Drug-induced Kidney Injury Research Articles

Drug-induced acute kidney injury: a cohort study on incidence, identification of pathophysiological mechanisms, and prognostic factors

IntroductionAcute Kidney Injury (AKI) is a common clinical syndrome characterized by an abrupt decline in the glomerular filtration rate (GFR), which can cause severe alterations in blood volume and acid-base balance. Drug-Induced Acute Kidney Injury (DI-AKI) is associated with exposure to nephrotoxic medications, particularly among hospitalized patients. Adverse drug reactions comprises type A and type B reactions. Type A reactions are predictable based on the pharmacology of the substance, dose-dependent, and manifest as Acute Tubular Necrosis (ATN). Type B reactions are unpredictable, idiosyncratic, not dose-dependent, and manifest as Acute Interstitial Nephritis (AIN), Crystal-Induced Nephropathy, among others.ObjectiveTo evaluate DI-AKI incidence, identify the main associated drugs and the pathophysiological mechanism of the observed injury, analyze prognostic factors associated with unfavorable outcomes, and compare the outcomes of death and the need for Acute Kidney Support Therapy (AKST) between patients with DI-AKI vs. AKI due to other etiologies.MethodsA retrospective cohort study conducted at the Hospital das Clínicas of the Faculty of Medicine of Botucatu – UNESP (HC-FMB), using data from patients hospitalized between January 2016 and April 2022 and followed, via consultation, by the AKI-Nephrology team. Inclusion criteria: diagnosis of AKI and Chronic Kidney Disease (CKD) with superimposed AKI. Exclusion criteria: patients under 18 years old or on chronic Renal Replacement Therapy. AKI was diagnosed based on creatinine increase as established by KDIGO 2012. Data were presented as mean and standard deviation or median with interquartile range and frequency. Statistical significance was set at 5% (p < 0.05). Comparative analyses were performed using the Chi-Square test for categorical variables and the T-test for continuous variables. Subsequently, logistic regression was performed to identify factors associated with the need for AKST and death.ResultsA total of 1,398 patients were analyzed, most of them males (61.4%), with a mean age of 64 years ±14.4 years. The most prevalent etiology of AKI was Mixed Ischemic + Septic AKI (28%). DI-AKI was a significant cause of AKI (19.3%). Of these, 25.2% were isolated DI-AKI and 74.8% were Mixed DI-AKI + Ischemia and/or Sepsis. Among patients with DI-AKI, the mean age was 61.15 ± 15.26, males were the most frequent, the majority were not subjected to AKST and survived. Most of these patients were hospitalized in the ward, did not need vasoactive drugs, nor did they use mechanical ventilation. DI-AKI showed lower severity and mortality compared to other AKI etiologies but had a similar need for AKST (26.3% vs. 35.4%, p < 0.05 and 31.8% vs. 36.8%, p > 0.05). Most nephrotoxic drugs caused type A reactions, with Vancomycin being the primary nephrotoxin. Among drugs associated with DI-AKI, Vancomycin was associated with a higher need for AKST and death, while Amphotericin B was associated with a lower risk of AKST and death.ConclusionAlthough the mortality rate is lower among DI-AKIs compared to other AKI etiologies, the need for AKST was similar. Therefore, it is recommended that DI-AKI be recognized early to enable dose reduction or even drug suspension, depending on the type of reaction, to reduce healthcare costs and improve clinical outcomes for patients.

7-Hydroxycoumarin and its conjugated metabolites interact with organic anion transporters 1 and 3 in vitro and in vivo.

