. Keratinocyte-derived chemokine is an early biomarker of ischemic acute kidney injury. Am J Physiol Renal Physiol 290: F1187-F1193, 2006. First published December 20, 2005 doi:10.1152/ajprenal.00342.2005.-Renal ischemia-reperfusion injury (IRI) is the leading cause of acute kidney injury [AKI; acute renal failure (ARF)] in native kidneys and delayed graft function in deceased donor kidney transplants. Serum creatinine rises late after renal IRI, which results in delayed diagnosis. There is an important need to identify novel biomarkers for early diagnosis and prognosis in renal IRI. Given the inflammatory pathophysiology of renal IRI, we used a protein array to measure 18 cytokines and chemokines in a mouse model of renal IRI at 3, 24, and 72 h postischemia. A rise in renal keratinocyte-derived chemokine (KC) was the earliest and most consistent compared with other molecules, with 3-h postischemia values being 9-and 13-fold greater than sham and normal animals, respectively. Histological changes were evident within 1 h of IRI but serum creatinine only increased 24 h after IRI. With the use of an ELISA, KC levels in serum and urine were highest 3 h postischemia, well before a significant rise in serum creatinine. The human analog of KC, Gro-␣, was markedly elevated in urine from humans who received deceased donor kidney transplants that required dialysis, compared with deceased donor kidney recipients with good graft function and live donor recipients with minimal ischemia. Measurement of KC and its human analog, Gro-␣, could serve as a useful new biomarker for ischemic ARF.growth-related oncogene-␣; transplantation; acute renal failure; allograft ACUTE RENAL FAILURE (ARF), also recently known as acute kidney injury (AKI), is a syndrome with high mortality and morbidity, for which there is no specific therapy except supportive care (5, 17). There is an urgent need to develop effective therapeutics for ARF. Histologically, ischemic ARF is characterized by acute tubular necrosis; however, a major limitation in approaching the disease is the lack of clinically feasible diagnostics for early detection of ischemic ARF, such as the use of serum troponin and creatine phosphokinase (CPK) for myocardial ischemia-reperfusion injury (IRI) (4). Recent studies have identified proteins including KIM-1, lipocalin, IL-18, NHE3, actin, and retinol binding protein among others as potential biomarker candidates in ischemic ARF (13). However, none of them has been fully validated or is in routine clinical use, and there remains a strong need for discovery and validation of additional candidate markers (1).There are significant data that early inflammatory changes underlie the pathogenesis of renal IRI (3,8,11,15,21). We therefore used a mouse model of renal IRI to examine kidney, blood, and urine for evidence of changes in cytokine and chemokine expression using a protein array adapted to small volume samples. The earliest and most striking change was an increase in keratinocyte-derived chemokine (KC), a CXC chemokine that is stru...

Aberrant promoter hypermethylation, also known as epigenetics, is thought to be a promising biomarker approach to diagnose malignancies. Kidney repair after injury is a recapitulation of normal morphogenesis, with similarities to malignant transformation. We hypothesized that changes in urine epigenetics could be a biomarker approach during early kidney transplant injury and repair. We examined urine DNA for aberrant methylation of 2 gene promoters (DAPK CALCA) by quantitative methylation specific PCR from 13 deceased and 10 living donor kidney transplant recipients on postoperative day 2 and 65 healthy controls. Results were compared with clinical outcomes and to results of the kidney biopsy. Transplant recipients were significantly more likely to have aberrant hypermethylation of the CALCA gene promoter in urine than healthy controls (100% vs. 31%, p<0.0001). There was increased CALCA hypermethylation in the urine of deceased vs. living donor transplants (21.60 +/− 12.5 vs. 12.19 +/− 4.7 P=0.04). Furthermore, there was a trend towards increased aberrant hypermethylation of urine CALCA in patients with biopsy-proven acute tubular necrosis vs. acute rejection and slow or prompt graft function (mean: 20.40 +/− 6.9, 13.87 +/− 6.49, 17.17 +/− 13.4, P=0.67). However, there was no difference of CALCA hypermethylation in urine of patients with delayed graft function vs. those with slow or prompt graft function (16.9 +/− 6.2 vs. 18.5 +/− 13.7, respectively; P=0.5). There was no aberrant hypermethylation of DAPK in the urine of transplant patients. Urine epigenetics is a promising biomarker approach for acute ischemic injury in transplantation that merits future study.

ZRC-3197 has been developed indigenously by Cadila Healthcare Ltd as a biosimilar adalimumab of originator HUMIRA ®. Biosimilarity has been demonstrated with a comprehensive set of state-of-the-art analytical techniques to characterize the physicochemical and functional properties of ZRC-3197 in comparison with originator HUMIRA ®. The biosimilar ZRC-3197 showed indistinguishable primary and secondary structures with similar level of purity and heterogeneity as compared to that of the originator product. When analyzed, in parallel, the two products were observed to show a high degree of sameness of the carbohydrate structure and charge heterogeneity profile. Both biosimilar ZRC-3197 and the originator HUMIRA ® appeared to show highly comparable key functional properties, as assessed by in vitro cell-based assay and surface plasmon resonance technique. The biosimilar ZRC-3197 exhibited highly similar tumor necrosis factor alpha neutralizing activity as well as binding affinity for FcγRIIIa receptor compared to that of the originator product. The biosimilar ZRC-3197 was observed to show similar level of efficacy and safety profile in rheumatoid arthritis patients, when submitted to a head-to-head double-blind trial, in India, with the originator (reference) product, HUMIRA ®. Based on the demonstrated biosimilarity, market authorization has been granted for ZRC-3197, as a biosimilar of originator HUMIRA ® , in India. Here, we report the characterization of physicochemical and functional properties of the biosimilar ZRC-3197 and originator HUMIRA ® .

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