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PubMed2002

Effect of cold-ischemia time on C-X-C chemokine expression and neutrophil accumulation in the graft liver after orthotopic liver transplantation in rats.

BACKGROUND: The precise mechanisms leading to polymorphonuclear neutrophil (PMN) recruitment and activation in the extended cold-preserved liver after transplantation are not yet fully understood. METHODS: We histologically evaluated the number of accumulated PMNs in graft livers, with varying time periods of cold ischemia (1, 6, and 24 hr in University of Wisconsin solution at 4 degrees C), after liver transplantation in rats. Intragraft expression of macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC) mRNA, as well as immunohistochemical expression of MIP-2 and CINC in the graft liver, were investigated after reperfusion. The levels of MIP-2 and CINC in the hepatic vein, and tumor necrosis factor (TNF)-alpha, which stimulates these chemokine production, were also monitored. RESULTS: The number of accumulated PMNs in sinusoids significantly increased in the 24-hr cold-ischemia group within 3 hr after reperfusion, compared with the 1-hr and 6-hr groups. Serum MIP-2 levels in the 24-hr group significantly increased at 3, 6, and 12 hr after reperfusion, compared with the other groups. Intragraft MIP-2 mRNA was also up-regulated to a greater extent in the 24-hr group. Similarly, serum CINC levels in the 24-hr group significantly increased at 3 hr, compared with the 1-hr group. CINC mRNA also increased as cold-ischemia time was prolonged. Immunohistochemical staining revealed that hepatocytes were the main source of both MIP-2 and CINC protein. In addition, TNF-alpha in the hepatic vein was detected only in the 24-hr group after reperfusion. CONCLUSION: Extended cold preservation of the graft liver might up-regulate MIP-2 and CINC expression of hepatocytes, most probably through elevated TNF-alpha, and might contribute to PMN recruitment and activation after reperfusion.

Alanine Transaminase↗

PubMedDate not supplied

Singlet oxygen energy illumination during moderate cold ischemia prolongs the survival of concordant hamster xeno-heart transplants.

INTRODUCTION: Singlet oxygen energy (SOE) is a potent inhibitor of reactive oxygen species (ROS) in vitro and in vivo in certain dose ranges and can improve the levels of high-energy phosphates (HEP) in concordant hamster xeno-heart transplants. Some data indicate that a certain degree of cold ischemia (CI) might be beneficial to xenotransplants. We investigated if SOE illumination of hamster xeno-hearts during moderate cold ischemia (CI) improved graft survival. MATERIALS AND METHODS: Eighteen hearts from Golden Syrian hamsters (70 to 80 g) were subjected to 8 hours of CI in cold (+4 degrees C) saline solution (NaCL, 0.9%) before heterotopic cervical transplantation to Lewis rats (220 g). Among the treatment group (n = 8), SOE was produced by illuminating the hearts for 10 minutes every 30 minutes with photons at lambda 634 nm with the Oxylight equipment. Graft function was evaluated every 6 hours after transplantation with digital exam until cessation of heart beats. RESULTS: The graft survival of SOE-illuminated ischemic hamster xenografts was 2.34 +/- 0.56 versus 1.15 +/- 0.37 days in the control group (P < .05). All hearts displayed immediate graft function versus 70% in the controls (NS). CONCLUSIONS: SOE illumination at lambda 634 nm during moderate cold ischemia (+4 degrees C) can improve the survival of concordant hamster xeno-heart transplants. The exact mechanism(s) are currently unknown, but the effect might in part be exerted by a combination of reduced production of ROS and increased oxidative phosphorylation.

Animals↗

PubMed2001

Cold ischemia augments allogeneic-mediated injury in rat kidney allografts.

