Babesiosis is an emerging tickborne illness that may result in acute organ injury/failure and death. However, detailed data on severe illness from babesiosis are limited. We performed a multicenter cohort study of 3,233 consecutive adults hospitalized with babesiosis at 84 hospitals from 24 medical centers across 8 states in the northeastern US from 2010 to 2024. Data on demographics, comorbidities, vital signs, physiologic parameters, labs, treatments, and outcomes were collected by detailed chart review. Using multivariable logistic regression, we identified independent risk factors for the primary composite outcome of in-hospital death or acute organ failure. The latter was defined as shock requiring vasopressors, respiratory failure requiring invasive mechanical ventilation, or acute kidney injury requiring kidney replacement therapy. We also characterized the incidence and associated in-hospital mortality for a broader spectrum of acute organ injuries. Characteristics of the 3,233 patients are shown in Figure 1 and Table 1. A total of 217 patients (6.7%) died or had acute organ failure. Higher parasitemia burden, LDH, total bilirubin, and serum creatinine, and lower hemoglobin and serum albumin on admission, were each associated with a higher odds of the primary outcome (Figure 2A). Ten independent risk factors for the primary outcome were identified (Figure 2B), with serum albumin, LDH, and creatinine having the highest relative importance (Figure 2C). A total of 2,163 patients (66.9%) developed ≥ 1 acute organ injury or failure during hospitalization (Figure 3A). Severe thrombocytopenia and acute kidney injury were the most common acute organ injuries, occurring in 32.3% and 27.0% of patients, respectively. Acute liver failure had the highest associated in-hospital mortality (55.6%), followed by disseminated intravascular coagulation (46.2%). The number of patients admitted per year with babesiosis increased over time, though the incidence of acute organ injury remained largely consistent (Figure 3B). This study identified demographic, clinical, and laboratory-based risk factors for in-hospital death or acute organ failure among hospitalized adults with babesiosis across a large number of sites and patients. Peter J. Krause, MD, 60 Degrees Pharmacueticals, Inc.: Grant/Research Support|Pfizer, Inc: Grant/Research Support David E. Leaf, MD, MMSc, Alexion Pharmaceuticals: Advisor/Consultant|Alexion Pharmaceuticals: Grant/Research Support|BTG International: Grant/Research Support|CardioRenal Systems, Inc: Advisor/Consultant|Metro International Biotech LLC: Grant/Research Support|Renibus Therapeutics, Inc: Grant/Research Support

OBJECTIVES:To examine the association between early rasburicase treatment and acute kidney injury requiring kidney replacement therapy or death among patients with tumour lysis syndrome (TLS). DESIGN:Emulated target trial. SETTING:36 US hospitals. PARTICIPANTS:1276 adults (≥18 years) admitted to hospital between 2014 and 2023 with active haematological malignancy or solid tumour with metastases, high tumour burden, or laboratory findings and clinical features consistent with TLS. MAIN OUTCOME MEASURES:The primary outcome was a composite of acute kidney injury requiring kidney replacement therapy or death during the index hospital admission. A key secondary outcome was 90 day mortality. Outcomes were compared between patients who received rasburicase within 12 hours after TLS onset and those who did not, using logistic regression with inverse probability of treatment weighting to adjust for confounding. RESULTS:Among 1276 patients included in the analysis, 705 (55.3%) received rasburicase within 12 hours after TLS onset. Among patients treated within 12 hours of TLS onset, rasburicase was administered at a median of 5.0 hours (interquartile range 3.1-7.5 hours). Patients who received rasburicase had higher uric acid concentrations than those who did not (median 0.71 v 0.59 mmol/L (11.9 v 9.9 mg/dL)); however, severity of illness was well balanced after applying inverse probability of treatment weighting. Early rasburicase treatment was associated with a lower risk of acute kidney injury requiring kidney replacement therapy or death (32.7% v 42.0%; adjusted odds ratio 0.67, 95% confidence interval 0.52 to 0.88; P<0.001). Results were consistent across multiple sensitivity analyses and for 90 day mortality (adjusted odds ratio 0.71, 0.54 to 0.94). CONCLUSIONS:Among adults with TLS, early rasburicase treatment for TLS was associated with about one third lower risk of acute kidney injury requiring kidney replacement therapy or death compared with delayed or no rasburicase treatment.

