Histidine-Tryptophan-Ketoglutarate (HTK) Is Associated with Reduced Graft Survival in Pancreas Transplantation

Prior single-center studies have reported that pancreas allograft survival is not affected by preservation in histidine-tryptophan-ketoglutarate (HTK) versus University of Wisconsin (UW) solution. To expand on these studies, we analyzed the United Network for Organ Sharing (UNOS) database of pancreas transplants from July 2004, through February 2008, to determine if preservation with HTK (N = 1081) versus UW (N = 3311) impacted graft survival. HTK preservation of pancreas allografts increased significantly in this time frame, from 15.4% in 2004 to 25.4% in 2008. After adjusting for other recipient, donor, graft and transplant center factors that impact graft survival, HTK preservation was independently associated with an increased risk of pancreas graft loss (hazard ratio [HR] 1.30, p = 0.014), especially in pancreas allografts with cold ischemia time (CIT) ≥12 h (HR 1.42, p = 0.017). This reduced survival with HTK preservation as compared to UW preservation was seen in both simultaneous pancreas-kidney (SPK) transplants and pancreas alone (PA) transplants. Furthermore, HTK preservation was also associated with a 1.54-fold higher odds of early (<30 days) pancreas graft loss as compared to UW (OR 1.54, p = 0.008). These results suggest that the increasing use of HTK for abdominal organ preservation should be re-examined.     

Histidine–Tryptophan–Ketoglutarate (HTK) Is Associated with Reduced Graft Survival in Deceased Donor Livers, Especially Those Donated After Cardiac Death

Single-center studies have reported that liver allograft survival is not affected by preservation in histidine–tryptophan–ketoglutarate (HTK) versus University of Wisconsin (UW) solution. We analyzed the UNOS database of liver transplants performed from July, 2004, through February, 2008, to determine if preservation with HTK (n = 4755) versus UW (n = 12 673) impacted graft survival. HTK preservation of allografts increased from 16.8% in 2004 to 26.9% in 2008; this was particularly striking among donor after cardiac death (DCD) allografts, rising from 20.7% in 2004 to 40.9% in 2008. After adjusting for donor, recipient and graft factors that affect graft survival, HTK preservation was associated with an increased risk of graft loss (HR 1.14, p = 0.002), especially with DCD allografts (HR 1.44, P = 0.025) and those with cold ischemia time over 8 h (HR 1.16, P = 0.009). Furthermore, HTK preservation was associated with a 1.2-fold higher odds of early (< 30 days) graft loss as compared to UW preservation (OR 1.20, p = 0.012), with a more pronounced effect on allografts with cold ischemia time over 8 h (OR 1.31, p = 0.007), DCD allografts (OR 1.63, p = 0.09) and donors over 70 years (OR 1.67, p = 0.081). These results suggest that the increasing use of HTK for abdominal organ preservation should be reexamined.     

Comparison of Histidine-Tryptophan-Ketoglutarate and University of Wisconsin Preservation in Renal Transplantation

Histidine-tryptophan-ketoglutarate (HTK) is replacing University of Wisconsin (UW) solution as the preservation fluid for renal allografts in many centers, but recent large-scale data to support this transition are lacking. We conducted a retrospective analysis of patient and graft outcomes after renal transplantation at our center, comparing 475 consecutive living donor and 317 deceased donor transplants since the adoption of HTK with equal numbers of grafts preserved using UW solution. Data collected included donor and recipient age, race, sex, comorbidities and graft ischemia time. Graft and patient survival, as well as the incidence of delayed graft function (DGF), were studied by Kaplan–Meier and Cox regression analysis. No significant difference was seen in either patient or graft survival. Deceased donor kidneys in the HTK group had a higher incidence of DGF than the UW cohort, whereas this trend was reversed in the case of living donor organs. In multivariate analysis, HTK was associated with a significant risk reduction on the incidence of DGF. Prolonged preservation with HTK compared to UW was not associated with excess risk to the graft or patient. In summary, HTK demonstrated efficacy similar to UW in terms of patient and graft survival.     

