Search Results (36)

Vancomycin remains a cornerstone for severe Gram-positive infections in the ICU, yet creatinine elevation—a sensitive marker of early renal stress—occurs frequently and complicates therapy. We developed a machine learning model to predict vancomycin-associated creatinine elevation using routinely available clinical data, enabling preemptive risk stratification. In this retrospective MIMIC-IV cohort study ($n=10,288$ ICU adults aged 18–80 receiving vancomycin), the primary outcome was creatinine elevation per KDIGO criteria (≥0.3 mg/dL within 48 h or ≥50% within 7 d). A two-stage feature selection (SelectKBest + Random Forest) identified 15 predictors from 30 candidates. Six algorithms were compared via 5-fold cross-validation. CatBoost was selected for final modeling; interpretability was assessed using SHAP values and Accumulated Local Effects (ALE) plots. Creatinine elevation occurred in 2903 patients (28.2%). CatBoost achieved AUROC 0.818 (95% CI: 0.801–0.834), sensitivity 0.800, specificity 0.681, and NPV 0.900. Top predictors were serum phosphate, total bilirubin, magnesium, Charlson Comorbidity Index, and APSIII score. SHAP analysis confirmed hyperphosphatemia as the strongest driver; ALE plots revealed non-linear, clinically plausible thresholds (e.g., phosphate >4.5 mg/dL sharply increased risk). This interpretable model accurately predicts vancomycin-associated creatinine elevation using standard ICU monitoring data. With high negative predictive value, it supports early exclusion of low-risk patients and targeted interventions (e.g., intensified TDM, nephrotoxin avoidance) in high-risk cases—facilitating precision antimicrobial stewardship in critical care. Full article

Nephrotoxin-mediated kidney injury is an important clinical problem, as it can lead to acute kidney injury and chronic kidney disease. Both entities are associated with significant morbidity, increased hospitalisation, healthcare utilisation, and cardiovascular mortality. With the loss of kidney function, there is an accumulation of uraemic toxins, of which the protein-bound toxins—indoxyl sulphate and p-cresyl sulphate—can further inflict damage to the kidneys and the cardiovascular system, culminating in a vicious cycle. Therefore, it is imperative that clinicians have a firm understanding of the common causes and mechanisms of toxin-mediated kidney injury, as well as their clinical presentations and histopathologic features, in order to reduce the prevalence of this pernicious condition. Full article

Hepatorenal syndrome (HRS) is a high-mortality, potentially reversible form of kidney failure that arises from a tight hemodynamic–inflammatory coupling in cirrhosis. Contemporary redefinitions prioritize creatinine kinetics over static thresholds and recognize non-acute kidney injury (AKI) functional phenotypes, enabling earlier recognition but heightening the need for precise etiologic triage. This narrative synthesis integrates current concepts across pathophysiology, diagnosis and management. Portal hypertension, bacterial translocation and inflammatory mediators amplify splanchnic vasodilation and effective arterial underfilling. Compensatory neurohumoral activation precipitates renal vasoconstriction, intrarenal microcirculatory dysfunction and sodium–water retention. The pivotal diagnostic fork remains HRS–AKI versus acute tubular necrosis. A pragmatic, tiered strategy, structured volume assessment, filtration markers and a parsimonious tubular-injury panel offer actionable discrimination, whereas fractional excretion indices serve as adjuncts only. Initial therapy should be bundled and time-sensitive: remove nephrotoxins, treat infection and initiate albumin plus a vasoconstrictor. The transplant strategy should default to isolated liver transplantation unless end-stage renal disease is established. Future priorities include validated biomarker cut-offs, ultrasound-guided volume algorithms and pathway-based trials to reduce diagnostic delay and improve survival. Full article

