One hundred ABO-incompatible kidney transplantations between 2004 and 2014: a single-centre experience.

BACKGROUND: ABO-incompatible kidney transplantation (ABOi KTx) expands the living donor transplantation options. However, long-term outcome data, especially in comparison with ABO-compatible kidney transplantation (ABOc KTx), remain limited. Since the first ABOi KTx in Germany on 1 April 2004 at our centre, we have followed 100 ABOi KTx over up to 10 years. METHODS: One hundred ABOi KTx and 248 ABOc KTx from 1 April 2004 until 28 October 2014 were analysed in this observational, single-centre study. Three ABOi KTx and 141 ABOc KTx were excluded because of cyclosporine A-based immunosuppression, and 1 ABOc KTx was lost to follow-up. RESULTS: Median estimated 10-year patient and graft survival in ABOi KTx was 99 and 94%, respectively, and surpassed ABOc-KTx patient and graft survival of 80 and 88%, respectively. The incidence rate of antibody-mediated rejections was 10 and 8%, and that of T-cell-mediated rejections was 17 and 20% in ABOi KTx and ABOc KTx, respectively. Infectious and malignant complications in ABOi KTx were not more common than in ABOc KTx. However, postoperative lymphoceles occurred more frequently in ABOi KTx. Subgroup analysis of ABOi-KTx patients revealed that patients with high-titre isohaemagglutinins before transplantation had equal long-term results compared with low-titre isohaemagglutinin patients. CONCLUSION: Taken together, long-term outcome of ABOi KTx is not inferior to ABOc KTx. Incidences of rejection episodes, infectious complications and malignancies are not increased, despite the more vigorous immunosuppression in ABOi KTx. Our data provide further evidence that ABOi KTx with living donation is a safe, successful and reasonable option to reduce the organ shortage.

Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma.

UNLABELLED: Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide with a poor prognosis and limited therapeutic options. To aid the development of novel immunological interventions, we studied the breadth, frequency, and tumor-infiltration of naturally occurring CD8(+) T-cell responses targeting several tumor-associated antigens (TAA). We used overlapping peptides spanning the entire alpha-fetoprotein (AFP), glypican-3 (GPC-3), melanoma-associated gene-A1 (MAGE-A1) and New York-esophageal squamous cell carcinoma-1 (NY-ESO-1) proteins and major-histocompatibility-complex-class-I-tetramers specific for epitopes of MAGE-A1 and NY-ESO-1 to analyze TAA-specific CD8(+) T-cell responses in a large cohort of HCC patients. After nonspecific expansion in vitro, we detected interferon-γ (IFN-γ)-producing CD8(+) T cells specific for all four TAA in the periphery as well as in liver and tumor tissue. These CD8(+) T-cell responses displayed clear immunodominance patterns within each TAA, but no consistent hierarchy was observed between different TAA. Importantly, the response breadth was highest in early-stage HCC and associated with patient survival. After antigen-specific expansion, TAA-specific CD8(+) T cells were detectable by tetramer staining but impaired in their ability to produce IFN-γ. Furthermore, regulatory T cells (Treg) were increased in HCC lesions. Depletion of Treg from cultures improved TAA-specific CD8(+) T-cell proliferation but did not restore IFN-γ-production. CONCLUSION: Naturally occurring TAA-specific CD8(+) T-cell responses are present in patients with HCC and therefore constitute part of the normal T-cell repertoire. Moreover, the presence of these responses correlates with patient survival. However, the observation of impaired IFN-γ production suggests that the efficacy of such responses is functionally limited. These findings support the development of strategies that aim to enhance the total TAA-specific CD8(+) T-cell response by therapeutic boosting and/or specificity diversification. However, further research will be required to help unlock the full potential of TAA-specific CD8(+) T-cell responses.

Poor organ quality and donor-recipient age mismatch rather than poor donation rates account for the decrease in deceased kidney transplantation rates in a Germany Transplant Center.