Comparison of histidine-tryptophan-ketoglutarate (HTK) solution versus University of Wisconsin (UW) solution for organ preservation in human liver transplantation

Over a 30-month period, 60 patients (30 in each group) suffering from end-stage liver disease or primary hepatic malignancy and scheduled for liver transplantation were enrolled in a prospective, randomized study to compare two methods of liver preservation: histidinetryptophan-ketoglutarate (HTK) solution versus University of Wisconsin (UW) solution. Entry criteria for both groups were: age (18–65 years), elective surgery (transplantable or urgent category of the recipients), first transplantations and harvesting procedure performed by the same team. The parameters under investigation were the clinical and laboratory data preand post-transplantation, as well as follow-up data such as complications and survival. There were no significant differences in the two groups as far as the evaluation criteria were concerned, even when cold ischemia time was more than 15h (n=7). A slight, yet not significant, increase in late complications of the biliary anastomoses could be seen in the UW group. Hepatocellular injury (SGOT, SGPT, GLDH, lactate) appeared to be more marked in the HTK group. These results suggest that both HTK and UW solutions are appropriate for clinical use in liver transplantation, even if cold ischemia time is more than 15h.     

Limited Survival of Rat Small Bowel Transplants Preserved in University of Wisconsin Solution for 48 Hours

We have previously shown that rat small bowel may successfully be transplanted after preservation for 24 hours. In this study, syngeneic rat small bowel transplants were studied by light microscopy and transmission electron microscopy during and after preservation in University of Wisconsin (UW) solution for 48 hours. A total of 6 transplants were carried out using a previously described, standardized technique. In most cases, the bowel appeared histologically well preserved at the end of the 48 hr storage period (prior to implantation). Upon revascularization, however, reperfusion injury was dramatic, with loss of villi and crypts and inflammatory cells in all layers. The bowel was abnormal grossly as well as microscopically. This injury was irreversible with persistently abnormal histology for up to 1 week in all but 2 cases.

We conclude that UW solution alone may allow satisfactory preservation of intestinal grafts for 48 hours only in isolated cases, and is therefore not adequate for predictable, satisfactory 48 hr preservation. Attempts to prevent reperfusion injury with oxygen-free radical scavengers are in progress.     

Increased Primary Non-Function in Transplanted Deceased-Donor Kidneys Flushed with Histidine-Tryptophan-Ketoglutarate Solution

Histidine-Tryptophan-Ketoglutarate (HTK) solution is increasingly used to flush and preserve organ donor kidneys, with efficacy claimed equivalent to University of Wisconsin (UW) solution. We observed and reported increased graft pancreatitis in pancreata flushed with HTK solution, which prompted this review of transplanting HTK-flushed kidneys. We analyzed outcomes of deceased-donor kidneys flushed with HTK and UW solutions with a minimum of 12 months follow-up, excluding pediatric and multi-organ recipients. We evaluated patient and graft survival and rejection rates, variables that might constitute hazards to graft survival and renal function. Two-year patient survival, rejection, renal function and graft survival were not different, but early graft loss (<6 months) was worse in HTK-flushed kidneys (p < 0.03). A Cox analysis of donor grade, cold ischemic time, panel reactive antibodies (PRA), donor race, first vs. repeat transplant, rejection and flush solution showed that only HTK use predicted early graft loss (p < 0.04; relative risk = 3.24), almost exclusively attributable to primary non-function (HTK, n = 5 (6.30%); UW, n = 1 (0.65%); p = 0.02). Delayed graft function and early graft loss with HTK occurred only in lesser grade kidneys, suggesting it should be used with caution in marginal donors.     