Importance:Babesiosis is a worldwide emerging tick-borne disease with an expanding geographic range in the US, Europe, and Asia. Red blood cell exchange transfusion (ET) is often used as an adjunctive treatment for severe illness from babesiosis, particularly in patients with high parasitemia, acute organ injury, or severe hemolytic anemia. Data supporting its clinical effectiveness, however, are lacking. Objective:To test whether ET improves clinical outcomes among hospitalized adult patients with severe babesiosis. Design, Settings, and Participants:This target trial emulation used data from a multicenter cohort study of 3233 consecutive adults hospitalized with babesiosis from 2010 to 2024 at 82 sites across the northeastern US. Patients were eligible if they had parasitemia greater than 10%, or 5% to 10% with either acute organ injury or severe hemolytic anemia. Data were analyzed from April to August 2025. Exposure:Treatment with ET in the first 7 days of hospitalization. Main Outcomes and Measures:A composite of in-hospital death or 30-day readmission. Outcomes were compared between patients who received ET within the first 7 days of admission and those who did not. The analysis used logistic regression, with inverse probability of treatment weighting (IPTW) to adjust for potential confounders. Results:The analysis included 629 patients (median [IQR] age, 71 [63-79] years; 446 male [70.9%]), among whom 209 (33.2%) received ET in the first 7 days of hospitalization. Patients treated with ET were more severely ill at baseline than those not treated with ET (median parasitemia, 14.0% vs 7.2%); however, severity of illness characteristics were well balanced after applying IPTW. In the main analysis, the primary end point occurred in 3.6% of patients who received ET and in 9.8% who did not (adjusted odds ratio, 0.22; 95% CI, 0.09-0.51). The benefit of ET was confirmed in multiple sensitivity analyses. Conclusions and Relevance:This multicenter cohort study found that among severely ill adults hospitalized with babesiosis, the adjusted risk of in-hospital death or 30-day readmission was nearly 5-fold lower in those treated with ET vs those not treated with ET. These data support ET for severely ill patients with babesiosis, although the findings may be susceptible to unmeasured confounding. Further research is needed to identify which patients are most likely to benefit.

Immune checkpoint inhibitor-associated immune thrombocytopenia (ICI-ITP) has been described in case reports and small case series, but comprehensive data on its incidence, risk factors, clinical features, treatment, and outcomes are lacking. We reviewed medical records of all adults initiating ICI therapy between 2016-2023 at 29 U.S. hospitals across seven major cancer centers to identify cases of ICI-ITP. Multivariable logistic regression was used to identify risk factors, and Cox modeling was performed to assess the association between ICI-ITP, its severity, and mortality. Among 86,467 patients, ICI-ITP occurred in 214 (0.25%). Independent risk factors included lower baseline platelet count, combination ICI therapy, stage 4 cancer, and additional immune-related adverse events. ICI-ITP occurred at a median of 8 weeks (IQR, 4-18) after ICI initiation, with a median nadir platelet count of 41 x109/L (IQR, 17-64). Patients were treated with glucocorticoids (n=106, [49.5%]), immune globulin (n=39 [18.2%]), and thrombopoietin receptor agonists (n=29 [13.6%]). Recovery occurred in 161 patients (75.2%) at a median of 2.3 weeks (IQR, 1.0-5.3). Of 76 patients rechallenged with ICIs, 23 (30.3%) developed recurrent ICI-ITP. ICI-ITP and its severity were associated with higher all-cause mortality, with a nearly threefold increase in risk among patients with severe ICI-ITP compared with those without ICI-ITP (adjusted HR 2.96 [95% CI, 2.14-4.08]). These findings establish ICI-ITP as a rare but clinically significant complication of ICI therapy, provide the first large-scale description of its risk factors and clinical course, and underscore the importance of timely recognition and management.