7-Hydroxycoumarin (7-HC) is a natural coumarin compound rich in Chinese herbal medicines and has various pharmacological activities. After oral administration of 7-HC in rodents, its conjugated metabolites 7-hydroxycoumarin-β-D-glucuronide (7-HCG) and 7-hydroxycoumarin sulfate (7-HCS), exhibit high systemic exposure and urinary excretion. Organic anion transporters 1 and 3 (OAT1 and OAT3), mainly expressed in the proximal renal tubules, play an important role in drug-drug interactions and drug-induced kidney injury. We aimed to explore the mechanisms of OAT-mediated drug interactions and renal protective mechanisms of 7-HC and its conjugates. OAT-overexpressing cell models revealed that 7-HC was not a substrate for OAT1 and OAT3, while 7-HCG was specifically transported by OAT3. In contrast, 7-HCS can be transported by both OATs. Besides, 7-HC significantly inhibited the activity of OAT1 and OAT3, while 7-HCS had a strong inhibitory effect on OAT1 (IC50<10 μM). After co-administration of 100 mg/kg of 7-HC to mice, systemic exposure and clearance of furosemide (a clinical substrate of OATs) were significantly increased and decreased, respectively. In addition, 7-HC decreased OAT-mediated cytotoxicity and reduced the renal distribution of adefovir in mice. Together, these findings will provide support for OAT-mediated drug interactions and the renal protection of 7-HC.

Renal Tubular Injury Biomarkers (BMs) in the Identification of Subclinical AKI and Drug-Induced Kidney Injury: IMI/SAFE-T/TransBioLine

Renal Tubular Injury Biomarkers (BMs) in the Identification of Subclinical AKI and Drug-Induced Kidney Injury: IMI/SAFE-T/TransBioLine

COMMD5 counteracts cisplatin-induced nephrotoxicity by maintaining tubular epithelial integrity and autophagy flux.

Oxidative stress mediated by reactive oxygen species (ROS) contributes to apoptosis of tubular epithelial cells (TECs) and renal inflammation during acute kidney injury (AKI). Copper metabolism MURR1 domain-containing 5 [COMMD5/hypertension-related, calcium-regulated gene (HCaRG)] shows strong cytoprotective properties. COMMD5 is highly expressed in proximal tubules (PTs), where it controls cell differentiation. We assessed its role in cisplatin-induced AKI using transgenic mice in which COMMD5 is overexpressed in the PTs. Cisplatin caused the accumulation of damaged mitochondria and cellular waste in PTs, thus increasing the apoptosis of TECs. COMMD5 overexpression effectively protected TECs from cisplatin nephrotoxicity by decreasing intracellular ROS levels, mitochondrial dysfunction, and apoptosis through the preservation of tubular epithelial integrity, thus alleviating morphological and functional kidney damage. Excessive ROS production by hydrogen peroxide led to long-term autophagy activation through an increased burden on the autophagy/lysosome degradation system in TECs, and autophagic elimination of damaged mitochondria and cellular waste was compromised. COMMD5 attenuated oxidative injury by increasing autophagy flux, possibly due to a reduction of intracellular ROS levels through maintained tubular epithelial integrity, which decreased JNK/caspase-3-dependent apoptosis. Meanwhile, COMMD5 inhibition by siRNA reduced the resistance of TECs to cisplatin cytotoxicity, as shown by disrupted tubular epithelial integrity and cell viability. These data indicated that COMMD5 protects TECs from drug-induced oxidative stress and toxicity by maintaining tubular epithelial integrity and autophagy flux and ultimately decreases mitochondrial dysfunction and apoptosis. Increasing COMMD5 content in PTs is proposed as a new protective and therapeutic strategy against AKI.NEW & NOTEWORTHY Oxidative stress overload by drug treatment causes the accumulation of damaged mitochondria that could contribute to tubulopathy. However, effective preventive treatment for drug-induced acute kidney injury remains incompletely understood. Our study showed that copper metabolism MURR1 domain-containing 5 (COMMD5) reduced mitochondrial dysfunction and increased autophagy flux by alleviating reactive oxygen species production through maintaining tubular epithelial integrity when tubular epithelial cells were under oxidative stress, thus ameliorating renal function in cisplatin-treated mice. These results uncover a novel renoprotective mechanism underlying tubular epithelial integrity and autophagy flux.

ID Consultant: Laboratory monitoring during long-term use of oral antimicrobials in pediatric patients.