A preliminary report of the HTK randomized multicenter study comparing kidney graft preservation with HTK and EuroCollins solutions

The main goal of transplantation is to restore good renal function and to improve the quality of life of thousands of dialysis patients, something which can only be achieved by providing them with well functioning grafts. Delayed renal allograft function is a serious problem. It is important to prevent this complication because it makes the diagnosis of acute rejection in the early postoperative period difficult, increases the necessity for diagnostic procedures, introduces dialysis treatments and prolongs hospital stay. The aetiology of delayed graft function (DGF) is multifactorial, and factors including donor management, technique used for organ procurement and preservation, age, anatomical variations in the graft, ischemia periods, use of cyclosporine A (CyA) or recipient immunological reactions have been implicated. Using different preservation solutions DGF rates vary from 30% to 60%. Recent clinical data have demonstrated better preservation and improved renal function posttransplant with HTK and University of Wisconsin (UW) solutions compared to EuroCollins solution. In a randomized multicenter study in collaboration with the Eurotransplant organ exchange organization, the efficacy of the HTK solution in renal transplantation was compared to EuroCollins and UW solutions in two parallel prospective randomized trials. The first preliminary results comparing HTK and EuroCollins solutions are reported here.     

Increased Pancreatitis in Allografts Flushed with Histidine-Tryptophan-Ketoglutarate Solution: A Cautionary Tale

We reviewed pancreas transplantation outcomes after Histidine-Tryptophan-Ketoglutarate (HTK) and University of Wisconsin (UW) preservation solution use between 2001 and 2007 at two transplant centers. While equivalence has been claimed for kidney and liver transplant outcomes after the use of HTK or UW preservation solution, consensus has not been reached on equivalence when flushing pancreata. Others have reported comparable patient and graft survival rates, but found an association between the use of HTK and an increase in the incidence of acute rejection and pancreatitis. In reviewing our experiences, we found in pancreata flushed with HTK a higher incidence of postoperative complications including graft pancreatitis, use of octreotide and a decreased rate of insulin-independence at hospital discharge. These findings prompted us to critically review our centers' experience to determine if there is a basis for suspecting a causal relationship.     

The impact of liver preservation in HTK and UW solution on microcirculation after liver transplantation

Severe microcirculatory disturbances due to endothelial cell damage and leukocyte adherence during reperfusion of transplanted livers are considered to contribute to early graft failure. Since the degree of reperfusion injury after liver transplantation depends on the length of preservation time and the solution used for preservation, the aim of our study was to assess three solutions with respect to microvascular perfusion and leukocyte adhesion. Therefore, rat livers were stored up to 24 h in Euro-Collins (EC), University of Wisconsin (UW), or histidin-tryphtophan-ketoglutarate (HTK) solutions prior to orthotopic transplantation. The livers were studied in situ 60 min postoperatively using intravital fluorescence video microscopy. Using simple syringe flushing (10 ml), sinusoidal perfusion decreased below 50% in EC preserved livers after 8 h preservation, in HTK preserved livers after 16 h preservation, and remained higher than 70% in livers preserved in UW up to 24 h. Permanent adhesion of leukocytes was increased more rapidly in organs after 1, 8, 16, and 24 h preservation in HTK (16%, 15%, 34%, and 49.7% ± 4.7%) compared to those preserved in UW (15%, 18%, 17%; and 32.7% ± 3.3%; P < 0.05). Using a 10-fold volumn of the organ weight of HTK solution during the harvesting procedure, with an 8 min equilibration period, sinusoidal perfusion (39.6 ± 4.7%) and leukocyte adhesion (42.7 ± 3.1%) were not improved after 24 h. In contrast, equilibration with a volumn of approximately 40-times the liver weight improved sinusoidal perfusion (70.8% ± 2.7%; P < 0.01) and leukocyte adhesion (24.9% ± 3.1%; P < 0.01) significantly. Thus, using HTK solution, simple flushing prior to long-term cold storage resulted in microcirculatory disturbances when compared to UW solution. Larger volumns of HTK solution with an additional equilibration period of 8 min, however, reduced leukocyte adhesion and improved sinusoidal perfusion to a similar degree as UW solution.     

Recovery of Graft Function Early Posttransplant Determines Long-Term Graft Survival in Deceased Donor Renal Transplants

Introduction

Because kidneys show remarkable resilience and can recover function, we examined the impact on long-term graft survival in deceased donor renal transplants of both immediate graft function (IGF) and the rate of renal function recovery over the first 3 months after transplantation.