Red cell exchange transfusion (ET) has been used as an adjunctive treatment for severe illness from babesiosis, particularly in patients with high parasitemia, acute organ injury, or severe hemolysis. However, data supporting the efficacy of ET on improving clinical outcomes are lacking. We performed a multicenter cohort study of 3,233 consecutive adults hospitalized with babesiosis at 84 hospitals across the northeastern US from 2010 to 2024. Data on demographics, comorbidities, vital signs, physiologic parameters, labs, treatments, and outcomes were collected by detailed chart review. Patients were eligible for this analysis if they had >10% parasitemia or 5-10% parasitemia with either acute organ injury or severe hemolytic anemia. To minimize the potential for indication- and immortal-time biases, we used a sequential target trial emulation (TTE) framework. To do so, we categorized eligible patients according to whether they did or did not initiate ET on each of the first 7 days of hospital admission. The primary outcome was a composite of in-hospital death or 30-day readmission. We used a logistic regression model with inverse probability of treatment weighting (IPTW) to adjust for confounding. A total of 254 of 3,233 patients (7.9%) received ET, 98.4% of whom initiated it in the first 7 days of hospitalization (Figure 1). Among 629 unique patients eligible for inclusion in at least 1 of the 7 sequential TTEs, 209 (33.2%) received ET (Figure 2). ET-treated patients had greater severity-of-illness compared to non-ET-treated patients; however, these characteristics were well-balanced after applying IPTW (Table 1). Overall, 60 patients (9.5%) had a primary outcome event. In the primary analysis, patients who received ET had a lower odds of developing the primary outcome compared to those who did not (odds ratio, 0.22 [95% CI, 0.09–0.51]; Figure 3). Results were consistent across a number of sensitivity and secondary analyses (Figure 3A) and in a time-to-event analysis (Figure 3B). In this multicenter cohort study of severely ill hospitalized adults with babesiosis, the risk of in-hospital death or 30-day readmission was nearly 5-fold lower in those treated with vs. without ET. These data support the use of ET for patients with severe illness from babesiosis. All Authors: No reported disclosures

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are associated with immune-related adverse events, including ICI-associated AKI (ICI-AKI). ICI-AKI presents diagnostic and management challenges and can influence decisions regarding immunosuppression and ICI rechallenge, with important implications for both kidney and cancer outcomes. An international, multidisciplinary panel convened at the 34th Acute Disease Quality Initiative (ADQI) consensus conference in September 2024. Systematic literature searches of PubMed were conducted to identify studies on the epidemiology, mechanisms, diagnosis, management, rechallenge, and outcomes of ICI-AKI. The meeting followed the established ADQI process and used a modified Delphi method to achieve consensus. Evidence was reviewed and appraised by workgroups, and consensus statements were developed through structured discussion and voting. Observational data suggest that AKI occurs in up to 20% of patients receiving ICIs, with ICI-AKI accounting for approximately 2%–5% of cases. Acute tubulointerstitial nephritis is the most common lesion, observed in 80%–90% of biopsies, although glomerular diseases are increasingly recognized. No clinical features reliably distinguish ICI-AKI from other causes of AKI, and kidney biopsy remains the diagnostic gold standard. Emerging urinary, circulating, and imaging biomarkers show promise but are not yet ready for routine clinical use. Early glucocorticoid initiation (within 3 days of ICI-AKI diagnosis versus >3 days after diagnosis) is associated with higher rates of kidney recovery, although optimal dosing and duration remain uncertain. Recurrent ICI-AKI occurs in fewer than 20% of patients undergoing ICI rechallenge. Management of high-risk populations, including kidney transplant recipients and patients with autoimmune disease or advanced CKD, requires individualized, multidisciplinary decision making. ICI-AKI is an important and potentially reversible complication of cancer immunotherapy; these consensus statements provide a framework for diagnosis and management, support cautious ICI rechallenge in selected patients, and identify priorities for future research.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are associated with immune-related adverse events, including ICI-associated AKI (ICI-AKI). ICI-AKI presents diagnostic and management challenges and can influence decisions regarding immunosuppression and ICI rechallenge, with important implications for both kidney and cancer outcomes. An international, multidisciplinary panel convened at the 34th Acute Disease Quality Initiative (ADQI) consensus conference in September 2024. Systematic literature searches of PubMed were conducted to identify studies on the epidemiology, mechanisms, diagnosis, management, rechallenge, and outcomes of ICI-AKI. The meeting followed the established ADQI process and used a modified Delphi method to achieve consensus. Evidence was reviewed and appraised by workgroups, and consensus statements were developed through structured discussion and voting. Observational data suggest that AKI occurs in up to 20% of patients receiving ICIs, with ICI-AKI accounting for approximately 2%-5% of cases. Acute tubulointerstitial nephritis is the most common lesion, observed in 80%-90% of biopsies, although glomerular diseases are increasingly recognized. No clinical features reliably distinguish ICI-AKI from other causes of AKI, and kidney biopsy remains the diagnostic gold standard. Emerging urinary, circulating, and imaging biomarkers show promise but are not yet ready for routine clinical use. Early glucocorticoid initiation (within 3 days of ICI-AKI diagnosis versus >3 days after diagnosis) is associated with higher rates of kidney recovery, although optimal dosing and duration remain uncertain. Recurrent ICI-AKI occurs in fewer than 20% of patients undergoing ICI rechallenge. Management of high-risk populations, including kidney transplant recipients and patients with autoimmune disease or advanced CKD, requires individualized, multidisciplinary decision making. ICI-AKI is an important and potentially reversible complication of cancer immunotherapy; these consensus statements provide a framework for diagnosis and management, support cautious ICI rechallenge in selected patients, and identify priorities for future research.

