Drug-induced Nephrotoxicity Research Articles

The endocytosis receptor megalin: from bench to bedside.

The large (~600kDa) endocytosis receptor megalin/low-density lipoprotein receptor-related protein 2 is highly expressed at the apical membrane of proximal tubular epithelial cells (PTECs). Megalin plays an important role in the endocytosis of various ligands via interactions with intracellular adaptor proteins, which mediate the trafficking of megalin in PTECs. Megalin mediates the retrieval of essential substances, including carrier-bound vitamins and elements, and impairment of the endocytic process may result in the loss of those substances. In addition, megalin reabsorbs nephrotoxic substances such as antimicrobial (colistin, vancomycin, and gentamicin) or anticancer (cisplatin) drugs and advanced glycation end product-modified or fatty acid-containing albumin. The megalin-mediated uptake of these nephrotoxic ligands causes metabolic overload in PTECs and leads to kidney injury. Blockade or suppression of the megalin-mediated endocytosis of nephrotoxic substances may represent a novel therapeutic strategy for drug-induced nephrotoxicity or metabolic kidney disease. Megalin reabsorbs urinary biomarker proteins such as albumin, α1-microglobulin, β2-microglobulin, and liver-type fatty acid-binding protein; thus, the above-mentioned megalin-targeted therapy may have an effect on the urinary excretion of these biomarkers. We have previously established a sandwich enzyme-linked immunosorbent assay to measure the ectodomain (A-megalin) and full-length (C-megalin) forms of urinary megalin using monoclonal antibodies against the amino- and carboxyl-terminals of megalin, respectively, and reported their clinical usefulness. In addition, there have been reports of patients with novel pathological anti-brush border autoantibodies targeting megalin in the kidney. Even with these breakthroughs in the characterization of megalin, a large number of issues remain to be addressed in future research.

Screening models of nephrotoxicity and their molecular mechanism

Kidney is among the most vital organs in the anatomy of human body which filters 200 litres of fluid every 24 hours and has many more function which include regulating acid-base balance, maintaining electrolytes balance, eliminating waste and toxins products from the human body. Nephrotoxicity refers as the deterioration in the kidney function due to toxic effect of drugs and chemical and is characterized by alterations in glomerular hemodyanmics, renal tubular failure and thrombotic microangiopathy. Drug-induced nephrotoxicity is becoming more well identified as a principal reasons of kidney illness, such as acute kidney injury (AKI) and chronic kidney disease (CKD) (CKD). Nephrotoxicity covers a broad range, displaying damage to various nephron segments as a result of distinct pharmacological actions. There are various agents which exerts nephrotoxic effects through pathogenic mechanisms like non-steroidal agents (Indomerhacin, Paracetamol, Mefenamic acid), anticancer agents (Carmustine, Cisplatin, Methotrexate), antibiotics (Gentamicin, Tobramycin, Amikacin), antiviral (Acyclovir, Tenofovir, Cidofovir), antifungal (Amphotericin B, Vancomycin, Nystatin)and immunosuppresant drugs(Cyclosporine, Tacrolimus). Alteration in glomerular hemodynamics, tubular cell toxicity, inflammation, crystal nephropathy, rhabdomyolysis, and thrombotic microangiopathy are all possibilities for drug-induced nephrotoxicity. In this review, we have explained different experimental models for nephrotoxicity that might assist in developing novel drugs to cure nephrotoxicity.

CORAL Models for Drug-Induced Nephrotoxicity.

Drug-induced nephrotoxicity is a major cause of kidney dysfunction with potentially fatal consequences. The poor prediction of clinical responses based on preclinical research hampers the development of new pharmaceuticals. This emphasises the need for new methods for earlier and more accurate diagnosis to avoid drug-induced kidney injuries. Computational predictions of drug-induced nephrotoxicity are an attractive approach to facilitate such an assessment and such models could serve as robust and reliable replacements for animal testing. To provide the chemical information for computational prediction, we used the convenient and common SMILES format. We examined several versions of so-called optimal SMILES-based descriptors. We obtained the highest statistical values, considering the specificity, sensitivity and accuracy of the prediction, by applying recently suggested atoms pairs proportions vectors and the index of ideality of correlation, which is a special statistical measure of the predictive potential. Implementation of this tool in the drug development process might lead to safer drugs in the future.