Methods

We included all cadaveric renal transplants from 1990 to 2007 (n = 583). Delayed graft function (DGF) was defined as the need for dialysis in the first 7 days posttransplant. Slow graft function (SGF) and IGF were defined by serum creatinine falls of <20% or >20% in the first 24 hours posttransplant respectively. Recovery of renal function was expressed as either the best creatinine clearance (CrCl) in the first 3 months post-renal transplantation (BCrCl-3mos) as calculated using the Cockcroft-Gault formula or as a percentage of actual versus expected value (as calculated from the donors' CrCl at procurement).

Results

There were 140 (23.6%) subjects who received extended criteria donor (ECD) organs. The overall graft survival at 1 and 5 years was 87.8% and 74%, respectively. The 5-year graft survivals for patients with IGF, SGF, and DGF were 85%, 76%, and 54%, respectively (P < .02). ECD kidneys showed twice the DGF rate (49% vs 23%, P < .001). BCrCl-3mos of <30 mL/min displayed a 5-year graft survival of 34%; 30 to 39 mL/min, 72%; 40 to 49 mL/min, 85%; and >50 mL/min, 82% (P < .001). Similarly, a recovery within 90% of expected CrCl in the first 3 months posttransplant correlated with 5-year graft survival of 81%; a recovery of 70% to 90%, with 65%; and a recovery of <70%, with 51% (P < .001).

Conclusion

Early graft function in the first 3 months showed a significant impact on long-term graft survival after deceased donor renal transplantation.     

Effects of various HTK solution regimens on proteinuria after renal transplantation in dogs

Investigations were carried out by means of an autologous, heterotopic model for kidney transplantation applied to dogs. Duration of cold ischemia was 48 h. Four experimental groups were arranged. During the first 20 min following revitalization of the transplanted kidney, group 1 (HTK solution/80 cm perfusion height) showed a significant glomerular and tubular malfunction. In group 2 (HTK solution/120 cm perfusion height), only four urinary proteins with molecular weights of 25 kDa, 67 kDa, 100 kDa and >100 kDa were found. The excretion of higher molecular proteins receded over the 20-min period of observation. In both group 3 (HTK/aspartate solution) and group 4 (HTK/tryptophan solution) the quantity of excreted glomerular and tubular protein was well above that of group 2. As opposed to the Tryptophan group, a complete restoration of renal function was observed in the Aspartate group after 4 weeks. In general, the standard HTK protective solution delivered with 120 cm perfusion pressure gave the most favorable results, with the lowest levels of proteinuria and a satisfactory recovery of renal function after revitalization.     

Long-Term Outcome of Deceased Donor Renal Transplants Correlates with the 30-Day Creatinine Reduction Ratio

A simplified model to correlate early allograft function with long-term allograft survival in recipients of deceased donor renal transplants (DDRT) remains challenging. We propose here a novel approach, using the change from the pretransplant creatinine to the 30-day posttransplant creatinine. The outcomes of 153 consecutive DDRT performed at our center between January 1998 and March 2001 were reviewed. The percentage change in creatinine from the pretransplant to 1 month posttransplant, termed here, the creatinine reduction ratio (CRR), was calculated as follows: (pretransplant creatinine-creatinine at 1 month)/pretransplant creatinine *100%. Patients were divided as follows: group 1 CRR>or=67% and group 2<67%. Group 1 had a graft survival at 1 and 5 years of 100% and 89.1% versus 88% and 69.1% for group 2 (log-rank p=0.0008). The risk ratio for graft loss during the follow-up period was four times lower for the patients on group 1. Using the Cox hazards model to compare CRR>or=67% with determinants of long-term outcome, the risk ratio of graft loss during the observational period was 0.26 (p=0.001). The creatinine reduction ratio, when stratified by a level of >or=67% has a strong correlation with superior long-term allograft survival in recipients of DDRT.     

