Traditional Renal Biomarkers and New Approaches to Diagnostics

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.

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Investigation of novel biomarkers of drug-induced kidney injury in renal transplant recipients undergoing graft biopsy

10.21203/rs.2.13591/v1 ◽

2019 ◽

Author(s):

Arthur Michon ◽

Antoine Durrbach ◽

Jean-Charles Gautier ◽

Xavier Benain ◽

Catherine Lunven ◽

...

Keyword(s):

Acute Rejection ◽

Serum Creatinine ◽

Diagnostic Performance ◽

Kidney Injury ◽

Renal Transplant Recipients ◽

Urinary Ngal ◽

Urinary Proteins ◽

Glomerular Injury ◽

Drug Induced ◽

Neutrophil Gelatinase Associated Lipocalin

Abstract Urinary and blood kidney biomarkers (BM) remain insufficient to detect early kidney injury. Our aim was to compare new kidney BM with histopathological data in kidney allograft recipients. Blood and urine samples of consecutive adult patients were collected just prior graft biopsy. All kidney samples were classified according to Banff 2007. The diagnostic performance (area under ROC curve, AUROC) of 16 new BM was compared to those of urinary proteins, blood urea nitrogen, eGFR and serum creatinine to identify histopathological groups. 223 patients were analyzed. Versus slightly modified renal parenchyma (SMRP), microalbuminuria and urinary proteins had the highest diagnostic performance toward glomerular injury. Urinary neutrophil gelatinase associated lipocalin (NGAL) had the best performance values for acute tubular necrosis (ATN) versus SMRP (AUROC 0.93). Others BM reached slightly lower AUROC reaching 0.89. When comparing ATN to acute rejection several new urinary BM (NGAL, cystatin C, and MCP1) and classical BM (eGFR, serum creatinine) reached similar AUROC values ranging from 0.80 to 0.85. Values of urinary NGAL were 10-fold higher in ATN compared to acute rejection (p = 0.0004). New BM did not outperform classical BM during renal transplantation. Urinary NGAL might be helpful to discriminate ATN and acute rejection.

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

Drug Discovery Toxicology ◽

10.1002/9781119053248.ch28 ◽

2016 ◽

pp. 429-442

Author(s):

Yafei Chen

Keyword(s):

Kidney Injury ◽

Functional Change ◽

Preclinical Studies ◽

Drug Induced

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Efficacy of Plasmapheresis in Nivolumab-Associated ANCA Glomerulonephritis: A Case Report and Pathophysiology Discussion

Case Reports in Nephrology and Dialysis ◽

10.1159/000518304 ◽

2021 ◽

pp. 376-383

Author(s):

Reda Laamech ◽

Florian Terrec ◽

Camille Emprou ◽

Anne Claire Toffart ◽

Thomas Pierret ◽

...

Keyword(s):

Checkpoint Inhibitors ◽

Kidney Injury ◽

Acute Interstitial Nephritis ◽

Exceptional Case ◽

Solid Organ ◽

Glomerular Injury ◽

Cancer Treatments ◽

Drug Induced ◽

Hematologic Cancer ◽

Lung Hemorrhage

Immune checkpoint inhibitors (ICIs) have revolutionized solid organ and hematologic cancer treatments by improving overall prognoses. However, they can lead to overactivation of the immune system and several immune-related adverse events and sometimes affecting the renal system. Although acute interstitial nephritis is well described, we know little about ICI-associated glomerular injury. Herein, we report an exceptional case of renal ANCA positive-associated vasculitis (AAV) after nivolumab therapy. Three weeks after the last nivolumab injection, the patient presented with proteinuria at 1.73 g/g of creatininuria, hematuria, and acute kidney injury needing dialysis associated with lung hemorrhage; anti-neutrophil cytoplasmic antibody (ANCA titer ≥1,280 with myeloperoxidase specificity of 780 U/mL) was positive, and kidney biopsy confirmed glomerular injury with crescents. The patient underwent treatment with steroid pulses, rituximab, and plasmapheresis, resulting in an improvement of the renal function and lung hemorrhage and produced a negative ANCA titer. Despite the results of the PEXIVAS study and the absence of clear benefit of plasmapheresis demonstrated in idiopathic AAV, we suggest that drug-induced AAV may be effectively treated by plasmapheresis, steroids, and rituximab.

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The Clinical Utility and Assessment of Renal Biomarkers in Acute Kidney Injury After Abdominal Endovascular Aneurysm Repair. A Systematic Review

Current Pharmaceutical Design ◽

10.2174/1381612825666191209122804 ◽

2020 ◽

Vol 25 (44) ◽

pp. 4695-4701 ◽

Cited By ~ 1

Author(s):

Georgios Karaolanis ◽

Zachary F. Williams ◽

Chris Bakoyiannis ◽

Dimitrios Hadjis ◽

Mitchell W. Cox ◽

...

