Derivation and external validation of a simple risk score for predicting severe acute kidney injury after intravenous cisplatin: cohort study.

OBJECTIVE: To develop and externally validate a prediction model for severe cisplatin associated acute kidney injury (CP-AKI). DESIGN: Multicenter cohort study. SETTING: Six geographically diverse major academic cancer centers across the US. PARTICIPANTS: Adults (≥18 years) receiving their first dose of intravenous cisplatin, 2006-22. MAIN OUTCOME MEASURES: The primary outcome was CP-AKI, defined as a twofold or greater increase in serum creatinine or kidney replacement therapy within 14 days of a first dose of intravenous cisplatin. Independent predictors of CP-AKI were identified using a multivariable logistic regression model, which was developed in a derivation cohort and tested in an external validation cohort. For the primary model, continuous variables were examined using restricted cubic splines. A simple risk model was also generated by converting the odds ratios from the primary model into risk points. Finally, a multivariable Cox model was used to examine the association between severity of CP-AKI and 90 day survival. RESULTS: A total of 24 717 adults were included, with 11 766 in the derivation cohort (median age 59 (interquartile range (IQR) 50-67)) and 12 951 in the validation cohort (median age 60 (IQR 50-67)). The incidence of CP-AKI was 5.2% (608/11 766) in the derivation cohort and 3.3% (421/12 951) in the validation cohort. Each of the following factors were independently associated with CP-AKI in the derivation cohort: age, hypertension, diabetes mellitus, serum creatinine level, hemoglobin level, white blood cell count, platelet count, serum albumin level, serum magnesium level, and cisplatin dose. A simple risk score consisting of nine covariates was shown to predict a higher risk of CP-AKI in a monotonic fashion in both the derivation cohort and the validation cohort. Compared with patients in the lowest risk category, those in the highest risk category showed a 24.00-fold (95% confidence interval (CI) 13.49-fold to 42.78-fold) higher odds of CP-AKI in the derivation cohort and a 17.87-fold (10.56-fold to 29.60-fold) higher odds in the validation cohort. The primary model had a C statistic of 0.75 and showed better discrimination for CP-AKI than previously published models, the C statistics for which ranged from 0.60 to 0.68 (DeLong P<0.001 for each comparison). Greater severity of CP-AKI was monotonically associated with shorter 90 day survival (adjusted hazard ratio 4.63 (95% CI 3.56 to 6.02) for stage 3 CP-AKI versus no CP-AKI). CONCLUSION: This study found that a simple risk score based on readily available variables from patients receiving intravenous cisplatin could predict the risk of severe CP-AKI, the occurrence of which is strongly associated with death.

Development and Validation of a Risk Model for Predicting Contrast-Associated Acute Kidney Injury in Patients With Cancer: Evaluation in Over 46,000 CT Examinations.

BACKGROUND. Patients with cancer undergo frequent CT examinations with iodinated contrast media and may be uniquely predisposed to contrast-associated acute kidney injury (CA-AKI). OBJECTIVE. The purpose of this study was to develop and validate a model for predicting the risk of CA-AKI after contrast-enhanced CT in patients with cancer. METHODS. This retrospective study included 25,184 adult patients (12,153 men, 13,031 women; mean age, 62.3 ± 13.7 [SD] years) with cancer who underwent 46,593 contrast-enhanced CT examinations between January 1, 2016, and June 20, 2020, at one of three academic medical centers. Information was recorded regarding demographics, malignancy type, medication use, baseline laboratory values, and comorbid conditions. CA-AKI was defined as a 0.3-mg/dL or greater increase in serum creatinine level from baseline within 48 hours after CT or a 1.5-fold or greater increase in the peak measurement within 14 days after CT. Multivariable models accounting for correlated data were used to identify risk factors for CA-AKI. A risk score for predicting CA-AKI was generated in a development set (n = 30,926) and tested in a validation set (n = 15,667). RESULTS. CA-AKI occurred after 5.8% (2682/46,593) of CT examinations. The final multivariable model for predicting CA-AKI included hematologic malignancy, diuretic use, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, chronic kidney disease (CKD) stage 3a, CKD stage 3b, CKD stage 4 or 5, serum albumin level less than 3.0 g/dL, platelet count less than 150 × 103/µL, 1+ or greater proteinuria on baseline urinalysis, diabetes mellitus, heart failure, and contrast medium volume 100 mL or greater. A risk score (range, 0-53 points) was generated with these variables. The most points (13) were for CKD stage 4 or 5 and for albumin level less than 3 g/dL. The frequency of CA-AKI progressively increased in higher risk categories. For example, in the validation set, CA-AKI occurred after 2.2% of CT examinations in the lowest risk category (score ≤ 4) and after 32.7% of CT examinations in the highest risk category (score ≥ 30). The Hosmer-Lemeshow test result indicated that the risk score was a good fit (p = .40). CONCLUSION. A risk model in which readily available clinical data are used to predict the likelihood of CA-AKI after contrast-enhanced CT in patients with cancer was developed and validated. CLINICAL IMPACT. The model may help facilitate appropriate implementation of preventive measures in the care of patients at high risk of CA-AKI.

