Sarcopenia, adiposity and large discordance between cystatin C and creatinine-based estimated glomerular filtration rate in patients with cancer.

BACKGROUND: Creatinine-based estimated glomerular filtration rate (eGFRCRE) may overestimate kidney function in patients with sarcopenia. While cystatin C-based eGFR (eGFRCYS) is less affected by muscle mass, it may underestimate kidney function in patients with obesity. We sought to evaluate the relationship between body composition defined by computed tomography (CT) scans and discordance between creatinine, eGFRCRE and eGFRCYS in adult patients with cancer. METHODS: This study is a cross-sectional study of consecutive adults with cancer with an abdominal CT scan performed within 90 days of simultaneous eGFRCRE and eGFRCYS measurements between May 2010 and January 2022. Muscle and adipose tissue cross-sectional areas were measured at the level of the third lumbar vertebral body using a validated deep-learning pipeline. CT-defined sarcopenia was defined using independent sex-specific cut-offs for skeletal muscle index (<39 cm2/m2 for women and <55 cm2/m2 for men). High adiposity was defined as the highest sex-specific quartile of the total (visceral plus subcutaneous) adiposity index in the cohort. The primary outcome was eGFR discordance, defined by eGFRCYS > 30% lower than eGFRCRE; the secondary outcome was eGFRCYS > 50% lower than eGFRCRE. The odds of eGFR discordance were estimated using multivariable logistic regression modelling. Unadjusted spline regression was used to evaluate the relationship between skeletal muscle index and the difference between eGFRCYS and eGFRCRE. RESULTS: Of the 545 included patients (mean age 63 ± 14 years, 300 [55%] females, 440 [80.7%] non-Hispanic white), 320 (58.7%) met the criteria for CT-defined sarcopenia, and 136 (25%) had high adiposity. A total of 259 patients (48%) had >30% eGFR discordance, and 122 (22.4%) had >50% eGFR discordance. After adjustment for potential confounders, CT-defined sarcopenia and high adiposity were both associated with >30% eGFR discordance (adjusted odds ratio [aOR] 1.90, 95% confidence interval [CI] 1.12-3.24; aOR 2.01, 95% CI 1.15-3.52, respectively) and >50% eGFR discordance (aOR 2.34, 95% CI 1.21-4.51; aOR 2.23, 95% CI 1.19-4.17, respectively). A spline model demonstrated that as skeletal muscle index decreases, the predicted difference between eGFRCRE and eGFRCYS widens considerably. CONCLUSIONS: CT-defined sarcopenia and high adiposity are both independently associated with large eGFR discordance. Incorporating valuable information from body composition analysis derived from CT scans performed as a part of routine cancer care can impact the interpretation of GFR estimates.

Adverse kidney outcomes of CDK 4/6 inhibitors for metastatic breast cancer.

Cyclin-dependent kinase (CDK) 4/6 inhibitors have significantly improved overall and progression free survival of patients with metastatic breast cancer, but their effect on short and long-term kidney function is unknown. We found that early, mild estimated glomerular filtration rate (eGFR) decline was common in patients treated with CDK 4/6 inhibitors; however, severe kidney injury is rare and long-term eGFR decline is uncommon.

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

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.

Brief Report: Use and Side Effects of Sodium-Glucose Transporter 2 Inhibitors Among US People With HIV With Clinical Indications.

