Detection Of Drug-induced Kidney Injury Research Articles

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.

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.

The Utility of Novel Urinary Biomarkers in Mice for Drug Development Studies.

Novel urinary protein biomarkers have recently been identified and qualified in rats for the early detection of renal injury in drug development studies. However, there are few reports on the utility of these renal biomarkers in mice, another important and widely used preclinical animal species for drug development studies. The purpose of this study was to assess the value of these recently qualified biomarkers for the early detection of drug-induced kidney injury (DIKI) in different strains of mice using multiple assay panels. To this end, we evaluated biomarker response to kidney injury induced by several nephrotoxic agents including amphotericin B, compound X, and compound Y. Several of the biomarkers were shown to be sensitive to DIKI in mice. When measured, urinary albumin and neutrophil gelatinase-associated lipocalin were highly sensitive to renal tubular injury, regardless of the assay platforms, mouse strain, and nephrotoxic agents. Depending on the type of renal tubular injury, kidney injury molecule-1 was also highly sensitive, regardless of the assay platforms and mouse strain. Osteopontin and cystatin C were modestly to highly sensitive to renal tubular injury, but the assay type and/or the mouse strain should be considered before using these biomarkers. Calbindin D28 was highly sensitive to injury to the distal nephron in mice. To our knowledge, this is the first report that demonstrates the utility of novel urinary biomarkers evaluated across multiple assay platforms and nephrotoxicants in different mice strains with DIKI. These results will help drug developers make informed decisions when selecting urinary biomarkers for monitoring DIKI in mice for toxicology studies.

Multiplex Optical Urinalysis for Early Detection of Drug-Induced Kidney Injury.

Drug-induced kidney injury (DIKI) is a significant contributor of both acute and chronic kidney injury and remains a major concern in drug development and clinical care. However, current clinical diagnostic methods often fail to accurately and timely detect nephrotoxicity. This study reports the development of activatable molecular urinary reporters (MURs) that are able to specifically detect urinary biomarkers including γ-glutamyl transferase (GGT), alanine aminopeptidase (AAP), and N-acetyl-β-d-glucosaminidase (NAG). By virtue of their discrete absorption and emission properties, the mixture of MURs can serve as a cocktail sensor for multiplex optical urinalysis in the mouse models of drug-induced acute kidney injury (AKI) and chronic kidney disease (CKD). The MURs cocktail not only detects nephrotoxicity earlier than the tested clinical diagnostic methods in drug-induced AKI and CKD mice models, but also possesses a higher diagnostic accuracy. Therefore, MURs hold great promise for detection of kidney function in both preclinical drug screening and clinical settings.

Managing chronic kidney disease in the older adults living with HIV.

HIV replication and immunodeficiency are important risk factors for chronic kidney disease (CKD). Widespread use of antiretrovirals that may affect kidney function underscores the need for monitoring kidney function, allowing early detection of drug-induced kidney injury and identification of patients who may benefit from antiretroviral therapy switches. Several cohorts have reported an increased incidence of CKD with tenofovir [tenofovir disoproxil fumarate (TDF)], atazanavir, and lopinavir, and CKD risk scores have been developed to identify those most at risk of kidney disease progression while receiving these agents. Recent data suggest that TDF discontinuation and substitution of atazanavir or lopinavir with darunavir may stabilize or improve renal function. Tenofovir alafenamide (TAF) is a new tenofovir formulation with minimal effect on renal tubular function. Patients with preserved or mild-moderately impaired renal function who switched from TDF to TAF-containing regimens experienced rapid and sustained improvement in proteinuria and stable renal function, suggesting that TAF will be the preferred tenofovir formulation for patients with CKD and those at increased risk of developing CKD. Suppression of HIV replication and antiretroviral switches away from TDF and atazanavir are important measures to maintain kidney function and reduce CKD risk in older adults living with HIV.

Recent successes in the identification, development, and qualification of translational biomarkers: the next generation of kidney injury biomarkers.

The development of novel safety or efficacy biomarkers has increasingly been used to improve safety monitoring and minimize attrition during drug development; however, for new biomarkers, the failure rate can equal or exceed that of new chemical entities. Drug-induced kidney injury is recognized to occur throughout the drug development process, with histopathology considered to be the gold standard for preclinical toxicologic screening. Renal biomarkers used clinically are primarily biomarkers of renal function and are considered insensitive for the detection of drug-induced kidney injury during first-in-man studies, particularly for compounds known to induce renal injury in preclinical species. Recent efforts by public-private partnerships have led to unprecedented success in the identification, development, and qualification of several new translatable biomarkers of kidney injury in the rat. To optimize the chance of success in current and future biomarker efforts in preclinical species and man, selection and development of biomarkers should emphasize biological considerations including marker variability and biology in both health and disease. The research to support the qualification of novel renal safety markers for routine use in the clinical setting is currently underway, and results from this work are greatly anticipated.