Introduction:Immune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN) is the most common finding on histopathology among patients with ICI-associated acute kidney injury (ICI-AKI). Patients with ICI-AIN often have T cell-dominant infiltration of the kidney and high tissue levels of CXCR3 ligands like CXCL9, 10, and 11; however, the mechanisms of inflammation in ICI-AIN are not well-understood. Methods:We applied a sub-cellular spatial transcriptomics platform (Xenium Prime 5K) to compare the cellular composition of kidney biopsy tissue from patients with ICI-AIN with ICI-treated patients with acute tubular necrosis (ICI-ATN). Results:Across 8 kidney biopsy specimens (4 with ICI-AIN, 4 with ICI-ATN), we analyzed 332,000 cells, comprising kidney parenchymal cells and infiltrating immune cells. Using a spatially-aware cellular neighborhood-based classification, we identified cellular niches corresponding to each part of the nephron, in addition to unique fibrotic and inflammatory niches. Gene pathway analysis identified interferon-gamma (IFN-γ)/STAT1 signaling as strongly increased in ICI-AIN compared to ICI-ATN. While all inflammatory niches were overrepresented in ICI-AIN, CD8+ T cell infiltration and proinflammatory myeloid cells were the dominant immune niches. Spatial niche crosstalk analysis revealed that CD8+ T cell-derived IFN-γ likely induced a proinflammatory program in myeloid cells, with increased production of CXCL9, 10, and 11. Furthermore, IFN-γ signaling in ICI-AIN was associated with reduced oxidative phosphorylation in kidney tubular niches. Conclusions:Spatial transcriptomics reveal novel insights into key differences in the pathophysiology of ICI-AIN versus ICI-ATN. IFN-γ-producing CD8+ T cells are likely key drivers of ICI-AIN and should be investigated as future therapeutic targets.

Acute kidney injury (AKI) is a frequent and often severe postoperative complication following cardiac surgery, which is associated with poor outcomes in both the short and long terms. Numerous randomized clinical trials have been conducted to investigate various strategies for prevention of cardiac surgery-associated AKI. Unfortunately, most trials conducted to date have been negative. However, encouraging results have been reported with several interventions, including preoperative implementation of oxygen delivery-directed perfusion, novel drugs such as teprasiran and amino acids. Many of these studies, however, require validation in larger, multicenter trials, before their routine use in clinical practice can be recommended.

