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.

Patient-Specific Pharmacokinetics and Dasatinib Nephrotoxicity.

BACKGROUND: Dasatinib has been associated with nephrotoxicity. We sought to examine the incidence of proteinuria on dasatinib and determine potential risk factors that may increase dasatinib-associated glomerular injury. METHODS: We examined glomerular injury through urine albumin-creatinine ratio (UACR) in 82 patients with chronic myelogenous leukemia who were on tyrosine-kinase inhibitor therapy for at least 90 days. t tests were used to compare mean differences in UACR, while regression analysis was used to assess the effects of drug parameters on proteinuria development while on dasatinib. We assayed plasma dasatinib pharmacokinetics using tandem mass spectroscopy and further described a case study of a patient who experienced nephrotic-range proteinuria while on dasatinib. RESULTS: Participants treated with dasatinib ( n =32) had significantly higher UACR levels (median 28.0 mg/g; interquartile range, 11.5-119.5) than participants treated with other tyrosine-kinase inhibitors ( n =50; median 15.0 mg/g; interquartile range, 8.0-35.0; P < 0.001). In total, 10% of dasatinib users exhibited severely increased albuminuria (UACR >300 mg/g) versus zero in other tyrosine-kinase inhibitors. Average steady-state concentrations of dasatinib were positively correlated with UACR ( ρ =0.54, P = 0.03) and duration of treatment ( P = 0.003). There were no associations with elevated BP or other confounding factors. In the case study, kidney biopsy revealed global glomerular damage with diffuse foot process effacement that recovered on termination of dasatinib treatment. CONCLUSIONS: Exposure to dasatinib was associated with a significant chance of developing proteinuria compared with other similar tyrosine-kinase inhibitors. Dasatinib plasma concentration significantly correlated with higher risk of developing proteinuria while receiving dasatinib. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_09_08_CJN0000000000000219.mp3.

Dasatinib nephrotoxicity correlates with patient-specific pharmacokinetics.

Introduction: Dasatinib has been associated with nephrotoxicity. We sought to examine the incidence of proteinuria on dasatinib and determine potential risk factors that may increase dasatinib-associated glomerular injury. Methods: We examine glomerular injury via urine albumin-to-creatinine ratio (UACR) in 101 chronic myelogenous leukemia patients who were on tyrosine-kinase inhibitor (TKI) therapy for at least 90 days. We assay plasma dasatinib pharmacokinetics using tandem mass spectroscopy, and further describe a case study of a patient who experienced nephrotic-range proteinuria while on dasatinib. Results: Patients treated with dasatinib (n= 32) had significantly higher UACR levels (median 28.0 mg/g, IQR 11.5 - 119.5) than patients treated with other TKIs (n=50; median 15.0 mg/g, IQR 8.0 - 35.0; p < 0.001). In total, 10% of dasatinib users exhibited severely increased albuminuria (UACR > 300 mg/g) versus zero in other TKIs. Average steady state concentrations of dasatinib were positively correlated with UACR (ρ = 0.54, p = 0.03) as well as duration of treatment ( p =0.003). There were no associations with elevated blood pressure or other confounding factors. In the case study, kidney biopsy revealed global glomerular damage with diffuse foot process effacement that recovered upon termination of dasatinib treatment. Conclusions: Exposure to dasatinib is associated a significant chance of developing proteinuria compared to other similar TKIs. Dasatinib plasma concentration significantly correlates with increased risk of developing proteinuria while receiving dasatinib. Screening for renal dysfunction and proteinuria is strongly advised for all dasatinib patients.

Acute Kidney Injury in the Modern Era of Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND AND OBJECTIVES: AKI is a major complication of allogeneic hematopoietic stem cell transplantation, increasing risk of nonrelapse mortality. AKI etiology is often ambiguous due to heterogeneity of conditioning/graft versus host disease regimens. To date, graft versus host disease and calcineurin inhibitor effects on AKI are not well defined. We aimed to describe AKI and assess pre-/post-hematopoietic transplant risk factors in a large recent cohort. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a single-center, retrospective study of 616 allogeneic hematopoietic cell transplant recipients from 2014 to 2017. We defined AKI and CKD based on Kidney Disease Improving Global Outcomes (KDIGO) criteria and estimated GFR using the Chronic Kidney Disease Epidemiology Collaboration equation. We assessed AKI pre-/post-hematopoietic transplant risk factors using cause-specific Cox regression and association of AKI with CKD outcomes using chi-squared test. AKI was treated as a time-dependent variable in relation to nonrelapse mortality. RESULTS: Incidence of AKI by day 100 was 64%. Exposure to tacrolimus and other nephrotoxins conferred a higher risk of AKI, but tacrolimus levels were not associated with severity. Reduced-intensity conditioning carried higher AKI risk compared with myeloablative conditioning. Most stage 3 AKIs were due to ischemic acute tubular necrosis and calcineurin inhibitor nephrotoxicity. KRT was initiated in 21 out of 616 patients (3%); of these 21 patients, nine (43%) recovered and five (24%) survived to hospital discharge. T cell-depleted transplants, higher baseline serum albumin, and non-Hispanic ethnicity were associated with lower risk of AKI. CKD developed in 21% (73 of 345) of patients after 12 months. Nonrelapse mortality was higher in those with AKI (hazard ratio, 2.77; 95% confidence interval, 1.8 to 4.27). CONCLUSIONS: AKI post-hematopoietic cell transplant remains a major concern. Risk of AKI was higher with exposure to calcineurin inhibitors. T cell-depleted hematopoietic cell transplants and higher serum albumin had lower risk of AKI. Of the patients requiring KRT, 43% recovered kidney function. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_09_07_CJN19801220.mp3.