Background and objectivesImmune checkpoint inhibitor use in oncology is increasing rapidly. We sought to determine the frequency, severity, cause, and predictors of AKI in a real-world population receiving checkpoint inhibitors.Design, setting, participants, & measurementsWe included all patients who received checkpoint inhibitor therapy from May 2011 to December 2016 at Massachusetts General Hospital. Baseline serum creatinine, averaged 6 months before checkpoint inhibitor start date, was compared with all subsequent creatinine values within 12 months of starting therapy. AKI was defined by Kidney Disease: Improving Global Outcomes criteria for fold changes in creatinine from baseline. Sustained AKI events lasted at least 3 days and was our primary outcome. The cause of sustained AKI was determined by chart review. Cumulative incidence and subdistribution hazard models were used to assess the relationship between baseline demographics, comorbidities, and medications, and sustained AKI and potential checkpoint inhibitor–related AKI.ResultsWe included 1016 patients in the analysis. Average age was 63 (SD 13) years, 61% were men, and 91% were white. Mean baseline creatinine was 0.9 mg/dl (SD 0.4 mg/dl), and 169 (17%) had CKD (eGFR<60 ml/min per 1.73 m2) at baseline. A total of 169 patients (17%) experienced AKI, defined by an increase in creatinine at least 1.5 times the baseline within 12 months; 82 patients (8%) experienced sustained AKI and 30 patients (3%) had potential checkpoint inhibitor–related AKI. The first episode of sustained AKI occurred, on average, 106 days (SD 85) after checkpoint inhibitor initiation. Sixteen (2%) patients experienced stage 3 sustained AKI and four patients required dialysis. Proton pump inhibitor use at baseline was associated with sustained AKI.ConclusionsAKI is common in patients receiving checkpoint inhibitor therapy. The causes of sustained AKI in this population are heterogenous and merit thorough evaluation. The role of PPI and other nephritis-inducing drugs in the development of sustained AKI needs to be better defined.

SummaryIn aged skeletal muscle, changes to the composition and function of the contractile machinery cannot fully explain the observed decrease in the specific force produced by the contractile machinery that characterizes muscle weakness during aging.

Hepatitis C virus (HCV) infection is common and can accelerate chronic kidney disease (CKD) progression. Direct-acting antiviral (DAA) therapies against hepatitis C have consistently shown rates of sustained viral remission. However, the effect on kidney function is unknown. In a retrospective observational cohort study of HCV-infected patients receiving DAA therapies from 2013 to 2017, the slopes of estimated glomerular filtration rate (eGFR) decline were compared in the three years before DAA therapy to the slope after therapy. Pre-and post-treatment albuminuria values were also compared. In all, 1,178 patients were included; mean age of 56, 64% male, 71% white, 21% were diabetic, and 42% with cirrhosis. In patients with eGFR less than 60ml/min per 1.73m 2 , the annual decline in eGFR in the three years prior to treatment was −5.98 ml/min per year (95% confidence interval −7.30 to −4.67) and improved to −1.32 ml/min per year (95% confidence interval −4.50 to 1.88) after DAA therapy. In patients with eGFR greater than 60ml/min per 1.73m 2 the annual decline in eGFR in the three years prior to treatment was −1.43 ml/min per year (95% confidence interval −1.78 to −1.08) and after DAA therapy was −2.32 ml/min per year (95% confidence interval −3.36 to −1.03). Albuminuria improved significantly in patients without diabetes, but not in those with diabetes. Predictors of eGFR improvement included having CKD at baseline and being non-diabetic. Events of acute kidney injury were rare, occurring in 29 patients, and unrelated to antiviral therapy in 76% of cases. Thus, DAA therapy for HCVs infection may slow CKD progression.

It was hypothesized that the four‐factor prothrombin complex concentrate (4F‐PCC) Kcentra 25 unit/kg would reverse impairment of thrombin generation in healthy volunteers dosed with apixaban to steady state. In this randomized, two‐period crossover, assessor‐blinded trial, 12 healthy subjects received 5 mg apixaban every 12 h. Three h after the fifth dose, four‐factor prothrombin complex concentrate (4F‐PCC) 25 unit/kg or saline were infused. Serial blood samples were assessed for thrombin generation using PPP‐reagent and PPP‐reagent low, anti‐Xa, PT, and PTT assays. Geometric mean ratio was calculated at 30 min postinfusion, and at 24, 48, and 72 h. Peak thrombin generation was 76% higher at 30 min postinfusion with 4F‐PCC (p = 0.025). The difference declined to 24% at 24 h and resolved by 48 h. Other thrombin generation parameters were also partially normalized. There was no difference between 4F‐PCC and saline in anti‐Xa assessment at 30 min or later time points.

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