The Impact of the New Kidney Allocation System on Prior Living Kidney Donors’ Access to Deceased Donor Kidney Transplants: An Early Look

This study investigated the early effects of the new kidney allocation system (KAS) on the access of prior living kidney donors (PLDs) to deceased donor kidney transplants. Using data from the Organ Procurement and Transplantation Network, we compared prevalent and incident cohorts of PLDs in the 1‐year periods before and after KAS implementation (pre‐KAS group: December 4, 2013, to December 3, 2014, n = 50 [newly listed PLDs]; post‐KAS group: December 4, 2014, to December 3, 2015, n = 39). We assessed transplant rates per active patient‐year, waiting times, and Kidney Donor Profile Index (KDPI) of transplanted kidneys. Transplant rates were not statistically different before and after KAS implementation for either prevalent (2.37 vs. 2.29, relative risk [RR] 0.96; 95% confidence interval [CI] 0.62–1.49) or incident (4.76 vs. 4.36, RR 0.92; 95% CI 0.53–1.60) candidates. Median waiting time (MWT) to deceased donor kidney transplant for prevalent PLDs in the post‐KAS cohort was 102.6 days compared with 82.3 days in the pre‐KAS cohort (p = 0.98). The median KDPI for PLD recipients was 31% with KAS versus 23% before KAS (p = 0.02). Despite a sharp decrease in the MWT for highly prioritized candidates with calculated panel reactive antibodies of 98–100% (from >7000 to 1164 days), PLDs still had much shorter waiting times (MWT 102.6 days). The new system continues to provide quick access to high‐quality organs for PLDs.     

UW器官保存液在胰腺移植中的研究进展

近年来,糖尿病发病率在全球呈快速增长的趋势,我国患病率已达到3%.多数Ⅰ型和部分Ⅱ型糖尿病患者需要采用外源性胰岛素注射控制血糖,患者不但要承受胰岛素注射带来的痛苦,而且还不可避免地要发生远期的并发症.因此,重建内源性胰岛分泌系统是近年来人们关注的热点.大量实验表明,胰腺移植不但可以中止胰岛素依赖性糖尿病并发症的发展,还可以转归已有的并发症,明显改善患者的预后.与其他器官移植一样,移植器官的获取及保存是移植成功的前提,由于胰腺组织的特殊性,不同的器官保存液对于保存胰腺效果不一.本文将对University of Wisconsin(UW)保存液在胰腺移植中作用作一论述.     

亲属活体供肾移植86例近期并发症分析

目的：总结和分析86例亲属活体供肾移植的近期并发症和诊治经验。方法：回顾性分析2003年11月～2009年4月86例亲属活体肾移植的临床资料。其中6例为夫妻间供肾,80例为直系血缘亲属供肾。供体均为开放手术取肾,受体首次移植84例,再次移植2例,术后采用环孢素A（或他克莫司）加霉酚酸酯（或硫唑嘌呤）加泼尼松预防排斥反应。结果：86例供体取肾术后7～10天出院,所有供体随访3～12个月,肾功能正常。86例受者中术后发生急性排斥反应8例,均经甲泼尼龙或抗胸腺细胞球蛋白治疗逆转。6例发生术后肺部感染,死亡2例。4例发生移植肾功能延迟恢复,其中1例并发移植肾周血肿合并弥漫性血管内凝血,最后因多器官功能衰竭死亡。术后移植肾周血肿再次手术6例,5例治愈。发生尿瘘6例,经保守治疗痊愈。83例存活者随访至今,其中术后1年发生慢性移植物失功2例,移植肾功能正常81例。结论：活体亲属供肾移植安全、疗效好,术后应高度重视和正确处理并发症,以获得人肾的长期存活。     

Efficient Utilization of the Expanded Criteria Donor (ECD) Deceased Donor Kidney Pool: An Analysis of the Effect of Labeling

We investigated the effect of the expanded criteria donor (ECD) label on (i) recovery of kidneys and (ii) acceptance for transplantation given recovery. An ECD is age ≥ 60, or age 50–59 with ≥ 2 of 3 specified comorbidities. Using data from the Scientific Registry of Transplant Recipients from 1999 to 2005, we modeled recovery rates through linear regression and transplantation probabilities via logistic regression, focusing on organs from donors just‐younger versus just‐older than the ECD age thresholds. We split the sample at July 1, 2002 to determine how decisions changed at the approximate time of implementation of the ECD definition. Before July 2002, the number of recovered kidneys with 0–1 comorbidities dropped at age 60, but transplantation probabilities given recovery did not. After July 2002, the number of recovered kidneys with 0–1 comorbidities rose at age 60, but transplantation probabilities contingent on recovery declined. No similar trends were observed at donor age 50 among donors with ≥ 2 comorbidities. Overall, implementation of the ECD definition coincided with a reversal of an apparent reluctance to recover kidneys from donors over age 59, but increased selectiveness on the part of surgeons/centers with respect to these kidneys.     

