Incidence and Predictors of CKD and Estimated GFR Decline in Patients Receiving Immune Checkpoint Inhibitors

Abstract

First approved in 2010 for treatment of metastatic melanoma, immune checkpoint inhibitors (ICIs) are now approved for more than 17 cancer types, and it is estimated that 1 in 3 patients with cancer now qualify for ICIs.1Haslam A. Gill J. Prasad V. Estimation of the percentage of US patients with cancer who are eligible for immune checkpoint inhibitor drugs.JAMA Netw Open. 2020; 3e200423Crossref PubMed Scopus (51) Google Scholar ICIs remove key regulators of T-cell function to unleash antitumor effects, but T-cell disinhibition can also cause immune-related adverse events in up to 60%-85% of patients.2Postow M.A. Sidlow R. Hellmann M.D. Immune-related adverse events associated with immune checkpoint blockade.N Engl J Med. 2018; 378: 158-168Crossref PubMed Scopus (1737) Google Scholar Though the epidemiology of ICI-induced acute kidney injury has been well characterized,3Seethapathy H. Zhao S. Chute D.F. et al.The incidence, causes, and risk factors of acute kidney injury in patients receiving immune checkpoint inhibitors.Clin J Am Soc Nephrol. 2019; 14: 1692-1700Crossref PubMed Scopus (71) Google Scholar, 4Seethapathy H. Zhao S. Strohbehn I.A. et al.Incidence and clinical features of immune-related acute kidney injury in patients receiving programmed cell death ligand-1 inhibitors.Kidney Int Rep. 2020; 5: 1700-1705Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar, 5Cortazar F.B. Kibbelaar Z.A. Glezerman I.G. et al.Clinical features and outcomes of immune checkpoint inhibitor-associated AKI: a multicenter study.J Am Soc Nephrol. 2020; 31: 435-446Crossref PubMed Scopus (94) Google Scholar there is extremely limited data on the long-term toxicities of ICIs. We sought to determine annual changes in kidney function in patients surviving at least 1 year by conducting a retrospective cohort study including all adults who received ICIs at Mass General Brigham in 2010-2018 with follow-up until December 31, 2019. The primary outcome was a composite of new-onset CKD (defined by eGFR <60 mL/min/1.73 m2 for >90 days), a sustained ≥30% decline in eGFR from baseline for >90 days with no interim eGFR reflecting a <20% decline from baseline, or kidney replacement therapy (KRT).6Siew E.D. Abdel-Kader K. Perkins A.M. et al.Timing of recovery from moderate to severe AKI and the risk for future loss of kidney function.Am J Kidney Dis. 2020; 75: 204-213Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar A ≥30% decline in eGFR was chosen based on data indicating this is predictive of future need for KRT.7Coresh J. Turin T.C. Matsushita K. et al.Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality.JAMA. 2014; 311: 2518-2531Crossref PubMed Scopus (593) Google Scholar As a secondary outcome, we defined “rapid eGFR decline” as >3 mL/min/1.73 m2 per year decline, which is associated with kidney failure and adverse cardiovascular outcomes.8Rifkin D.E. Shlipak M.G. Katz R. et al.Rapid kidney function decline and mortality risk in older adults.Arch Intern Med. 2008; 168: 2212-2218Crossref PubMed Scopus (266) Google Scholar,9Kovesdy C.P. Coresh J. Ballew S.H. et al.Past decline versus current eGFR and subsequent ESRD risk.J Am Soc Nephrol. 2016; 27: 2447-2455Crossref PubMed Scopus (54) Google Scholar Data on cancer type, ICI type and start date, comorbidities, medications, laboratory values, and prior nephrotoxic cancer therapies used were obtained from electronic medical records (Item S1). Cox proportional hazard models were performed to identify predictors of the primary outcome; patients were censored at death or loss to follow-up. We examined traditional risk factors associated with CKD progression as well as cancer-related factors; final model selection was guided by a combination of clinical plausibility and Akaike and Bayesian information criteria. We identified 5,934 adult patients who began treatment with ICIs in 2010-2018. After exclusion of 844 patients (14%) without baseline or at least 1 repeat creatinine, 72 (1%) who were enrolled in a placebo-controlled trial involving ICIs, and 14 (0.2%) with kidney failure, 5,004 (84%) remained. Of these, 2,563 (51%) survived ≥1 year and were included in the primary analysis. Baseline characteristics are shown in Table 1. Patients were followed for a median of 688 (interquartile range [IQR], 496-1,031) days and had a median of 20 (IQR, 13-29) creatinine measurements per year.Table 1Baseline CharacteristicsCharacteristicAll Patients (N = 5,004)Patients Surviving ≥1 Year (n = 2,563)DemographicsAge, years64 ± 1363 ± 13Male sex2,699 (54%)1,377 (54%)Race/ethnicity White, non-Hispanic4,529 (91%)2,356 (92%) Black, non-Hispanic112 (2%)47 (2%) Asian157 (3%)59 (2%) Hispanic51 (1%)28 (1%) Other or unknown155 (3%)73 (3%)Coexisting conditionsaBaseline comorbidities (defined using ICD-9/ICD-10 codes) and medications were determined at the time of ICI initiation.Hypertension2,930 (59%)1,479 (58%)Diabetes mellitus819 (16%)427 (17%)Cirrhosis78 (2%)36 (1%)Chronic obstructive pulmonary disease515 (10%)227 (9%)Coronary artery disease1,168 (23%)605 (24%)eGFR category ≥90 mL/min/1.73 m21,956 (39%)959 (37%) 60-89 mL/min/1.73 m22,249 (45%)1,195 (47%) 45-59 mL/min/1.73 m2745 (15%)384 (15%) <45 mL/min/1.73 m252 (1%)25 (1%)Baseline medicationsACEI/ARB1,390 (28%)670 (26%)Uric acid–lowering agent243 (5%)93 (4%)NSAIDs2,499 (50%)1,256 (49%)Diuretics1,315 (26%)544 (21%)Nephrotoxic antineoplastic therapies2,081 (42%)889 (35%)Histamine 2 receptor blockade2,616 (52%)1,212 (47%)Proton pump inhibitors2,127 (43%)929 (36%)ICI classPD13,720 (74%)1,846 (72%)PDL1519 (10%)283 (11%)CTLA4355 (7%)205 (8%)Combination CTLA4/PD1410 (8%)229 (9%)Cancer typeLung1,706 (34%)723 (28%)Melanoma1,157 (23%)810 (32%)Head and neck506 (10%)241 (9%)Genitourinary365 (7%)241 (9%)Gynecologic317 (7%)153 (6%)Gastrointestinal243 (5%)74 (3%)Blood196 (4%)98 (4%)Breast162 (3)64 (3)Sarcoma86 (2%)38 (1%)Other266 (5%)119 (5%)Age given as mean ± standard deviation; all other values as count (%). Baseline comorbidities (defined using ICD-9/ICD-10 codes) and medications were determined at the time of ICI initiation. Nephrotoxic chemotherapies had been prescribed within 1 year prior to ICI start. Full list of nephrotoxic agents are shown in Table S3. Blood cancers included myeloma, lymphoma, and leukemia.Abbreviations and definitions: ACEI/ARB, angiotensin-converting enzyme inhibitor or angiotensin receptor blockade; CTLA4, cytotoxic T lymphocyte–associated antigen; eGFR, estimated glomerular filtration rate (calculated by CKD-EPI equation); ICI, immune checkpoint inhibitor; NSAIDs, nonsteroidal anti-inflammatory drugs; PD1, programmed death 1; PDL1, programmed death ligand 1.a Baseline comorbidities (defined using ICD-9/ICD-10 codes) and medications were determined at the time of ICI initiation. Open table in a new tab Age given as mean ± standard deviation; all other values as count (%). Baseline comorbidities (defined using ICD-9/ICD-10 codes) and medications were determined at the time of ICI initiation. Nephrotoxic chemotherapies had been prescribed within 1 year prior to ICI start. Full list of nephrotoxic agents are shown in Table S3. Blood cancers included myeloma, lymphoma, and leukemia. Abbreviations and definitions: ACEI/ARB, angiotensin-converting enzyme inhibitor or angiotensin receptor blockade; CTLA4, cytotoxic T lymphocyte–associated antigen; eGFR, estimated glomerular filtration rate (calculated by CKD-EPI equation); ICI, immune checkpoint inhibitor; NSAIDs, nonsteroidal anti-inflammatory drugs; PD1, programmed death 1; PDL1, programmed death ligand 1. Among the 2,563 patients, 334 (13%) developed the primary composite outcome (new-onset CKD, 30% eGFR decline, or KRT) at a median of 471 (IQR, 304-782) days after the first ICI dose; the incidence rate was 6.34 per 100 patient-years. The cumulative incidence of the primary composite outcome and death are shown in Fig 1A. The rate of the primary composite outcome by year survived post-ICI is shown in Fig S1. Independent predictors of the primary outcome included age (AHR per 5 years, 1.13 [95% CI, 1.07-1.20]) and proton pump inhibitor use (AHR, 1.38 [95% CI, 1.10-1.73]). ICI class was not associated with the primary outcome (Fig 1B, Table S1). Rapid eGFR decline was also common, affecting 35% of those who survived ≥3 years (Table S2). Analysis of eGFR slope pre- versus post-ICI initiation among patients who had ≥1 year of baseline data prior to ICI initiation and who survived ≥1 year following ICI initiation (n = 1,335) showed significantly faster eGFR decline after ICI initiation (1.4 vs 3.7 mL/min/1.73 m2 per year average decline prior to vs after ICI, P = 0.01, Fig S2). This retrospective cohort study of kidney function in 2,563 patients who survived ≥1 year after treatment with ICIs shows that incident CKD or a clinically significant eGFR decline is common. The robustness of this finding is supported by the high incidence of rapid eGFR decline and results of multiple sensitivity analyses (Item S1, Table S4-S6). Our study is limited by the lack of a control group, which is absent because the very limited survival in many metastatic cancers prior to ICIs make it challenging to find a well-matched population with the potential for long-term survival. Using patients as their own controls by looking at pre- and posttreatment eGFR slope, we observed substantially faster eGFR decline after treatment. Because the rapid expansion of ICI use only began in 2015, the number of patients with >4 years follow-up is small; our findings will need to be validated in this and other cohorts with longer follow-up. Our study has important implications for patients treated with ICIs: a subset of survivors may experience significant eGFR decline that may contribute to long-term health consequences and may limit the use or dosage of other anticancer drugs and eligibility for clinical trial enrollment. We identified age and use of proton pump inhibitors as important risk factors for new-onset CKD and sustained 30% eGFR decline; both have previously been shown to be risk factors for AKI patients with cancer.3Seethapathy H. Zhao S. Chute D.F. et al.The incidence, causes, and risk factors of acute kidney injury in patients receiving immune checkpoint inhibitors.Clin J Am Soc Nephrol. 2019; 14: 1692-1700Crossref PubMed Scopus (71) Google Scholar,10Kitchlu A. McArthur E. Amir E. et al.Acute kidney injury in patients receiving systemic treatment for cancer: a population-based cohort study.J Natl Cancer Inst. 2019; 111: 727-736Crossref PubMed Scopus (45) Google Scholar Future studies will be needed to determine the pathophysiology of kidney function decline after ICIs and evaluate strategies to slow eGFR decline. Research idea and study design: MES, KLR, TGN; data acquisition: DFC, IAS, HS, ML, LZ; data analysis/interpretation: DFC, SG, DEL, OR, ZDD, TGN, LZ, KLR, MES; statistical analysis: SZ, NR, MES; supervision or mentorship: MES, TGN, KLR. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual’s own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate. MES is supported by National Institutes of Health (NIH) K23 DK 117014 and the Claflin Distinguished Scholars Award. TGN is supported by NIH R01HL137562, R01HL130539, and K24HL150238, and, in part, through a kind gift from A. Curtis Greer and Pamela Kohlberg. DEL is supported by NIH R01HL144566 and R01DK125786. The NIH had no role in study design; collection, analysis, and interpretation of data; writing the report; or the decision to submit the report for publication. LZ serves as a consultant for Merck. TGN has been a consultant to and received fees from Parexel Imaging, Intrinsic Imaging, H3-Biomedicine, and AbbVie, outside of the current work. TGN also reports consultant fees from Bristol Myers Squibb for a Scientific Advisory Board focused on myocarditis related to ICIs and has received grant funding from AstraZeneca. The remaining authors declare that they have no relevant financial interests. A preprint version of this Research Letter was posted December 22, 2020 at medRxiv with doi 10.1101/2020.12.18.20248471. Received January 5, 2021. Evaluated by 2 external peer reviewers, with direct editorial input from a Statistics/Methods Editor and an Associate Editor, who served as Acting Editor-in-Chief. Accepted in revised form May 7, 2021. The involvement of an Acting Editor-in-Chief was to comply with AJKD’s procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies. 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