BACKGROUND: Sodium-glucose transporter 2 (SGLT2) inhibitors have been approved for treatment of diabetes mellitus (DM), chronic kidney disease, and heart failure, but little is known about prescription levels and safety profiles among people with HIV (PWH). METHODS: We leveraged data from the US Mass General Brigham electronic healthcare database to determine the use/uptake of SGLT2 inhibitors among PWH with type II diabetes (DM2) (with or without chronic kidney disease, proteinuria, or heart failure) and to assess rates of adverse events among PWH with DM2 taking SGLT2 inhibitors. RESULTS: Among eligible PWH with DM2 receiving care at US Mass General Brigham (N = 907), SGLT2 inhibitors were prescribed to 8.8%. SGLT2 inhibitors were prescribed to a fraction of eligible PWH with DM2 and a concomitant diagnosis of chronic kidney disease (3.8%), proteinuria (13.2%), or heart failure (8.2%). PWH with DM2 on SGLT2 inhibitors experienced side effects (urinary tract infection, diabetic ketoacidosis, and acute kidney injury) at rates comparable with PWH with DM2 prescribed glucagon-like peptide-1 agonists. Rates of mycotic genitourinary infections were higher among those prescribed SGLT2 inhibitors (5% vs. 1%, P = 0.17), but no cases of necrotizing fasciitis ensued. CONCLUSIONS: Additional studies are needed to characterize population-specific salutary and adverse effects of SGLT2 inhibitors among PWH and potentially augment prescription rates when guideline indicated.

Effect of remdesivir on adverse kidney outcomes in hospitalized patients with COVID-19 and impaired kidney function.

BACKGROUND: Chronic kidney disease (CKD) is an important risk factor for mortality from COVID-19. Remdesivir has been shown to shorten time to recovery in patients with severe COVID-19. However, exclusion of patients with severe kidney function impairment in clinical trials has led to concerns about kidney safety of remdesivir in patients with pre-existing kidney disease. METHODS: Retrospective propensity score matched cohort study of hospitalized patients with COVID-19 admitted with estimated glomerular filtration rate (eGFR) between 15 - 60 mL/min/1.73m2. Remdesivir-treated patients were 1:1 matched to historical comparators admitted during the first wave of COVID-19 (between March-April 2020) prior to emergency use authorization of remdesivir using propensity scores accounting for factors predicting treatment assignment. Dependent outcomes included in-hospital peak creatinine, incidence of doubling of creatine, rate of kidney replacement therapy initiation and eGFR among surviving patients at day 90. RESULTS: 175 remdesivir-treated patients were 1:1 matched to untreated historical comparators. Mean age was 74.1 (SD 12.8), 56.9% were male, 59% patients were white, and the majority (83.1%) had at least one co-morbidity. There were no statistically significant differences in peak creatinine during hospitalization (2.3mg/dL vs. 2.5 mg/dL, P = 0.34), incidence of doubling of creatinine (10.3% vs. 13.1%, P = 0.48), and rate of kidney replacement therapy initiation (4.6% vs. 6.3%, P = 0.49) in remdesivir-treated patients versus matched untreated historical comparators, respectively. Among surviving patients, there was no difference of the average eGFR at day 90 (54.7 ± 20.0 mL/min/1.73m2 for remdesivir-treated patients vs. 51.7 ± 19.5 mL/min/1.73m2 for untreated comparators, P = 0.41). CONCLUSIONS: Remdesivir use in patients with impaired kidney function (eGFR between 15 - 60 mL/min/1.73m2) who present to the hospital with COVID-19 is not associated with increased risk of adverse kidney outcomes.

Medication-related adverse events in patients with cancer and discrepancies in cystatin C- versus creatinine-based eGFR.

