Citations

Abstract Background and Hypothesis Thrombotic microangiopathy (TMA) is increasingly recognized as a complication of both cancer and anti-cancer therapies. C5 complement inhibition is used in selected cases, but evidence supporting its effectiveness, particularly in kidney biopsy-proven disease, remains limited. Methods This retrospective cohort study included adult patients with biopsy-proven TMA attributed to anti-cancer therapies between 2015 and 2026 at Mayo Clinic, USA. Patients were stratified according to treatment with complement inhibition versus no complement inhibition therapy. The primary outcome was renal recovery; secondary outcomes included hematological recovery, composite outcome, overall survival, and longitudinal changes in hematologic and renal function parameters. Results A total of 31 patients with kidney biopsy-proven TMA related to anti-cancer therapy were included. Nine received complement inhibition, and 22 did not. A higher proportion of patients in the treated group achieved complete or partial renal recovery at 3 months (p = 0.008), hematologic recovery at 1 month (p = 0.007) and composite outcome (complete-partial renal plus hematologic recovery) (p = 0.041). During follow-up, platelet counts increased significantly at 1 month and 3 months (p = 0.045, both) in the treated group. Mixed-effects modeling showed significantly lower longitudinal estimated glomerular filtration rate (eGFR) values in the untreated group (β = −13.9 mL/min per 1.73 m², p = 0.028). In the gemcitabine-associated TMA subgroup, complete-partial renal recovery occurred only in treated patients (p = 0.021) and hematologic recovery was achieved in the whole cohort but occurred significantly faster in the complement inhibition group (p = 0.019). The higher rate of renal recovery persisted in sensitivity analysis (p = 0.021). Conclusions In this rigorously phenotyped cohort of patients with biopsy-proven, anti-cancer therapy-associated renal TMA, we observed a signal of benefit from C5 inhibition, most consistently for renal recovery and possibly extending to hematologic outcomes, particularly among patients with gemcitabine-associated TMA.

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but are associated with immune-related adverse events, including ICI–associated acute kidney injury (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.

Abstract Introduction Acute interstitial nephritis is an important differential diagnosis in patients with deteriorating kidney function. Diagnosis currently requires kidney biopsy, an invasive procedure associated with risks. We hypothesized that urinary T cells may serve as a non-invasive biomarker for acute interstitial nephritis. Methods A total of 320 patients undergoing clinically indicated kidney biopsy were enrolled in a discovery cohort at Charité Berlin (n = 80), an internal validation cohort at Charité (n = 100), and an external validation cohort at The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou (n = 140). Urinary immune cells were assessed by flow cytometry. Renal T cell infiltration was evaluated by immunofluorescence in kidney biopsy specimens from the discovery and internal validation cohorts, including 16 patients with acute interstitial nephritis and 9 patients without acute interstitial nephritis. Additionally, CXCL9 was measured by ELISA in 102 urine samples from these cohorts. Results Across all cohorts, 27 patients (8.4%) were diagnosed with acute interstitial nephritis. In the discovery cohort, multiple urinary T cell subsets were increased in acute interstitial nephritis, with activated CD4 + effector memory T cells expressing CD38 and HLA-DR showing the strongest diagnostic performance. This marker outperformed urinary monocytes, eosinophils, and CXCL9 and was validated in both independent cohorts. Across all cohorts, the area under the receiver operating characteristic curve was 0.84 and increased to 0.91 after exclusion of 8 patients receiving corticosteroids. A cutoff of 211 activated CD4 + effector memory T cells per 100 mL urine yielded a sensitivity of 78% and a specificity of 81%. Urinary activated CD4 + effector memory T cell counts correlated with renal CD4 + and CD4 + CD38 + T cell infiltration in acute interstitial nephritis. Conclusions Urinary activated CD4 + effector memory T cells expressing CD38 and HLA-DR represent a promising non-invasive biomarker for the diagnosis of acute interstitial nephritis. Lay Summary Acute interstitial nephritis is a frequent cause of acute kidney injury and is usually diagnosed by kidney biopsy, an invasive procedure that carries risks. We investigated whether immune cells in urine could help identify AIN in a less invasive manner. In this multicenter study, urine samples from 320 patients undergoing kidney biopsy in Germany and China were analyzed. We found that a specific population of activated T cells was markedly increased in the urine of patients with AIN compared with patients with other kidney diseases. This urinary marker outperformed other immune cell types and the inflammatory cytokine CXCL9 and was successfully validated in independent cohorts from both Germany and China. Importantly, urinary activated T cell counts correlated with immune cell infiltration within the kidney. These findings suggest that urinary activated T cells may serve as a non-invasive biomarker to support the diagnosis of AIN and facilitate earlier clinical decision-making.

