Ingelheim. T.K. received lecture fees from Abbott Medical Japan LLC., Ono Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Novartis Pharma K.K., AstraZeneca K.K., Bristol-Myers Squibb Co., and Abiomed Japan K.K. J.J.J.V.M. reports payments to his employer, Glasgow University, for work on clinical trials, consulting, lecturing, and other activities: Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GSK, Ionis, KBP Biosciences, Novartis, Pfizer, Theracos. Personal lecture fees: Abbott, Hikma, Sun Pharmaceuticals, Servier, Theracos; and personal payments from Abbott, Hikma, Ionis, Sun Pharmaceuticals, Servier. The other authors report no conflicts.

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