Clinical features of acute kidney injury in patients receiving dabrafenib and trametinib.

BACKGROUND: Our objective was to characterize the incidence, risk factors and clinical features of acute kidney injury (AKI) in patients receiving dabrafenib and trametinib. METHODS: We performed a retrospective cohort study examining the kidney outcomes of patients in a large healthcare system who received dabrafenib/trametinib between 2010 and 2019. The primary outcome was AKI, defined as a 1.5-fold increase in serum creatinine from baseline within a 12-month study period. AKI severity and etiology was determined for each case by chart review. Logistic regression was used to evaluate baseline predictors of AKI. RESULTS: A total of 199 patients who received dabrafenib in our healthcare system from 2010 to 2019 were included in the analysis. Forty-two patients (21%) experienced AKI within 12 months; 10 patients (5% of the total cohort, 24% of AKI patients) experienced AKI occurring during a dabrafenib/trametinib-induced febrile syndrome characterized by fever, chills, gastrointestinal symptoms and elevated liver enzymes. Preexisting liver disease was the only significant predictor of AKI in the cohort. One patient had biopsy-proven granulomatous acute interstitial nephritis that resolved with corticosteroids. CONCLUSIONS: Oncologists and nephrologists should be aware that AKI is common after dabrafenib/trametinib and a substantial number of cases occur in the setting of treatment-induced pyrexia.

Immune-related adverse events and kidney function decline in patients with genitourinary cancers treated with immune checkpoint inhibitors.

BACKGROUND: In patients with genitourinary cancers, the effect of immune checkpoint inhibitors (ICIs) on kidney function is unknown. PATIENTS AND METHODS: This is a retrospective cohort study of patients with renal cell carcinoma (RCC) and urothelial carcinoma who received ICIs at two major cancer centers between 2012 and 2018. Cumulative incidence and Fine and Gray subdistribution hazard models were performed to determine predictors of the co-primary outcomes, (1) acute kidney injury (AKI) and (2) sustained estimated glomerular filtration rate (eGFR) loss, defined as a >20% decline in eGFR sustained ≥90 days. We also determined the association between immune-related adverse events (irAE) and adverse kidney outcomes among patients surviving ≥1 year. RESULTS: 637 patients were included; 320 (50%) patients had RCC and 317 (50%) patients had urothelial carcinoma. Half of the cohort had eGFR<60 mL/min/1.73 m2 at baseline. irAEs, AKI, and sustained eGFR loss were common, occurring in 33%, 25% and 16%, respectively. Compared to patients with urothelial carcinoma, patients with RCC were more likely to develop irAEs (aHR 1.61, 95% CI 1.20-2.18) and sustained eGFR loss (aHR 1.97, 95% CI 1.24-3.12), but not AKI (aHR 1.53, 95% CI 0.97-2.41). Among patients surviving ≥1 years, experiencing a non-renal irAE was associated with a significantly higher risk of sustained eGFR loss (aHR 1.71, 95% CI 1.14-2.57). CONCLUSION: AKI and sustained eGFR loss are common in patients with genitourinary cancers receiving ICIs. irAEs may be a novel risk factor for kidney function decline among patients receiving ICIs.

Hyponatremia and other electrolyte abnormalities in patients receiving immune checkpoint inhibitors.

BACKGROUND: Hyponatremia due to endocrinopathies such as adrenal insufficiency and hypothyroidism has been reported in patients receiving immune checkpoint inhibitors (ICIs). We determined the risk and predictors of hyponatremia and other electrolyte abnormalities in a 'real-world' sample of patients receiving ICIs to treat advanced malignancies. METHODS: This was a retrospective observational study of all patients who received ICIs from a single cancer center between 2011 and 2018. Patients were followed for 12 months after initiation of ICIs or until death. Common Terminology for Cancer Adverse Events version 5.0 criteria were used to grade the severity of hyponatremia and other electrolyte abnormalities. The predictors of severe (Grade 3 or 4) hyponatremia were determined using a multivariable logistic regression model. The etiology of Grade 3 or 4 hyponatremia was determined by chart review. RESULTS: A total of 2458 patients were included. Their average age was 64 years [standard deviation (SD) 13], 58% were male and 90% were white. In the first year after starting ICIs, 62% experienced hyponatremia (sodium <134 mEq/L) and 136 (6%) experienced severe hyponatremia (<124 mEq/L). Severe hyponatremia occurred on average 164 days (SD 100) after drug initiation. Only nine cases of severe hyponatremia were due to endocrinopathies (0.3% overall incidence). Risk factors for severe hyponatremia included ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor) use, diuretic use and non-White race. Other severe electrolyte abnormalities were also commonly observed: severe hypokalemia (potassium <3.0 mEq/L) occurred in 6%, severe hyperkalemia (potassium ≥6.1 mEq/L) occurred in 0.6%, severe hypophosphatemia (phosphorus <2 mg/dL) occurred in 17% and severe hypocalcemia (corrected calcium <7.0 mg/dL) occurred in 0.2%. CONCLUSIONS: Hyponatremia is common in cancer patients receiving ICIs. However, endocrinopathies are an uncommon cause of severe hyponatremia.