Kidney transplantation is limited not by technical or immunological challenges but by lack of donor organs. Whereas the number of patients on waiting list increased, the transplantation rate decreased. We analyzed the development of decline rates and reasons as well as the fate of declined organs. In total, 1403 organs offered to 1950 patients between 2001 and 2010 were included. Of 440 organs offered between 2009 and 2011 that were declined, we investigated whether these organs were transplanted elsewhere and requested delayed graft function, creatinine, graft and patient survival. Data were compared to results of transplantations at the same time at our center. Decline rate increased from 47% to 87%. Main reasons were poor organ quality and donor-recipient age or size mismatch. Of the rejected organs, 55% were transplanted at other centers with function, graft and patient survival equivalent to patients transplanted at our center during that period. The number of decline has increased over time mainly due to a growing number of marginal donors accounting for poor organ quality or a mismatch of donor and recipient. If proper donor-recipient selection is performed, many organs that would otherwise be discarded can be transplanted successfully.

One hundred consecutive kidney transplantations with simultaneous ipsilateral nephrectomy in patients with autosomal dominant polycystic kidney disease.

PURPOSE: Surgical management of autosomal dominant polycystic kidney disease (ADPKD) in patients awaiting renal transplantation is a challenging task. METHODS: From 1998 to 2009, a total of 100 consecutive renal transplantations with simultaneous unilateral nephrectomy were performed in 59 men and 41 women with ADPKD and end-stage renal failure. About 38% received kidney allografts from living donors. The ipsilateral polycystic kidney was removed at the time of renal transplantation. Immunosuppressive therapy was not modified. Cold ischaemia time was 155 (38-204 min) versus 910 min (95-2760 min) for living versus deceased donor transplantation. Mean weight of removed kidneys was 2002 g (414-8850 g). Mean follow-up was 3.0 years (0.8-10.0 years). RESULTS: Overall patient and graft survival were 97 and 96% at 1 year and 93 and 80% at 5 years, respectively. Serum creatinine at current follow-up was 1.49 (0.8-2.8) mg/dL. Surgical complications, which might be associated with simultaneous nephrectomy requiring re-operation, occurred in 12% (lymphocele 4%, hernia 4%, post-operative haematoma or bleeding 4%). None of the patients died peri-operatively. CONCLUSION: Renal transplantation with simultaneous unilateral nephrectomy in ADPKD is a reasonable procedure for patients suffering from massively enlarged native kidneys.

Outcome after repeat resection of liver metastases from colorectal cancer.

INTRODUCTION: Although advances in multimodal treatment have led to prolongation of survival in patients after resection of colorectal liver metastasis (CRC-LM), most patients develop recurrence, which is often confined to the liver. Repeat hepatic resection (RHR) may prolong survival or even provide cure in selected patients. We evaluated the perioperative and long-term outcomes after RHR for CRC-LM in a single institution series. PATIENTS AND METHODS: Since 1999, 92 repeat hepatic resections (63% wedge/segmental, 37% hemihepatectomy or greater) for recurrent CRC-LM were performed in 80 patients. Median interval from initial liver resection to first RHR was 1.25 years. Any kind of chemotherapy (CTx) had been given in 88% before RHR. Neoadjuvant CTx was given in 38%. RESULTS: Hepatic margin-negative resection was achieved in 79%. Mortality was 3.8%. Overall complication rates were 53%, including infection (17%), operative re-intervention (12%), and hepatic failure (5.4%). Overall 5-year survival after first RHR was 50.3%. Univariately, primary tumor stage, the extent of liver resection, postoperative complications, and the overall resection margin correlated with survival. By multivariate analysis, primary T stage, size of metastasis, and overall R0 resection influenced survival. Survival was not independently influenced by hepatic resection margins or (neoadjuvant) CTx. CONCLUSIONS: Repeat hepatic resection for recurrent CRC-LM can be performed with low mortality and acceptable morbidity. Survival after repeat hepatic resection in this selected group of patients is encouraging and comparable to results after first liver resections.

