The influence of innate immunity gene receptors polymorphisms in renal transplant infections

BACKGROUND: Genetically defined deficiencies in key components of the innate immune system have been associated with a greater risk of infection. The aim of this study was to assess the influence of genetic variability of innate immune receptors (mannose-binding lectin [MBL], mannose-associated serine-protease-2 [MASP-2], and Toll-like receptors [TLR4]) in the risk of infections after a kidney transplantation. METHODS: All patients undergoing a kidney or kidney-pancreas transplantation during a 3-year period were included. Functionally relevant mutations in MBL2, MASP2, and TLR4 genes were determined by DNA sequencing. The incidence of major bacterial infections, asymptomatic cytomegalovirus (CMV) infection, and CMV disease were compared among groups. RESULTS: There were no differences regarding major transplant characteristics among groups. Older age, requirements for posttransplant hemodialysis, and pretransplant diabetes, but not gene polymorphisms, were associated with a greater number of bacterial infections. In univariate analysis, low-MBL genotypes were associated with CMV disease in pretransplant CMV seropositive patients (P=0.015), whereas the TLR4 mutation was associated with higher risk of CMV primary infection (P=0.024). TLR4 mutation was an independent factor associated with CMV disease (odds ratio 5.84, 95% confidence interval 1.35-25.20, P=0.018). CONCLUSION: Polymorphisms of innate immunity receptors, especially TLR4 mutation, were associated with higher risk of CMV disease, while susceptibility to other infectious disorders was not observed.     

The impact of CTLA4 and PTPN22 genes polymorphisms on long-term renal allograft function and transplant outcomes

Abstract

Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) downregulates the immune system. Lymphoid tyrosine phosphatase (Lyp)—PTPN22 protein—is suggested to be negative regulator of T-cell reaction. There are several polymorphisms in the CTLA4 and PTPN22 genes, which can influence the immune response and allograft function after kidney transplantation. The aim of this study was to examine the impact of CTLA4 and PTPN22 genes polymorphisms on the long-term renal transplant function and recipients’ outcomes during a 5-year follow-up observation. The study enrolled 268 Caucasian renal transplant recipients. Genotyping of the rs231775 (+49AG) CTLA4 gene polymorphism was performed using real-time PCR and rs2476601 (C1858T) PTPN22 gene polymorphism using PCR-RFLP method. The 5-year graft survival rate was 81.7%. Dialysis was necessary in 22 (8%) patients, 7 (2.6%) patients died and 20 (7.4%) switched to another transplantation center. We found no association between studied polymorphisms and graft loss/dialysis. Comparison of the distribution of the +49AG CTLA4 and C1858T PTPN22 genes polymorphisms genotypes among dead and living patients showed no statistically significant differences. Above results suggest that the rs231775 (+49AG) CTLA4 and rs2476601 (C1858T) PTPN22 genes polymorphisms are not associated with long-term allograft failure, graft loss and mortality after transplantation.     

Possible association of CTLA-4 gene polymorphism with cyclosporine-induced gingival overgrowth in kidney transplant recipients

T-lymphocytes may play a role in the pathogenesis of inflammatory periodontal diseases and cyclosporine (CsA)-induced gingival overgrowth (GO). The gene encoding CTLA-4 (Cytotoxic T-lymphocyte antigen 4, a molecule influencing T-cell activation), is known to have a single nucleotide polymorphism (SNP) in promoter C>T -318; an exon 1 A>G 49, and a microsatellite dinucleotide repeat polymorphism (AT)(n) in exon 4. The purpose of this study was to analyze the possible influence of polymorphisms of CTLA-4, interleukin (IL)-2, and tumor necrosis factor (TNF)-alpha on GO incidence in eighty two renal transplant recipients. 34 CsA-treated with significant GO (CsAGO+); 22, CsA-treated with no GO (CsAGO-), and 26 tacrolimus (Tac)-treated without GO (TacGO-). The SNPs of CTLA-4 (-318 C>T and +49 A>G), IL-2 (-330T>G), and TNF-alpha (-308 G>A) were determined by SSP-PCR methods. The CTLA-4 (AT)(n) genotype was determined using polymerase chain reaction and fluorescence-based analysis with capillary electrophoresis. Allele frequencies in all patient groups were similar for CTLA-4 -318C>T, IL-2, and TNF-alpha. However, patients with CsAGO+ showed differences from CsAGO- for allele and genotype frequencies in position +49A>G of the CTLA-4 gene. The +49G allele was two times less frequent among CsAGO+ than CsAGO- (P = .0052; P corrected = .008). Slight differences between CsAGO+ and CsAGO- were noticed for the genotype distribution of CTLA-4 (AT)(n) (P = .056). The results suggested that appearance of an adenosine allele(A) in position +49 of the CTLA-4 gene may be a permissive element for CsA-induced GO.     

