Human Anti-Human HAVCR1 monoclonal Antibody, clone SFB495 [PE]

The results of deceased donor kidney transplantation largely depend on the extent of organ injury induced by brain death and the transplantation procedure. In this study, we analyzed the preprocurement intragraft expression of 29 genes involved in apoptosis, tissue injury, immune cell migration, and activation. We also assessed their influence on allograft function. Before flushing with cold solution we obtained 50 kidney core biopsies of deceased donor kidneys immediately after organ retrieval. The control group included 18 biopsies obtained from living donors. Gene expression was analyzed with low-density arrays (Taqman). LCN2/lipocalin-2 is considered a biomarker of kidney epithelial ischemic injury with a renoprotective function. HAVCR1/KIM-1 is associated with acute tubular injury. Comparison of deceased donor kidneys to control organs revealed a significantly higher expression of LCN2 (8.0-fold P = .0006) and HAVCR1 (4.7-fold, P < .0001). Their expressions positively correlated with serum creatinine concentrations after 6 months after transplantation: LCN2 (r = .65, P < .0001), HAVCR1 (r = .44, P = .006). Kidneys displaying delayed graft function and/or an acute rejection episode in the first 6 months after showed higher LCN2 expression compared to event-free ones (1.7-fold, P = .027). A significantly higher increase in expression of TLR2 (5.2-fold), Interleukin (IL) 18 (4.6-fold), HMGB1 (4.1-fold), GUSB (2.4-fold), CASP3 (2.0-fold) FAS (1.8-fold), and TP53 (1.6-fold) was observed among deceased donor kidneys compared with the control group. Their expression levels were not related to clinical outcomes: however, they showed significant correlations with one another (r > .6, P < .0001). We also observed a slightly reduced expression of IL10 (0.6-fold, P = .004). Our data suggested that increased LCN2 and HAVCR1 expression observed in the kidneys after donor brain death were hallmarks of the organ injury process. LCN2 expression level in retrieved kidneys can predict kidney transplantation outcomes.

Sensitive biomarkers are needed to detect kidney injury at the earliest stages. The objective of this study was to determine whether the appearance of kidney injury molecule-1 (Kim-1) protein ectodomain in urine and kidney injury molecule-1/ hepatitis A viral cellular receptor-1 (Kim-1/Havcr1) gene expression in kidney tissue may be more predictive of renal injury after exposure to nephrotoxicants when compared to traditionally used biomarkers. Male Sprague-Dawley rats were injected with a range of doses of gentamicin, mercury (Hg; HgCl2), or chromium (Cr; K2Cr2O7). The results showed that increases in urinary Kim-1 and kidney Kim-1/Havcr1 gene expression paralleled the degree of severity of renal histopathology and were detected at lower doses of nephrotoxicants when compared to blood urea nitrogen (BUN), serum creatinine, and urinary N-acetyl-beta-D-glucosaminidase (NAG). In a time course study, urinary Kim-1 was elevated within 24 h after exposure to gentamicin (100 mg/kg), Hg (0.25 mg/kg), or Cr (5 mg/kg) and remained elevated through 72 h. NAG responses were nephrotoxicant dependent with elevations occurring early (gentamicin), late (Cr), or no change (Hg). At 72 h, after treatment with any of the three nephrotoxicants, there was increased Kim-1 immunoreactivity and necrosis involving similar to 50% of the proximal tubules; however, only urinary Kim-1 was significantly increased, while BUN, serum creatinine, and NAG were not different from controls. In rats treated with the hepatotoxicant galactosamine (1.1 mg/kg), serum alanine aminotransferase was increased, but no increase in urinary Kim-1 was observed. Urinary Kim-1 and kidney Kim-1/Havcr1 expression appear to be sensitive and tissue-specific biomarkers that will improve detection of early acute kidney injury following exposure to nephrotoxic chemicals and drugs.