scholarly journals A Review of Specific Biomarkers of Chronic Renal Injury and Their Potential Application in Nonclinical Safety Assessment Studies

2021 ◽  
pp. 019262332098504
Author(s):  
Leslie A. Obert ◽  
Susan A. Elmore ◽  
Daniela Ennulat ◽  
Kendall S. Frazier
Keyword(s):  
Renal Disease ◽  
Renal Injury ◽  
Chronic Renal Disease ◽  
Kidney Injury ◽  
Drug Induced ◽  
Clinical Biomarkers ◽  
Safety Studies ◽  
Novel Biomarkers ◽  
Underlying Mechanisms ◽  
Dimethyl Arginine

A host of novel renal biomarkers have been developed over the past few decades which have enhanced monitoring of renal disease and drug-induced kidney injury in both preclinical studies and in humans. Since chronic kidney disease (CKD) and acute kidney injury (AKI) share similar underlying mechanisms and the tubulointerstitial compartment has a functional role in the progression of CKD, urinary biomarkers of AKI may provide predictive information in chronic renal disease. Numerous studies have explored whether the recent AKI biomarkers could improve upon the standard clinical biomarkers, estimated glomerular filtration rate (eGFR), and urinary albumin to creatinine ratio, for predicting outcomes in CKD patients. This review is an introduction to alternative assays that can be utilized in chronic (>3 months duration) nonclinical safety studies to provide information on renal dysfunction and to demonstrate specific situations where these assays could be utilized in nonclinical drug development. Novel biomarkers such as symmetrical dimethyl arginine, dickkopf homolog 3, and cystatin C predict chronic renal injury in animals, act as surrogates for GFR, and may predict changes in GFR in patients over time, ultimately providing a bridge from preclinical to clinical renal monitoring.

scholarly journals Renalase and Biomarkers of Contrast-Induced Acute Kidney Injury

2015 ◽  
Vol 6 (1) ◽  
pp. 25-36 ◽  
Author(s):  
Maciej T. Wybraniec ◽  
Katarzyna Mizia-Stec
Keyword(s):  
Acute Kidney Injury ◽  
Renal Injury ◽  
Amine Oxidase ◽  
Kidney Injury ◽  
Cardiorenal Syndrome ◽  
Creatinine Concentration ◽  
Invasive Cardiology ◽  
Proximal Tubular ◽  
Novel Biomarkers

Background: Contrast-induced acute kidney injury (CI-AKI) remains one of the crucial issues related to the development of invasive cardiology. The massive use of contrast media exposes patients to a great risk of contrast-induced nephropathy and chronic kidney disease development, and increases morbidity and mortality rates. The serum creatinine concentration does not allow for a timely and accurate CI-AKI diagnosis; hence numerous other biomarkers of renal injury have been proposed. Renalase, a novel catecholamine-metabolizing amine oxidase, is synthesized mainly in proximal tubular cells and secreted into urine and blood. It is primarily engaged in the degradation of circulating catecholamines. Notwithstanding its key role in blood pressure regulation, renalase remains a potential CI-AKI biomarker, which was shown to be markedly downregulated in the aftermath of renal injury. In this sense, renalase appears to be the first CI-AKI marker revealing an actual loss of renal function and indicating disease severity. Summary: The purpose of this review is to summarize the contemporary knowledge about the application of novel biomarkers of CI-AKI and to highlight the potential role of renalase as a functional marker of contrast-induced renal injury. Key Messages: Renalase may constitute a missing biochemical link in the mutual interplay between kidney and cardiac pathology known as the cardiorenal syndrome.

Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs

2014 ◽  
Vol 280 (1) ◽  
pp. 30-35 ◽  
Author(s):  
Xiaobing Zhou ◽  
Ben Ma ◽  
Zhi Lin ◽  
Zhe Qu ◽  
Yan Huo ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Kidney Injury ◽  
Beagle Dogs ◽  
Drug Induced ◽  
Novel Biomarkers

scholarly journals Toxicologic Pathology Forum Opinion Paper*: Recommendations for a Tiered Approach to Nonclinical Mechanistic Nephrotoxicity Evaluation

2018 ◽  
Vol 46 (6) ◽  
pp. 636-646 ◽  
Author(s):  
Daniela Ennulat ◽  
Michael Ringenberg ◽  
Kendall S. Frazier
Keyword(s):  
Renal Injury ◽  
Kidney Injury ◽  
Mechanistic Study ◽  
Potential Mechanism ◽  
Drug Induced ◽  
Additional Hypothesis ◽  
Tiered Approach ◽  
Road Map ◽  
New Information ◽  
Microscopic Evaluation

Nephrotoxicity is one of the more common causes of attrition in nonclinical drug development. Like most tissues, the kidney has a limited number of ways of responding to toxicological insults from diverse mechanistic pathways, which can limit the ability to determine mechanisms of renal injury using the assays routinely performed in preclinical toxicologic studies. In situations where the renal injury is unusual in morphology or if a therapeutic margin is low, additional investigative techniques may be needed to identify a potential mechanism of toxicity in order to inform clinical risk assessment or establish human relevance and translatability of the toxicity. While routine microscopic evaluation can suggest a specific pathogenesis, understanding the mechanism of renal injury often requires additional hypothesis-driven investigations and specialized techniques to obtain the data necessary to identify a nephrotoxic mechanism. Nonclinical mechanistic investigations can be resource-intensive and often yield limited new information. Although there are multiple avenues to investigate renal toxicity, no single mechanistic study or prescriptive battery of tests will identify the pathophysiologic basis for every potential mechanism of renal injury. To aid the nonclinical investigator, we outline a tiered approach for prioritizing investigations to provide a rational and linear road map for the exploration of mechanisms of drug-induced kidney injury. [Box: see text]

scholarly journals New Frontiers: Approaches to Understand the Mechanistic Basis of Renal Toxicity

2018 ◽  
Vol 46 (8) ◽  
pp. 1002-1005
Author(s):  
Mary B. Nabity ◽  
Joseph W. Polli ◽  
Vishal Vaidya ◽  
Andrzej Krolewski ◽  
Warren E. Glaab
Keyword(s):  
Renal Toxicity ◽  
Kidney Injury ◽  
Scientific Session ◽  
Diabetic Patients ◽  
Drug Induced ◽  
Research Areas ◽  
Novel Biomarkers ◽  
Mechanistic Basis ◽  
New Research

A scientific session entitled “New Frontiers: Approaches to Understand the Mechanistic Basis of Renal Toxicity” focused on novel biomarkers to monitor kidney injury both preclinically and clinically, as well as providing mechanistic insight of the induced injury. Further, the role and impact of kidney membrane transporters in drug-induced kidney toxicity provided additional considerations when understanding kidney injury and the complex role of drug transporters in either sensitivity or resistance to drug-induced injury. The onset of nephropathy in diabetic patients was also presented, focusing on the quest to discover novel biomarkers that would differentiate diabetic populations more susceptible to nephropathy and renal failure. The session highlighted exciting new research areas and novel biomarkers that will enhance our understanding of kidney injury and provide tools for ensuring patient safety clinically.

A CLINICAL STUDY OF ETIOLOGY, OUTCOME AND PROGNOSTIC FACTORS OF ACUTE KIDNEY INJURY AMONG ICU ADMISSIONS IN RURAL TERTIARY CARE HOSPITAL

2021 ◽  
pp. 201-204
Author(s):  
Shashikantha Shashikantha ◽  
Sohil Sharda. ◽  
Bernice Robert ◽  
Gangurde Bhushan Daulatrao
Keyword(s):  
Acute Kidney Injury ◽  
Prognostic Factors ◽  
Renal Disease ◽  
Tertiary Care Hospital ◽  
Chronic Renal Disease ◽  
Tertiary Care ◽  
Ventilatory Support ◽  
Kidney Injury ◽  
Care Hospital ◽  
Study Results