Nicotinamide adenine dinucleotide (NAD+) plays an important role in the innate immune response and is depleted during SARS-CoV-2 infection due to increased turnover. It is unknown whether treatment with NAD+ precursors can safely raise NAD+ levels in patients with COVID-19. To determine whether MIB-626 (β-nicotinamide mononucleotide), an NAD+ precursor, can safely increase blood NAD+ levels and attenuate acute kidney injury (AKI) and inflammation in hospitalized patients with COVID-19, 42 adults, ≥ 18 years, hospitalized with COVID-19 and AKI, were randomized in a 3:2 ratio to MIB-626 1.0-g or placebo tablets twice daily for 14 days. Circulating NAD+ and its metabolites, markers of AKI, inflammation, and disease severity, were assessed. MIB-626 treatment significantly but gradually raised blood NAD+ levels to a peak between 5 to 14 days (16.0 ± 6.9, 25.5 ± 12.6, and 42.6 ± 25.6 μg/mL at baseline, days 5 and 14) and raised plasma concentrations of NAD+ metabolites 1-methylnicotinamide, N-methyl, 2-pyridone, 4-carboxamide rapidly to a peak by day 3. Changes in serum creatinine, cystatin-C, and serum markers of AKI did not differ significantly between groups. Serum CRP, IL-6, and TNFα and indices of disease severity also did not differ between groups. MIB-626 treatment of patients with COVID-19 and AKI safely and substantially raised blood NAD+ and plasma concentrations of NAD+ metabolites. Markers of AKI, inflammation, and disease severity did not differ between groups, likely due to the slow rise in NAD+ levels. Future studies should assess whether a rapid increase in NAD+ by parenteral administration can attenuate disease severity and AKI. Trial Registration: ClinicalTrials.gov Identifier: NCT05038488.

Importance Cisplatin-associated acute kidney injury (CP-AKI) is a frequent complication of cisplatin chemotherapy and is associated with considerable morbidity and mortality. Prophylactic administration of intravenous (IV) magnesium attenuates CP-AKI in animal models; however, its association with CP-AKI in humans has not been rigorously evaluated. Objective To evaluate the association of prophylactic IV magnesium administration with CP-AKI in patients with cancer undergoing cisplatin chemotherapy. Design, Settings, and Participants This multicenter study was conducted at 5 major cancer centers across the US and included adult patients with cancer who were treated with a first dose of IV cisplatin between 2006 to 2022. Data analyses were performed from February to December 2024. Exposure IV magnesium vs no IV magnesium receipt on the first day of cisplatin treatment. Main Outcomes and Measures Composite outcome of CP-AKI or death, with CP-AKI defined as a 2-fold or greater increase in serum creatinine levels from baseline or receipt of kidney replacement therapy within 14 days after first dose of IV cisplatin. Secondary outcomes were CP-AKI or death, defined using alternative definitions, as well as major adverse kidney events at 90 days. Inverse probability treatment weighting was used to estimate the association between IV magnesium receipt and CP-AKI. Models were adjusted for demographics, comorbidities, laboratory values, receipt of concurrent nephrotoxic anticancer therapies, site, year of cisplatin administration, and cisplatin dose. Results A total of 13 719 patients were included (median [IQR] age, 59 [49-67] years; 7817 male [57%]), of whom 3893 (28.4%) received IV magnesium on the first day of cisplatin chemotherapy. The median (IQR) dose of IV magnesium was 2 (1-2) g. CP-AKI or death occurred in 104 of 3893 patients (2.7%) who received IV magnesium, and in 520 of 9826 (5.3%) who did not (adjusted odds ratio, 0.80; 95% CI, 0.66-0.97). Results were similar across a number of sensitivity analyses and secondary outcomes, including major adverse kidney events at 90 days. Conclusions and Relevance This multicenter cohort study found that patients with cancer who received prophylactic IV magnesium before initiating treatment with IV cisplatin had a lower risk of CP-AKI compared to those who did not receive magnesium. Randomized clinical trials are needed to confirm these findings.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer and are now the backbone of therapy for several malignancies. However, ICIs can cause a spectrum of kidney immune-related adverse events including acute kidney injury (AKI), most commonly manifesting as acute interstitial nephritis (AIN), although glomerular disease and electrolyte disturbances have also been reported. In this position statement by the American Society of Onco-nephrology (ASON), we summarize the incidence and risk factors for ICI-AKI, pathophysiological mechanisms, and clinicopathologic features of ICI-AKI. We also discuss novel diagnostic approaches and promising biomarkers for ICI-AKI. From expert panel consensus, we provide clinical practice points for the initial assessment and diagnosis of ICI-AKI, management and immunosuppressive therapy, and consideration for rechallenge with ICI following AKI episodes. In addition, we explore ICI use in special populations, such as kidney transplant recipients, and propose key areas of focus for future research and clinical investigation.