BACKGROUND: Some clinical studies demonstrate that kidney grafts with prolonged cold ischemia experience early acute rejection more often than those with minimal ischemia. The mechanism, however, is putative. Therefore, the aim of this study was to unravel the impact of ischemia on the immune response in rat kidney allografts compared with that in isografts. METHODS: To induce ischemic injury, donor kidneys were preserved for 24 hours in 4 degrees C University of Wisconsin solution before transplantation. No immunosuppression was administered. The histomorphology according to the BANFF criteria for acute rejection and infiltrating cells were assessed at days 1, 2, 3, 4, 6, and 8 post-transplantation. RESULTS: In allografts, exposure of the kidney to ischemia led to a significantly earlier onset of interstitial cell infiltration and tubulitis compared with nonischemic allografts. The BANFF score of interstitial cell infiltration was 1 +/- 0 vs. 0.25 +/- 0.29 at day 3 and 2 +/- 0 vs. 1.25 +/- 0.25 at day 4. In contrast, in isografts, the effect of ischemia on the histology was not significant. From day 6, the histologic differences between ischemic and nonischemic grafts disappeared. Ischemia led to a more intense expression of P-selectin (day 1), intercellular adhesion molecule-1 (ICAM-1; day 2), and major histocompatibility complex (MHC) class II on endothelium and proximal tubular cells (day 2) in both allografts and isografts. Concurrently with the up-regulated ICAM-1 and MHC expression, significantly more CD4(+) cells and macrophages infiltrated the ischemic allografts at days 2 and 3 and the ischemic isografts at day 4. Importantly, the influx of these cells after ischemia was significantly greater in allografts than in isografts. CONCLUSIONS: Cold ischemia augments allogeneic-mediated cell infiltration in rat kidney allografts. The earlier onset of acute rejection in 24-hour cold preserved allografts may be prevented by better preservation or treatment using tailored immunosuppression.

Animals↗

PubMed1996

[Analysis of ischemic lesions of the liver after various periods of warm and cold ischemia].

Liver and sinusoidal wall cells become swollen very fast due to ischemia in liver allograft, with Eurocollins preservation solution. This process consequently narrows the sinusoidal lumen and significantly disturbs the "functional structure" of Rapaport microcirculation units. Advanced changes on "functional structure" microcirculation liver units can cause outflow block phenomenon of the liver and a consequential primary graft dysfunction. In order to avoid this unfavorable consequence of transplantation, it is necessary to assess the potential allograft vitality in advance. The assessment can be based on measuring values of sinusoidal volume, increase of the serum glutaminpyruvic transaminaze (SGPT) level per mass unit of liver tissue in the preservation solution and increase of necrotizing hepatocytes' number in liver lobules. During the first 8 hours of cold ischemia these values do not change significantly, so we can conclude that in this interval of cold ischemia liver is suitable for transplantation, which is not the case with warm ischemia where changes occur much earlier. Practically, the intensity of lesions with 4 hour period of warm ischemia equals the intensity of lesions with 16 hour period of cold ischemia.

Animals↗

PubMed2002

Human islet transplantation from pancreases with prolonged cold ischemia using additional preservation by the two-layer (UW solution/perfluorochemical) cold-storage method.

BACKGROUND: A two-layer (University of Wisconsin solution/perfluorochemical [UW/PFC]) cold-storage method delivers sufficient oxygen to the pancreas during preservation and restores the ischemically damaged pancreas. In this study, we determined whether the additional preservation by the two-layer method could improve islet recovery from human pancreases with prolonged cold storage in UW. METHODS: Human pancreases were procured from cadaveric organ donors and preserved by the two-layer method (UW/PFC) for 2.9+/-0.7 hours (mean+/-SEM) at 4 degrees C after 11.8+/-1.5 hours of cold storage in UW (UW/PFC group, n=7), or by cold UW alone for 11.3+/-0.3 hours (UW group, n=14). The selected pancreases met the criteria of having at least 10 hours of cold storage in UW. All were processed by using a standard protocol of Liberase perfusion with Pefabloc by way of the duct, gentle mechanical dissociation, and Ficoll gradient purification. Transplanted islets were selected with the criteria of the Edmonton protocol (>5,000 islet equivalents [IE]/kg recipient body weight). RESULTS: The islet recovery was significantly increased in the UW/PFC group compared with the UW group (349.2+/-44.1 x 10 and 214.0+/-31.0 x 10 IE, respectively; <0.05). This resulted in islet yields of 4.6+/-1.0 x 10 IE/g of pancreas in the UW/PFC group compared with 2.0+/-0.3 x 10 IE/g of pancreas in the UW group ( <0.05). Five of 7 cases (71%) in the UW/PFC group and 5 of 14 cases (36%) in the UW group were transplanted. The islet grafts in the UW/PFC group improved the ability of glycemic control and decreased exogenous insulin administration in all recipients. CONCLUSIONS: Improvements in methods to preserve and recover ischemically damaged human pancreases before islet isolation and transplant could be extremely beneficial to the field of clinical islet transplantation. This preliminary study shows that additional short preservation by the two-layer (UW/PFC) cold-storage method can significantly improve islet recovery and increase opportunities of islet transplantation from human pancreases after prolonged cold ischemia.