Although cancer is often considered a genetic disease, genotoxic damage to nuclear DNA caused by carcinogens is not always sufficient to stimulate cancer cell growth, suggesting that other etiological factors are involved. Indeed, many carcinogens are also nephrotoxic and can impair kidney function. In turn, impaired renal function can dysregulate serum inorganic phosphate, leading to hyperphosphatemia and excess phosphate storage in tissues, which causes phosphate toxicity. Moreover, phosphate toxicity can contribute to cancer cell growth by activating cell signaling pathways, overexpressing sodium phosphate cotransporters, and stimulating excessive RNA biogenesis and protein synthesis. The present narrative review proposes a general underlying mechanism by which phosphate toxicity mediates the association of toxin nephropathy with carcinogenesis. This proposed pathway could explain why any factor that impairs renal function, including an overload of nontoxic substances, may indirectly contribute to excess phosphate sequestration in the tumor microenvironment which stimulates cancer cellular growth. Importantly, chemotherapy agents are often nephrotoxic, and carcinogenicity associated with such nephrotoxins could explain the occurrence of second tumors in treated cancer patients. More research is needed to investigate the mediating role of phosphate toxicity in the association of toxin nephropathy with carcinogenesis. Full article

Indoxyl sulfate—a bacterially derived metabolite—has been identified as a toxin that is elevated in children with autism spectrum disorder (ASD). As a neurotoxin, uremic toxin, nephrotoxin, cardiotoxin, osteotoxin, and myotoxin, indoxyl sulfate has been associated with several other conditions, including chronic kidney disease, acute kidney injury, Parkinson’s disease, cognitive disorders, and mood disorders such as anxiety and depression. Indoxyl sulfate is derived from bacterial modification of host tryptophan, and elevated levels of indoxyl sulfate are associated with decreased levels of important neurotransmitters including serotonin, dopamine, and norepinephrine. This article will review what is currently known about indoxyl sulfate in relation to ASD and its comorbidities. A systematic review identified six studies of levels of indoxyl sulfate in children with ASD. All six studies found that indoxyl sulfate was significantly elevated in the urine of children with ASD compared to typically developing children. Through this review, indoxyl sulfate was identified as a toxic microbially derived metabolite that is significantly increased in a subset of children with ASD and may contribute to both core and co-morbid ASD symptoms. Full article

Destabilization of heme proteins is recognized to play a role in acute kidney injury (AKI). Hemopexin (Hpx), known for its role in binding heme, mitigates free heme toxicity. Despite this, the potential adverse effects of Hpx deposition in kidney tissues and its impact on kidney function are not fully understood. Deferoxamine (DFO) chelates iron released from heme and mitigates associated kidney damage. Therefore, this study aimed to evaluate whether Hpx contributes to kidney injury in an ischemia-reperfusion injury (IRI) induced AKI model and to investigate if DFO could alleviate this damage. Mice were categorized into five groups: Sham-Vehicle, Sham-Hpx, IRI-Vehicle, IRI-Hpx, and IRI-Hpx-DFO. Decline in kidney function was observed exclusively in the IRI group, independent of Hpx injection. Serum Hpx levels remained comparable across all groups, and administration of Hpx did not alter serum Hpx levels or kidney function after 24 hours. Although increased Hpx deposition in kidneys was noted in both the IRI and Hpx groups, this accumulation did not correlate with impaired kidney function. Additionally, DFO did not exhibit a protective effect against kidney injury. In summary, Hpx does not directly induce kidney injury and cannot be considered a biomarker for kidney damage caused by IRI. Full article

