Explore the vast range of titles available.

BackgroundAcute tubulointerstitial nephritis (AIN) is one of the few causes of acute kidney injury with diagnosis-specific treatment options. However, due to the need to obtain a kidney biopsy for histological confirmation, AIN diagnosis can be delayed, missed, or incorrectly assumed. Here, we identify and validate urinary CXCL9, an IFN-γ-induced chemokine involved in lymphocyte chemotaxis, as a diagnostic biomarker for AIN.MethodsIn a prospectively enrolled cohort with pathologist-adjudicated histological diagnoses, termed the discovery cohort, we tested the association of 180 immune proteins measured by an aptamer-based assay with AIN and validated the top protein, CXCL9, using sandwich immunoassay. We externally validated these findings in 2 cohorts with biopsy-confirmed diagnoses, termed the validation cohorts, and examined mRNA expression differences in kidney tissue from patients with AIN and individuals in the control group.ResultsIn aptamer-based assay, urinary CXCL9 was 7.6-fold higher in patients with AIN than in individuals in the control group (P = 1.23 × 10-5). Urinary CXCL9 measured by sandwich immunoassay was associated with AIN in the discovery cohort (n = 204; 15% AIN) independently of currently available clinical tests for AIN (adjusted odds ratio for highest versus lowest quartile: 6.0 [1.8-20]). Similar findings were noted in external validation cohorts, where CXCL9 had an AUC of 0.94 (0.86-1.00) for AIN diagnosis. CXCL9 mRNA expression was 3.9-fold higher in kidney tissue from patients with AIN (n = 19) compared with individuals in the control group (n = 52; P = 5.8 × 10-6).ConclusionWe identified CXCL9 as a diagnostic biomarker for AIN using aptamer-based urine proteomics, confirmed this association using sandwich immunoassays in discovery and external validation cohorts, and observed higher expression of this protein in kidney biopsies from patients with AIN.FundingThis study was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) awards K23DK117065 (DGM), K08DK113281 (KM), R01DK128087 (DGM), R01DK126815 (DGM and LGC), R01DK126477 (KNC), UH3DK114866 (CRP, DGM, and FPW), R01DK130839 (MES), and P30DK079310 (the Yale O'Brien Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Aristolochic acid nephropathy (AAN), a progressive renal interstitial fibrosis frequently associated with urothelial malignancies, was initially reported in a Belgian cohort of more than 100 patients after the intake of slimming pills containing a Chinese herb, Aristolochia fangchi. Although botanicals known or suspected to contain aristolochic acid (AA) were no longer permitted in many countries, several AAN cases were regularly observed all around the world. The incidence of AAN is probably much higher than initially thought, especially in Asia and the Balkans. In Asian countries, where traditional medicines are very popular, the complexity of the pharmacopoeia represents a high risk for AAN because of the frequent substitution of the botanical products by AA-containing herbs. In the Balkan regions, the exposure to AA found in flour obtained from wheat contaminated with seeds of Aristolochia clematitis could be responsible for the so-called Balkan-endemic nephropathy. Finally, despite the Food and Drug Administration's warnings concerning the safety of botanical remedies containing AA, these herbs are still sold via the Internet.

Drug-induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug-induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug-induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular, and nephrolithiasis, along with the primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease, and chronic kidney disease. Establishing causality in drug-induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course, and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry, and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is the first step to recognizing drug-induced kidney disease and developing strategies to prevent and manage this condition.

The role of steroid treatment in drug-induced acute interstitial nephritis (DI-AIN) is controversial. We performed a multicenter retrospective study to determine the influence of steroids in 61 patients with biopsy-proven DI-AIN, 52 of whom were treated with steroids. The responsible drugs were antibiotics (56%), non-steroidal anti-inflammatory drugs (37%) or other drugs. The final serum creatinine was significantly lower in treated patients while almost half of untreated patients remained on chronic dialysis. Among treated patients, over half showed a complete recovery of baseline renal function, whereas the rest remained in renal failure. There were no significant initial differences between these two subgroups in terms of duration or dosage of steroids. After withdrawal of the presumed causative drug, we found that when steroid treatment was delayed (by an average of 34 days) renal function did not return to baseline levels compared to those who received steroid treatment within the first 2 weeks after withdrawal of the offending agent. We found a significant correlation between the delay in steroid treatment and the final serum creatinine. Renal biopsies, including three patients who underwent a second biopsy, showed a progression of interstitial fibrosis related to the delay in steroid treatment. Our study shows that steroids should be started promptly after diagnosis of DI-AIN to avoid subsequent interstitial fibrosis and an incomplete recovery of renal function.

