Diana Zepeda-Orozco

OBJECTIVE: To reduce acute kidney injury (AKI) associated with nephrotoxic medication (NTM) exposure in critically ill pediatric patients through a structured quality improvement (QI) initiative. DESIGN: Prospective, multi-phased QI project. SETTING: A single-center, free-standing, quaternary care children’s hospital. PATIENTS: All patients admitted to the PICU during the study period. INTERVENTIONS: A three-phase intervention strategy was implemented to increase awareness surrounding NTM exposures in PICU and their role in subsequent AKI development. Phase 1 introduced monthly pharmacist-led educational session for resident physicians. Phase 2 incorporated an informational handout reviewed during monthly resident orientations. In phase 3, clinical pharmacists provided daily notifications to attending physicians for patients meeting NTM exposure criteria, offering timely alternatives and AKI monitoring recommendations. MEASUREMENTS AND MAIN RESULTS: NTM exposure and NTM-associated AKI (NAKI) rates per 1000 patient-days were measured across pre-intervention and post-intervention periods. From May 1, 2021, to December 31, 2023, a total of 34,631 patient-days were included. During this period, 2410 and 388 patient-days, respectively, satisfied NTM exposure and NAKI criteria. This accounted for 1039 NTM exposure events in 742 patients and 159 NAKI episodes in 125 unique patients. Following interventions, NTM exposure rates declined from 30.6 to 26.9 per 1000 patient-days (a 12.4% reduction), and NAKI rates decreased from 5.6 to 2.5 per 1000 patient-days (a 55% reduction). CONCLUSIONS: Targeted PICU-specific interventions, including routine stakeholder education and pharmacy-driven daily provider notifications, were associated with reductions in NTM exposure and subsequent NAKI rates in critically ill patients. Efforts to integrate and sustain these strategies at the institutional level are currently in progress.

OBJECTIVES: To test whether urine olfactomedin 4 (uOLFM4) can predict furosemide responsiveness in patients at high risk for acute kidney injury (AKI) early in the PICU course. A secondary outcome was prediction of kidney replacement therapy (KRT) initiation in this cohort. DESIGN: Prospective observational cohort study. SETTING: Two quaternary care PICUs. PATIENTS: Two hundred forty PICU patients with a renal angina index greater than or equal to 8 and a urine sample collected on PICU days 0–1. Fifty-six patients received a furosemide dose on PICU days 1–4 and 44 received KRT. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: uOLFM4 was measured via enzyme-linked immunosorbent assay. Urine neutrophil gelatinase-associated lipocalin (uNGAL) was measured via particle-enhanced turbidimetric immunoassay by the clinical laboratory. We compared groups using Mann-Whitney U tests or Kruskal-Wallis tests and calculated area under the receiver operating characteristic curve for performance of uOLFM4 and uNGAL to predict furosemide responsiveness on PICU days 1–4 and KRT receipt. Median (interquartile range) uOLFM4 and uNGAL concentrations were higher in patients who were furosemide nonresponsive (uOLFM4 694 ng/mL [214–1478 ng/mL] vs. 139 ng/mL [46–529 ng/mL]; p = 0.0004 and uNGAL 1149 ng/mL [204–2284 ng/mL] vs. 53 ng/mL [50–1533 ng/mL]; p = 0.0076) and higher in patients who received KRT. uOLFM4 and uNGAL had similar moderate discriminatory ability to predict furosemide responsiveness (area under the curve, 0.77 [95% CI, 0.65–0.90]; p = 0.0005 and 0.71 [95% CI, 0.57–0.85]; p = 0.0088, respectively). uOLFM4 of 156 ng/mL had 59% sensitivity, 96% specificity, a positive predictive value of 64%, and negative predictive value (NPV) of 95% to predict furosemide responsiveness. CONCLUSIONS: In critically ill children at high risk for AKI, both uOLFM4 and uNGAL have moderate discriminatory ability to predict furosemide responsiveness and KRT receipt on the first day of PICU stay. The NPV greater than or equal to 95% for uOLFM4 for both outcomes make it a promising candidate for implementation into clinical decision support to facilitate early KRT initiation decision-making.