Adenosine↗

PubMed1993

Islet cell hormone release immediately after human pancreatic transplantation. A marker of tissue damage associated with cold ischemia.

Pancreatic graft procurement, preservation, and transplantation surgery may result in damage to and loss of the integrity of endocrine cells and consequently in leakage of cell products into the insular vascular capillaries. Thus, the amount of alpha-, beta-, and pancreatic polypeptide (PP) cell products released into the vascular space of the recipient immediately after graft reperfusion may reflect islet cell injury. To test this hypothesis, we assessed glucagon, PP, C-peptide, and insulin levels in a prospective study of 22 consecutive renal-pancreatic transplantations. Transplantation-related parameters were used to account for differences in hormone release. Five grafts were preserved using Euro-Collins preservation fluid and 17 grafts were preserved using University of Wisconsin solution (UW). The first sign of a reinstalled physiological axis was the decrease of the blood glucose concentration after a median duration of 40 min (range 5-90 min) and the association of the recipient's ambient blood glucose levels with insulin release between 25 and 180 min after reperfusion. The delay period before a fall in blood glucose was observed correlated with cold ischemia time (rs = 0.73, P < 0.001, n = 21). An immediate and marked increase in plasma levels of glucagon (from 180 +/- 18 to 585 +/- 99 ng/L, mean +/- SEM), PP (from 57 +/- 8 to 122 +/- 13 pmol/L), C-peptide (from < 0.06 +/- 0.02 to 5.43 +/- 0.63 nmol/L), and insulin (from 0.15 +/- 0.21 to 2.05 +/- 0.26 nmol/L) was observed. C-peptide release correlated with glucagon (r = 0.76, P < 0.001) and PP (r = 0.60, P < 0.01). The hormone release was compared with computed tomography scans that were performed in the immediate postoperative period in 15 UW-preserved allografts. The diameter of the pancreatic head was increased and ranged from 4.5 to 7.7 cm (mean 6.2 cm). Peroperative C-peptide release significantly correlated with morphological graft changes reflected by the pancreatic head diameter (r = 0.58, P = 0.02). In a stepwise multiple regression analysis, cold ischemia time was a significant factor for the release of PP (r2 = 0.18, P = 0.049) and C-peptide (r2 = 0.35, P = 0.004). We suggest that peroperative hormone release reflects endocrine tissue damage. Furthermore, cold ischemia time may jeopardize the pancreatic allograft after relatively short preservation times, even when UW is used.

Adult↗

PubMed2001

Deletrious effect of prolonged cold ischemia on renal function.

The detrimental effect of prolonged cold ischemia (CI) on posttransplant renal function has long been recognized. However, the cellular consequences of CI have not been clearly defined. This study describes a model for the identification of CI-induced injury by evaluating ex-vivo renal metabolism and function prior to reperfusion. Small bovine kidneys were cold stored in Viaspan for 24-, 48-, 72-, and 96 h. Kidneys were then warm perfused (32 degrees C) using Exsangiunous Metabolic Support (EMS) technology and evaluated for oxidative metabolism, vascular dynamics and function. Oxygen consumption, vascular resistance, and diuresis were stable in kidneys with CI up to 48 h. After 72- and 96 h of CI, vascular resistance was increased while oxygen consumption and diuresis were reduced (P < 0.05). Glomerular filtration rate was diminished at CI greater than 24 h (P < 0.05). Results show that function was compromised with CI greater than 24 h and preceded the loss of cell viability following 48 h of CI.