Understanding chronic kidney disease (CKD) through the lens of evolutionary biology highlights the mismatch between our Paleolithic-optimized genes and modern diets, which led to the dramatically increased prevalence of CKD in modern societies. In particular, the Standard American Diet (SAD), high in carbohydrates and ultra-processed foods, causes conditions like type 2 diabetes (T2D), chronic inflammation, and hypertension, leading to CKD. Autosomal dominant polycystic kidney disease (ADPKD), a genetic form of CKD, is characterized by progressive renal cystogenesis that leads to renal failure. This review challenges the fatalistic view of ADPKD as solely a genetic disease. We argue that, just like non-genetic CKD, modern dietary practices, lifestyle, and environmental exposures initiate and accelerate ADPKD progression. Evidence shows that carbohydrate overconsumption, hyperglycemia, and insulin resistance significantly impact renal health. Additionally, factors like dehydration, electrolyte imbalances, nephrotoxin exposure, gastrointestinal dysbiosis, and renal microcrystal formation exacerbate ADPKD. Conversely, carbohydrate restriction, ketogenic metabolic therapy (KMT), and antagonizing the lithogenic risk show promise in slowing ADPKD progression. Addressing disease triggers through dietary modifications and lifestyle changes offers a conservative, non-pharmacological strategy for disease modification in ADPKD. This comprehensive review underscores the urgency of integrating diet and lifestyle factors into the clinical management of ADPKD to mitigate disease progression, improve patient outcomes, and offer therapeutic choices that can be implemented worldwide at low or no cost to healthcare payers and patients. Full article

Introduction: Adverse drug reactions are a significant problem in modern society, stemming from the increase in prescribed medications, over-the-counter drugs, and overall polypharmacy. Glomerular disorders are one of the frequently reported renal conditions associated with medication use. VigiBase is a significant tool for evaluating events associated with drug use, and, to the authors’ knowledge, no study has yet assessed this database to identify the primary medications associated with glomerular disorders. Materials and Methods: We collected data from VigiBase for 54 years and evaluated data based on global frequencies, disproportionality (IC₀₂₅ values), nephrotoxic potential, and physiopathological mechanisms. Results: Over the evaluation period, 33.932.051 spontaneous notifications of adverse drug reactions reported in VigiBase were assessed, from which 106.775 notifications of drug-associated glomerular disorders were extracted. The isolated medications were classified as ‘potential nephrotoxins’ (47.0%), with 40% of the medications lacking scientific references to report any association with the development of glomerular disorders. Among the evaluated medications, Inotersen (IC₀₂₅ of 8.3), Penicillamine (IC₀₂₅ 6.8), Bevacizumab (IC₀₂₅ 5.9) and Lenvatinib (IC₀₂₅ 5.4) were identified as having the strongest association with these glomerular disorders. For medications classified as ‘non-nephrotoxic’, a high disproportionality index was observed, suggesting drugs that might be considered as new potential nephrotoxins. Conclusions: Drug-induced glomerular disorders were significantly associated with medications that had no established nephrotoxic role but demonstrated a high disproportionality index in VigiBase. These newly alleged nephrotoxic drugs warrant further evaluation in dedicated studies to assess their true nephrotoxic potential. Full article

Acute kidney injury (AKI) affects 10–15% of hospitalised patients and arises after severe infections, major surgeries, or exposure to nephrotoxic drugs. AKI diagnosis based on creatinine level changes lacks specificity and may be delayed. MicroRNAs are short non-coding RNA secreted by all cells. This review of studies measuring miRNAs in AKI aimed to verify miRNAs as diagnostic markers. The study included data from patients diagnosed with AKI due to sepsis, ischaemia, nephrotoxins, radiocontrast, shock, trauma, and cardiopulmonary bypass. Out of 71 studies, the majority focused on AKI in sepsis patients, followed by cardiac surgery patients, ICU patients, and individuals receiving nephrotoxic agents or experiencing ischaemia. Studies that used untargeted assays found 856 differentially regulated miRNAs, although none of these were confirmed by more than one study. Moreover, 68 studies measured miRNAs by qRT-PCR, and 2 studies reported downregulation of miR-495-3p and miR-370-3p in AKI patients with sepsis after the AKI diagnosis. In three studies, upregulation of miR-21 was reported at the time of the AKI diagnosis with a significant pooled effect of 0.56. MiR-21 was also measured 19–24 h after cardiac surgery in three studies. However, the pooled effect was not significant. Despite the considerable research into miRNA in AKI, there is a knowledge gap in their applicability as diagnostic markers of AKI in humans. Full article