INTRODUCTION: Acute kidney injury is a common occurrence in ICU admissions causing increased morbidity and mortality. Present study aimed to determine the causes and prognostic factors of acute kidney injury in intensive care unit. MATERIAL AND METHODS: This Hospital based Cross sectional Study was conducted at a tertiary care Hospital and Research Center, including 100 patients aged >18 years with Acute Kidney Injury admitted in ICU from the period of October 2018 to June 2020. Patients with chronic renal disease, previous renal transplantation, congenital renal disease were excluded from the study. RESULTS: Most of the patients (63%) were aged above 50 years. Diabetes was found in 55% and hypertension in 26% of AKI cases. Most common cause identied were sepsis, CLD, renal, CNS and CVD. Hypotension occurred in 48% patients, while oliguria occurred in 45% patients. Ventilatory support was required by 43% patients, while 31% patients required haemodialysis. Mortality rate in AKI was 51%. Mortality was signicantly associated with advanced age, presence of Diabetes, and RIFLE criteria. Spot urine <40 meq/L, hyperkalemia, serum creatinine >4 mg/dl, blood urea >100 mg/dl and acidosis were associated with higher mortality. CONCLUSION: Continuous monitoring parameters like Spot Fe Na, Serum Potasium and pH especially in patients at risk, like elderly patients with diabetes, those with sepsis, can help in early identication and appropiate management, thus reduce the incidence or severity of AKI.

Chronic Kidney Failure and Dialysis

2018 ◽  
Author(s):  
Raghu V Durvasula ◽  
Jonathan Himmelfarb
Keyword(s):  
United States ◽  
Chronic Kidney Disease ◽  
Peritoneal Dialysis ◽  
Kidney Disease ◽  
Renal Disease ◽  
Chronic Renal Disease ◽  
Clinical Manifestations ◽  
Kidney Injury ◽  
The United States ◽  
Clinical Syndrome

Chronic kidney disease (CKD) is a clinical syndrome arising from progressive kidney injury, formerly known as chronic renal failure, chronic renal disease, and chronic renal insufficiency. It is classified into five stages based primarily on glomerular filtration rate (GFR). This article discusses the epidemiology of CKD and end-stage renal disease (ESRD), as well as etiology and genetics, pathophysiology, and pathogenesis. The section on diagnosis looks at clinical manifestations and physical findings, laboratory (and other) tests, imaging studies, and biopsy. A short section on differential diagnosis is followed by a discussion of treatment, including hemodialysis and peritoneal dialysis. Long-term complications of patients on dialysis include cardiovascular disease, renal osteodystrophy, dialysis-related amyloidosis, and acquired cystic disease (renal cell carcinoma). The final section addresses prognosis and socioeconomic burden. Figures include the classification system for CKD, prevalence of CKD in the United States, rising prevalence, risk of, and leading causes of ESRD in the United States, plus the changing prevalence of ESRD over time, clinical manifestations of uremia, and an overview of hemodialysis circuit. Tables look at the burden of CKD relative to other chronic disorders, the specific hereditary causes of kidney disease, and situations when serum creatinine does not accurately predict GFR. Other tables list equations for estimating GFR, the causes of CKD without shrunken kidneys, and clinical features distinguishing chronic kidney disease from acute kidney injury. ESRD and indications for initiation of dialysis are presented, as well as typical composition of dialysate and reasons for failure of peritoneal dialysis. This chapter contains 71 references.