Prolongation of liver xenograft survival by adenovirus vector-mediated CTLA-4Ig gene transfer

Cytotoxic T lymphocyte-associated antigen-4/immunoglobulin fusion products (CTLA-4Ig), a structural homologue of CD28, has been shown to inhibit cellular and humoral immune responses. In this study, we investigated the efficacy of an adenovirus vector containing the CTLA-4Ig gene (AdCTLA-4Ig) on recipient survival after hamster-to-rat liver xenografting. AdCTLA-4Ig was administrated intravenously immediately after grafting. Gene expression was achieved a maximum of 7 days after vector injection and continued for more than 4 weeks. The proportion of CD25(+) T-cells in recipient lymph nodes was significantly reduced 7 days after administration of AdCTLA-4Ig, compared to a group given an adenoviral vector containing LacZ gene (AdLacZ) or to an untreated control group. AdCTLA-4Ig markedly reduced CD2(+) T-cell infiltration into the graft and significantly prolonged recipient survival time (9.2+/-4.12 days), compared to the untreated group (5.4+/-0.78 days) (P<0.001) and the AdLacZ-treated group (5.2+/-0.28 days) (P<0.001). These results indicate that a blockade of T-cell co-stimulation by AdCTLA-4Ig inhibited T-cell activation and attenuated CD2(+) T-cell infiltration into the xenograft, resulting in significant prolongation of recipient survival time. Thus, AdCTLA-4Ig therapy may provide a novel approach to immune regulation.     

Immune response gene polymorphisms in renal transplant recipients

BACKGROUND: T-cell activation and regulation are under genetic control and vary between individuals. However, the influence of functional immune response gene polymorphisms on transplant outcomes remains controversial. METHODS: A case-control design compared 100 white renal transplant recipients with or without acute graft rejection during the first year posttransplant and 50 normal controls. The polymorphic frequencies of the T-cell signaling genes CD45, CD40L and CTLA-4, and the cytokine genes TNF-alpha, IFN-gamma, IL-10 and TGF-beta1 were studied. The primary analysis examined rejection risk, and subsidiary analyses graft failure and patient death. RESULTS: Multivariate analysis showed no significant association between acute rejection and single nucleotide polymorphisms in CTLA-4, TGF-beta1, IL-10 or TNF-alpha genes or dinucleotide repeat polymorphisms in IFN-gamma and CD40L genes. Allele CD40L-147 was associated with reduced graft failure (P=0.004), and TGFb-25pro with increased graft failure (P=0.0007), although the latter showed a bidirectional dose effect. There was no significant association between patient death and any polymorphisms in the genes examined. The variant (G) allele of the CD45 gene was not detected in the study population. Minor differences in carriage rates observed by univariate analysis did not predict graft or patient outcome in multivariate analysis. CONCLUSION: The primary analysis demonstrated no significant association between the immune response gene polymorphisms examined and acute renal graft rejection in Caucasian patients receiving triple immunosuppression. Subsidiary analyses suggesting an influence of CD40L and TGFbeta1 genes on graft survival require independent confirmation.     

Domino liver transplant: influence on the number of donors and transplant coordination

The shortage of organs forces coordinators to seek new forms of generating organs for transplantation of the increasing numbers of patients on waiting lists. A recent technique called sequential transplant or domino liver transplant (DLT) allows the transplantation of a patient with chronic liver disease by implantation of a full-size liver derived from a patient with familial amyloidosis polyneuropathy (FAP) who receives a cadaveric graft. Therefore, it is possible to transplant two patients with only one cadaveric liver. The present report illustrates the use of this technique for the first time in our country, thereby increasing the number of hepatic transplants by 25%.     