BACKGROUND:Increased urinary iron can result from (i) increased delivery of iron to the kidneys, (ii) increased glomerular passage of iron, and/or (iii) decreased tubular reuptake. Currently, the relevance of urinary iron levels is unknown. We investigated urinary iron with different pathways and clinical outcomes in kidney transplant recipients (KTRs). METHODS:We measured urinary iron in samples from the prospective TransplantLines Food & Nutrition Biobank and Cohort study. Multivariable linear and Cox regression models were applied. RESULTS:We included 693 stable KTRs (age 53±13 years, 43% female, estimated glomerular filtration rate [eGFR] 52±20 ml/min/1.73m2). Higher urinary iron was associated with lower eGFR and higher kidney damage markers, including albuminuria, 24h urinary liver-type fatty acid-binding protein excretion, urinary endothelial growth factor to creatinine ratio, and plasma neutrophil-gelatinase associated lipocalin (all P<0.001). In contrast, urinary iron was not associated with systemic iron status, but was increased with oral iron supplementation. During a follow-up of 5.3 years, 83 KTRs experienced graft failure, and 150 died. Prospectively, higher urinary iron was associated with graft failure, but the association was decreased after adjustment for proteinuria. In contrast, urinary iron was independently associated with increased mortality risk (HR per doubling: 1.29; 95% CI: 1.08-1.56). CONCLUSIONS:Higher urinary iron levels are associated with worse kidney function, more proteinuria, increased tubular damage markers and higher mortality. Oral iron supplementation seems to be an important determinant of urinary iron levels. These findings raise the possibility that urinary iron acts as a tubulotoxic agent and mechanistic studies are warranted.

BACKGROUND Active vitamin D metabolites, including 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D), have potent immunomodulatory effects that attenuate acute kidney injury (AKI) in animal models.METHODS We conducted a phase 2, randomized, double-blind, multiple-dose, 3-arm clinical trial comparing oral calcifediol (25D), calcitriol (1,25D), and placebo among 150 critically ill adult patients at high risk of moderate to severe acute kidney injury (AKI). The primary endpoint was a hierarchical composite of death, kidney replacement therapy (KRT), and kidney injury (baseline-adjusted mean change in serum creatinine), each assessed within 7 days following enrollment using a rank-based procedure. Secondary endpoints included new or progressive AKI and a composite of KRT or death. Hypercalcemia was the key safety endpoint. We also performed RNA-Seq on circulating CD14+ monocytes collected immediately prior to randomization and 2 days later.RESULTS The global rank score for the primary endpoint was similar among calcifediol- (n = 51) versus placebo- (n = 49) treated patients (P = 0.85) and for calcitriol (n = 50) versus placebo-treated patients (P = 0.58). Secondary endpoints also occurred at similar rates across groups. Hypercalcemia occurred in 1 patient in the calcifediol group (1.7%), 1 patient in the calcitriol group (2.0%), and no patients in the placebo group. Compared with placebo, calcitriol upregulated more individual genes and pathways in circulating monocytes than did calcifediol, including pathways involving IFN-α, IFN-γ, oxidative phosphorylation, DNA repair, and heme metabolism.CONCLUSION Treatment with calcifediol or calcitriol in critically ill adults upregulated multiple genes and pathways involving immunomodulation, DNA repair, and heme metabolism, but it did not attenuate AKI.TRIAL REGISTRATION ClinicalTrials.gov (NCT02962102)FUNDING NIH/NIDDK grant K23DK106448 (to DEL) and NIH/NHLBI grant R01HL16687 (to EYK).