The kidney is one of the most susceptible organs to age-related impairments. Generally, renal aging is accompanied by renal fibrosis, which is the final common pathway of chronic kidney diseases. Aristolochic acid (AA), a nephrotoxic agent, causes AA nephropathy (AAN), which is characterized by progressive renal fibrosis and functional decline. Although renal fibrosis is associated with renal aging, whether AA induces renal aging remains unclear. The aim of the present study is to investigate the potential use of AAN as a model of renal aging. Here, we examined senescence-related factors in AAN models by chronically administering AA to C57BL/6 mice. Compared with controls, the AA group demonstrated aging kidney phenotypes, such as renal atrophy, renal functional decline, and tubulointerstitial fibrosis. Additionally, AA promoted cellular senescence specifically in the kidneys, and increased renal p16 mRNA expression and senescence-associated β-galactosidase activity. Furthermore, AA-treated mice exhibited proximal tubular mitochondrial abnormalities, as well as reactive oxygen species accumulation. Klotho, an antiaging gene, was also significantly decreased in the kidneys of AA-treated mice. Collectively, the results of the present study indicate that AA alters senescence-related factors, and that renal fibrosis is closely related to renal aging.

Elevated C-reactive protein (CRP) was proposed as a biomarker instead of renal biopsy in drug-induced acute tubulointerstitial nephritis (D-ATIN) in adults. However, there is no study in which patients were followed up with serial CRP without kidney biopsy. We evaluated the significance of CRP levels in predicting the clinical course of D-ATIN in children. Children with a clinical diagnosis of D-ATIN were evaluated for sex, age, symptoms, offending drug(s), latent period after exposure, blood pressure, urine output, urinalysis, eosinophiluria, urine albumin/total protein, serum creatinine, and CRP at presentation. In addition, serial CRP and creatinine levels were recorded daily until discharge and thereafter. Correlations of CRP with creatinine and of peak CRP with creatinine normalization time were evaluated. There were 13 patients (8 female, median age 15 years). None had oliguria or hypertension. Median CRP and creatinine at presentation were 36 mg/L and 1.6 mg/dL, respectively. Median times to peak CRP and creatinine were 6 and 7 days after drug exposure, respectively. The decrease in CRP preceded the fall in creatinine. Median CRP and creatinine normalization times after their peaks were 5 and 14 days, respectively. None required renal biopsy or corticosteroid treatment. CRP was correlated with creatinine throughout the study period. However, peak CRP was not correlated with creatinine normalization time. CRP was increased at presentation and decreasing CRP predicted favorable outcome. Renal biopsy and corticosteroid treatment could be postponed safely in these children.

This study aims to figure out the worldwide prevalence of anticancer therapy-associated acute kidney injury (AKI) and tubulointerstitial nephritis (TIN) and the relative risk of each cancer drug. We conducted an analysis of VigiBase, the World Health Organization pharmacovigilance database, 1967–2023 via disproportionate Bayesian reporting method. We further categorized the anticancer drugs into four groups: cytotoxic therapy, hormone therapy, immunotherapy, and targeted therapy. Reporting odds ratio (ROR) and information component (IC) compares observed and expected values to investigate the associations of each category of anticancer drugs with AKI and TIN. We identified 32,722 and 2056 reports (male, n = 17,829 and 1,293) of anticancer therapy-associated AKI and TIN, respectively, among 4,592,036 reports of all-drug caused AKI and TIN. There has been a significant increase in reports since 2010, primarily due to increased reports of targeted therapy and immunotherapy. Immunotherapy exhibited a significant association with both AKI (ROR: 8.92; IC 0.25 : 3.06) and TIN (21.74; 4.24), followed by cytotoxic therapy (7.14; 2.68), targeted therapy (5.83; 2.40), and hormone therapy (2.59; 1.24) for AKI, and by cytotoxic therapy (2.60; 1.21) and targeted therapy (1.54; 0.61) for TIN. AKI and TIN were more prevalent among individuals under 45 years of age, with a female preponderance for AKI and males for TIN. These events were reported in close temporal relationship after initiation of the respective drug (16.53 days for AKI and 27.97 days for TIN), and exhibited a high fatality rate, with 23.6% for AKI and 16.3% for TIN. These findings underscore that kidney-related adverse drug reactions are of prognostic significance and strategies to mitigate such side effects are required to optimize anticancer therapy.