Chronic Kidney Failure and Dialysis

2017 ◽  
Author(s):  
Raghu V Durvasula ◽  
Jonathan Himmelfarb
Keyword(s):  
United States ◽  
Chronic Kidney Disease ◽  
Peritoneal Dialysis ◽  
Kidney Disease ◽  
Renal Disease ◽  
Chronic Renal Disease ◽  
Clinical Manifestations ◽  
Kidney Injury ◽  
The United States ◽  
Clinical Syndrome

Chronic kidney disease (CKD) is a clinical syndrome arising from progressive kidney injury, formerly known as chronic renal failure, chronic renal disease, and chronic renal insufficiency. It is classified into five stages based primarily on glomerular filtration rate (GFR). This article discusses the epidemiology of CKD and end-stage renal disease (ESRD), as well as etiology and genetics, pathophysiology, and pathogenesis. The section on diagnosis looks at clinical manifestations and physical findings, laboratory (and other) tests, imaging studies, and biopsy. A short section on differential diagnosis is followed by a discussion of treatment, including hemodialysis and peritoneal dialysis. Long-term complications of patients on dialysis include cardiovascular disease, renal osteodystrophy, dialysis-related amyloidosis, and acquired cystic disease (renal cell carcinoma). The final section addresses prognosis and socioeconomic burden. Figures include the classification system for CKD, prevalence of CKD in the United States, rising prevalence, risk of, and leading causes of ESRD in the United States, plus the changing prevalence of ESRD over time, clinical manifestations of uremia, and an overview of hemodialysis circuit. Tables look at the burden of CKD relative to other chronic disorders, the specific hereditary causes of kidney disease, and situations when serum creatinine does not accurately predict GFR. Other tables list equations for estimating GFR, the causes of CKD without shrunken kidneys, and clinical features distinguishing chronic kidney disease from acute kidney injury. ESRD and indications for initiation of dialysis are presented, as well as typical composition of dialysate and reasons for failure of peritoneal dialysis. This chapter contains 71 references.

P6358Novel biomarkers for prediction of acute cardiorenal syndrome

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Dankova ◽  
Z Minarikova ◽  
J Danko ◽  
J Gergel ◽  
P Pontuch ◽  
...  
Keyword(s):  
Renal Injury ◽  
Diagnostic Yield ◽  
Kidney Injury ◽  
Cardiorenal Syndrome ◽  
Urine Concentration ◽  
Reduced Ejection Fraction ◽  
Frequent Event ◽  
Novel Biomarkers ◽  
New Biomarkers ◽  
Time Of Admission

Abstract Objectives Acute kidney injury (AKI) is frequent event in patients with acute heart failure (AHF) and is associated with poor short and longterm outcome. Aim of the study was to decribe diagnostic yield of selected novel biomarkers in prediction of AKI in patients addmitted for AHF. Methods We performed a prospective cohort study of 72 consecutive patients (46/26 M/F) aged 69±10,3 years admitted for AHF. Renal damage was defined according to KDIGO guidelines. Patients were divided into two groups: AKI- (without renal injury, n=52) and AKI+ (with renal injury, n=20). Urine samples for AKI biomarkers measurements (NGAL, TIMP2, IGFBP7) were collected at admission. The ROC and linear logistic regression of new biomarkers and selected clinical variables was performed for evaluation of the AKI prediction. Results Patients with AKI + were older (median age: 75 vs. 64 years, p=0,01), had lower BMI (median: 28 vs. 29,5 kg/m2, p=0,04), were with higher proportion of patients with HF with reduced ejection fraction (55% vs 23,1%, p=0,01) and higher level of serum NTproBNP. Urinary NGAL at admission was significantly higher in the AKI+ compared to AKI – group (152 vs. 19,5 ng/ml, p <.0001); also median of u-TIMP-2 and u-IGFBP-7 in the AKI+ patients were significantly higher: 194,1 versus 42,5 ng/ml (p<0.0001) and 379 versus 92,4 pg/ml (p<0.0001) resp. Age, u-NGAL, u-TIMP2, u-IGFBP7, s-hemoglobin, NTproBNP and LVEF were associated with the development of AKI. Urine concentration IGFBP-7 performs the best for the prediction AKI (AUC 0,94). Conclusion Urine concentrations of NGAL, TIMP2, IGFBP7 at the time of admission for AHF predict developement of AKI. Age, NTproBNP, LVEF and s-hemoglobin are also associated with AKI in AHF patients. Acknowledgement/Funding Project was supported by Slovak Society of Cardiology research grant 2015-2018.

