Assessing and Predicting Drug-Induced Kidney Injury, Functional Change, and Safety in Preclinical Studies in Rats

2016 ◽  
pp. 429-442
Author(s):  
Yafei Chen
Keyword(s):  
Kidney Injury ◽  
Functional Change ◽  
Preclinical Studies ◽  
Drug Induced

scholarly journals Traditional Renal Biomarkers and New Approaches to Diagnostics

2018 ◽  
Vol 46 (8) ◽  
pp. 999-1001 ◽  
Author(s):  
Mary B. Nabity
Keyword(s):  
Kidney Injury ◽  
Small Rna Sequencing ◽  
Successful Implementation ◽  
Preclinical Studies ◽  
Glomerular Injury ◽  
Drug Induced ◽  
Irreversible Damage ◽  
Urine Biomarkers ◽  
Renal Biomarkers ◽  
Highly Sensitive

Traditional biomarkers of renal disease have a number of limitations, whether evaluating veterinary patients or performing preclinical toxicity studies. Serum creatinine and urea nitrogen are affected by nonrenal influences that limit their usefulness for detecting small but significant decreases in glomerular filtration rate (GFR) in veterinary patients. These nonrenal influences can be more controlled in preclinical studies than in clinical patients; however, because of its high functional reserve, these estimates of GFR are insensitive for detecting kidney injury prior to loss of a substantial proportion of functioning nephrons. Urine biomarkers can be highly sensitive for tubular or glomerular injury that might lead to irreversible damage to the nephron. Several proteins are qualified by the Food and Drug Administration for nonclinical application as urinary biomarkers of drug-induced nephrotoxicity, and many of these also have preliminary data supporting their usefulness for kidney injury in dogs and cats. In addition to these relatively recently identified biomarkers, efforts are underway to discover new renal biomarkers using a variety of techniques including liquid chromatography–mass spectrometry and small RNA sequencing. Ultimately, the interplay between preclinical studies and clinical patients in discovery and validation of renal biomarkers is critical to their successful implementation.

Serial Quantification of Urinary Protein Biomarkers to Predict Drug-induced Acute Kidney Injury

2019 ◽  
Vol 20 (8) ◽  
pp. 656-664 ◽  
Author(s):  
Yi Da ◽  
K. Akalya ◽  
Tanusya Murali ◽  
Anantharaman Vathsala ◽  
Chuen-Seng Tan ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Cystatin C ◽  
Calcineurin Inhibitors ◽  
Kidney Injury ◽  
Tubular Dysfunction ◽  
Renal Tubular Dysfunction ◽  
Protein Biomarkers ◽  
Drug Induced ◽  
Beta 2 ◽  
Beta 2 Microglobulin

Background: : Drug-induced Acute Kidney Injury (AKI) develops in 10-15% of patients who receive nephrotoxic medications. Urinary biomarkers of renal tubular dysfunction may detect nephrotoxicity early and predict AKI. Methods:: We prospectively studied patients who received aminoglycosides, vancomycin, amphotericin, or calcineurin inhibitors, and collected their serial urine while on therapy. Patients who developed drug-induced AKI (fulfilling KDIGO criteria) were matched with non-AKI controls in a 1:2 ratio. Their urine samples were batch-analyzed at time-intervals leading up to AKI onset; the latter benchmarked against the final day of nephrotoxic therapy in non- AKI controls. Biomarkers examined include clusterin, beta-2-microglobulin, KIM1, MCP1, cystatin-C, trefoil-factor- 3, NGAL, interleukin-18, GST-Pi, calbindin, and osteopontin; biomarkers were normalized with corresponding urine creatinine. Results:: Nine of 84 (11%) patients developed drug-induced AKI. Biomarkers from 7 AKI cases with pre-AKI samples were compared with those from 14 non-AKI controls. Corresponding mean ages were 55(±17) and 52(±16) years; baseline eGFR were 99(±21) and 101(±24) mL/min/1.73m2 (all p=NS). Most biomarker levels peaked before the onset of AKI. Median levels of 5 biomarkers were significantly higher in AKI cases than controls at 1-3 days before AKI onset (all µg/mmol): clusterin [58(8-411) versus 7(3-17)], beta-2-microglobulin [1632(913-3823) versus 253(61-791)], KIM1 [0.16(0.13-0.76) versus 0.07(0.05-0.15)], MCP1 [0.40(0.16-1.90) versus 0.07(0.04-0.17)], and cystatin-C [33(27-2990) versus 11(7-19)], all p<0.05; their AUROC for AKI prediction were >0.80 (confidence intervals >0.50), with average accuracy highest for clusterin (86%), followed by beta-2-microglobulin, cystatin-C, MCP1, and KIM1 (57%) after cross-validation. Conclusion: : Serial surveillance of these biomarkers could improve the lead time for nephrotoxicity detection by days.