The protective impact of glutamine on anti-tuberculosis drug-induced nephrotoxicity in Wistar rats

This study assessed the protective effect of glutamine (GTN) against rifampicin/isoniazid/pyrazinamide/ethambutol (RIPE)-induced nephrotoxicity in rats. Thirty adult Wistar rats (200±20 g) of both sexes were grouped into 6 of 5 rats/group. The rats were treated daily for 30 days as follows: Group 1 (Vehicle control [normal saline 0.2mL]), group 2 (GTN 200 mg/kg), group 3 (RIPE 150, 75, 400 and 275 mg/kg in vehicle), group 4 (GTN 50 mg/kg +RIPE), group 5 (GTN 100 mg/kg +RIPE) and group 6 (GTN 200 mg/kg +RIPE). After treatment, blood samples were obtained and assessed for serum renal biomarkers. Kidneys were harvested, weighed and assessed for oxidative stress markers and histology. RIPE significantly (p<0.01) decreased body weight and significantly (p<0.01) increased kidney weight when compared to the control. Serum urea, creatinine, uric acid levels and kidney malondialdehyde levels were significantly (p<0.001) increased in RIPE-treated rats when compared to the control. Serum total protein, albumin, kidney glutathione, catalase, superoxide dismutase and glutathione peroxidase levels were significantly decreased (p<0.001) in RIPE-treated rats when compared to the control. RIPE caused tubular necrosis and collapsed glomeruli in the kidneys of rats. However, body and liver weights were significantly restored in GTN 100 mg/kg +RIPE and GTN 200 mg/kg +RIPE-treated rats at p<0.05 and p<0.01, respectively when compared to RIPE. Serum and kidney oxidative stress markers were restored in GTN 50 mg/kg +RIPE, GTN 100 mg/kg +RIPE and GTN 200 mg/kg +RIPE-treated rats at p<0.05, p<0.01 and p<0.001 respectively, when compared to RIPE. GTN restored kidney histology. GTN protects against RIPE-induced nephrotoxicity in a dose-related fashion.

The Role of Ketone Bodies in Various Animal Models of Kidney Disease

The kidney is a vital organ that carries out significant metabolic functions in our body. Due to the complexity of its role, the kidney is also susceptible to many disease conditions, such as acute kidney injury (AKI) and chronic kidney disease (CKD). Despite the prevalence and our increased understanding of the pathophysiology of both AKI and CKD as well as the transition of AKI to CKD, no well-established therapeutics have been applied clinically to these conditions, rendering an urgent need for a novel potential therapeutic target to be developed. In this article, we reviewed the function of ketone bodies in some common kidney conditions, such as drug-induced nephrotoxicity, ischemia and reperfusion injury, fibrosis development, diabetic kidney disease, kidney aging, hypertension, and CKD progression. All the selected studies reviewed were performed in animal models by primarily utilizing rodents, which also provide invaluable sources for future clinical applications. Ketone bodies have shown significant renal protective properties via attenuation of oxidative stress, increased expression of anti-inflammatory proteins, gene regulation, and a reduction of apoptosis of renal cells. A physiological level of ketone bodies could be achieved by fasting, a ketogenic diet, and an exogenous ketone supplement. Finally, the limitations of the long-term ketogenic diet were also discussed.

Targeted Desorption Electrospray Ionization Mass Spectrometry Imaging for Drug Distribution, Toxicity, and Tissue Classification Studies.

With increased use of mass spectrometry imaging (MSI) in support of pharmaceutical research and development, there are opportunities to develop analytical pipelines that incorporate exploratory high-performance analysis with higher capacity and faster targeted MSI. Therefore, to enable faster MSI data acquisition we present analyte-targeted desorption electrospray ionization-mass spectrometry imaging (DESI-MSI) utilizing a triple-quadrupole (TQ) mass analyzer. The evaluated platform configuration provided superior sensitivity compared to a conventional time-of-flight (TOF) mass analyzer and thus holds the potential to generate data applicable to pharmaceutical research and development. The platform was successfully operated with sampling rates up to 10 scans/s, comparing positively to the 1 scan/s commonly used on comparable DESI-TOF setups. The higher scan rate enabled investigation of the desorption/ionization processes of endogenous lipid species such as phosphatidylcholines and a co-administered cassette of four orally dosed drugs-erlotininb, moxifloxacin, olanzapine, and terfenadine. This was used to enable understanding of the impact of the desorption/ionization processes in order to optimize the operational parameters, resulting in improved compound coverage for olanzapine and the main olanzapine metabolite, hydroxy-olanzapine, in brain tissue sections compared to DESI-TOF analysis or matrix-assisted laser desorption/ionization (MALDI) platforms. The approach allowed reducing the amount of recorded information, thus reducing the size of datasets from up to 150 GB per experiment down to several hundred MB. The improved performance was demonstrated in case studies investigating the suitability of this approach for mapping drug distribution, spatially resolved profiling of drug-induced nephrotoxicity, and molecular-histological tissue classification of ovarian tumors specimens.