生长激素对肝移植患者术后恢复的影响

目的 了解肝移植术后使用重组生长激素(rhGH)对患者蛋白质代谢的影响和其安全性.方法 随机选择40例肝移植患者分为对照组和治疗组,每组各20例.治疗组在术后使用重组生长激素和肠外营养,对照组仅使用肠外营养,观察两组患者术后肝、肾功能,总蛋白和白蛋白水平的变化.结果 治疗组在经过10d重组生长激素治疗后总蛋白和白蛋白水平明显高于治疗前,总蛋白水平显著高于对照组,两组患者的肝、肾功能恢复和排斥反应发生率相似.结论 肝移植术后使用重组生长激素,可以有效提高患者的蛋白水平,有利于患者恢复.     

Renal biopsy donor group: the influence of glomerulosclerosis on transplant outcomes

The UNOS donor population was examined from 1999 to 2002, and approximately 25% of the over 23,000 donors were biopsied (Bx). There was a significant trend (P < .001) of older donors, cardiovascular accident, and hypertension in the Bx group versus the non-Bx group. The percent GS was directly correlated (P < .001) to graft survival, delayed graft function, and primary nonfunction. Cox regression showed significant relative risk (RR) for >10% GS, hypertension, donors over the age of 50, and African American recipients. RR in donors with >10% GS could be ameliorated (P < .001) by choosing donors with <5 HLA-A, -B, or -DR mismatches (MM), or recipients who were nonsensitized, and/or first transplant. Risk should be managed in donors by choosing appropriate recipients and high-risk immunosuppresion protocols.     

Splenic embolization in liver transplant recipients: early outcomes

Clinical improvement has been reported following splenic embolization for a wide variety of indications. Improvement following splenic embolization has been described in cirrhotic patients awaiting hepatic transplantation who are not candidates for surgical splenectomy. Occasionally, patients who have undergone hepatic transplantation have conditions that may also benefit from nonsurgical intervention with splenic embolization. Indications include persistent hypersplenism and pancytopenia precluding optimal treatment with antiviral therapy or chemotherapy, risk for persistent gastroesophageal variceal hemorrhage, and splenic artery steal syndrome attenuating hepatic arterial perfusion. Limited data is available on the outcome of splenic embolization in liver transplant recipients. We present the early outcomes of liver transplant recipients who were treated with splenic embolization. A retrospective chart review of all liver transplant recipients who underwent splenic embolization between 1997 and 2006 was performed, under minimal-risk study approval by the institutional review board. Five liver transplant recipients received splenic embolization: 3 for persistent hypersplenism, 1 for increased risk of gastroesophageal variceal hemorrhage, and 1 for splenic artery steal syndrome. The patients with hypersplenism demonstrated hematologic improvement, the patient with gastroesophageal varices did not experience any hemorrhage on follow-up, and the patient with splenic artery steal experienced resolution of the steal phenomenon. Postembolization syndrome was observed but no splenic abscess or death occurred. Mean follow-up was 20.2 months. In conclusion, splenic embolization is a safe and effective nonsurgical alternative for a variety of indications in liver transplant recipients.     

The effect of obesity on renal transplant outcomes

BACKGROUND: Although obesity has been associated with improved survival on dialysis, its effects on renal transplant outcomes remain unclear. Previous studies have reported conflicting findings and have been limited by the use of outdated patient data, univariate analyses, and liberal transplant selection criteria. The present study aimed to evaluate the effect of obesity on renal transplant outcomes in a rigorously screened population. METHODS: A retrospective analysis was undertaken of all patients transplanted at the Princess Alexandra Hospital from 1 April 1994 to 31 March 2000. Patients were rigorously screened for cardiovascular disease before acceptance for transplantation. The effects of obesity on renal transplant outcomes were assessed by logistic and multivariate Cox regressions. RESULTS: Of the 493 patients transplanted, 59 (12%) were obese (body mass index [BMI] 30 kg/m ). Obese patients were more likely to experience superficial wound breakdown (14% vs. 4%, P<0.01) and complete wound dehiscence (3% vs. 0%, P<0.01). Wound infections also tended to be more frequent in obese recipients (15% vs. 8%, P=0.11). There were no significant differences between the two groups with respect to operative duration, postoperative complications, hospitalization, delayed graft function, or acute rejection episodes. Five-year actuarial survival rates were comparable between the two groups with respect to graft survival (83% vs. 84%, P=NS) and patient survival (91% vs. 91%, P=NS). On multivariate analysis, BMI was an independent risk factor for wound breakdown (odds ratio 1.21, 95% CI 1.09-1.34, P<0.001), but not for other posttransplant complications, hospitalization, graft loss, or patient survival. CONCLUSIONS: The only significant adverse effect of obesity on renal transplant outcomes was an increase in wound complications, which were generally of minor consequence. Provided that adequate care is taken to avoid transplanting patients with significant cardiovascular disease, obese recipients can achieve excellent long-term patient and graft survivals that are on par with their nonobese counterparts. Denying patients access to renal transplantation on the basis of obesity per se does not appear to be justified.     