Background: Creatinine-based estimated glomerular filtration rate (eGFRCRE) may overestimate kidney function in patients with cancer. Cystatin C-based eGFR (eGFRCYS) is an alternative marker of kidney function. We investigated whether patients with an eGFR discrepancy, defined as eGFRCYS >30% lower than the concurrent eGFRCRE, had an increased risk of adverse events resulting from renally-cleared medications. Patients and Methods: We conducted a cohort study of adult patients with cancer who had serum creatinine and cystatin C measured on the same day between May 2010 and January 2022 at two academic cancer centers in Boston, MA. The primary outcome was the incidence of each of the following medication-related adverse events: 1) supratherapeutic vancomycin levels (>30µg/mL); 2) trimethoprim-sulfamethoxazole-related hyperkalemia (>5.5mEq/L); 3) baclofen-induced neurotoxicity; and 4) supratherapeutic digoxin levels (>2.0ng/mL). Results: 1988 patients with cancer had simultaneous eGFRCYS and eGFRCRE. The mean age was 66 years (SD±14), 965 (49%) were female, and 1555 (78%) were non-Hispanic white. eGFR discrepancy occurred in 579 patients (29%). Patients with eGFR discrepancy were more likely to experience medication-related adverse events compared to those without eGFR discrepancy: vancomycin levels >30µg/mL (24% vs. 10%, p=0.004), trimethoprim- sulfamethoxazole-related hyperkalemia (24% vs. 12%, p=0.013), baclofen-induced neurotoxicity (25% vs. 0%, p=0.13), and supratherapeutic digoxin levels (38% vs. 0%, p=0.03). The adjusted OR for vancomycin levels >30µg/mL was 2.30 (95% CI 1.05 - 5.51, p = 0.047). Conclusion: Among patients with cancer with simultaneous assessment of eGFRCYS and eGFRCRE, medication-related adverse events occur more commonly in those with eGFR discrepancy. These findings underscore the importance of accurate assessment of kidney function and appropriate dosing of renally-cleared medications in patients with cancer.

Soluble and cell-based markers of immune checkpoint inhibitor-associated nephritis.

BACKGROUND: Non-invasive biomarkers of immune checkpoint inhibitor-associated acute tubulointerstitial nephritis (ICI-nephritis) are urgently needed. Because ICIs block immune checkpoint pathways that include cytotoxic T lymphocyte antigen 4 (CTLA4), we hypothesized that biomarkers of immune dysregulationpreviously defined in patients with congenital CTLA4 deficiency, including elevated soluble interleukin-2 receptor alpha (sIL-2R) and flow cytometric cell-based markers of B and T cell dysregulation in peripheral blood may aid the diagnosis of ICI-nephritis. METHODS: A retrospective cohort of patients diagnosed with ICI-nephritis was compared with three prospectively enrolled control cohorts: ICI-treated controls without immune-related adverse events, patients not on ICIs with hemodynamic acute kidney injury (hemodynamic AKI), and patients not on ICIs with biopsy proven acute interstitial nephritis from other causes (non-ICI-nephritis). sIL-2R level and flow cytometric parameters were compared between groups using Wilcoxon rank sum test or Kruskal-Wallis test. Receiver operating characteristic curves were generated to define the accuracy of sIL-2R and flow cytometric biomarkers in diagnosing ICI-nephritis. The downstream impact of T cell activation in the affected kidney was investigated using archived biopsy samples to evaluate the gene expression of IL2RA, IL-2 signaling, and T cell receptor signaling in patients with ICI-nephritis compared with other causes of drug-induced nephritis, acute tubular injury, and histologically normal controls. RESULTS: sIL-2R level in peripheral blood was significantly higher in patients with ICI-nephritis (N=24) (median 2.5-fold upper limit of normal (ULN), IQR 1.9-3.3), compared with ICI-treated controls (N=10) (median 0.8-fold ULN, IQR 0.5-0.9, p<0.001) and hemodynamic AKI controls (N=6) (median 0.9-fold-ULN, IQR 0.7-1.1, p=0.008). A sIL-2R cut-off point of 1.75-fold ULN was highly diagnostic of ICI-nephritis (area under the curve >96%) when compared with either ICI-treated or hemodynamic AKI controls. By peripheral blood flow cytometry analysis, lower absolute CD8+T cells, CD45RA+CD8+ T cells, memory CD27+B cells, and expansion of plasmablasts were prominent features of ICI-nephritis compared with ICI-treated controls. Gene expressions for IL2RA, IL-2 signaling, and T cell receptor signaling in the kidney tissue with ICI-nephritis were significantly higher compared with controls. CONCLUSION: Elevated sIL-2R level and flow cytometric markers of both B and T cell dysregulation may aid the diagnosis of ICI-nephritis.