Digital Health Transformers and Opportunities for Artificial Intelligence-Enabled Nephrology.

Digital Health Transformers and Opportunities for Artificial Intelligence-Enabled Nephrology.

Nephrotoxicity assessment of Esculentoside A using human-induced pluripotent stem cell-derived organoids.

Drug-induced nephrotoxicity is a leading cause of acute kidney injury (AKI). A major obstacle in predicting AKI is the lack of a comprehensive experimental model that mimics stable and physiologically relevant kidney functions and accurately reflects the changes a drug induces. Organoids derived from human-induced pluripotent stem cells (iPSCs) are promising models because of their reproducibility and similarity to the in vivo conditions. In this study, Esculentoside A, the triterpene saponin with the highest concentration isolated from the root of Phytolacca acinose Roxb., was used to induce kidney injury models in vivo and kidney organoids. Esculentoside A induced AKI in mice, together with pathological changes and enhanced apoptosis. Moreover, Esculentoside A damaged podocytes and proximal tubular endothelial cells in kidney organoids in a similar way as in vivo. We also found that treatment with 60 μM Esculentoside A induced the known biomarkers of kidney damage and inflammatory cytokines (such as kidney injury molecule (KIM-1), β2-microglobulin (β2-M), and cystatin C (CysC)) in the organoids, in which activation of Cleaved Caspase-3 was involved, possibly due to lowered mitochondrial membrane potential. In summary, this study strongly suggests using kidney organoids as a reliable platform to assess Chinese medicine-induced nephrotoxicity.

Drug induced nephrotoxicity and associated factors a narrative review

Drugs are a common reason for kidney injury. Antibiotic like gentamicin which is clinically a highly effective drug, is not preferred by physicians primarily because of the renal damage caused by it. Medication-induced renal injury has an intricate mechanism that includes a multitude of elements together with the innate nature of medications, innate patient characteristics that increase the chances of renal damage, and the pharmacokinetics of the drug. A particular drug can produce varied amount of damage in different individuals, which implies that the risk is not same for all. The reason behind this is that, there are different factors which determine the amount of renal damage that occurs due to drugs. In this article, we have reviewed the various elements linked to drug-induced nephrotoxicity.

Bevacizumab-Induced Thrombotic Microangiopathy (TMA) in Metastatic Lung Adenocarcinoma Patients Receiving Nivolumab Combined with Bevacizumab, Carboplatin and Paclitaxel: Two Case Reports

Anti-programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint inhibitors (ICIs), combined with bevacizumab and platinum-based chemotherapy, have shown promising efficacy in treating metastatic non-squamous cell lung cancer in phase 3 clinical trials. However, drug-induced nephrotoxicity is an uncommon but threatening adverse effect when using this combination therapy, and should be evaluated and managed carefully. Here, we present two patients experiencing late-onset asymptomatic heavy proteinuria during the clinical trial. Kidney biopsies performed finally identified bevacizumab-induced thrombotic microangiopathy (TMA), and the proteinuria was decreased after discontinuing bevacizumab permanently. Our report suggests that a kidney biopsy is needed for those receiving ICIs in combination with bevacizumab and chemotherapy and experiencing nephrotoxicity such as heavy proteinuria.

A Synopsis of Current Theories on Drug-Induced Nephrotoxicity

The overriding goal of the treatment of patients is its effectiveness and safety. However, all medications currently being used also exert some adverse pharmaceutical reactions, which may be regarded as an unintended but inevitable cost of pharmacotherapy. The kidney, as the main organ that eliminates xenobiotics, is an organ especially predisposed and vulnerable to the toxic effects of drugs and their metabolites during their excretion from the body. Moreover, some drugs (e.g., aminoglycosides, cyclosporin A, cisplatin, amphotericin B, and others) have a "preferential" nephrotoxicity potential, and their use is associated with an increased risk of kidney damage. Drug nephrotoxicity is, therefore, both a significant problem and a complication of pharmacotherapy. It should be noted that, currently, there is no generally recognized definition of drug-induced nephrotoxicity and no clear criteria for its diagnosis. This review briefly describes the epidemiology and diagnosis of drug-induced nephrotoxicity and characterizes its pathomechanisms, including immunological and inflammatory disturbances, altered kidney blood flow, tubulointerstitial injury, increased lithogenesis-crystal nephropathy, rhabdomyolysis, and thrombotic microangiopathy. The study also lists the basic drugs with nephrotoxicity potential and provides a short overview of the preventive methods for reducing the risk of drug-related kidney damage developing.