Autosomal dominant polycystic kidney disease: prevalence of renal neoplasias in surgical kidney specimens.

BACKGROUND: The role of autosomal dominant polycystic kidney disease (ADPKD) as a risk factor for renal cell carcinoma (RCC) is still under discussion. Data on prevalence of RCC in ADPKD are limited, especially on a large population scale. The aim of this study was to analyze the prevalence of RCC in ADPKD kidneys and characterize the clinical features of this coincidence. METHODS: Based on our histopathological registry for ADPKD and the Else Kröner-Fresenius Registry, we retrospectively reviewed malignant and benign renal lesions in patients with ADPKD who had undergone renal surgery from 1988 to 2011. RESULTS: 240 ADPKD patients underwent 301 renal surgeries. Mean age at surgery was 54 years. Overall, 16 malignant and 11 benign lesions were analyzed in 301 kidneys (5.3%; 3.7%), meaning that 12/240 (5%; 1:20) patients presented with malignant renal lesions. 66.7% (8/12) of these patients had undergone dialysis prior to surgery. We found 10/16 (63%) papillary RCC, 5/16 (31%) clear cell RCC, and 1/16 (6%) papillary noninvasive urothelial cancer. Regarding all renal lesions, 6/17 (35.3%) patients had more than one histological finding in their kidneys. In 2 cases, metachronous metastases were removed. Mean follow-up was 66.7 months. CONCLUSION: Kidney-related prevalence of RCC in ADPKD kidneys was surprisingly high. Whether or not this is due to chronic dialysis or due to the underlying disease is still speculative. Like other cystic renal diseases with an increased risk for RCC, the attending physician should be aware of the malignant potential of ADPKD, especially with concomitant dialysis.

Analysis of CD161 expression on human CD8+ T cells defines a distinct functional subset with tissue-homing properties.

CD8(+) T lymphocytes play a key role in host defense, in particular against important persistent viruses, although the critical functional properties of such cells in tissue are not fully defined. We have previously observed that CD8(+) T cells specific for tissue-localized viruses such as hepatitis C virus express high levels of the C-type lectin CD161. To explore the significance of this, we examined CD8(+)CD161(+) T cells in healthy donors and those with hepatitis C virus and defined a population of CD8(+) T cells with distinct homing and functional properties. These cells express high levels of CD161 and a pattern of molecules consistent with type 17 differentiation, including cytokines (e.g., IL-17, IL-22), transcription factors (e.g., retinoic acid-related orphan receptor gamma-t, P = 6 x 10(-9); RUNX2, P = 0.004), cytokine receptors (e.g., IL-23R, P = 2 x 10(-7); IL-18 receptor, P = 4 x 10(-6)), and chemokine receptors (e.g., CCR6, P = 3 x 10(-8); CXCR6, P = 3 x 10(-7); CCR2, P = 4 x 10(-7)). CD161(+)CD8(+) T cells were markedly enriched in tissue samples and coexpressed IL-17 with high levels of IFN-gamma and/or IL-22. The levels of polyfunctional cells in tissue was most marked in those with mild disease (P = 0.0006). These data define a T cell lineage that is present already in cord blood and represents as many as one in six circulating CD8(+) T cells in normal humans and a substantial fraction of tissue-infiltrating CD8(+) T cells in chronic inflammation. Such cells play a role in the pathogenesis of chronic hepatitis and arthritis and potentially in other infectious and inflammatory diseases of man.

Impact of preoperative targeted therapy on postoperative complications after resection of colorectal liver metastases.