Prevalence of donor-transmitted coronary artery disease and its influence on heart transplant outcomes

Background

It is uncertain whether donor-transmitted coronary artery disease (DTCAD) affects heart transplant (HT) recipients.

Methods

This retrospective analysis includes records of all patients who underwent a HT at our center over an 8-year period, who survived for at least 1 month, and who were examined by coronary angiography within 2 months post-HT. We distinguished angiographically from keep ultrasonography (IVUS) detected DTCAD. Major adverse cardiovascular events (MACE) comprised death, myocardial infarction, unstable angina, coronary revascularization, and admission because of heart failure not due to an acute rejection episode.

Results

Among the 171 patients of mean age 53 ± 13 years and including 83% men, 65 (38%) were evaluated by IVUS. Donors were aged 40 ± 14 years (range = 14-73). Angiographic DTCAD affected seven patients (4.1%), and IVUS-detected DTCAD, 35 (53.8% of those examined by IVUS). DTCAD donors were older than non-DTCAD donors, by an average of 13 years (P = .001) for angiographic DTCAD and 18 years (P < .0001) for IVUS-detected DTCAD. Two patients underwent percutaneous revascularization upon detection of angiographic DTCAD. The angiographic- and IVUS-detected DTCAD groups did not differ significantly from the corresponding non-DTCAD groups as regards MACE incidence during 54 ± 41 and 38 ± 20 months follow-up, respectively. Cox regression analysis with adjustment for relevant confounders confirmed that IVUS-detected DTCAD was not a predictor of MACE (hazard ratio 1.2, 95% confidence interval 0.2-8.1).

Conclusions

Among HT patients surviving ≥ 1 month, angiographic- and IVUS-detected DTCAD showed prevalences of <10% and >50%, respectively. Neither detection method was associated with a greater long-term incidence of MACE.     

共刺激信号阻断剂基因局部转染对大鼠移植肾存活的影响

目的　观察CTLA 4Ig基因局部转染延长移植肾存活的效能。 方法　以CTLA 4Ig基因重组腺病毒为载体 ,将CTLA 4Ig基因转入BN大鼠肾脏。以BN大鼠为供者 ,Lewis大鼠为受者 ,行同种肾移植术。用经CTLA 4Ig基因转染的供肾移植给受者为转染组 ;用未转染CTLA 4Ig基因的供肾移植给受者为对照组。观察移植肾存活时间和术后肾功能变化。结果　转染组移植肾存活 (32± 8.0 )d ,对照组移植肾存活 (8.5± 1.4 )d ,转染组存活时间明显延长 ;转染组术后血清肌酐较同期对照组明显为低。结论　CTLA 4Ig基因局部转染供肾可明显延长移植肾的存活时间。     

The influence of organ acceptance criteria on long-term graft survival: outcomes of a kidney transplant program

