Abstract
Delayed graft function remains an important complication after renal transplantation. In this study, we investigated the influence of trimetazidine (TMZ), a cytoprotective agent, on renal medullary damage after prolonged preservation and autotransplantation. Pig kidneys were cold-flushed and preserved (48 h at 4°C) with two standard renal preservation solutions Euro-Collins and University of Wisconsin supplemented or not with TMZ (10−6 M). Analysis of plasma and urine from 48-h-cold-stored and autotransplanted kidneys was performed with biochemical methods and proton NMR spectroscopy. Histological study by light and electron microscopy was performed after reperfusion (30–40 min) and on day 14. The results showed that the preservation in either Euro-Collins or University of Wisconsin solution containing TMZ improved significantly glomerular filtration rate compared with kidneys preserved without TMZ. TMZ significantly reduced renal medullary damage, evidenced by decreased excretion of trimethylamine-N-oxide, dimethylamine, dimethylglycine, and acetate in urine. Proximal tubular injury in TMZ-free groups was assessed by significantly greater Na+ excretion, amino aciduria, and lactic aciduria than in TMZ-supplemented groups. Urinary concentrating ability was significantly improved in TMZ-preserved groups compared with TMZ-free groups. In TMZ-supplemented groups, there was also a greater excretion of citrate, which is a citric acid cycle metabolite. An extensive reduction in apical brush border of tubular cells, notably those of the proximal tubules, was noted in TMZ-free groups. This study clearly shows that TMZ has a beneficial action on in vivo renal preservation and its major impact is the vulnerable renal medulla.
Footnotes
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Send reprint requests to: Thierry Hauet, Laboratoire de Transplantation Expérimentale, Institut National de la Recherche Agronomique, Domaine du Magneraud, BP 52, 17700 Surgères, France. E-mail: hauet{at}magneraud.inra.fr
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↵1 This work was supported by grants from the Etablissement Français des Greffes, the Ministère de la recherche (92C0746), The Conseil Régional Poitou-Charentes, the Association pour le Développement de la Dialyse à Domicile en Charente Maritime (ADA 17), and the Institut de Recherches Internationales Servier.
- Abbreviations:
- GFR
- glomerular filtration rate
- DGF
- delayed graft function
- TMZ
- trimetazidine
- MTP
- mitochondrial permeability transition pore
- CS
- cold storage
- EC
- Euro-Collins solution
- UW
- University of Wisconsin solution
- Ct
- creatinine
- TMAO
- trimethylamine
- DMA
- dimethylamine
- FENa
- fractional excretion of sodium
- DMG
- dimethylglycine
- Received May 12, 1999.
- Accepted August 30, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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