Renoprotective Effect of Taxifolin in Paracetamol-Induced Nephrotoxicity: Emerging Evidence from an Animal Model.

Taxifolin (TXF) is a flavonoid found abundantly in citrus/onion. Encouraging results on its renoprotective effect have been reported in a limited number of drug-induced nephrotoxicity animal models. The present study aimed to evaluate for the first time the potential renoprotective effects of TXF in a paracetamol (PAR)-induced nephrotoxicity rat model. Rats were divided into three equal groups (n = 6 animals per group). Group 1 (PAR group, PARG) received PAR diluted in normal saline by gavage (1000 mg/kg). Group 2 (TXF group, TXFG) received TXF diluted in normal saline by gavage (50 mg/kg) one hour after PAR administration. Group 3 (control group, CG) received normal saline. Twenty-four hours after PAR administration, all animals were sacrificed using high-dose anesthesia. Blood samples were collected and kidneys were removed. The serum blood urea nitrogen, creatinine levels and serum malondialdehyde levels were significantly increased in the PARG. The serum glutathione peroxidase, glutathione reductase and total glutathione levels were significantly higher in the TXFG. At the same time, the kidneys of the PARG animals demonstrated tubular epithelium swelling, distension and severe vacuolar degeneration. The kidneys of the TXFG animals showed mildly dilated/congested blood vessels. The TXF renoprotective effects are promising in preventing PAR-induced nephrotoxicity, mainly through antioxidant activity, and warrant further testing in future studies.

Steady-state monitoring of oxygen in a high-throughput organ-on-chip platform enables rapid and non-invasive assessment of drug-induced nephrotoxicity.

High-throughput, rapid and non-invasive readouts of tissue health in microfluidic kidney co-culture models would expand their capabilities for pre-clinical assessment of drug-induced nephrotoxicity. Here, we demonstrate a technique for monitoring steady state oxygen levels in PREDICT96-O2, a high-throughput organ-on-chip platform with integrated optical-based oxygen sensors, for evaluation of drug-induced nephrotoxicity in a human microfluidic co-culture model of the kidney proximal tubule (PT). Oxygen consumption measurements in PREDICT96-O2 detected dose and time-dependent injury responses of human PT cells to cisplatin, a drug with known toxic effects in the PT. The injury concentration threshold of cisplatin decreased exponentially from 19.8 μM after 1 day to 2.3 μM following a clinically relevant exposure duration of 5 days. Additionally, oxygen consumption measurements resulted in a more robust and expected dose-dependent injury response over multiple days of cisplatin exposure compared to colorimetric-based cytotoxicity readouts. The results of this study demonstrate the utility of steady state oxygen measurements as a rapid, non-invasive, and kinetic readout of drug-induced injury in high-throughput microfluidic kidney co-culture models.

Adrenomedullin Mitigates Doxorubicin-Induced Nephrotoxicity in Rats: Role of Oxidative Stress, Inflammation, Apoptosis, and Pyroptosis.

Doxorubicin (DOX) is an anticancer antibiotic which has various effects in human cancers. It is one of the commonly known causes of drug-induced nephrotoxicity, which results in acute renal injury. Adrenomedullin (ADM), a vasodilator peptide, is widely distributed in many tissues and has potent protective effects. Therefore, the current study aimed to examine the protective potential mechanisms of ADM against DOX-induced nephrotoxicity. A total of 28 male Wistar rats were randomized into four groups: control group, doxorubicin group (15 mg/kg single intraperitoneal injection of DOX), adrenomedullin + doxorubicin group (12 μg/kg/day intraperitoneal injection of ADM) 3 days prior to DOX injection and continuing for 14 days after the model was established, and adrenomedullin group. Kidney function biomarkers, oxidative stress markers, and inflammatory mediators (TNF-α, NLRP3, IL-1β, and IL-18) were assessed. The expressions of gasdermin D and ASC were assessed by real-time PCR. Furthermore, the abundances of caspase-1 (p20), Bcl-2, and Bax immunoreactivity were evaluated. ADM administration improved the biochemical parameters of DOX-induced nephrotoxicity, significantly reduced oxidative damage markers and inflammatory mediators, and suppressed both apoptosis and pyroptosis. These results were confirmed by the histopathological findings and revealed that ADM's antioxidant, anti-inflammatory, anti-apoptotic, and anti-pyroptotic properties may have prospective applications in the amelioration of DOX-induced nephrotoxicity.