Animals↗

PubMed1988

Effects of cold ischemia and reperfusion on trapping of erythrocytes in the rat kidney.

After reperfusion of kidneys subjected to a period of warm ischemia, the medulla displays a vascular congestion of erythrocytes, especially in the inner stripe of the outer zone, a phenomenon referred to as "trapping." This trapping causes reflow alterations, thus contributing to postperfusion medullary ischemia. The purpose of the present investigation was to study whether trapping also occurs after reperfusion of kidneys following varying periods of cold ischemia and to determine if there is any correlation between the degree of cold ischemic injury and the extent of erythrocyte trapping. Rat kidneys stored at +4 degrees C for 0-30 h were transplanted into recipient animals pretreated with a 51Cr-labelled erythrocyte suspension. Twenty minutes after reperfusion, the grafts were removed and microdissected into cortex, outer and inner stripes of the outer medullary zone, and inner zone, respectively. The radioactivity of these specimens was measured, and the erythrocyte content for each specimen was calculated. The results show a maximal trapping for cold ischemia time (CIT) of about 12-15 h. A linear correlation between the amount of trapping and CIT could be found in all parts of the kidney (except for the cortex) for CIT 0-15 h. The best correlation was found in the part where the trapping was most prominent, i.e., in the inner stripe. After CIT of 15 h or more, no correlation could be found. It is suggested, as described in models of warm ischemia, that the obstructions of the capillaries by trapped erythrocytes following reperfusion is of pathophysiological significance for the development of post-transplant acute renal failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Anastomosis, Surgical↗

PubMed1976

Influence of warm and cold ischemia time on initial function and one-year survival of renal allografts.

The influence of the duration of warm and cold ischemia on initial graft function on patient survival, graft survival, and graft function one year after transplantation was assessed in 234 consecutive cadaveric renal transplants. The number of grafts with delayed function was found to increase with increasing duration of the warm and cold ischemia times. On the other hand, the duration of the ischemia times and consequently the initial function, whether immediate or delayed, did not influence the survival of graft and patient nor the function of the graft one year after transplantation.

Adult↗

PubMed2001

The effect of nitric oxide production by sinusoidal endothelial cells on preservation injury during cold ischemia.

Multifactorial elements are responsible for preservation and reperfusion injury in liver allografts. Sinusoidal endothelial cells (SECs) are a primary target of cold preservation injury of the liver. We examined the correlation between nitric oxide (NO) production by SECs and their injury during cold preservation. SECs were isolated from rat livers and preserved in either Euro-Collins (EC) or University of Wisconsin (UW) solution. Injury to the SECs was more severe when preserved in the EC solution than in the UW solution during cold ischemia. In addition, NO production by SECs was found to be proportionate to the cell injury. Cell viability was not improved by the addition of NO inhibitor, L-NMMA. Further, NO inhibitor was detrimental to the SECs in a 24-h preservation in UW solution. LDH release by SECs preserved in UW solution supplemented with L-NMMA was 11.10+/-2.03 IU/l, while that in UW solution alone was 3.70+/-0.70 IU/l (P<0.01). Together, our results suggest that NO protects SECs during cold preservation and that NO from SECs may have beneficial effects on the liver during cold ischemia.

Journal Article↗

PubMed1988

Assessment of prostacyclin and thromboxane A2 release during reperfusion after global ischemia induced by crystalloid cardioplegia--comparison between warm and cold ischemia.