Oral antimicrobials remain the mainstay of long-term treatment for many infections. Meanwhile, the use of oral agents is becoming commonplace for treatment of several pediatric infections once managed exclusively with parenteral therapies. Unfortunately, antimicrobials are associated with several laboratory toxicities, particularly when high doses or combination therapies are used, but there is a paucity of data on optimal laboratory monitoring strategies. In this ID Consultant piece, we offer a summary of the three most common lab-based toxicities seen with long-term use of oral antimicrobials - drug-induced kidney injury, liver injury, and hematological toxicities - and we provide our recommended approach to monitoring.

Drug-induced Acute Kidney Injury: A Clinico-etiological Study from a Tertiary Care Center in Northeast India

Drug-induced Acute Kidney Injury: A Clinico-etiological Study from a Tertiary Care Center in Northeast India

Causal Deep Learning for the Detection of Adverse Drug Reactions: Drug-Induced Acute Kidney Injury as a Case Study.

Causal Deep/Machine Learning (CDL/CML) is an emerging Artificial Intelligence (AI) paradigm. The combination of causal inference and AI could mine explainable causal relationships between data features, providing useful insights for various applications, e.g. Pharmacovigilance (PV) signal detection upon Real-World Data. The objective of this study is to demonstrate the use of CDL for potential PV signal validation using Electronic Health Records as input data source.

Complex Assessment of the Functional State of the Urinary System in Preclinical Studies. Part 2. Markers of Nephrotoxicity (Review)

INTRODUCTION. The determination of nephrotoxicity markers is a useful and necessary step in the detection of renal injury in animal experiments; these markers help accurately localise organ damage. With multiple damaging agents, known nephrotoxicity mechanisms, and laboratory animal species, there is currently no widely accepted renal injury marker that meets all the prerequisites.AIM. This study aimed to collate literature data on nephrotoxicity markers, evaluate their prognostic significance, and formulate general recommendations for assessing urinary system function in preclinical studies.DISCUSSION. This article describes a comparative analysis of the nephrotoxicity markers recommended by regulatory authorities for monitoring drug-induced kidney injury. According to the results, the most commonly used and prognostically significant markers of acute kidney injury in preclinical studies are cystatin C, albumin, total protein, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin-2 (NGAL), and clusterin. Chronic kidney injury markers include the above, plus the glomerular filtration rate, creatinine, urea, and osteopontin. An electrolyte panel can be used for the differential diagnosis of pre-renal azotaemia and acute kidney injury. Potential limitations for the routine use of kidney injury markers in preclinical research include the high cost of their quantitative determination and the lack of information on the applicability of data obtained from different species of laboratory animals.CONCLUSIONS. Having compared the prognostic significance of common biomarkers, the authors provided general recommendations for a comprehensive preclinical assessment of urinary system function, including laboratory investigations, instrument-based tests, and necropsy. A preclinical study design should be based on the study aims, the species and number of animals used, and special considerations for the test article.

Three-dimensional Culture of Human Proximal Tubular Epithelial Cells for an in vitro Evaluation of Drug-induced Kidney Injury

Drug-induced kidney injury (DIKI) is the major cause of acute kidney injury (AKI). Renal proximal tubular epithelial cells (RPTECs) are the primary target sites of DIKI and express transporters involved in renal drug disposition. In the present study, we focused on three-dimensionally cultured human RPTECs (3D-RPTECs) with elevated expression of drug transporters to investigate their utility in DIKI evaluation. Intracellular ATP levels in 3D-RPTECs are reduced by tenofovir and cisplatin that are substrates of an organic anion transporter 1 and an organic cation transporter 2, respectively. In addition, 3D-RPTECs were exposed to 17 and 15 drugs that are positive and negative to RPTEC toxicity, respectively, for up to 28 d. The 20 % decreasing concentration of drugs for ATP amount (EC20) was obtained, and the ratio of EC20 values and clinical maximum concentration (Cmax) ≤100 were used as cut-off value to evaluate potential of DIKI. The sensitivities of 3D-RPTECs were 82.4 % and 88.2 % after 7 d and 28 d of drug exposure, respectively, and the specificities were 100 % and 93.3 %, respectively. The predictive performance of 3D-RPTECs was higher than that of two-dimensional cultured RPTECs and the kidney cell line HK-2. In conclusion, 3D-RPTECs are useful for in vitro evaluation of RPTEC injury by measuring intracellular ATP levels.