A very low incidence of acute kidney injury (AKI) has been observed in COVID-19 patients purposefully treated with early pressure support ventilation (PSV) compared to those receiving mainly controlled ventilation. The prevention of subdiaphragmatic venous congestion through limited fluid intake and the lowering of intrathoracic pressure is a possible and attractive explanation for this observed phenomenon. Both venous congestion, or “venous bagging”, and a positive fluid balance correlate with the occurrence of AKI. The impact of PSV on venous return, in addition to the effects of limiting intravenous fluids, may, at least in part, explain this even more clearly when there is no primary kidney disease or the presence of nephrotoxins. Optimizing the patient–ventilator interaction in PSV is challenging, in part because of the need for the ongoing titration of sedatives and opioids. The known benefits include improved ventilation/perfusion matching and reduced ventilator time. Furthermore, conservative fluid management positively influences cognitive and psychiatric morbidities in ICU patients and survivors. Here, it is hypothesized that cranial lymphatic congestion in relation to a more positive intrathoracic pressure, i.e., in patients predominantly treated with controlled mechanical ventilation (CMV), is a contributing risk factor for ICU delirium. No studies have addressed the question of how PSV can limit AKI, nor are there studies providing high-level evidence relating controlled mechanical ventilation to AKI. For this perspective article, we discuss studies in the literature demonstrating the effects of venous congestion leading to AKI. We aim to shed light on early PSV as a preventive measure, especially for the development of AKI and ICU delirium and emphasize the need for further research in this domain. Full article

Ochratoxin A (OTA), a potent nephrotoxin, is one of the most deleterious mycotoxins, with its prevalence in agricultural crops and their processed foods around the world. OTA is a major concern to food safety, as OTA exposure through dietary intake may lead to a significant level of accumulation in the body as a result of its long half-life (about 35 days). Its potent renal toxicity and high risk of exposure as well as the difficulty in controlling environmental factors OTA production has prompted the need for timely information on practical strategies for the food industry to effectively manage OTA contamination during food processing. The effects of various food processes, including both nonthermal and thermal methods, on the reduction in OTA were summarized in this review, with emphasis on the toxicity of residual OTA as well as its known and unknown degradation products. Since complete removal of OTA from foodstuffs is not feasible, additional strategies that may facilitate the reduction in OTA in food, such as adding baking soda and sugars, was also discussed, so that the industry may understand and apply practical measures to ensure the safety of its products destined for human consumption. Full article

Proximal tubular epithelial cells (PTEC) are constantly exposed to potentially toxic metabolites and xenobiotics. The regenerative potential of the kidney enables the replacement of damaged cells either via the differentiation of stem cells or the re-acquisition of proliferative properties of the PTEC. Nevertheless, it is known that renal function declines, suggesting that the deteriorated cells are not replaced by fully functional cells. To understand the possible causes of this loss of kidney cell function, it is crucial to understand the role of toxins during the regeneration process. Therefore, we investigated the sensitivity and function of human induced pluripotent stem cells (hiPSC), hiPSC differentiating, and hiPSC differentiated into proximal tubular epithelial-like cells (PTELC) to known nephrotoxins. hiPSC were differentiated into PTELC, which exhibited similar morphology to PTEC, expressed prototypical PTEC markers, and were able to undergo albumin endocytosis. When treated with two nephrotoxins, hiPSC and differentiating hiPSC were more sensitive to cisplatin than differentiated PTELC, whereas all stages were equally sensitive to cyclosporin A. Both toxins also had an inhibitory effect on albumin uptake. Our results suggest a high sensitivity of differentiating cells towards toxins, which could have an unfavorable effect on regenerative processes. To study this, our model of hiPSC differentiating into PTELC appears suitable. Full article