PURPOSE: The impact of chemotherapy (CTx) on morbidity after liver resection for colorectal metastases (CRC-LM) has been increasingly investigated during recent years. Biologic agents like bevacizumab (BEV) or cetuximab (CET) are now added as "targeted therapy" (TT), also in neoadjuvant settings. Initial series could demonstrate the safety of those regimens in liver resection but data are still scarce. We evaluated the impact of CTx with BEV or CET (CTx + TT) on perioperative morbidity and mortality. METHODS: Two hundred thirty-seven patients who underwent liver resections for CRC-LM after chemotherapy before surgery since 1999 were included. One hundred eighty-five patients (78%) had preoperative CTx regimen without biologic agents (fluoropyrimidine-, oxaliplatin-, or irinotecan-based) and 52 (22%) had CTx + TT (39 BEV, 11 CET, 2 CET/BEV). After preoperative CTx + TT, a time interval of at least 4-6 weeks and a residual liver volume of >35% before surgery were required. RESULTS: Hemihepatectomy or more was performed in about half of the patients. The median amount of intraoperatively transfused blood was 0 ml in both groups (p = 0.34). Overall mortality was 1.7% and slightly elevated in patients with CTx + TT (3.8% vs. 1.1%, p = 0.17). Any complication occurred in (CTx + TT vs. CTx) 52% and 46%, respectively (p = 0.47). The rates of liver failure (9.6% vs. 9.7%, p = 0.98), infectious complications such as wound infection (19% vs. 16%, p = 0.62) and abdominal abscess (8% vs. 6.5%, p = 0.71), as well as the rate of relaparotomies (11.5% vs. 7.0%, p = 0.29) showed no significant differences between the groups with TT or without. In multivariate analyses, neither type nor duration of CTx nor the time interval between CTx and surgery showed any influence on complication rates. CONCLUSIONS: Our data confirm the safety of targeted therapy before liver resection for CRC-LM. This effect may in part be due to our treatment policy (time interval to resection and residual liver volume) after intensive preoperative CTx.

Lack of ex vivo peripheral and intrahepatic α-fetoprotein-specific CD4+ responses in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common malignancies with a poor prognosis and limited therapeutic options that is often characterized by the expression of the tumor-associated antigen α-fetoprotein (AFP). CD4+ helper T cells are important in generating potent anticancer immunity as they prime and expand CD8+ T-cell memory and may also have direct antitumor activity. However, very little information is currently available about the relative frequency, immunodominance and peripheral versus intratumoral distribution of AFP-specific CD4+ T-cell responses in patients with HCC. We, therefore, analyzed AFP-specific CD4+ responses in blood and tumor tissue of patients with HCC by using overlapping peptides spanning the entire AFP protein and novel sensitive approaches such as antigen-specific upregulation of CD154. We found that AFP-specific CD4+ T-cell responses were not detectable in the peripheral blood ex vivo. However, after in vitro stimulation, AFP-specific CD4+ T-cell responses were detectable in a large fraction of patients targeting different previously unreported epitopes with no clear immunodominance. These results indicate that AFP-specific CD4+ T-cell responses are not completely deleted but only present at very low frequencies. Importantly, AFP-specific CD4+ T-cell responses were also rarely detectable in tumor tissue, suggesting that the relative absence of these cells in the circulation ex vivo is not due to a rapid accumulation to the tumor side. Taken together, these results suggest that the lack of sufficient CD4+ T-cell help, especially within the tumor tissue, may be one central mechanism responsible for the failure of AFP-specific immune responses to control HCC progression.

Long-term outcome of ABO-incompatible living donor kidney transplantation based on antigen-specific desensitization. An observational comparative analysis.