Inhibition of the NF-κB pathway and ERK-mediated mitochondrial apoptotic pathway takes part in the mitigative effect of betulinic acid on inflammation and oxidative stress in cyclophosphamide-triggered renal damage of mice

Betulinic acid (BA), an occurring pentacyclic triterpenoid, has various biological activities, such as anti-inflammation and antioxidation. Previous studies found that BA attenuated cyclophosphamide (CYP)-induced intestinal mucosal damage by inhibiting intestinal mucosal barrier dysfunctions and cell apoptosis. However, the effects and regulation mechanisms of BA on CYP-induced renal damage has not been reported in literature. Here, we found that BA pretreatment alleviated the elevation of serum urea level and inhibited the increase in serum neutrophil gelatinase-associated lipocalin level induced by CYP. Meanwhile, BA ameliorated renal tubular epithelial cell edema, and vacuolization of renal cortical tubular and renal glomerulus. Moreover, pretreatment with BA inhibited the mRNA expressions of pro-inflammatory cytokines interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α, and increased mRNA expressions of anti-inflammatory cytokines such as IL-10 and transforming growth factor-β by inactivation nuclear factor kappa-B. Simultaneously, BA decreased the accumulation of reactive oxygen species and malondialdehyde, and lowered the levels of superoxide dismutase and glutathione, while increased the activity of glutathione peroxidase in CYP-induced kidney damage mice. Besides, BA reduced the phosphorylation of extracellular signal-regulated kinases (ERK), inhibited the ratio of Bcl-2/Bax and cell apoptosis in CYP-triggered kidney damage. Furthermore, BA and/or PD98059 (an inhibitor of ERK) regulated mitigation of CYP-elicited renal injury and deactivation of the ERK pathway and mitochondrial apoptotic pathway, indicating that the protective effect of BA on CYP-induced renal damage may be associated with the down-regulation of ERK-mediated mitochondrial apoptotic pathway. Thus, BA could be a candidate agent against chemotherapy drug-induced nephrotoxicity by reducing inflammation and oxidative stress through suppression of ERK-mediated mitochondrial apoptotic pathway.

Exploring the Molecular and Structural Mechanism for Drug Induced Nephrotoxicity: A Virtual Based Approach

Main Article Content Yunusa Abdulmajeed Department of Pharmacology & Therapeutics, Usmanu Danfodiyo University, Sokoto, Nigeria Salihu Lawan Department of Pharmacology & Therapeutics, Usmanu Danfodiyo University, Sokoto, Nigeria Abstract Drug-induced nephrotoxicity is increasingly recognized as a significant contributor to acute kidney injury and chronic kidney disease. Acute kidney injury is a very common diagnosis, present in up to 60% of critical patients, and its third main cause is drug toxicity. Systematic and quantitative studies of nephrotoxicity have become increasingly important due to rising concerns of drug induced nephrotoxicity. Drugs frequently interact with more than one target, with hundreds of these targets linked to the side effects of clinically used therapeutics. This is based on the hypothesize that drugs with same side effects are likely to have similar targets (Zhang et al., 2017). Developing a computational model to predict drug induced nephrotoxicity will provide a screening tool for nephrotoxicity thereby minimizing the number of nephrotoxic drugs released to the market. The study was aimed at exploring the various molecular and structural mechanisms for drug induced nephrotoxicity using computer simulation techniques; pharmacophore studies, PASSONLINE target identification and molecular docking simulation techniques. Hydrogen bond donor and hydrogen bond acceptor were the features common to nephrotoxic drugs, kidney injury molecule 1, neutrophil gelatinase associated lipocalin and type IV collagen were the common nephrotoxic targets. The nephrotoxic drugs demonstrated excellent binding affinities against the common targets and superimpose with each other and the co-crystalized ligand in the active pocket of each of the targets. These findings imply that nephrotoxic drugs potentiate the effects of these targets and might be molecular mechanism responsible for the nephrotoxicity associated with drugs.