scholarly journals Acute interstitial nephritis and drug-induced systemic lupus erythematosus due to chlorthalidone and amiodarone: A case report

2020 ◽  
Vol 8 ◽  
pp. 2050313X2091002 ◽  
Author(s):  
Umut Selamet ◽  
Ramy M Hanna ◽  
Anthony Sisk ◽  
Lama Abdelnour ◽  
Lena Ghobry ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
Interstitial Nephritis ◽  
Lupus Erythematosus ◽  
Kidney Biopsy ◽  
Kidney Injury ◽  
Acute Interstitial Nephritis ◽  
Systemic Lupus ◽  
Drug Induced ◽  
Systemic Manifestations

Drug-induced lupus erythematosus has features distinct from primary systemic lupus erythematosus. It can occur with a wide variety of agents that result in the generation of anti-histone or other types of antibodies. Systemic manifestations of drug-induced systemic lupus erythematosus may include renal dysfunction due to circulating immune complexes or due to other immune reactions to the culprit medication(s). Acute interstitial nephritis occurs due to DNA–drug or protein–drug complexes that trigger an allergic immune response. We report a patient who developed acute kidney injury, rash, and drug-induced systemic lupus diagnosed by serologies after starting chlorthalidone and amiodarone. A renal biopsy showed acute interstitial nephritis and not lupus-induced glomerulonephritis. It is important to note that systemic lupus erythematosus and acute interstitial nephritis can occur together, and this report highlights the role of the kidney biopsy in ascertaining the pathological diagnosis and outlining therapy in drug-induced lupus erythematosus.

scholarly journals Drug-Induced Acute Kidney Injury: A Study from the French Medical Administrative and the French National Pharmacovigilance Databases Using Capture-Recapture Method

2021 ◽  
Vol 10 (2) ◽  
pp. 168
Author(s):  
Anne-Lise Rolland ◽  
Anne-Sophie Garnier ◽  
Katy Meunier ◽  
Guillaume Drablier ◽  
Marie Briet
Keyword(s):  
Acute Kidney Injury ◽  
Medical Information ◽  
Significant Proportion ◽  
Kidney Injury ◽  
International Classification Of Diseases ◽  
Administrative Databases ◽  
Health Concern ◽  
Medical Information System ◽  
Drug Induced ◽  
Capture Recapture

Background: Acute kidney injury (AKI) is a public health concern. Among the pathological situations leading to AKI, drugs are preventable factors but are still under-notified. We aimed to provide an overview of drug-induced AKI (DIAKI) using pharmacovigilance and medical administrative databases Methods: A query of the PMSI database (French Medical Information System Program) of adult inpatient hospital stays between 1 January 2017 and 31 December 2018 was performed using ICD-10 (International Classification of Diseases 10th revision) codes to identify AKI cases which were reviewed by a nephrologist and a pharmacovigilance expert to identify DIAKI cases. In parallel, DIAKIs notified in the French Pharmacovigilance Database (FPVDB) were collected. A capture-recapture method was performed to estimate the total number of DIAKIs. Results: The estimated total number of DIAKIs was 521 (95%CI 480; 563), representing 20.0% of all AKIs. The notification was at a rate of 12.9% (95%CI 10.0; 15.8). According to the KDIGO classification, 50.2% of the DIAKI cases were stage 1 and 49.8% stage 2 and 3. The mortality rate was 11.1% and 9.6% required hemodialysis. Conclusion: This study showed that drugs are involved in a significant proportion of patients developing AKI during a hospital stay and emphasizes the severity of DIAKI cases.

Biomarkers of drug-induced acute kidney injury in the adult

2015 ◽  
Vol 11 (11) ◽  
pp. 1683-1694 ◽  
Author(s):  
Glenda C Gobe ◽  
Jeff S Coombes ◽  
Robert G Fassett ◽  
Zoltan H Endre
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Drug Induced

scholarly journals Drug Induced Pneumonitis Secondary to Treatment with Paritaprevir/Ritonavir/Ombitasvir and Dasabuvir (VIEKIRA PAK®) for Chronic Hepatitis C: Case Report of an Unexpected Life-Threatening Adverse Reaction

2017 ◽  
Vol 2017 ◽  
pp. 1-5 ◽  
Author(s):  
Shih Yea Sylvia Wu ◽  
Bridget Faire ◽  
Edward Gane
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Chronic Hepatitis C ◽  
Kidney Injury ◽  
Complete Recovery ◽  
Final Diagnosis ◽  
Community Acquired Pneumonia ◽  
Drug Induced ◽  
First Case ◽  
Life Threatening