Global evidence on the association between vaccines and renal adverse events (AEs) is inconclusive. This pharmacovigilance study analyzed a total of 120,715,116 reports from VigiBase collected between 1967 and 2022. We evaluated the global reporting of acute kidney injury (AKI), glomerulonephritis (GN), and tubulointerstitial nephritis (TIN) and assessed disproportionate signals between vaccines and renal AEs using reporting odds ratios (ROR) and the lower limit of the 95% confidence interval of the information component (IC 025 ) in comparison with the entire database. The number and proportion of reports on AKI, GN, and TIN gradually increased, with a substantial increase after 2020. Disproportionate reporting of AKI was significant for COVID-19 mRNA vaccines (ROR, 2.38; IC 025 , 1.09). Fourteen vaccines were significantly disproportionate for higher GN reporting, and the highest disproportionality for GN reporting was observed for COVID-19 mRNA (ROR, 13.41; IC 025 , 2.90) and hepatitis B vaccines (ROR, 11.35; IC 025 , 3.18). Disproportionate TIN reporting was significant for COVID-19 mRNA (ROR, 2.43; IC 025 , 0.99) and human papillomavirus (ROR, 1.75; IC 025 , 0.19) vaccines. Significant disproportionality in the reporting of AKI, GN, and TIN was observed in patients exposed to multiple vaccines, including COVID-19 mRNA vaccines, alongside increasing global reports of vaccine-associated renal AEs.

Background Acute interstitial nephritis (AIN) is an important cause of kidney injury accounting for up to 27% of unexplained renal impairment. In up to 70% of cases, drugs, including aminosalicylates, are reported as the underlying cause. Following two recent paediatric cases of suspected mesalazine induced AIN within our own department, we performed a systematic review of the literature to address the following question: In patients with inflammatory bowel disease (IBD), is interstitial nephritis associated with 5-aminosalicylate (5-ASA) treatment? Our primary objective was to identify the number of cases reported in the literature of biopsy-proven 5-ASA induced interstitial nephritis, in children and adults with IBD. We also aimed to identify which variables influence the onset, severity and recovery of 5-ASA interstitial nephritis. Methods Embase and PubMed databases were searched from inception to 07/10/20. Search terms had three main themes: “inflammatory bowel disease”, “interstitial nephritis” and “aminosalicylates”. Studies were included if they reported an outcome of AIN, confirmed on biopsy, suspected to be secondary to a 5-ASA drug in those with IBD. A narrative synthesis was performed. Results Forty-one case reports were identified. Mesalazine was the most frequently reported aminosalicylate associated with AIN (95%). The median duration of treatment before AIN was diagnosed was 2.3 years (Interquartile Range (IQR) 12–48 months). The median rise in creatinine was 3.3 times the baseline measurement (IQR 2.5–5.5). Aminosalicylate withdrawal and steroids were the most frequently used treatments. Despite treatment, 15% of patients developed end-stage renal failure. Conclusions AIN is a serious adverse drug reaction associated with aminosalicylates, with mesalazine accounting for most reports. The current guidance of annual monitoring of renal function may not be sufficient to identify cases early. Given the severity of AIN and reports in the literature that early treatment with steroids may be beneficial, we would recommend at least 6 monthly monitoring of renal function. PROSPERO registration number CRD42020205387.

Acute tubulointerstitial nephritis (ATIN) is an immunomediated cause of acute kidney injury. The prevalence of ATIN among the causes of acute kidney injury (AKI) is not negligible, especially those cases related to certain drugs. To date, there is a lack of reliable non-invasive diagnostic and follow-up markers. The gold standard for diagnosis is kidney biopsy, which shows a pattern of tubulointerstitial leukocyte infiltrate. The urinalysis findings can aid in the diagnosis but are no longer considered sensitive or specific. Atthe present time, there is a rising attentiveness tofinding trustworthy biomarkers of the disease, with special focus in urinary cytokines and chemokines that may reflect kidney local inflammation. Cell-based tests are of notable interest to identify the exact drug involved in hypersensitivity reactions to drugs, manifesting as ATIN. Certain single-nucleotide polymorphisms in HLA or cytokine genes may confer susceptibility to the disease according to pathophysiological basis. In this review, we aim to critically examine and summarize the available evidence on this topic.