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Short term ex vivo storage of kidneys cause progressive nuclear ploidy changes of renal tubular epitheliocytes.

ABSTRACT: In renal transplantation, there has been considerable success, mainly in term of post-transplant graft function. However, upon closer scrutiny, it is known that severe dysfunction, including persistence of renal failure is seen after transplantation. The major condition that potentially cause significant lesion may be hypothesized to be related to the hypothermic approach to storage. To systematically examine these issues, we stored mammalian (sheep) kidneys in UWS at 4 °C for four different time points (0, 1, 3 and 6 hours). We obtained renal histological sections and examined tubular architecture as well as nuclear characteristics of tubular epitheliocytes. The results of our preliminary investigations suggest that there are temporal changes of tubular epitheliocytes, as well as genomic changes. These changes were also seen in tissues stored at room temperature. Our observations suggest the need for additional studies for redesigning of improvised storage solutions. Pilot studies using Celsior also revealed similar kind of nuclear changes, suggesting that storage conditions are contributory, including perfusion versus static conditions. The results may explain persistence of tubular injury several days after orthotopic transplantation, and may potentially be contributory to delayed graft function (DGF).

SUBMITTER: Sun H

PROVIDER: S-EPMC4453160 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Project description:Intravascular hemolysis of any cause can induce acute kidney injury (AKI). Hemolysis-derived product heme activates the innate immune complement system and contributes to renal damage. Therefore, we explored the role of the master complement regulator Factor H (FH) in the kidney's resistance to hemolysis-mediated AKI. Acute systemic hemolysis was induced in mice lacking liver expression of FH (hepatoFH-/-, ~20% residual FH) and in WT controls, by phenylhydrazine injection. The impaired complement regulation in hepatoFH-/- mice resulted in a delayed but aggravated phenotype of hemolysis-related kidney injuries. Plasma urea as well as markers for tubular (NGAL, Kim-1) and vascular aggression peaked at day 1 in WT mice and normalized at day 2, while they increased more in hepatoFH-/- compared to the WT and still persisted at day 4. These were accompanied by exacerbated tubular dilatation and the appearance of tubular casts in the kidneys of hemolytic hepatoFH-/- mice. Complement activation in hemolytic mice occurred in the circulation and C3b/iC3b was deposited in glomeruli in both strains. Both genotypes presented with positive staining of FH in the glomeruli, but hepatoFH-/- mice had reduced staining in the tubular compartment. Despite the clear phenotype of tubular injury, no complement activation was detected in the tubulointerstitium of the phenylhydrazin-injected mice irrespective of the genotype. Nevertheless, phenylhydrazin triggered overexpression of C5aR1 in tubules, predominantly in hepatoFH-/- mice. Moreover, C5b-9 was deposited only in the glomeruli of the hemolytic hepatoFH-/- mice. Therefore, we hypothesize that C5a, generated in the glomeruli, could be filtered into the tubulointerstitium to activate C5aR1 expressed by tubular cells injured by hemolysis-derived products and will aggravate the tissue injury. Plasma-derived FH is critical for the tubular protection, since pre-treatment of the hemolytic hepatoFH-/- mice with purified FH attenuated the tubular injury. Worsening of acute tubular necrosis in the hepatoFH-/- mice was trigger-dependent, as it was also observed in LPS-induced septic AKI model but not in chemotherapy-induced AKI upon cisplatin injection. In conclusion, plasma FH plays a key role in protecting the kidneys, especially the tubules, against hemolysis-mediated injury. Thus, FH-based molecules might be explored as promising therapeutic agents in a context of AKI.

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Short term ex vivo storage of kidneys cause progressive nuclear ploidy changes of renal tubular epitheliocytes.

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