The metabolites of prostacyclin (PGI2) and thromboxane A2 (TxA2), 6-keto-PGF1 alpha and thromboxane B2 (TxB2), were investigated during reperfusion (RP) following warm (37 degrees C, 60 min, n = 9) or cold (15 degrees C, 120 min, n = 11) ischemia induced by cold (4 degrees C) or normothermic (30 degrees C) K+ cardioplegia (CP) in isolated canine hearts subjected to global ischemia and RP. 6-Keto-PGF1 alpha flux was significantly higher (p less than 0.025) in the warm group at 1, 5, and 10 min of RP (4,202 +/- 1,412, 2,475 +/- 1,875, and 1,255 +/- 633 pg/g.min, mean +/- SD) compared to those in the cold group (1,504 +/- 1,245, 434 +/- 641, and 370 +/- 329 pg/g.min). TxB2 flux was small in amount compared to 6-keto-PGF1 alpha in both groups. Regarding the coronary hemodynamics, the cold group alone showed statistically significant relationships of coronary sinus blood flow to TxB2 level and TxB2/6-keto-PGF1 alpha ratio in coronary sinus blood. Also, coronary vascular resistance showed linear relations to these two parameters of the metabolites. In a supplementary experiment only with cold ischemia for 180 min, 6-keto-PGF1 alpha was released at each coronary flush-out by CP and the incremental amount showed a gradual increase during ischemia. These results indicated that significant production and release of PGI2 occurred during ischemia and RP following CP arrest and these related to the degree of myocardial damage while the response of TxA2 seemed less significant. The role of PGI2 release during RP following cardioplegic arrest was discussed.

6-Ketoprostaglandin F1 alpha↗

PubMed2004

Assessment of connective tissue fibres in walls of allogenic arterial grafts preserved by the method of cold ischemia--a preliminary report.

The aim of the study was to evaluate microscopic changes in the wall structures of allogenic arterial grafts, preserved by the method of cold ischemia in relation to the storage period and to test the possibility of the storage period prolongation by allograft freezing at -70 degrees C. The middle layer ultrastructure is well preserved till 30 days from allograft harvesting, however, allograft freezing results in total destruction of elastic and collagen fibres in the arterial wall. An application of allogenic arterial grafts, preserved by the method of cold ischemia till 30 days from their harvesting, seems an efficient therapeutic method in the treatment of patients with synthetic vascular graft infection. Further prolongation of the storage period at -70 degrees C made the allograft useless for implantation.

Aorta, Abdominal↗

PubMed2006

Perflubron emulsion prevents PMN activation and improves myocardial functional recovery after cold ischemia and reperfusion.

BACKGROUND: In cardiopulmonary bypass, extracorporeal circulation activates neutrophils, which contribute to ischemia reperfusion injury and postoperative myocardial dysfunction. Perfluorocarbons (PFCs) are compounds that dissolve oxygen and have anti-inflammatory and neutrophil-stabilizing properties. We hypothesized that perflubron emulsion (PFE), a PFC, would attenuate neutrophil activation during simulated extracorporeal circulation (SECC) and would preserve myocardial functional recovery during reperfusion after cold ischemia. METHODS: In a SECC, diluted blood was circulated for 120 min and subsequently used to reperfuse isolated rat hearts after 2 h of cold (12 degrees C) ischemia. Three groups were studied: noncirculated control; SECC/no additive; and SECC/PFE added. In control and SECC/no additive groups, whole blood was diluted 1:1 with plasmalyte. SECC/PFE blood was diluted 1:1 with plasmalyte and PFE (0.075 mL/mL diluted whole blood). Blood counts and neutrophil activation experiments were performed before and after 120 min of SECC. Reperfusion was accomplished using a modified Langendorff preparation. Left ventricular developed pressure, dP/dt, and coronary flow were measured at 10, 15, and 20 min of reperfusion. RESULTS: After 120 min SECC, neutrophil activation was significantly reduced in the SECC/PFE group compared to the SECC/no additive group (38.1 +/- 2.3% versus 51.7 +/- 1.0%, P < 0.05). Compared to cold ischemic hearts reperfused with fresh, non-recirculated blood, left ventricular developed pressure and dP/dt were significantly impaired in the cold ischemic hearts reperfused with SECC/no additive blood (P < 0.05). In contrast, myocardial functional recovery was not impaired in the hearts reperfused with SECC/PFE blood. CONCLUSIONS: SECC-induced neutrophil activation was attenuated with Perflubron treatment. In addition, the progressive impairment in myocardial functional recovery after cold ischemia was significantly improved with treatment. PFE has clinical potential to limit neutrophil-mediated reperfusion injury following cold ischemia.

Animals↗

PubMed1996

Effects of cold ischemia time on the graft after orthotopic liver transplantation. A bile cytological study.

