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

Abstract

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.

Biomarkers for renal transplantation: where are we?

“…9 Apart from specimens from peripheral blood, urine was utilized to identify qualified biomarkers for early detection of glomerular injury. 6 Research findings exhibited that urinary cystatin C, clusterin, and beta-2 microglobulin could significantly monitor kidney injury better than serum creatinine or blood urea nitrogen, as supported by in situ hybridization, gene and protein expression analysis, and immunohistochemistry. 6 Other multiple platforms are also used in empirical studies, such as enzyme-linked immunosorbent assay, flow cytometry, and immune cell functional assays, although their efficiency is unsatisfactory (Table 1).…”

“…1,6 Indeed, the development of laboratory techniques has facilitated the production of novel biomarkers. Firstly, the real-time polymerase chain reaction (RT-PCR) is a sensitive and accurate technique, wellaccepted to identify and validate potential biomarkers at the gene level for decades.…”

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“…Only few authors studied the diagnostic value of changes in the enzyme activities [16,30], interleukin concentrations [1,20] and serum/urine β2-MG [12,15] concentrations in the patients with chronic RAD. Neither has been sufficiently studied the diagnostic value of combinations of various biochemical parameters [12,16]. The published results of investigations are rather contradictory [21,32].…”

“…One of the methods of laboratory kidney function diagnostic is the estimation of blood concentration and urine excretion of the low-molecular proteins such as beta-2-microglobulin (β2-MG) [12,31]. Such estimation can reveal respectively the degree of injury of the glomerula basal membrane of the glomerules and of the epithelium of the proximal channels [7,10,31].…”

“…of the blood serum and urine [16,29], low-molecular proteins [5], cytokines [14,20] as well as specific molecules produced in the kidneys [12,23].…”