Identification of a substrate of the renal tubular transporters for detecting drug-induced early acute kidney injury.

Early identification of drug-induced acute kidney injury (AKI) is essential to prevent renal damage. The renal tubules are typically the first to exhibit damage, frequently accompanied by changes in renal tubular transporters. With this in mind, we have identified an endogenous substrate of the renal tubular transporters that may serve as a biomarker for early detection of drug-induced AKI. Using gentamicin- and vancomycin-induced AKI models, we found that traumatic acid (TA), an end metabolite, was rapidly increased in both AKI models. TA, a highly albumin-bound compound (96% to 100%), could not be filtered by the glomerulus and was predominantly eliminated by renal tubules via the OAT1, OAT3, OATP4C1, and P-gp transporters. Importantly, there is a correlation between elevated serum TA levels and reduced OAT1 and OAT3 levels. A clinical study showed that serum TA levels rose before an increase in serum creatinine in 13 out of 20 AKI patients in an intensive care unit setting. In addition, there was a notable rise in TA levels in the serum of individuals suffering from nephrotic syndrome, chronic renal failure, and acute renal failure. These results indicate that the decrease in renal tubular transporter expression during drug-induced AKI leads to an increase in the serum TA level, and the change in TA may serve as a monitor for renal tubular injury. Acute kidney injury (AKI) has a high clinical incidence, and if patients do not receive timely treatment and intervention, it can lead to severe consequences. During AKI, tubular damage is often the primary issue. Endogenous biomarkers of tubular damage are critical for the early diagnosis and treatment of AKI. However, there is currently a lack of reliable endogenous biomarkers for diagnosing tubular damage in clinical practice. Tubular secretion is primarily mediated by renal tubular transporters (channels), which are also impaired during tubular damage. Therefore, we aim to identify endogenous biomarkers of tubular damage from the perspective of renal tubular transporters, providing support for the early detection and intervention of AKI. TA is a substrate of multiple channels, including OAT1, OAT3, OATP4C1, and P-gp, and is primarily secreted by the renal tubules. In the early stages of rat AKI induced by GEN and VCA, serum TA levels are significantly elevated, occurring earlier than the rise in serum creatinine (SCr). Thus, TA is expected to become a potential endogenous biomarker for the early diagnosis of tubular damage.

Qualified kidney injury biomarkers demonstrate value during early clinical drug development.

Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer's portfolio (PFE-1 and PFE-2, respectively) that induced kidney tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N-acetyl-beta-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from (i) Phase 1 healthy volunteers (HVs; n = 12) dosed with PFE-1, (ii) Phase 2 rheumatoid arthritis (RA) patients (n = 266) dosed with PFE-2, (iii) lupus patients on standard-of-care therapies (n = 121), and (iv) healthy volunteers (n = 60). The FDA-defined composite measure (CM), calculated as the geometric mean response across the 6 biomarkers, was increased ∼30% in HVs administered 100 mg PFE-1 relative to placebo, providing evidence of DIKI. In contrast, the CM for RA patients dosed with PFE-2 was comparable to placebo controls, helping to de-risk the concern for DIKI at clinically relevant doses. Comparing individual biomarker concentrations across disease states revealed that CLU, KIM-1, NAG, NGAL, and OPN are elevated in the urine of RA and lupus patients (those without severe active proliferative lupus nephritis) relative to HVs. Overall, these case studies demonstrate the value of using the FDA-qualified kidney biomarker panel to guide risk assessment, dose selection, and clinical decision making for novel therapeutics, both in HVs and patient populations.