Background: Nephrotoxic chemotherapy, nephrectomy, abdominal radiotherapy exposure, and the presence of kidney or pelvic tumors are risk factors associated with long‐term kidney complications. This study aimed to determine the prevalence of long‐term kidney complications in patients who survived pediatric and young adult cancer and were exposed to those risk factors in the current anticancer treatment era.Methods: This retrospective study included patients who survived pediatric and young adult cancer and received nephrotoxic chemotherapy, nephrectomy, abdominal radiotherapy, and/or had kidney or pelvic tumors. Patients were under follow‐up at Nationwide Children's Hospital pediatric cancer survivors’ clinic between January 1, 2016 and December 31, 2021.Results: A total of 109 patients met inclusion criteria. Long‐term kidney complications included low glomerular filtration rate (GFR) (11.9%), hyperfiltration (22.9%), and hypertension (49.5%). Risk factors associated with low GFR included surviving childhood solid tumors, nephrectomy, carboplatin, and ifosfamide treatments. Urinalysis was available in 64 patients (58.7%), and of those, five had proteinuria‐associated long‐term kidney complications.Conclusions: Long‐term kidney complications are prevalent in patients who survived pediatric and young adult solid tumors. Current guidelines do not recommend evaluation of urinalysis or albuminuria in patients at risk of long‐term kidney complications, which can significantly impact their treatment.

Identifying and targeting pathogenic protein kinases holds potential for drug discovery in treating acute kidney injury. Our study, using novel germline knockout mice, revealed that Cdkl1 kinase deficiency does not affect mouse viability but provides protection against acute kidney injury. This underscores the importance of Cdkl1 kinase in kidney injury and supports the development of targeted small-molecule inhibitors as potential therapeutics.

Key Points: Szeto–Schiller-31–mediated mitoprotection is phospholipid scramblase 3–dependent. Phospholipid scramblase 3 is required for recovery after AKI. Background: The synthetic tetrapeptide Szeto–Schiller (SS)-31 shows promise in alleviating mitochondrial dysfunction associated with common diseases. However, the precise pharmacological basis of its mitoprotective effects remains unknown. Methods: To uncover the biological targets of SS-31, we performed a genome-scale clustered regularly interspaced short palindromic repeats screen in human kidney-2, a cell culture model where SS-31 mitigates cisplatin-associated cell death and mitochondrial dysfunction. The identified hit candidate gene was functionally validated using knockout cell lines, small interfering RNA-mediated downregulation, and tubular epithelial–specific conditional knockout mice. Biochemical interaction studies were also performed to examine the interaction of SS-31 with the identified target protein. Results: Our primary screen and validation studies in hexokinase 2 and primary murine tubular epithelial cells showed that phospholipid scramblase 3 (PLSCR3), an understudied inner mitochondrial membrane protein, was essential for the protective effects of SS-31. For in vivo validation, we generated tubular epithelial–specific knockout mice and found that Plscr3 gene ablation did not influence kidney function under normal conditions or affect the severity of cisplatin and rhabdomyolysis-associated AKI. However, Plscr3 gene deletion completely abrogated the protective effects of SS-31 during cisplatin and rhabdomyolysis-associated AKI. Biochemical studies showed that SS-31 directly binds to a previously uncharacterized N-terminal domain and stimulates PLSCR3 scramblase activity. Finally, PLSCR3 protein expression was found to be increased in the kidneys of patients with AKI. Conclusions: PLSCR3 was identified as the essential biological target that facilitated the mitoprotective effects of SS-31 in vitro and in vivo.

Purpose: Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli, followed by potential reabsorption of a fraction by proximal tubules, which may cause acute kidney injury (AKI) and chronic kidney disease (CKD). Because tubular cells are considered the primary site of radiopeptides’ renal reabsorption and potential injury, the current use of kidney biomarkers of glomerular functional loss limits the evaluation of possible nephrotoxicity and its early detection. This study aimed to investigate whether urinary secretion of tubular injury biomarkers could be used as an additional non-invasive sensitive diagnostic tool to identify unrecognizable tubular damage and risk of long-term α-RLT nephrotoxicity. Methods: A bifunctional cyclic peptide, melanocortin 1 ligand (MC1L), labeled with [²⁰³Pb]Pb-MC1L, was used for [²¹²Pb]Pb-MC1L biodistribution and absorbed dose measurements in CD-1 Elite mice. Mice were treated with [²¹²Pb]Pb-MC1L in a dose-escalation study up to levels of radioactivity intended to induce kidney injury. The approach enabled prospective kidney functional and injury biomarker evaluation and late kidney histological analysis to validate these biomarkers. Results: Biodistribution analysis identified [²¹²Pb]Pb-MC1L reabsorption in kidneys with a dose deposition of 2.8, 8.9, and 20 Gy for 0.9, 3.0, and 6.7 MBq injected [²¹²Pb]Pb-MC1L doses, respectively. As expected, mice receiving 6.7 MBq had significant weight loss and CKD evidence based on serum creatinine, cystatin C, and kidney histological alterations 28 weeks after treatment. A dose-dependent urinary neutrophil gelatinase-associated lipocalin (NGAL, tubular injury biomarker) urinary excretion the day after [²¹²Pb]Pb-MC1L treatment highly correlated with the severity of late tubulointerstitial injury and histological findings. Conclusion: Urine NGAL secretion could be a potential early diagnostic tool to identify unrecognized tubular damage and predict long-term α-RLT-related nephrotoxicity.