VIEKIRA PAK (ritonavir-boosted paritaprevir/ombitasvir and dasabuvir) is an approved treatment for compensated patients with genotype 1 (GT1) chronic hepatitis C virus (HCV) infection. This oral regimen has minimal adverse effects and is well tolerated. Cure rates are 97% in patients infected with HCV GT 1a and 99% in those with HCV GT 1b. We report the first case of life-threatening allergic pneumonitis associated with VIEKIRA PAK. This unexpected serious adverse event occurred in a 68-year-old Chinese female with genotype 1b chronic hepatitis C and Child-Pugh A cirrhosis. One week into treatment with VIEKIRA PAK without ribavirin, she was admitted to hospital with respiratory distress and acute kidney injury requiring intensive care input. She was initially diagnosed with community acquired pneumonia and improved promptly with intravenous antibiotics and supported care. No bacterial or viral pathogens were cultured. Following complete recovery, she recommenced VIEKIRA PAK but represented 5 days later with more rapidly progressive respiratory failure, requiring intubation and ventilation, inotropic support, and haemodialysis. The final diagnosis was drug induced pneumonitis.

Metabolomics for early detection of drug-induced kidney injury: review of the current status

Bioanalysis ◽  
2009 ◽  
Vol 1 (9) ◽  
pp. 1645-1663 ◽  
Author(s):  
Kurt J Boudonck ◽  
Donald J Rose ◽  
Edward D Karoly ◽  
Douglas P Lee ◽  
Kay A Lawton ◽  
...  
Keyword(s):  
Early Detection ◽  
Kidney Injury ◽  
Current Status ◽  
Drug Induced

scholarly journals A systematic review of in vitro models of drug induced kidney injury

2021 ◽  
Author(s):  
Alasdair R. Irvine ◽  
Damiën van Berlo ◽  
Rawan Shekani ◽  
Rosalinde Masereeuw
Keyword(s):  
Systematic Review ◽  
Kidney Injury ◽  
In Vitro Models ◽  
Drug Induced

Metabolomic profiling of urine-derived extracellular vesicles from rat model of drug-induced acute kidney injury

2021 ◽  
Vol 546 ◽  
pp. 103-110
Author(s):  
Masayoshi Saito ◽  
Satoshi Horie ◽  
Hidenori Yasuhara ◽  
Akane Kashimura ◽  
Eiji Sugiyama ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Extracellular Vesicles ◽  
Rat Model ◽  
Kidney Injury ◽  
Drug Induced ◽  
Metabolomic Profiling

scholarly journals Effects of Shiga Toxin Type 2 on a Bioengineered Three-Dimensional Model of Human Renal Tissue

2014 ◽  
Vol 83 (1) ◽  
pp. 28-38 ◽  
Author(s):  
Teresa M. DesRochers ◽  
Erica Palma Kimmerling ◽  
Dakshina M. Jandhyala ◽  
Wassim El-Jouni ◽  
Jing Zhou ◽  
...  
Keyword(s):  
Cell Culture ◽  
Renal Failure ◽  
Shiga Toxin ◽  
Three Dimensional ◽  
Kidney Injury ◽  
Renal Tissue ◽  
Three Dimensional Model ◽  
Drug Induced ◽  
Tissue Model

Shiga toxins (Stx) are a family of cytotoxic proteins that can cause hemolytic-uremic syndrome (HUS), a thrombotic microangiopathy, following infections by Shiga toxin-producingEscherichia coli(STEC). Renal failure is a key feature of HUS and a major cause of childhood renal failure worldwide. There are currently no specific therapies for STEC-associated HUS, and the mechanism of Stx-induced renal injury is not well understood primarily due to a lack of fully representative animal models and an inability to monitor disease progression on a molecular or cellular level in humans at early stages. Three-dimensional (3D) tissue models have been shown to be morein vivo-like in their phenotype and physiology than 2D cultures for numerous disease models, including cancer and polycystic kidney disease. It is unknown whether exposure of a 3D renal tissue model to Stx will yield a morein vivo-like response than 2D cell culture. In this study, we characterized Stx2-mediated cytotoxicity in a bioengineered 3D human renal tissue model previously shown to be a predictor of drug-induced nephrotoxicity and compared its response to Stx2 exposure in 2D cell culture. Our results demonstrate that although many mechanistic aspects of cytotoxicity were similar between 3D and 2D, treatment of the 3D tissues with Stx resulted in an elevated secretion of the kidney injury marker 1 (Kim-1) and the cytokine interleukin-8 compared to the 2D cell cultures. This study represents the first application of 3D tissues for the study of Stx-mediated kidney injury.

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