BACKGROUND: ABO-incompatible living donor kidney transplantation based on specific conditioning has been successfully adopted by transplant centres worldwide. Excellent short-term results have been reported in small cohorts. However, long-term data and comparative analyses are still sparse. We report on the outcome of 40 consecutive ABO-incompatible living donor kidney transplant recipients and compare their clinical course to a control group of 43 ABO-compatible living donor transplant patients transplanted during the same time period. METHODS: This is an observational single-centre analysis of 40 consecutive patients undergoing ABO-incompatible kidney grafting between April 2004 and April 2009, using a protocol of rituximab, antigen-specific immunoadsorption, intravenous immunoglobulin, basiliximab induction and oral triple immunosuppression with tacrolimus, mycophenolic acid and prednisone. Forty-three ABO-compatible kidney transplant recipients served as controls. The control group had also received basiliximab induction and an identical initial maintenance immunosuppression. The two groups were observed for an average of 39 and 19 months, respectively. RESULTS: There was a significantly higher incidence of lymphoceles requiring surgical revisions in the ABO-incompatible group. However, this surgical complication did not affect patient or graft survival. Mean serum creatinine, estimated glomerular filtration rate and proteinuria did not differ between the two groups. Furthermore, ABO-incompatible and ABO-compatible patients had the same incidence of humoral and cellular rejections. Despite a more aggressive induction therapy, no differences in infectious or malignant complications were observed. CONCLUSIONS: ABO-incompatible living donor kidney transplantation utilizing a combination of rituximab and antigen-specific immunoadsorption yielded results identical to ABO-compatible transplantation despite a significantly higher number of human leukocyte antigen mismatches.

Impact of different crystalloid volume regimes on intestinal anastomotic stability.

BACKGROUND: Anastomotic insufficiency still remains an unsolved problem in digestive surgery. Little clinical data, regarding the impact of perioperative volume management exist, which suggest lower complication rates in intestinal surgery under restrictive volume regimens. The aim of our study was to investigate the effect of the extent of intraoperative fluid administration with crystalloids on the stability of intestinal anastomoses. MATERIAL AND METHODS: Twenty-one rats were randomly assigned to 3 experimental groups (n = 7 rats/group): control group CO (9 mL kg h crystalloid infusion), volume restriction group V (-) (3 mL kg h), and animals with volume overload V (+) (36 mL kg h). After midline incision, all animals received the corresponding infusion for a 30-minute period. Infusion was continued for further 30 minutes whereas an end-to-end small bowel anastomosis was performed 15 cm proximal to the Bauhin valve with 8 nonabsorbable interrupted inverting sutures. At reoperation on the 4th postoperative day, the anastomotic segment was dissected and the bursting pressure [mmHg] was measured. As a second parameter for the quality of anastomotic healing, hydroxyproline concentration was examined with a spectrophotometric method [microg/g dry tissue]. Histologically, structural changes of the anastomotic segments were assessed by 2 pathologists. Data are given as mean +/- SEM. RESULTS: Anastomotic insufficiency was not seen in all animals. Bursting pressure of CO animals was 102 +/- 8 mmHg. Bursting pressure was lowest in V (+) with high volume exposure at 77 +/- 6 mmHg and significantly lower than V (-) (112 +/- 9 mmHg; P = 0.01) whereas the difference compared with the CO group did not reach significant values. Hydroxyproline concentration in V (+) (64.4 microg/g dry tissue +/- 7.7) was significantly lower compared with V (-) (91.7 microg/g dry tissue +/- 9.1) animals (P < 0.05). In all animals with volume overload a marked submucosal edema was found. CONCLUSION: We could demonstrate for the first time in a systematic investigation, that the quantity of crystalloid infusion, applied intraoperatively, has a significant impact on functional (bursting pressure) and structural (hydroxyproline) stability of intestinal anastomoses in the early postoperative period. Because the stability and quality of an intestinal anastomosis have an impact on insufficiency rates, it should be noted that volume overload may have deleterious effects on anastomotic healing and postoperative complications in digestive surgery, possibly because of a marked bowel wall edema.

Long-term results after intraoperative radiation therapy for gastric cancer.