scholarly journals Microvascular rarefaction and hypertension in the impaired recovery and progression of kidney disease following AKI in preexisting CKD states

2018 ◽  
Vol 315 (6) ◽  
pp. F1513-F1518 ◽  
Author(s):  
Aaron J. Polichnowski
Keyword(s):  
Kidney Disease ◽  
Renal Disease ◽  
Kidney Injury ◽  
Major Complication ◽  
Progression Of Kidney Disease ◽  
Underlying Mechanisms ◽  
Stage Renal Disease ◽  
End Stage ◽  
Progression Of Renal Disease ◽  
Microvascular Rarefaction

Acute kidney injury (AKI) is a major complication in hospitalized patients and is associated with elevated mortality rates. Numerous recent studies indicate that AKI also significantly increases the risk of chronic kidney disease (CKD), end-stage renal disease (ESRD), hypertension, cardiovascular disease, and mortality in those patients who survive AKI. Moreover, the risk of ESRD and mortality after AKI is substantially higher in patients with preexisting CKD. However, the underlying mechanisms by which AKI and CKD interact to promote ESRD remain poorly understood. The recently developed models that superimpose AKI on rodents with preexisting CKD have provided new insights into the pathogenic mechanisms mediating the deleterious interactions between AKI and CKD. These studies show that preexisting CKD impairs recovery from AKI and promotes the development of mechanisms of CKD progression. Specifically, preexisting CKD exacerbates microvascular rarefaction, failed tubular redifferentiation, disruption of cell cycle regulation, hypertension, and proteinuria after AKI. The purpose of this review is to discuss the potential mechanisms by which microvascular rarefaction and hypertension contribute to impaired recovery from AKI and the subsequent progression of renal disease in preexisting CKD states.

scholarly journals Endothelial injury due to eNOS deficiency accelerates the progression of chronic renal disease in the mouse

2009 ◽  
Vol 296 (2) ◽  
pp. F317-F327 ◽  
Author(s):  
Takahiro Nakayama ◽  
Waichi Sato ◽  
Tomoki Kosugi ◽  
Li Zhang ◽  
Martha Campbell-Thompson ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cell ◽  
Renal Disease ◽  
Renal Injury ◽  
Chronic Renal Disease ◽  
Endothelial Cell Proliferation ◽  
Capillary Endothelium ◽  
Tubular Damage ◽  
No Production ◽  
Peritubular Capillaries

The vascular endothelium expresses endothelial nitric oxide synthase (eNOS) that generates nitric oxide (NO) to help maintain vascular integrity due to its anti-inflammatory, antiproliferative, and antithrombogenic effects. Pharmacological blockade of NO production has been shown to exacerbate renal injury in chronic renal disease and induces endothelial cell loss. However, pharmacological inhibition of NO nonspecifically blocks other types of NOS and therefore does not define the specific role of eNOS in kidney disease. We hypothesized that a lack of endothelial eNOS can induce a loss of glomerular and peritubular capillary endothelium and exacerbate renal injury in progressive renal disease. We tested out this hypothesis using remnant kidney (RK) in eNOS knockout (eNOS KO) mice. Systolic blood pressure was significantly higher, and renal function was worse in RK-eNOS KO mice compared with those in RK-C57BL6 mice. eNOS deficiency resulted in more severe glomerulosclerosis, mesangiolysis, and tubular damage. Glomerular and tubular macrophage infiltration and collagen deposition were also greater in RK-eNOS KO mice. Renal injuries in the RK-eNOS KO mice were accompanied by a greater loss of endothelial cells that was shown to be due to both a decrease in endothelial cell proliferation and an increase in apoptosis. A lack of eNOS accelerates both glomerular and tubulointerstitial injury with a loss of glomerular capillaries and peritubular capillaries. Impaired endothelial function is likely a direct risk factor for renal disease.

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