Global burden of anticancer drug-induced acute kidney injury and tubulointerstitial nephritis from 1967 to 2023

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; IC0.25: 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.

Drug-induced kidney injury: challenges and opportunities.

Drug-induced kidney injury (DIKI) is a frequently reported adverse event, associated with acute kidney injury, chronic kidney disease, and end-stage renal failure. Prospective cohort studies on acute injuries suggest a frequency of around 14%-26% in adult populations and a significant concern in pediatrics with a frequency of 16% being attributed to a drug. In drug discovery and development, renal injury accounts for 8 and 9% of preclinical and clinical failures, respectively, impacting multiple therapeutic areas. Currently, the standard biomarkers for identifying DIKI are serum creatinine and blood urea nitrogen. However, both markers lack the sensitivity and specificity to detect nephrotoxicity prior to a significant loss of renal function. Consequently, there is a pressing need for the development of alternative methods to reliably predict drug-induced kidney injury (DIKI) in early drug discovery. In this article, we discuss various aspects of DIKI and how it is assessed in preclinical models and in the clinical setting, including the challenges posed by translating animal data to humans. We then examine the urinary biomarkers accepted by both the US Food and Drug Administration (FDA) and the European Medicines Agency for monitoring DIKI in preclinical studies and on a case-by-case basis in clinical trials. We also review new approach methodologies (NAMs) and how they may assist in developing novel biomarkers for DIKI that can be used earlier in drug discovery and development.

Urinary MicroRNA biomarkers of nephrotoxicity in Macaca fascicularis

Drug-induced kidney injury (DIKI) refers to kidney damage resulting from the administration of medications. The aim of this project was to identify reliable urinary microRNA (miRNAs) biomarkers that can be used as potential predictors of DIKI before disease diagnosis. This study quantified a panel of six miRNAs (miRs-210-3p, 423-5p, 143-3p, 130b-3p, 486-5p, 193a-3p) across multiple time points using urinary samples from a previous investigation evaluating effects of a nephrotoxicant in cynomolgus monkeys. Exosome-associated miRNA exhibited distinctive trends when compared to miRNAs quantified in whole urine, which may reflect a different urinary excretion mechanism of miRNAs than those released passively into the urine. Although further research and mechanistic studies are required to elucidate how these miRNAs regulate signaling in disease pathways, we present, for the first time, data that several miRNAs displayed strong correlations with histopathology scores, thus indicating their potential use as biomarkers to predict the development of DIKI in preclinical studies and clinical trials. Also, these findings can potentially be translated into other non-clinical species or human for the detection of DIKI.

Inhibitory effect of flavonoids on multidrug and toxin extrusion protein 1 function: Implications for food/herb-drug interaction and drug-induced kidney injury.

Multidrug and toxin extrusion protein 1 (MATE1), an efflux transporter mainly expressed in renal proximal tubules, mediates the renal secretion of organic cationic drugs. The inhibition of MATE1 will impair the excretion of drugs into the tubular lumen, leading to the accumulation of nephrotoxic drugs in the kidney and consequently potentiating nephrotoxicity. Screening and identifying potent MATE1 inhibitors can predict or minimize the risk of drug-induced kidney injury. Flavonoids, a group of polyphenols commonly found in foodstuffs and herbal products, have been reported to cause transporter-mediated food/herb-drug interactions. Our objective was to investigate the inhibitory effects of flavonoids on MATE1 in vitro and in vivo and to assess the effects of flavonoids on cisplatin-induced kidney injury. Thirteen flavonoids exhibited significant transport activity inhibition (>50%) on MATE1 in MATE1-MDCK cells. Among them, the six strongest flavonoid inhibitors, including irisflorentin, silymarin, isosilybin, sinensetin, tangeretin, and nobiletin, markedly increased cisplatin cytotoxicity in these cells. In cisplatin-induced in vivo renal injury models, irisflorentin, isosilybin, and sinensetin also increased serum creatinine and blood urea nitrogen levels to different degrees, especially irisflorentin, which exhibited the most potent nephrotoxicity with cisplatin. The pharmacophore model indicated that the hydrogen bond acceptors at the 3, 5, and 7 positions may play a critical role in the inhibitory effect of flavonoids on MATE1. Our findings provide helpful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions and avoiding the exacerbation of drug-induced kidney injury via MATE1 mediation.