Scattered tubular-like cells (STCs) are dedifferentiated renal tubular cells that repair other damaged kidney cells. This study shows that renovascular disease (RVD) induces site-specific 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications in DNA associated with transcriptional changes and impaired proliferative capacity of swine STCs, which could be mitigated in RVD-STCs treated with an epigenetic modulator. Therefore, our observations may contribute to the development of novel approaches to preserve the reparative capacity of STCs in individuals with RVD.

Abstract Aims Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce major adverse cardiovascular events in diabetics. This study aimed to investigate the cardiac, cancer, and overall mortality effects of GLP-1 RAs in diabetics treated with anthracyclines. Methods and results We retrospectively identified 1384 diabetics treated with anthracyclines from 2013 to 2023; 56 received GLP-1 RAs between their first and last dose of anthracycline. These patients were propensity score matched 4:1 to 224 controls without concurrent GLP-1 RA use. Because stage was not available for 10 of the 56 patients, a repeat analysis was conducted with additional matching for cancer stage in 46 cases and 92 controls. Major endpoints were rate of all-cause and cancer-related and cardiovascular disease (CVD)–related mortality, no evidence of disease (NED), and hospitalization for CVD including heart failure (HF), over 5 years. Survival analyses were conducted using cause-specific hazards Cox regression. Patients on GLP-1 RAs had a significantly lower 5 year overall mortality (HR 0.46, CI 0.24–0.87, P = 0.007) and cancer-related mortality (HR 0.42, CI 0.19–0.91, P = 0.03). This mortality risk reduction remained significant even when accounting for covariates (HR 0.39, CI 0.20–0.75, P = 0.002). The percentage of patients with NED was higher in the GLP-1 RA than control group (60.9% vs. 38.0%, P = 0.007). A decline in left ventricular ejection fraction was seen in controls but not in patients on GLP-1 RAs. There was no significant difference in CVD hospitalization; the rate of HF-related hospitalization was very low overall. Conclusion GLP-1 RAs may offer survival benefits and better cancer- and cardiac function-related outcomes in diabetics undergoing anthracycline chemotherapy.

Immune checkpoint inhibitors (ICIs) can cause immune-related adverse events (irAEs), with acute interstitial nephritis (ICI-AIN) being the most common irAE. While the exact mechanism remains unclear, upregulation of IFN-γ and TNF-α pathways has been implicated. This study used a humanized chimeric PD-1/PD-L1 mouse model to assess renal effects of ICIs, alone or combined with proinflammatory cytokines, and to test if selective TNF-α blockade could prevent ICI-AIN. Mice were randomly divided into 4 experimental groups: Control, ICI-Only, ICI-Cytokines (ICI-Cyt), and ICI-Block (ICI-TNF-α blockade). Renal function and cytokine profiles were assessed, while kidney tissue was analyzed using microscopy and single-cell RNA-seq. Histology revealed increased renal infiltration of CD4 + /CD8 + T cells in ICI-treated groups and decreased TNF-α expression following TNF-α blockade. Additionally, kidney tissue ELISA demonstrated reduced IFN-γ levels following TNF-α blockade. Plasma IL-6, MCP-1, and TNF-α were lower in ICI-Block mice. Single-cell RNA-seq revealed shifts in immune cell populations and genes of interest including Bcl2a1 , Icos , Il18r1 , Ccr2 , and Jaml . This humanized model replicates ICI-AIN key features, revealing a synergistic role of ICIs and proinflammatory cytokines. TNF-α blockade demonstrated protective effects, supporting its potential role in mitigating the risk of ICI-AIN.

Background: A summary of pharmacist-based practices and preferences regarding the prevention and management of high-dose methotrexate (HDMTX) toxicity in patients with lymphoma does not exist. The objective of the study was to describe current practices surrounding management of HDMTX therapy. This was done through a self-administered, web-based, cross-sectional survey of hematology/oncology pharmacists to ascertain practices and individual attitudes about HDMTX therapy management. Responses were summarized with descriptive statistics. Response comparisons were made using Chi-square or Fisher’s exact test for categorical data, and Kruskal-Wallis test for variables on the Likert scale. A total of 175 pharmacists provided 116 eligible surveys [68 (59%) complete responses and 48 (41%) partial responses] for analysis. The Cockcroft-Gault estimated creatinine clearance formula was the most preferred method (61%) to estimate kidney function and determine HDMTX dosing. Respondents would proceed with HDMTX therapy until the predicted risk of AKI, or AKI stage 2 or 3, exceeded 50% and 20%, respectively. Preferred treatment modifications for a high predicted AKI risk after HDMTX exposure included additional prehydration, HDMTX dose reduction, and increased kidney function monitoring, although levels and degrees of agreement varied. Respondents indicated that serum cystatin C-based GFR estimates lacked evidence, accuracy, and practicality in HDMTX therapy management. There was limited familiarity with cell cycle arrest biomarker use during HDMTX therapy. Glucarpidase was considered time-sensitive and highly effective; however, acquisition cost represented a barrier to use, and the optimal dose was felt to be unknown. In conclusion, there is significant heterogeneity in supportive practices and beliefs about the optimal management for patients with lymphoma receiving HDMTX therapy.