We conducted a daily analysis of bile cellularity in 16 orthotopic liver transplant patients fitted with a T-tube, and correlated the cytological parameters (number of cells per slide, and percentage of difference cell types) with the duration of cold ischemia time (CIT). Two groups were established: one comprised patients whose CIT was less than 7 hr (CIT averaged 345 min) and the other comprised patients with a CIT of more than 7 hr (CIT averaged 505 min). The control group consisted of 15 patients who had received cholecystectomy for biliary lithiasis and were fitted with a T-tube. All 3 groups showed the highest cell density on the 1st postoperative day (control: 53.3 +/- 15.5 cells/slide; short ischemia: 70 +/0 21.4 cells/slide; long ischemia: 158.8 +/- 53.2 cells/slide), which steadily ischemia group showed a higher cell density than did the control group for the first 2 days, although this was not significant. The long ischemia group showed the highest cell density, although only significantly for the first 2 days when compared with the controls, and basically at the expense of a increase in ductal epithelial cells. Our results show that prolonged cold ischemia causes an increase in bile cell density at the expense of ductal epithelial cells: the longer the preservation time, the greater the increase.

Adolescent↗

PubMed2004

Effect of cold-ischemia time on nuclear factor-kappaB activation and inflammatory response in graft after orthotopic liver transplantation in rats.

AIM: To study the mechanism and effect of nuclear factor-kappaB (NF-kappaB) activation and inflammatory response on the extended cold-preserved graft injury after orthotopic liver transplantation (OLT). METHODS: OLT was performed in rats with varying time of cold ischemia grafts (6, 18 and 24 h in University Wisconsin solution at 4 degrees ). We determined the time of NF-kappaB activation and expression of tumor necrosis factor-alpha (TNF-alpha), cytokine-inducible neutrophil chemoattractant (CINC), and intercellular adhesion molecule-1 (ICAM-1) within 6 h after reperfusion. Serum alarming aminotransferase (ALT), neutrophil sequestration, circulating neutrophil CD11b and L- selectin expression were also evaluated. RESULTS: The accumulation of neutrophils in the graft was significantly increased in the 18 h and 24 h cold-ischemia groups within 0.5 h after reperfusion, compared with the 6 h group. But the strongly activated neutrophils was slightly increased at 2 h after reperfusion and remained at high levels 4 h after reperfusion, which was synchronized with the common situation of recipients after transplantation. Prolonged cold-preservation did not affect neutrophil accumulation and activation. NF-kappaB activation preceded the expression of TNF-alpha, CINC, and ICAM-1 in the liver, which was significantly increased with prolonged cold preservation. In prolonged cold preserved grafts, prominently elevated NF-kappaB activation occurred at 0.5 h and 1 h, compared with that at 2 h after reperfusion, which was consistent with greatly increased intrahepatic TNF-alpha response. CONCLUSION: NF-kappaB activation is correlated with the expression of TNF-alpha, CINC, and ICAM-1 in vivo in OLT rats. Extended cold preservation of grafts might up-regulate TNF-alpha, CINC, and ICAM-1 expression in the grafts, most probably through elevated NF-kappaB activation, and might contribute to neutrophil infiltration in the grafts after reperfusion. Elevated NF-kappaB activity is harmful to inflammatory response in the grafts, and inhibited NF-kappaB activity might protect against early graft injury after liver transplantation.

Animals↗

PubMed2003

Cytokine gene expression in kidney allograft donor biopsies after cold ischemia and reperfusion using in situ RT-PCR analysis.

It was previously reported that ischemia-reperfusion injury initiates an inflammatory response and may significantly affect the transplanted organ function. The aim of this study was to assess changes of intragraft cytokine mRNA expression in kidneys after cold ischemia (CI) and following reperfusion. We examined mRNA of a product of activated T lymphocytes (IFN-gamma) and a monocyte product (IL-6). Eleven kidneys were transplanted after CI time ranging from 16 to 39 hours. Renal needle core biopsies were obtained from donors after cold ischemia and approximately after 20 minutes of reperfusion. Tubular and glomerular expression of IFN-gamma and IL-6 mRNA were assessed using semiquantitative evaluation of the RT-PCR in situ. After reperfusion an intense increase of IL-6 mRNA expression was observed in four specimens, a slight increase was noticed in five specimens, and a very slight decrease in two specimens. Changes in IL-6 mRNA expression were limited only to tubules. In contrast, the glomerular and tubular mRNA expression of IFN-gamma and glomerular of IL-6 remained stable. Mean CI time for patients with an intense increase was higher than for patients with a slight increase and with the decrease of IL-6 mRNA expression (32.0 +/- 6.8 vs 25.2 +/- 7.3 and 26.0 +/- 5.7 hours). Our results suggest that early inflammatory changes at the time of implantation of renal allografts depends mainly on monocyte/macrophage-associated products. The observed intensity of their expression in tubules was connected to longer CI time.