Gentamicin concentration and acute kidney injury in term neonates treated for neonatal sepsis with gentamicin and ampicillin-cloxacillin combination.

Gentamicin is widely used to treat neonatal infections caused by both Gram-negative and Gram-positive bacteria, and the WHO recommends its use while monitoring serum creatinine and gentamicin concentrations to avoid drug-induced nephrotoxicity and ototoxicity. Yet in some resource-limited settings, the drug is used without monitoring. A population pharmacokinetics study involving term neonates with neonatal infection admitted to a neonatal unit. Participants were started on intravenous gentamicin 5 mg/kg once a day in combination with ampicilin-cloxacillin. Blood samples for serum gentamicin concentration were taken at 0.25, 0.5, 1, 2, 3, 5, 6, 8, 10, 12, 14, 16, 18, 20, 23, and 24 hours after the initial dose, each participant contributing two samples to the 24 hour sampling schedule. An additional sample for trough concentration was taken from each participant just before the third gentamicin dose while serum creatinine concentration was measured before and after treatment. Twenty-four participants were enrolled into the study and included in the final analysis. Mean (SD) peak and trough serum gentamicin concentrations were 16.66 (0.64) µg/mL and 3.28 (0.70) µg/mL, respectively. Gentamicin clearance (CL) was 0.40 mL min-1 kg-1 and volume of distribution (VD) was 0.31 L kg-1. Mean (SD) serum creatinine level after treatment was 209.7 (70.4) µmol/L compared to 103.3 (23.6) µmol/L before treatment [mean difference (106.4 ± 67.1; 95% confidence interval (CI): 78.1; 134.7 µmol/L; t (23) = 7.77; P < 0.001]. All participants fulfilled the Kidney Disease Improving Global Outcomes (KDIGO) criteria for acute kidney injury after treatment. Treatment of neonatal infection with antimicrobial regimen containing gentamicin, without renal function and gentamicin concentration monitoring, carries a significant risk for drug-induced acute kidney injury.

Serum Amyloid A3 Promoter-Luciferase Reporter Mice Are Useful for Early Drug-Induced Nephrotoxicity Detection.

Early detection of drug-induced kidney injury is essential for drug development. In this study, multiple low-dose aristolochic acid (AA) and cisplatin (Cis) injections increased renal mRNA levels of inflammation, fibrosis, and renal tubule injury markers. We applied a serum amyloid A3 (Saa3) promoter-driven luciferase reporter (Saa3 promoter-luc mice) to these two tubulointerstitial nephritis models and performed in vivo bioluminescence imaging to monitor early renal pathologies. The bioluminescent signals from renal tissues with AA or CIS injections were stronger than those from normal kidney tissues obtained from normal mice. To verify whether the visualized bioluminescence signal was specifically generated by the injured kidney, we performed in vivo bioluminescence analysis after opening the stomachs of Saa3 promoter-luc mice, and the Saa3-mediated bioluminescent signal was specifically detected in the injured kidney. This study showed that Saa3 promoter activity is a potent non-invasive indicator for the early detection of drug-induced nephrotoxicity.

Source Tracing of Kidney Injury via the Multispectral Fingerprint Identified by Machine Learning-Driven Surface-Enhanced Raman Spectroscopic Analysis.