PURPOSE: We retrospectively analyzed the impact of intraoperative radiation therapy (IORT) on long-term survival in patients with resectable gastric cancer. METHODS AND MATERIALS: From 1991 to 2001, a total of 84 patients with gastric neoplasms underwent gastectomy or subtotal resection with IORT (23 Gy, 6-15 MeV; IORT-positive [IORT(+)] group). Patients with a history of additional neoadjuvant chemotherapy, histologically confirmed R1 or R2 resection, or reoperation with curative intention after local recurrence were excluded from further analysis. The remaining 61 patients were retrospectively matched with 61 patients without IORT (IORT-negative [IORT(-)] group) for Union Internationale Contre le Cancer (UICC) stage, patient age, histologic grading, extent of surgery, and level of lymph node dissection. Subgroups included postoperative UICC Stages I (n = 31), II (n = 11), III (n = 14), and IV (n = 5). RESULTS: Mean follow-up was 4.8 years in the IORT(+) group and 5.0 years in the IORT(-) group. The overall 5-year patient survival rate was 58% in the IORT(+) group vs. 59% in the IORT(-) group (p = 0.99). Subgroup analysis showed no impact of IORT on 5-year patient survival for those with UICC Stages I/II (76% vs. 80%; p = 0.87) and III/IV (21% vs. 14%, IORT(+) vs. IORT(-) group; p = 0.30). Perioperative mortality rates were 4.9% and 4.9% in the IORT(+) vs. IORT(-) group. Total surgical complications were more common in the IORT(+) than IORT(-) group (44.3% vs. 19.7%; p < 0.05). The locoregional tumor recurrence rate was 9.8% in the IORT(+) group. CONCLUSIONS: Use of IORT was associated with low locoregional tumor recurrence, but had no benefit on long-term survival while significantly increasing surgical morbidity in patients with curable gastric cancer.

Preemptive postoperative antigen-specific immunoadsorption in ABO-incompatible kidney transplantation: necessary or not?

Several standard protocols for ABO-incompatible kidney transplantation use scheduled preemptive antigen-specific immunoadsorption during the postoperative period. Our center has developed a different approach. Our patients undergo antigen-specific immunoadsorption postoperatively only if their isoagglutinine titers (immunoglobulin G anti-A/B) exceed 1:8 in the first postoperative week and 1:16 in the second postoperative week. Using this strategy, 22 ABO-incompatible kidney transplantations have been performed at our center since 2004. Only 32% of these patients (7 of 22) needed to undergo postoperative immunoadsorption (mean 4.1 immunoadsorption sessions per patient). The renal outcome in patients receiving postoperative immunoadsorption treatment versus the outcome in patients without postoperative immunoadsorption remained equal at a mean follow-up of 17 months. We identified a shorter pretransplant time on dialysis, a blood type constellation of donor A1/recipient O, and high initial starting titers as predictors for the need for postoperative immunoadsorption treatment. A more detailed version of this study, with modified tables and figures, has been accepted for publication in Nephrology Dialysis Transplantation.

[Kidney transplantation with simultaneous nephrectomy: inappropriate or sensible?]. / Krankes Organ entfernen oder nicht?

In conventional single kidney transplantation, the patient's kidneys are left in place. However, in certain patient collectives, the removal of the kidney may be indicated under some circumstances. This applies especially to patients whose own kidney may be a source of infection, bleeding, severe proteinuria and physical impairment due to a considerable increase in the kidney volume (cystic kidneys). Up until now, the procedure planned for either a bilateral nephrectomy after inclusion on the waiting list or a sequential procedure, which involves nephrectomy of one kidney and the removal of the other after kidney transplantation (sandwich technique). The concept presented here, kidney transplantation with concomitant ipsilateral nephrectomy is a safe procedure that leads to neither a significant increase in the incidence of surgical complications nor to a decrease in patient-and transplant survival. The major advantage of this method, in addition to a high measure of patient satisfaction, is the definitive surgical restoration of the kidney transplant recipient on the transplanted side with only one surgical intervention.

Kidney transplantation with concomitant unilateral nephrectomy: a matched-pair analysis on complications and outcome.

