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

Abstract

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.

Cell interactome in sarcopenia during aging

“…The global study of these markers can provide us with important information about the muscular state of the individual, even if each marker can separately be a classic marker of another pathology. Thus, albumin and creatinine are typical markers of kidney damage 18 . Furthermore, the albumin and sodium decreases observed in DP with clear downward trends in glucose and detected total proteins are also clear indicators of malnutrition and poor intestinal absorption, 19 which have a devastating effect on muscles and promotes protein catabolism that further accelerates muscle wasting, and recent articles support their role as a warning signal in elderly people 20 .…”

“…Furthermore, the albumin and sodium decreases observed in DP with clear downward trends in glucose and detected total proteins are also clear indicators of malnutrition and poor intestinal absorption, 19 which have a devastating effect on muscles and promotes protein catabolism that further accelerates muscle wasting, and recent articles support their role as a warning signal in elderly people 20 . Creatinine, in turn, is filtered out of the blood by the renal glomeruli, so increased blood levels of creatinine are often used as an indicator of renal dysfunction 18 . However, creatinine is also a breakdown product of creatine phosphate in muscle, and as a waste product of muscle metabolism, 21 it is released into the blood.…”

“… 20 Creatinine, in turn, is filtered out of the blood by the renal glomeruli, so increased blood levels of creatinine are often used as an indicator of renal dysfunction. 18 However, creatinine is also a breakdown product of creatine phosphate in muscle, and as a waste product of muscle metabolism, 21 it is released into the blood. Therefore, the increase in its presence at the systemic level could also be a marker of muscle degradation, and it not only reflects kidney function.…”

Evaluation of Renal Biomarkers, Including Symmetric Dimethylarginine, following Gentamicin-Induced Proximal Tubular Injury in the Rat

“…While in this study serum SDMA and creatinine were found to provide complimentary information on renal function, SDMA has been found to be a more sensitive renal function biomarker than serum creatinine when evaluated in the context of naturally occurring chronic kidney disease in humans and animals [8,[10][11][12]. A recent review of chronic renal injury biomarkers for nonclinical safety assessment highlighted SDMA as one of the most promising candidates for a chronic renal biomarker, and evaluation of SDMA in future nonclinical study designs is warranted to better define performance of this biomarker with regard to time-course, species, as well as type and extent of renal injury [37]. Interestingly serum SDMA and creatinine were both more responsive than the tubular injury markers KIM-1 and CLU for identification of gentamicin-induced renal toxicity in the 4-dose treatment groups.…”

Estimated Glomerular Filtration Rate in Chronic Kidney Disease: A Critical Review of Estimate-Based Predictions of Individual Outcomes in Kidney Disease

“…It is obvious that more research is needed to determine the accuracy of GFR estimations; these research efforts may include more precise assessments of novel filtration markers [20,21]. In the meantime, clinicians should keep in mind the limitations of using currently available equations.…”