Purpose: Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli, followed by potential reabsorption of a fraction by proximal tubules, which may cause acute kidney injury (AKI) and chronic kidney disease (CKD). Because tubular cells are considered the primary site of radiopeptides’ renal reabsorption and potential injury, the current use of kidney biomarkers of glomerular functional loss limits the evaluation of possible nephrotoxicity and its early detection. This study aimed to investigate whether urinary secretion of tubular injury biomarkers could be used as additional non-invasive sensitive diagnostic tool to identify unrecognizable tubular damage and risk of long-term α-RLTs nephrotoxicity. Methods: A bifunctional cyclic peptide, melanocortin ligand-1(MC1L), labeled with [ ²⁰³ Pb]Pb-MC1L, was used for [ ²¹² Pb]Pb-MC1L biodistribution and absorbed dose measurements in CD-1 Elite mice. Mice were treated with [ ²¹² Pb]Pb-MC1L in a dose escalation study up to levels of radioactivity intended to induce kidney injury. The approach enabled prospective kidney functional and injury biomarker evaluation and late kidney histological analysis to validate these biomarkers. Results: Biodistribution analysis identified [ ²¹² Pb]Pb-MC1L reabsorption in kidneys with a dose deposition of 2.8, 8.9, and 20 Gy for 0.9, 3.0, and 6.7 MBq injected [ ²¹² Pb]Pb-MC1L doses, respectively. As expected, mice receiving 6.7 MBq had significant weight loss and CKD evidence based on serum creatinine, cystatin C, and kidney histological alterations 28 weeks after treatment. A dose-dependent urinary Neutrophil gelatinase-associated lipocalin (NGAL, tubular injury biomarker) urinary excretion the day after [ ²¹² Pb]Pb-MC1L treatment highly correlated with the severity of late tubulointerstitial injury and histological findings. Conclusion: urine NGAL secretion could be a potential early diagnostic tool to identify unrecognized tubular damage and predict long-term α-RLT-related nephrotoxicity.

Cisplatin, a potent chemotherapeutic agent, is marred by severe nephrotoxicity that is governed by mechanisms involving oxidative stress, inflammation, and apoptosis pathways. The transcription factor Nrf2, pivotal in cellular defense against oxidative stress and inflammation, is the master regulator of the antioxidant response, upregulating antioxidants and cytoprotective genes under oxidative stress. This review discusses the mechanisms underlying chemotherapy-induced kidney injury, focusing on the role of Nrf2 in cancer therapy and its redox regulation in cisplatin-induced kidney injury. We also explore Nrf2's signaling pathways, post-translational modifications, and its involvement in autophagy, as well as examine redox-based strategies for modulating Nrf2 in cisplatin-induced kidney injury while considering the limitations and potential off-target effects of Nrf2 modulation. Understanding the redox regulation of Nrf2 in cisplatin-induced kidney injury holds significant promise for developing novel therapeutic interventions. This knowledge could provide valuable insights into potential strategies for mitigating the nephrotoxicity associated with cisplatin, ultimately enhancing the safety and efficacy of cancer treatment.

Chronic kidney disease (CKD) predisposes one toward end-stage renal disease (ESRD) and its associated morbidity and mortality. Significant metabolic perturbations in conjunction with alterations in redox status during CKD may induce increased production of reactive oxygen species (ROS), including superoxide (O₂^●−) and hydrogen peroxide (H₂O₂). Increased O₂^●− and H₂O₂ may contribute to the overall progression of renal injury as well as catalyze the onset of comorbidities. In this review, we discuss the role of mitochondrial oxidative metabolism in the pathology of CKD and the recent developments in treating CKD progression specifically targeted to the mitochondria. Recently published results from a Phase 2b clinical trial by our group as well as recently released data from a ROMAN: Phase 3 trial (NCT03689712) suggest avasopasem manganese (AVA) may protect kidneys from cisplatin-induced CKD. Several antioxidants are under investigation to protect normal tissues from cancer-therapy-associated injury. Although many of these antioxidants demonstrate efficacy in pre-clinical models, clinically relevant novel compounds that reduce the severity of AKI and delay the progression to CKD are needed to reduce the burden of kidney disease. In this review, we focus on the various metabolic pathways in the kidney, discuss the role of mitochondrial metabolism in kidney disease, and the general involvement of mitochondrial oxidative metabolism in CKD progression. Furthermore, we present up-to-date literature on utilizing targets of mitochondrial metabolism to delay the pathology of CKD in pre-clinical and clinical models. Finally, we discuss the current clinical trials that target the mitochondria that could potentially be instrumental in advancing the clinical exploration and prevention of CKD.