Early diagnosis of drug-induced kidney injury (DIKI) is essential for clinical treatment and intervention. However, developing a reliable method to trace kidney injury origins through retrospective studies remains a challenge. In this study, we designed ordered fried-bun-shaped Au nanocone arrays (FBS NCAs) to create microarray chips as a surface-enhanced Raman scattering (SERS) analysis platform. Subsequently, the principal component analysis (PCA)-two-layer nearest neighbor (TLNN) model was constructed to identify and analyze the SERS spectra of exosomes from renal injury induced by cisplatin and gentamycin. The established PCA-TLNN model successfully differentiated the SERS spectra of exosomes from renal injury at different stages and causes, capturing the most significant spectral features for distinguishing these variations. For the SERS spectra of exosomes from renal injury at different induction times, the accuracy of PCA-TLNN reached 97.8% (cisplatin) and 93.3% (gentamicin). For the SERS spectra of exosomes from renal injury caused by different agents, the accuracy of PCA-TLNN reached 100% (7 days) and 96.7% (14 days). This study demonstrates that the combination of label-free exosome SERS and machine learning could serve as an innovative strategy for medical diagnosis and therapeutic intervention.

Renal Lesions with Low-level Enhancement on Contrast-enhanced CT Promotes Early Detection of Drug-induced Kidney Injury in Patients Administered Anticancer Drugs.

Some patients with cancer-administered anti-cancer drugs may develop renal lesions with low-level enhancement on follow-up abdominal computed tomography (CT). To explore the clinical significance of renal lesions with low-level enhancement on CT after exposure to anti-cancer drugs. Medical records of patients with cancer who developed renal lesions on CT after exposure to anti-cancer drugs were retrospectively reviewed. Renal lesions were scored according to the extent of involvement, CT attenuation values of lesions and normal parenchyma were measured on precontrast CT and three phases of contrast-enhanced CT, and changes in serum creatinine (SCr) from one week before exposure to drugs to one week before and after the appearance of renal lesions were recorded. This study included 54 patients (86 lesions). Lesions were slightly lower density on pre-contrast CT, and less enhancing than normal renal parenchyma, especially in the delayed phase. Lesions were wedge-shaped, and involved the renal pyramid and associated renal cortex, as well as, were single or multiple, and occurred in the unilateral or bilateral kidneys. There were patchy and cord-like shadows of increased density in adjacent perirenal adipose tissue. During follow-up, lesions disappeared in 15 patients and persisted in 39 patients without significant progression. There were significant differences in renal lesions and normal renal parenchyma CT attenuation values in each phase of contrast-enhanced CT. Change in SCr level was significantly positively correlated with lesion score. Renal lesions with low-level enhancement on CT suggest early drug-induced kidney injury. These findings will inform clinical decision-making.

Exploration of Risk Factors of the Onset of Antibiotics-induced Acute Kidney Injury and Its Transfer to Chronic Kidney Disease Using the Medical Information Database

Drug-induced acute kidney injury (AKI) is a serious adverse drug reaction, which results in a significant decline in renal function and is known to progress to chronic kidney disease (CKD). Therefore, appropriate drug therapy is important to avoid the risk of drug-induced AKI and CKD, which are serious concerns in clinical practice. In this study, using the medical information database of Hamamatsu University Hospital, we investigated the risk factors that accelerate the onset of drug-induced AKI or its progression to CKD in patients who received aminoglycoside antibiotics (AGs) or glycopeptide antibiotics (GPs), which are strongly associated with drug-induced AKI and CKD. We performed logistic regression analysis using patients' background, laboratory test results, and concomitant drug use, among other such factors as explanatory variables and drug-induced AKI or CKD onset as objective variables to explore the risk factors for drug-induced AKI and CKD. Our results showed that co-administration of amphotericin B, piperacillin-tazobactam and other AGs and GPs, increased serum creatinine (Scr) and chloride concentrations, serum lactate dehydrogenase activity, and decreased serum albumin concentration were risk factors for drug-induced AKI onset. Moreover, a reduced blood urea nitrogen:Scr ratio at drug-induced AKI onset served as a risk factor for CKD. These results suggest that careful monitoring of the aforementioned factors is important to ensure appropriate usage of these drugs in patients treated with AGs and GPs.