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. 2023 Jul 3;6(7):e2321715.
doi: 10.1001/jamanetworkopen.2023.21715.

Medication-Related Adverse Events and Discordancies in Cystatin C-Based vs Serum Creatinine-Based Estimated Glomerular Filtration Rate in Patients With Cancer

Paul E Hanna  1 , Qiyu Wang  1 , Ian A Strohbehn  1 , Daiana Moreno  1 , Destiny Harden  1 , Tianqi Ouyang  1 , Nurit Katz-Agranov  1 , Harish Seethapathy  1 , Kerry L Reynolds  2 , Shruti Gupta  3   4 , David E Leaf  3 , Meghan E Sise  1
Affiliations

Medication-Related Adverse Events and Discordancies in Cystatin C-Based vs Serum Creatinine-Based Estimated Glomerular Filtration Rate in Patients With Cancer

Paul E Hanna et al. JAMA Netw Open. .

Abstract

Importance: Serum creatinine-based estimated glomerular filtration rate (eGFRcr) may overestimate the glomerular filtration rate (GFR) in patients with cancer. Cystatin C-based eGFR (eGFRcys) is an alternative marker of GFR.

Objective: To determine whether the therapeutic drug levels and adverse events (AEs) associated with renally cleared medications were higher in patients with cancer whose eGFRcys was more than 30% lower than their eGFRcr.

Design, setting, and participants: This cohort study analyzed adult patients with cancer at 2 major academic cancer centers in Boston, Massachusetts. These patients had their creatinine and cystatin C measured on the same day between May 2010 and January 2022. The date of the first simultaneous eGFRcr and eGFRcys measurement was considered to be the baseline date.

Exposure: The primary exposure was eGFR discordance, defined as an eGFRcys that was more than 30% lower than the eGFRcr.

Main outcomes and measures: The primary outcome was risk of the following medication-related AEs within 90 days of the baseline date: (1) supratherapeutic vancomycin trough level greater than 30 μg/mL, (2) trimethoprim-sulfamethoxazole-related hyperkalemia (>5.5 mEq/L), (3) baclofen toxic effect, and (4) supratherapeutic digoxin level (>2.0 ng/mL). For the secondary outcome, a multivariable Cox proportional hazards regression model was used to compare 30-day survival of those with vs without eGFR discordance.

Results: A total of 1869 adult patients with cancer (mean [SD] age, 66 [14] years; 948 males [51%]) had simultaneous eGFRcys and eGFRcr measurement. There were 543 patients (29%) with an eGFRcys that was more than 30% lower than their eGFRcr. Patients with an eGFRcys that was more than 30% lower than their eGFRcr were more likely to experience medication-related AEs compared with patients with concordant eGFRs (defined as eGFRcys within 30% of eGFRcr), including vancomycin levels greater than 30 μg/mL (43 of 179 [24%] vs 7 of 77 [9%]; P = .01), trimethoprim-sulfamethoxazole-related hyperkalemia (29 of 129 [22%] vs 11 of 92 [12%]; P = .07), baclofen toxic effects (5 of 19 [26%] vs 0 of 11; P = .19), and supratherapeutic digoxin levels (7 of 24 [29%] vs 0 of 10; P = .08). The adjusted odds ratio for vancomycin levels more than 30 μg/mL was 2.59 (95% CI, 1.08-7.03; P = .04). Patients with an eGFRcys more than 30% lower than their eGFRcr had an increased 30-day mortality (adjusted hazard ratio, 1.98; 95% CI, 1.26-3.11; P = .003).

Conclusions and relevance: Results of this study suggest that among patients with cancer with simultaneous assessment of eGFRcys and eGFRcr, supratherapeutic drug levels and medication-related AEs occurred more commonly in those with an eGFRcys more than 30% lower than their eGFRcr. Future prospective studies are needed to improve and personalize GFR estimation and medication dosing in patients with cancer.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Reynolds reported receiving clinical trial funding for Massachusetts General Hospital from Bristol-Myers Squibb during the conduct of the study and being an employee at Teladoc, receiving research funding from Project Datasphere, and receiving personal fees from CME Outfitters and MedScape outside the submitted work. Dr Gupta reported receiving a grant from the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (NIDDK/NIH) during the conduct of the study as well as personal fees from GlaxoSmithKline, Secretome, and Proletariat Therapeutics and grants from GE Healthcare and BTG International outside the submitted work. Dr Leaf reported receiving grants from the NIH during the conduct of the study. Dr Sise reported receiving a grant from the NIH during the conduct of the study; personal fees from Novartis, Travere, and Mallinckrodt outside the submitted work; and grants from Gilead, Merck, Angion, EMD Serono, and Otsuka outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Factors in Estimated Glomerular Filtration Rate (eGFR) Discordance
Logistic regression models were used to estimate the association between baseline characteristics and having a cystatin C–based eGFR (eGFRcys) that was more than 30% lower than the serum creatinine–based eGFR (eGFRcr) or an eGFRcys that was more than 30% higher than the eGFRcr. AOR indicates adjusted odds ratio; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); eGFRcr-cys, eGFR using the Chronic Kidney Disease Epidemiology Collaboration race-free combined equation. To convert hemoglobin level to grams per liter, multiply by 10.0; serum albumin level to grams per liter, multiply by 10. aRace and ethnicity were self-identified. Minoritized racial and ethnic groups included African American or Black, Asian, Hispanic or Latino, and other (including Alaskan Indian or American Indian, Hawaiian Native, declined to answer, and not recorded).
Figure 2.
Figure 2.. Scatterplots of Serum Creatinine–Based Estimated Glomerular Filtration Rate (eGFRcr) and Cystatin C–Based eGFR (eGFRcys) by Serum Albumin and Hemoglobin Levels
The identity line (line of equality) is shown in black.
Figure 3.
Figure 3.. Supratherapeutic Trough Levels and Adverse Events in Patients With a Cystatin C–Based Estimated Glomerular Filtration Rate (eGFRcys) More Than 30% Lower Than the Serum Creatinine–Based eGFR (eGFRcr), Concordant eGFR, or an eGFRcys More Than 30% Higher Than the eGFRcr
A, Highest trough levels were obtained within 30 days of starting vancomycin. B. Hyperkalemia was graded using Common Terminology Criteria for Adverse Events, version 5. C, There were no cases of baclofen toxic effects in patients with a concordant eGFR or an eGFRcys more than 30% higher than the eGFRcr. D, Supratherapeutic level was more than 2.0 ng/mL. Both cases of clinical toxic effects occurred in patients with an eGFRcys more than 30% lower than the eGFRcr. There were no cases of supratherapeutic digoxin toxic effects in patients with a concordant eGFR or an eGFRcys more than 30% higher than the eGFRcr.
Figure 4.
Figure 4.. Kaplan-Meier Curve of 30-Day Survival in Patients With a Cystatin C–Based Estimated Glomerular Filtration Rate (eGFRcys) More Than 30% Lower Than the Serum Creatinine–Based eGFR (eGFRcr), Concordant eGFR, or an eGFRcys More Than 30% Higher Than the eGFRcr
Unadjusted and adjusted models are provided in eTable 7 in Supplement 1. Shaded areas represent 95% CIs.
See this image and copyright information in PMC

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