Review On Nephroprotective Activity of Medicinal Plants On Drug-Induced Nephrotoxicity

Review On Nephroprotective Activity of Medicinal Plants On Drug-Induced Nephrotoxicity

Evaluation of rapid transepithelial electrical resistance (TEER) measurement as a metric of kidney toxicity in a high-throughput microfluidic culture system

Rapid non-invasive kidney-specific readouts are essential to maximizing the potential of microfluidic tissue culture platforms for drug-induced nephrotoxicity screening. Transepithelial electrical resistance (TEER) is a well-established technique, but it has yet to be evaluated as a metric of toxicity in a kidney proximal tubule (PT) model that recapitulates the high permeability of the native tissue and is also suitable for high-throughput screening. We utilized the PREDICT96 high-throughput microfluidic platform, which has rapid TEER measurement capability and multi-flow control, to evaluate the utility of TEER sensing for detecting cisplatin-induced toxicity in a human primary PT model under both mono- and co-culture conditions as well as two levels of fluid shear stress (FSS). Changes in TEER of PT-microvascular co-cultures followed a dose-dependent trend similar to that demonstrated by lactate dehydrogenase (LDH) cytotoxicity assays and were well-correlated with tight junction coverage after cisplatin exposure. Additionally, cisplatin-induced changes in TEER were detectable prior to increases in cell death in co-cultures. PT mono-cultures had a less differentiated phenotype and were not conducive to toxicity monitoring with TEER. The results of this study demonstrate that TEER has potential as a rapid, early, and label-free indicator of toxicity in microfluidic PT-microvascular co-culture models.

Drug-Induced Nephrotoxicity: A Review

Background: Nephrotoxicity is referred to as rapid degeneration in kidney functioning due to the toxic effects of medications. The glomerulus and proximal renal tubule are the fundamental portions of the nephron to be affected by drugs leading to nephrotoxicity. Prescribed medications like antibiotics (aminoglycoside, and vancomycin), amphotericin B, antidepressants (amitriptyline, fluoxetine), acyclovir, angiotensin-converting enzyme inhibitors, Angiotensin receptor blockers, non-steroidal anti-inflammatory drugs, cocaine, statins, antihistamines (Diphenhydramine), and sulfonamides can result in specific outcomes relative to nephrotoxicity, such as renal injury, inflammation, platelet aggregation, cell cytotoxicity, thrombosis, reduced renal blood flow, and crystal precipitation result in nephrotoxicity. Objective: we aimed to review the various pathogenic mechanisms responsible for drug-induced nephrotoxicity including, altered intra-glomerular hemodynamics, tubular cell toxicity, renal inflammation, crystal nephropathy, rhabdomyolysis, and thrombotic microangiopathy. The review also highlights risk factors related to the patient and the drugs being prescribed. The majority of the nephrotoxicity risk factors depend on the patients' age, gender, pre-existing renal insufficiency, drug dosage, and hypersensitivity to drug toxicity. Methods: We have searched the different databases to recruit published material mainly focusing on Pubmed, GoogleScholars, and Iraqi Virtual Science Library. Conclusion: To sum up, the review explains the necessity of evaluating nephrotoxicity, drug dosage, and risk factors as primary preventive measures to avoid drug-induced Nephrotoxicity.

Genome-wide gene expression analysis reveals molecular insights into the drug-induced toxicity of nephrotoxic agents

Drug-induced nephrotoxicity is frequently reported. However, the mechanisms underlying nephrotoxic medications and their overlapping molecular events, which might have therapeutic value, are unclear. We performed a genome-wide analysis of gene expression and a gene set enrichment analysis to identify common and unique pathways associated with the toxicity of colistin, ifosfamide, indomethacin, and puromycin. Rats were randomly allocated into the treatment or control group. The treatment group received a toxic dose once daily of each investigated drug for 1 week. Differentially expressed genes were found in the drug-treated kidney and liver compared to the control, except for colistin in the liver. Upregulated pathways were mainly related to cell death, cell cycle, protein synthesis, and immune response modulation in the kidney. Cell cycle was upregulated by all drugs. Downregulated pathways were associated with carbon metabolism, amino acid metabolism, and fatty acid metabolism. Indomethacin, colistin, and puromycin shared the most altered pathways in the kidney. Ifosfamide and indomethacin affected molecular processes greatly in the liver. Our findings provide insight into the mechanisms underlying the renal and hepatic adverse effects of the four drugs. Further investigation should explore the combinatory drug therapies that attenuate the toxic effects and maximize the effectiveness of nephrotoxic drugs.