Adolescent↗

PubMed2000

Glutathione supplementation during cold ischemia does not confer early functional advantage in renal transplantation.

BACKGROUND: Reduced glutathione (GSH), a component of University of Wisconsin (UW) solution, is reported to oxidize during storage. Consequently the commercial manufacturer of UW recommends the supplemental addition of GSH to UW before utilization. We investigated the influence of supplemental GSH during cold ischemia on early renal allograft function. METHODS: One hundred kidneys were locally procured from heart-beating donors, preserved in our laboratory, and transplanted during an 18-month period. Selected donor, preservation, and outcome characteristics were collected and compared by presence of supplemental GSH and method of preservation. All kidneys were randomized to receive 3.0 mM supplemental GSH to perfusate or no supplementation (control) and were preserved by either cold storage (CS) in UW or machine perfused (MP) in UW-machine perfusate solution (MPS). During MP, perfusion characteristics (flow, resistance, perfusate electrolytes, and pH) were serially measured. RESULTS: There were no significant differences among the groups when the donor characteristics of age, serum creatinine, and intra-operative urine output were compared. Preservation characteristics were similar among the groups with the exception of cold ischemia time, which was longer in the MP group compared to CS (26.1 h vs. 21.9 h, P=0.03). When compared with CS, kidneys preserved by MP exhibited a 33.4% increase in immediate function (93% vs. 62%, P=0.01), a corresponding 29.4% decrease in the incidence of delayed graft function (10% vs. 34%, P=0.02), and a 10% improvement in short-term (6-month) graft survival (98% vs. 88%, P=0.02). The addition of GSH supplementation to perfusate resulted in no significant differences in graft outcomes. CONCLUSIONS: Despite recommendations by the manufacturer that UW solution be routinely supplemented with GSH, supplemental GSH does not influence early renal allograft function. Our data suggest that a far greater beneficial impact on early graft function is achieved by machine perfusion. We conclude that GSH supplementation of commercially available UW is not necessary.

Adenosine↗

PubMed1985

The effect of verapamil on renal function after warm and cold ischemia in the isolated perfused rat kidney.

The potential usefulness of verapamil, a calcium channel blocker to renal allograft preservation, was investigated using the isolated perfused rat kidney. Two models of ischemic injury were used. In the first model, rat kidneys were exposed to 40 min of 37 degrees C ischemia on the perfusion circuit. Addition of verapamil in doses of 2.5, 5, and 100 microM concentration to the perfusate significantly improved inulin clearance (Cin) and total sodium absorption (TNa) in the hour of reperfusion following ischemia. Regeneration of adenosine triphosphate (ATP) and total adenine nucleotide TAN levels during reperfusion following warm ischemia were also significantly higher in verapamil-treated kidneys. In the second model, rat kidneys were flushed in situ with Collins C2 solution and stored at 0 degrees C for 8 hr. After this period of cold ischemia, they were perfused on a perfusion circuit with perfusion media. Verapamil 2.5 microM was absent from both flush and perfusate (control), or added to just the flush, both the flush and perfusate, or just the perfusate. Addition of verapamil to the flush or the flush and perfusate significantly improved Cin, urine flow rate (V) and TNa during reperfusion, compared with control. Addition of verapamil to just the perfusate did not effect Cin, TNa, or V but did significantly increase RPF. These findings suggest the verapamil may protect against organ damage occurring during both warm and cold ischemia in the absence of any systemic effects and thus may be useful for renal allograft preservation.

Adenine Nucleotides↗