Diagnostic utility of CT for suspected immune checkpoint inhibitor enterocolitis.

BACKGROUND AND AIMS: Immune checkpoint inhibitor (ICI) enterocolitis is a common immune-related adverse event and can be fatal, especially when not diagnosed and treated promptly. The current gold standard for diagnosis is endoscopy with biopsy, but CT scan is a possible alternative. The primary objective of this study is to identify the diagnostic performance of CT in the evaluation of ICI enterocolitis. METHODS: With institutional review board approval, we conducted a retrospective cohort study of patients who received ICI therapy between 2015 and 2019 across a healthcare system. Patients were included if they underwent both abdominal CT and endoscopy with biopsy within 3 days. The radiological and pathological diagnoses, as well as clinical characteristics, were extracted from the electronic medical record. We calculated the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of CT for diagnosing ICI enterocolitis when compared with tissue diagnosis. RESULTS: Of the 4474 patients screened, 138 met inclusion criteria. Most common tumor types were melanoma (37%) and lung cancer (19%). Seventy-four per cent were treated with antiprogrammed cell death (PD-1)/PD-L1 therapy. Thirty-nine per cent had signs of enterocolitis on CT scan and 58% had biopsy-proven ICI enterocolitis. Sensitivity and specificity of CT were 50% and 74%, respectively. PPV was 73% and NPV was 52%. Of those with confirmed ICI enterocolitis, 70% had grade 3 or higher symptoms, 91% received steroids and 40% received infliximab. CONCLUSION: The performance of CT scan for diagnosis of ICI enterocolitis is moderate to poor and does not replace endoscopy with biopsy.

Severe Neurological Toxicity of Immune Checkpoint Inhibitors: Growing Spectrum.

Expanding use of immune-checkpoint inhibitors (ICIs) underscores the importance of accurate diagnosis and timely management of neurological immune-related adverse events (irAE-N). We evaluate the real-world frequency, phenotypes, co-occurring immune-related adverse events (irAEs), and long-term outcomes of severe, grade III to V irAE-N at a tertiary care center over 6 years. We analyze how our experience supports published literature and professional society guidelines. We also discuss these data with regard to common clinical scenarios, such as combination therapy, ICI rechallenge and risk of relapse of irAE-N, and corticosteroid taper, which are not specifically addressed by current guidelines and/or have limited data. Recommendations for management and future irAE-N reporting are outlined. ANN NEUROL 2020;87:659-669.

The Incidence, Causes, and Risk Factors of Acute Kidney Injury in Patients Receiving Immune Checkpoint Inhibitors.

BACKGROUND AND OBJECTIVES: Immune 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, & MEASUREMENTS: We 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. RESULTS: We 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. CONCLUSIONS: AKI 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.

Varied phenotypes and management of immune checkpoint inhibitor-associated neuropathies.

OBJECTIVE: To describe the spectrum, clinical course, and management of neuropathies associated with immune checkpoint inhibitors (ICIs). METHODS: Patients with ICI-related neuropathy (irNeuropathy) were identified and their clinical characteristics compared to neuropathy attributed to cytotoxic agents. RESULTS: We identified 19 patients with irNeuropathies. ICIs included anti-programmed death-1 (PD1), 9; anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA4), 2; and combination of anti-CTLA4 and anti-PD1, 8. Median number of ICI doses prior to neuropathy onset was 4. Rate of neuropathies following ICI therapy was 0.7%. Underlying malignancies included melanoma (n = 15), lung adenocarcinoma (n = 3), and cholangiocarcinoma (n = 1). Neuropathy phenotypes were cranial neuropathies with or without meningitis (n = 7), nonlength-dependent polyradiculoneuropathies with and without cranial nerve involvement (n = 6), small-fiber/autonomic neuropathy (n = 2), ANCA-associated mononeuritis multiplex (n = 1), sensory neuronopathy (n = 1), length-dependent sensorimotor axonal polyneuropathy (n = 1), and neuralgic amyotrophy (n = 1). Immune-related adverse events involving other organ systems were common (58%). Corticosteroid use for management of neuropathy was associated with improvement in median modified Rankin Scale score (1 vs 0, p = 0.001) and Inflammatory Neuropathy Cause and Treatment Disability score (2 vs 0.5, p = 0.012) (Class IV). Significantly higher proportion of irNeuropathies had acute or subacute and nonlength-dependent presentations (p < 0.001) and rate of hospitalization for irNeuropathy was also higher (p = 0.002) compared to toxic neuropathy from chemotherapy. CONCLUSION: Neuropathy is a rare complication of ICIs that often responds to immunosuppression. Recognition of its wide phenotypic spectrum and distinct clinical characteristics and prompt management with corticosteroids may lead to favorable outcomes.