Urinary kidney biomarkers for early detection of nephrotoxicity in clinical drug development

Early detection of drug-induced kidney injury is vital in drug development. Generally accepted biomarkers such as creatinine and blood urea nitrogen (BUN) lack sensitivity and early injury responses are missed. Many new biomarkers to detect nephrotoxicity for pre-clinical utilization have been described and their use is adopted in regulatory guidelines. However, guidance on appropriate biomarkers for clinical trials is minimal. We provide an overview of potentially useful kidney biomarkers that can be used in clinical trials. This includes guidance to select biomarkers suitable to capture specific characteristics of the (expected) kidney injury. We conclude that measurement of urinary kidney injury marker-1 (KIM-1) serves many purposes and is often an appropriate choice. Cystatin C captures effects on glomerular filtration rate (GFR), but this marker should preferably be combined with more specific markers to localize the origin of the observed effect. Untoward effects on tubules can be captured relatively well with several markers. Direct detection of glomerular injury is currently impossible since specific biomarkers are lacking. Indirect assessment of toxic effects on glomeruli is possible by using carefully selected panels of other injury markers. We conclude that it is possible to obtain appropriate information on nephrotoxicity in clinical drug development by using carefully selected panels of injury markers and suggest that identification and validation of specific glomerular biomarkers could be of great value.

Deleterious effects of gentamicin and cisplatin on renal function in rats and early detection of drug-induced kidney injury using biomarkers

Deleterious effects of gentamicin and cisplatin on renal function in rats and early detection of drug-induced kidney injury using biomarkers

Cystatin C in HIV-infected patients: promising but not yet ready for prime time

With the development of highly active antiretroviral therapy, chronic kidney disease has become a prominent cause of morbidity in individuals infected by HIV. Because serum creatinine has significant limitations in this specific population, cystatin C is emerging as a promising biomarker for both the evaluation of glomerular filtration rate (GFR) and the detection of drug-induced kidney injury. Along with renal function, serum cystatin C concentration is associated with several biological parameters such as C-reactive protein, HIV viral load and CD4+ cells count. All these determinants of cystatin C are, however, more or less independent of GFR. Studies evaluating the accuracy of cystatin C for estimating GFR in the setting of HIV infection are scarce and methodology is often questionable (lack of reference method or inadequate statistical analyses). Thus far, data are insufficient to encourage the use of cystatin C or cystatin C-based equations to estimate GFR in the HIV-infected population. Further research is needed to explore the clinical utility of cystatin C in this setting. Beyond the use of cystatin C as a GFR marker, future studies will have to evaluate its role as a predictor of patient outcome, particularly in regard to cardiovascular morbi-mortality.

Urinary clusterin, cystatin C, β2-microglobulin and total protein as markers to detect drug-induced kidney injury

Earlier and more reliable detection of drug-induced kidney injury would improve clinical care and help to streamline drug-development. As the current standards to monitor renal function, such as blood urea nitrogen (BUN) or serum creatinine (SCr), are late indicators of kidney injury, we conducted ten nonclinical studies to rigorously assess the potential of four previously described nephrotoxicity markers to detect drug-induced kidney and liver injury. Whereas urinary clusterin outperformed BUN and SCr for detecting proximal tubular injury, urinary total protein, cystatin C and beta2-microglobulin showed a better diagnostic performance than BUN and SCr for detecting glomerular injury. Gene and protein expression analysis, in-situ hybridization and immunohistochemistry provide mechanistic evidence to support the use of these four markers for detecting kidney injury to guide regulatory decision making in drug development. The recognition of the qualification of these biomarkers by the EMEA and FDA will significantly enhance renal safety monitoring.

Metabolomics for Early Detection of Drug-Induced Kidney Injury: Review of The Current Status

The identification of biomarkers of drug-induced kidney injury is an area of intensive focus in drug development. Traditional markers of renal function, including blood urea nitrogen and serum creatinine, are not region-specific and only increase significantly after substantial kidney injury. Therefore, more sensitive markers of kidney injury are needed. The ideal biomarkers will identify nephrotoxicity early in the drug-discovery process, resulting in decreased development costs and safer drugs. Metabolomics, the study of the small biochemicals present in a biological sample, has become a promising player in the nephrotoxicity arena. In this review, we describe the current status of the identification of metabolic biomarkers for drug-induced kidney toxicity screening. Many of these markers have been confirmed across multiple studies and can detect nephrotoxicity earlier than the traditional clinical chemistry and histopathology methods. Upon further validation, such markers will offer clear benefits for the pharmaceutical industry and regulatory agencies.