Keyword(s):

Systematic Review ◽

Acute Kidney Injury ◽

Systematic Reviews ◽

Clinical Utility ◽

Binding Protein ◽

Endovascular Aneurysm Repair ◽

Kidney Injury ◽

Aortic Aneurysms ◽

Renal Biomarkers ◽

Aneurysm Repair

: The widespread adoption of endovascular aneurysm repair (EVAR) for abdominal aortic aneurysms (AAA) is due to the obvious advantages of the procedure compared to the traditional open repair. However, these advantages have to be weighed against the increased risk of renal dysfunction with EVAR. The evaluation of the perioperative renal function after EVAR has been hampered by the lack of sensitive and specific biochemical markers of acute kidney injury (AKI). The purpose of this study was to summarize all novel renal biomarkers and to evaluate their clinical utility for the assessment of the kidney function after EVAR. A systematic review of the current literature, as the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guidelines, was performed to identify relevant studies with novel renal biomarkers and EVAR. Pubmed and Scopus databases were systemically searched. Studies reporting on thoracic endovascular aortic repair (TEVAR), case reports, case series, letters to the editor, and systematic reviews were excluded. Neutrophil-Gelatinase-Associated Lipocalin, Cystatin C, Liver-type fatty-acid-binding protein were the most common among the eligible studies while Interleukin-18, Retinol binding protein, N-acetyle-b-D-glucosaminidase and microalbumin have a sparse appearance in the literature. These biomarkers have been assessed in plasma as well as urine samples with each sample material having its own advantages and drawbacks. Which of these biomarkers has the most potential for assessing postoperative renal failure after EVAR, remains to be proved. The few studies presented in the literature show the potential clinical utility of these biomarkers, but larger studies with longer follow-up are required to determine the precise relationship between these biomarkers and postoperative acute kidney injury.

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

Current Drug Metabolism ◽

10.2174/1389200220666190711114504 ◽

2019 ◽

Vol 20 (8) ◽

pp. 656-664 ◽

Cited By ~ 4

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.

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

SAGE Open Medical Case Reports ◽

10.1177/2050313x20910029 ◽

2020 ◽

Vol 8 ◽

pp. 2050313X2091002 ◽

Cited By ~ 1

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.

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Small RNA Sequencing to Discover Circulating MicroRNA Biomarkers of Testicular Toxicity in Dogs

International Journal of Toxicology ◽

10.1177/1091581820961515 ◽

2020 ◽

pp. 109158182096151

Author(s):

Jennifer C. Shing ◽

Kai Schaefer ◽

Shaun E. Grosskurth ◽

Andy H. Vo ◽

Tatiana Sharapova ◽

...

Keyword(s):

Rna Sequencing ◽

Small Rna ◽

Exploratory Study ◽

Quantitative Polymerase Chain Reaction ◽

Small Rna Sequencing ◽

Circulating Microrna ◽

Testicular Toxicity ◽

Potential Candidate ◽

Drug Induced ◽

Organ Systems

Predictive indicators of testicular toxicity could improve drug development by allowing early in-life screening for this adverse effect before it becomes severe. We hypothesized that circulating microRNAs (miRNAs) could serve as testicular toxicity biomarkers in dogs. Herein, we describe the results of an exploratory study conducted to discover biomarkers of drug-induced testicular injury. Following a dose-selection study using the testicular toxicant ethylene glycol monomethyl ether (EGME), we chose a dose of 50 mg/kg/d EGME to avoid systemic toxicity and treated 2 groups of dogs (castrated, non-castrated) for 14 to 28 days. Castrated animals were used as negative controls to identify biomarkers specific for testicular toxicity because EGME can cause toxicity to organ systems in addition to the testis. Blood was collected daily during the dosing period, followed by recovery for 29 to 43 days with less frequent sampling. Dosing was well tolerated, resulting in mild-to-moderate degeneration in testes and epididymides. Global profiling of serum miRNAs at selected dosing and recovery time points was completed by small RNA sequencing. Bioinformatics data analysis using linear modeling demonstrated several circulating miRNAs that were differentially abundant during the dosing period compared with baseline and/or castrated control samples. Confirmatory reverse transcription quantitative polymerase chain reaction data in these animals was unable to detect sustained alterations of miRNAs in serum, except for 1 potential candidate cfa-miR-146b. Taken together, we report the results of a comprehensive exploratory study and suggest future directions for follow-up research to address the challenge of developing diagnostic biomarkers of testicular toxicity.

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

Journal of Clinical Medicine ◽

10.3390/jcm10020168 ◽

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.

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