BACKGROUND: We sought to determine the impact of kidney transplantation with simultaneous unilateral nephrectomy on perioperative morbidity and patient and graft survival. METHODS: From January 1990 to May 2004, 75 kidney transplantations with simultaneous unilateral nephrectomy (group NE+) were performed at the University of Freiburg. Of these, 49 had polycystic kidney disease. Patients of group NE+ were matched with 75 kidney transplants without nephrectomy (group NE-). Immunosuppressive maintenance therapy in both groups was based on cyclosporine A, mycophenolate mofetil or azathioprine, and prednisone. Mean follow up was 4.1 yrs (range 0.3-11.7 yrs). RESULTS: Patient survival rate at 1 and 5 yrs was 95% and 84% versus 95% and 93% in group NE+ and NE-, resp. (P=0.56). Accordingly, kidney function rate was 85% and 74% in group NE+ versus 89% and 79% in group NE- (P=0.89). Perioperative (90 days) mortality rate in group NE+ was 1.3% and 2.7% in group NE- (P=0.56). Perioperative surgical complications were similar in both groups. CONCLUSIONS: Kidney transplantation with concomitant unilateral nephrectomy has no negative impact on patient or graft survival and is associated with a reasonable morbidity rate.

Characterization of ischemia/reperfusion-induced gene expression in experimental pancreas transplantation.

BACKGROUND: The aim of this study was to identify genes that are differentially expressed in the early period after pancreatic cold ischemia/reperfusion (I/R) injury. METHODS: Grafts of isogeneic rat pancreaticoduodenal transplantation were subjected to different preservation solutions and cold ischemia times (CITs): University of Wisconsin (UW), 6-hour CIT; UW, 18-hour CIT; and physiologic saline solution, 6-hour CIT. Animals that did not receive transplants served as controls. At 2-hour reperfusion, grafts were removed and pancreatic RNA was isolated, pooled, and hybridized to Affymetrix RG-U34A arrays. Quantitative reverse-transcription polymerase chain reaction was used to confirm the results of microarray technology. RESULTS: A total of 49 genes were consistently upregulated (more than threefold) in all three groups of transplant recipient animals. Prominent genes include transcription factors; cytoskeletal factors; heat-shock proteins (e.g. Hsp27, Hsp90); molecules involved in inflammation (e.g. PAPIII), immunology, signal transduction, and translation; and genes that have not been associated with I/R injury so far (e.g. Best5). Messenger RNA levels of some genes were exclusively downregulated in response to the different conditions applied to the pancreatic grafts: Cybb, Reg3a, Per2, BMAL1, MAP, and Isl2. CONCLUSIONS: These results provide new insight in I/R-induced gene expression after experimental pancreas transplantation. The reported upregulation of heat shock proteins, Best5, and PAPIII may play a pathologic role in pancreatic cold I/R injury and could therefore provide a promising perspective for further investigations.

Long-term follow-up of 78 simultaneous pancreas-kidney transplants at a single-center institution in Europe.

BACKGROUND: The objective of this study was to determine the long-term results after simultaneous pancreas-kidney transplantation (SPK) at a single-center institution in Europe. PATIENTS AND METHODS: Seventy-eight consecutive patients with insulin-dependent diabetes mellitus and end-stage nephropathy were followed for a median of 7 years after SPK. Immunosuppressive protocol consisted of cyclosporine A, azathioprine, prednisone, and antithymocyte globulin. Multivariate Cox proportional hazard model was used to investigate the impact of different putative risk factors on long-term patient survival. Health-related quality of life was assessed by a validated questionnaire (SF-36). RESULTS: Patient survival at 5 and 10 years was 81% and 67%, respectively. Pancreas function rate was 73% and 60% and kidney function 67% and 44%, respectively. In multivariate analysis, preexisting myocardial infarction (relative risk [RR] 5.1, 95% confidence interval [CI] 1.5-16.6) and amputation (RR 3.7, 95% CI 1.1-12.9) were strongly associated with a diminished long-term patient survival. Analysis of patients with long-term functioning pancreas and kidney grafts revealed excellent results for quality of life posttransplant that were comparable with average scores of the normal German population. CONCLUSIONS: This series representing the largest experience with long-term follow-up in Europe confirms an excellent long-term survival and an exceptional quality of life after SPK.

Postoperative oral glucose tolerance and stimulated insulin secretion: a predictor of endocrine graft function more than 10 years after pancreas-kidney transplantation.