The high prevalence of kidney diseases and the low identification rate of drug nephrotoxicity in preclinical studies reinforce the need for representative yet feasible renal models. Although in vitro cell-based models utilizing renal proximal tubules are widely used for kidney research, many proximal tubule cell (PTC) lines have been indicated to be less sensitive to nephrotoxins, mainly due to altered expression of transporters under a two-dimensional culture (2D) environment. Here, we selected HK-2 cells to establish a simplified three-dimensional (3D) model using gelatin sponges as scaffolds. In addition to cell viability and morphology, we conducted a comprehensive transcriptome comparison and correlation analysis of 2D and 3D cultured HK-2 cells to native human PTCs. Our 3D model displayed stable and long-term growth with a tubule-like morphology and demonstrated a more comparable gene expression profile to native human PTCs compared to the 2D model. Many missing or low expressions of major genes involved in PTC transport and metabolic processes were restored, which is crucial for successful nephrotoxicity prediction. Consequently, we established a cost-effective yet more representative model for in vivo PTC studies and presented a comprehensive transcriptome analysis for the systematic characterization of PTC lines. Full article

The human kidney is known to possess renal progenitor cells (RPCs) that can assist in the repair of acute tubular injury. The RPCs are sparsely located as single cells throughout the kidney. We recently generated an immortalized human renal progenitor cell line (HRTPT) that co-expresses PROM1/CD24 and expresses features expected on RPCs. This included the ability to form nephrospheres, differentiate on the surface of Matrigel, and undergo adipogenic, neurogenic, and osteogenic differentiation. These cells were used in the present study to determine how the cells would respond when exposed to nephrotoxin. Inorganic arsenite (iAs) was chosen as the nephrotoxin since the kidney is susceptible to this toxin and there is evidence of its involvement in renal disease. Gene expression profiles when the cells were exposed to iAs for 3, 8, and 10 passages (subcultured at 1:3 ratio) identified a shift from the control unexposed cells. The cells exposed to iAs for eight passages were then referred with growth media containing no iAs and within two passages the cells returned to an epithelial morphology with strong agreement in differential gene expression between control and cells recovered from iAs exposure. Results show within three serial passages of the cells exposed to iAs there was a shift in morphology from an epithelial to a mesenchymal phenotype. EMT was suggested based on an increase in known mesenchymal markers. We found RPCs can undergo EMT when exposed to a nephrotoxin and undergo MET when the agent is removed from the growth media. Full article

Citrinin (CIT), a mycotoxin known to exert nephrotoxicity, is a contaminant in food and feed. Since CIT contamination is not regularly analyzed, data on its occurrence and especially levels in food commodities are insufficient for conducting a conventional exposure assessment. Yet, human biomonitoring, i.e., an analysis of CIT and its metabolite dihydrocitrinone (DH-CIT) in urine samples allows to estimate exposure. This study investigated CIT exposure in young (2–14 years) and adult (24–61 years) residents of three federal states in Germany. A total of 179 urine samples from children and 142 from adults were collected and analyzed by a targeted LC-MS/MS based method for presence of CIT and DH-CIT. At least one of the biomarkers was detected and quantified in all urines, which indicated a widespread dietary exposure to the mycotoxin in Germany. Interestingly, the biomarker concentrations of CIT_total (sum of CIT and DH-CIT) were higher in children’s urine (range 0.05–7.62 ng/mL; median of 0.54 ng/mL) than in urines from adults (range 0.04–3.5 ng/mL; median 0.3 ng/mL). The biomarker levels (CIT_total) of individual urines served to calculate the probable daily CIT intake, for comparison to a value of 0.2 µg/kg bw/day defined as ‘level of no concern for nephrotoxicity’ by the European Food Safety Authority. The median exposure of German adults was 0.013 µg/kg b.w., with only one urine donor exceeding this provisional tolerable daily intake (pTDI) for CIT. The median exposure of children was 0.05 µg/kg bw per day (i.e., 25% of the pTDI); however, CIT exposure in 12 individuals (6.3% of our study group) exceeded the limit value, with a maximum intake of 0.46 µg/kg b.w. per day. In conclusion, these results show evidence for non-negligible exposure to CIT in some individuals in Germany, mainly in children. Therefore, further biomonitoring studies and investigations aimed to identify the major sources of CIT exposure in food commodities are required. Full article