ABSTRACT Background Immune checkpoint inhibitor-associated acute interstitial nephritis (ICI-AIN) requires a kidney biopsy for a definitive diagnosis. A recent study suggested that 2-deoxy-2-[18F] fluoro-D-glucose positron emission tomography-computed tomography (F18-FDG PET–CT) may offer a noninvasive alternative, but lack of kidney biopsies in all patients and a proper control group receiving ICI therapy remained important limitations. We conducted the first study addressing these limitations and examined whether PET–CT could differentiate biopsy-proven ICI-AIN from other causes of acute kidney injury (AKI) in patients on ICI therapy. Methods This retrospective cohort study comprises 105 patients on ICI therapy who underwent F18-FDG PET–CT and had a kidney biopsy, along with data from a control group receiving ICIs without AKI. PET–CT scans were performed within 14 days before or 10 days after biopsy, and baseline PET-CTs obtained during ICI therapy before AKI, were reviewed by a blinded nuclear radiologist. Renal cortical standardized uptake values (SUV) were measured in five regions of interest, liver and blood-pool SUVs served as internal references. Results Thirty-two patients were included (5 ICI-AIN, 7 AKI from other causes, 20 controls). Renal SUVs did not differ significantly among groups. In patients with serial PET-CTs, kidney SUVs tended to increase from baseline to AKI in ICI-AIN, but these changes were not statistically significant. Conclusions In this biopsy-validated cohort, PET-CTs did not reliably distinguish ICI-AIN from other causes of AKI in patients receiving ICI therapy. Larger prospective studies are needed to validate these findings.

ABSTRACT Background Although kidney biopsy remains the gold standard for diagnosing immune checkpoint inhibitors–associated acute interstitial nephritis (ICI-AIN), several promising urinary biomarkers have emerged as potential non-invasive diagnostics. Notably, recent studies have highlighted tumor necrosis factor alpha (TNF-α), CXC motif chemokine ligand 9 (CXCL-9) and others as potential biomarkers to help distinguish ICI-AIN from other causes of acute kidney injury (AKI). However, a direct systematic comparison between these two biomarkers in a cohort of patients undergoing immunotherapy has not been performed. Methods We prospectively enrolled a cohort of ICI-treated cancer patients who developed AKI (including both ICI-AIN and ICI-Non-AIN AKI), as well as those without AKI, referred to as the internal validation cohort. Urinary CXCL-9 and TNF-α were measured across all groups using the human Quantikine ELISA Kit. We externally validated our findings in a cohort of biopsy proven ICI-AIN patients from Spain, referred to as the external validation cohort. Results Urinary CXCL-9 levels were significantly higher in ICI-AIN patients from Mayo (n = 40) compared with those with ICI-Non-AIN AKI (n = 36) and ICI-treated patients without AKI (n = 16) (both P ≤ .0001); these findings were confirmed in the validation cohort from Spain (n = 19) with P-values of .0008 and <.0001, respectively. The area under the curve (AUC) for urinary CXCL-9 distinguishing ICI-AIN biopsy proven (combined from both cohorts, n = 45) from ICI-Non-AIN AKI was 0.83 (95% confidence interval 0.74–0.92), while for urinary TNF-α the AUC was 0.63 (0.51–0.75). Conclusions Increased urinary CXCL-9 was superior to TNF-α as a biomarker for the non-invasive diagnosis of ICI-AIN, even after prior corticosteroid exposure, highlighting its promise as clinical diagnostic tool.

Immunotherapy has transformed oncology, yet kidney complications increasingly affect outcomes. This review summarizes nephrotoxicity from immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell (CAR-T) therapies, and bispecific T-cell engagers (BiTEs). ICIs remain most used, with acute interstitial nephritis (AIN) as the hallmark lesion, while glomerular diseases and electrolyte abnormalities are less common. CAR-T therapy, though highly effective in hematologic cancers, carries risks of cytokine release syndrome, tumor lysis syndrome, and acute kidney injury (AKI). BiTEs, particularly teclistamab, show higher AKI rates than CAR-T, though mechanisms remain unclear. Early recognition, tailored management, and multidisciplinary collaboration are essential to ensure safe therapy and preserve kidney function.