BACKGROUND: In an effort to improve our transplant program's dead-donor kidney acceptance criteria, we compared 2 different consecutive time periods in our transplant program. Period I, in which the program used more-restrictive criteria in accepting dead-donor kidneys for our patients, and period II, when the program used less-restrictive criteria for the dead-donor kidneys that were accepted. The less-restrictive criteria resulted in an increase in the number of renal transplants performed. METHODS: A retrospective database analysis was performed of all organ-donor offers to a single kidney transplant program from July 1, 2004, to September 30, 2006 (period I = July 1, 2004, through July 10, 2005, and period II = July 11, 2005 through September 30, 2006). Kidney acceptance rates were compared between 2 consecutive time periods during which the program used different organ acceptance criteria. Data analysis included a comparison of donor characteristics, reason for organ refusal, creatinine clearance, and graft survival. Graft survival was obtained for both kidneys associated with each offer, even if 1 or both of the organs were transplanted at a different center. RESULTS: Donor age and kidney quality were the most common reasons for refusal during both transplant periods. The organ acceptance rate improved markedly during period II. There was a marked increase in the number of kidney transplants performed during a 12-month period when comparing the 2 periods: 16 transplants during period I versus 46 transplants during period II. Graft survival was not significantly different between the 2 periods. Calculated creatinine clearance, which we used as a marker of organ quality, was statistically lower during period II. CONCLUSIONS: Increased acceptance rate was not associated with statistically significant decreased graft survival. Although an increase in delayed graft function was associated with broader acceptance criteria, this factor did not affect overall graft survival. By increasing our kidney acceptance rate, we were able to successfully transplant more patients.     

The hepatorenal syndrome in liver transplant recipients.

The hepatorenal syndrome (HRS) is a well-known complication of liver failure, and medical treatment is usually not successful unless liver function can be improved. The authors review their experience with 130 adults undergoing orthotopic liver transplantation (OLT) over a 20-month period to determine the incidence of HRS and its effects on patient outcome, need for hemodialysis (HD), and the degree of recovery of renal function. The clinical diagnosis of HRS preoperatively was made by using criteria to exclude prerenal azotemia, acute tubular necrosis, and primary renal diseases. Nineteen patients were identified as having the HRS for a preoperative incidence of 15.1 per cent. Overall, 41 of the 126 patients reviewed required postoperative HD, and the mortality in this group was 54 per cent. Fifty-eight per cent of the HRS patients were dialyzed postoperatively vs 28 per cent of non-HRS patients. The mean posttransplant creatinine improved over time in the HRS patients while it worsened slightly in the non-HRS group. At 12 weeks posttransplant, there was a significant difference in the mean creatinine levels (1.8 +/- 0.3 mg/dl vs 1.2 +/- 0.04 mg/dl, P = .001). However, at 24 weeks the small difference was not statistically significant between the two groups (1.6 +/- 0.15 mg/dl vs 1.3 +/- 0.06 mg/dl, P = NS). The current survival of the hepatorenal group is comparable to the nonhepatorenal patients at a follow-up of 6 to 25 months: 68 per cent vs 78 per cent, P = NS. The authors conclude that liver transplantation reverses the HRS, and that hepatorenal patients can undergo liver transplantation with outcomes comparable to nonhepatorenal patients.     

Incidence and clinical outcomes of ventilator-associated pneumonia in liver transplant and non-liver transplant surgical patients

The aim of this study was to compare the incidence of ventilator-associated pneumonia (VAP) and clinical outcome among patients undergoing orthotopic liver transplantation (OLT) admitted to our surgical intensive care unit (ICU). Patients with an ICU stay longer than 4 days who had undergone surgery within 48 hours of admission were included in the study. Patients were subdivided into a liver transplant group (OLT) and no-liver transplant group (noLT). Diagnosis of VAP was based on microbiological data with a positive culture from a sample collected >or=48 hours after admission. VAP was defined as early if the positive culture occurred within the 4th day of admission, and late if after the 4th day. Three hundred seventy-three noLT and 71 OLT patients showed no differences in sex, mean severity score on admission (SAPS II), length of stay, and outcomes. The incidence of VAP was also similar in the 2 groups (27.3% in the noLT group vs 25.3% in the OLT group). Both in the OLT and noLT groups, the VAP patients showed higher (P< .05) SAPS II scores on admission, length of ICU stay, and mortality rates than the non-VAP patients, without any difference between the 2 groups. VAP is a frequent complication in ICU surgical patients, particularly those with high severity scores on admission. In an ICU surgical population, liver transplantation per se does not seem to increase the patients' risk either for VAP acquisition or for bad outcomes.