BACKGROUND: After pancreas transplantation, endocrine function is determined by the insulin secretory capacity of the transplanted pancreas. The authors evaluated the predictive value of postoperative oral glucose tolerance test (OGTT) and stimulated insulin secretion on long-term endocrine function. METHODS: Forty-one patients after pancreas-kidney transplantation with systemic venous drainage were studied. Patients were categorized to have normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) (World Health Organization criteria: NGT, <7.8 mM; IGT, 7.8-11.1 mM 120 min after glucose intake) and high or low total insulin secretion. Mean follow-up of graft function and patient outcome was 10.2+/-0.5 years after OGTT. RESULTS: Patients with IGT had grafts with a longer ischemia time and a significantly worse urine amylase excretion as compared with patients with NGT. Using Kaplan-Meier survival analysis, patients with NGT had better long-term pancreatic function as compared with IGT in the follow-up after performing the first OGTT (mean, 10.9+/-0.2 vs. 8.8+/-0.9 years of graft function; P=0.02), but there was no difference in patient survival and kidney graft function. Also, high insulin secretion predicted significantly longer pancreas graft function as compared with low insulin secretion (P=0.04). CONCLUSIONS: Although IGT does not lead to poorer long-term patient survival and kidney graft function, it does predict compromised long-term endocrine function of the transplanted pancreas. Therefore, postoperative OGTT are useful tools for identification of patients at risk of long-term endocrine graft failure after pancreas transplantation.

Impact of transplant nephrectomy on peak PRA levels and outcome after kidney re-transplantation.

AIM: To determine the impact of transplant nephrectomy on peak panel reactive antibody (PRA) levels, patient and graft survival in kidney re-transplants. METHODS: From 1969 to 2006, a total of 609 kidney re-transplantations were performed at the University of Freiburg and the Campus Benjamin Franklin of the University of Berlin. Patients with PRA levels above (5%) before first kidney transplantation were excluded from further analysis (n = 304). Patients with graft nephrectomy (n = 245, NE+) were retrospectively compared to 60 kidney re-transplants without prior graft nephrectomy (NE-). RESULTS: Peak PRA levels between the first and the second transplantation were higher in patients undergoing graft nephrectomy (P = 0.098), whereas the last PRA levels before the second kidney transplantation did not differ between the groups. Age adjusted survival for the second kidney graft, censored for death with functioning graft, were comparable in both groups. Waiting time between first and second transplantation did not influence the graft survival significantly in the group that underwent nephrectomy. In contrast, patients without nephrectomy experienced better graft survival rates when re-transplantation was performed within one year after graft loss (P = 0.033). Age adjusted patient survival rates at 1 and 5 years were 94.1% and 86.3% vs 83.1% and 75.4% group NE+ and NE-, respectively (P < 0.01). CONCLUSION: Transplant nephrectomy leads to a temporary increase in PRA levels that normalize before kidney re-transplantation. In patients without nephrectomy of a non-viable kidney graft timing of re-transplantation significantly influences graft survival after a second transplantation. Most importantly, transplant nephrectomy is associated with a significantly longer patient survival.

Hyperacute rejection of a living unrelated kidney graft.

We present a case report of a 59-year-old man, who received a blood group identical living unrelated kidney graft. This was his second kidney transplantation. Pretransplant T-cell crossmatch resulted negative. B-cell crossmatch, which is not considered a strict contraindication for transplantation, resulted positive. During surgery no abnormalities occurred. Four hours after the transplantation diuresis suddenly decreased. In an immediately performed relaparotomy the transplanted kidney showed signs of hyperacute rejection and had to be removed. Pathological examination was consistent with hyperacute rejection. Depositions of IgM or IgG antibodies were not present in pathologic evaluation of the rejected kidney, suggesting that no irregular endothelial specific antibodies had been involved in the rejection. We recommend examining more closely recipients of second allografts, considering not only a positive T-cell crossmatch but also a positive B-cell crossmatch as exclusion criteria for transplantation.