Peritransplant Immunoadsorption for Positive Crossmatch Deceased Donor Kidney Transplantation

Various desensitization protocols were shown to enable successful living donor kidney transplantation across a positive complement‐dependent cytotoxicity crossmatch (CDCXM). Positive crossmatch transplantation, however, is less well established for deceased donor transplantation. We report a cohort of 68 deceased donor renal allograft recipients who, on the basis of broad sensitization (lymphocytotoxic panel reactivity ≥40%), were subjected to a protocol of peritransplant immunoadsorption (IA). Treatment consisted of a single session of immediate pretransplant IA (protein A) followed by posttransplant IA and antilymphocyte antibody therapy. Twenty‐one patients had a positive CDCXM, which could be rendered negative by pretransplant apheresis. Solid phase HLA antibody detection revealed preformed donor‐specific antibodies (DSA) in all 21 CDCXM‐positive and in 30 CDCXM‐negative recipients. At 5 years, overall graft survival, death‐censored graft survival and patient survival were 63%, 76% and 87%, respectively, without any differences between CDCXM‐positive, CDCXM‐negative/DSA‐positive and CDCXM‐negative/DSA‐negative recipients. Furthermore, groups did not differ regarding rates of antibody‐mediated rejection (24% vs. 30% vs. 24%, p = 0.84), cellular rejection (14% vs. 23% vs. 18%, p = 0.7) or allograft function (median 5‐year serum creatinine: 1.3 vs. 1.8 vs. 1.7 mg/dL, p = 0.62). Our results suggest that peritransplant IA is an effective strategy for rapid desensitization in deceased donor transplantation.     

Eurotransplant randomized multicenter kidney graft preservation study comparing HTK with UW and Euro-Collins

The aim was to evaluate the effect of HTK compared to UW and Euro-Collins (EC) on the initial graft function and long term graft survival in two prospective randomized studies. Only kidneys from heart-beating, kidney-only or kidney + heart donors were eligible for entry. Initial non-function (INF) was defined as the absence of life-sustaining renal function, requiring dialysis treatment on two or more occasions, during the first week after transplantation. To evaluate the contribution of the preservation solutions on INF in relation to other factors, a multivariate, 2-step logistic regression model was used. Randomization was performed between July 1990 and September 1992. The UW-HTK study comprised 342 donors and 611 transplants (UW: 168 donors and 297 transplants, HTK: 174 donors and 314 transplants). In the EC-HTK study 317 donors and 569 transplants were included (EC: 155 donors and 277 transplants, HTK: 162 donors and 292 transplants). INF occurred in 33 % of either HTK-(n = 105) or UW-(n = 99) preserved kidneys (P = NS), and in 29 % of the HTK-(n = 85) and in 43 % of the EC-(n = 119) preserved kidneys (P = 0.001). Multivariate analysis showed no significant influence of the preservation solution on the incidence of INF in the UW-HTK study, but factors contributing to INF were donor age, cause of death, retransplantation, and cold ischemic period. The EC-HTK study showed a significantly higher risk of INF, using EC as preservation, in addition to cold ischemic period and donor quality. The 3-year graft survival of HTK-preserved kidneys was 73 %, compared to 68 % for UW-preserved kidneys in the UW-HTK study (P = NS); while the 3-year graft survival of HTK preserved kidneys was 70 % compared to 67 % for EC-preserved kidneys in the EC-HTK study (P = NS). We can conclude that HTK is comparable to UW in its preservative abilities, using kidneys from heart-beating kidney-only donors, whereas EC as renal preservation solution should be avoided. Received: 2 November 1998 Received after revision: 10 August 1999 Accepted: 16 September 1999