FTO rs9939609 Gene Polymorphism and Obesity: Lack of Association in Kidney Transplantation.

The fat mass and obesity-associated (FTO) gene is one of the most important obesity susceptibility genes. Some FTO gene polymorphisms have been associated with obesity, diabetes, and hypertension, all conditions for which, after transplant, there is increased susceptibility, due to effects of immunosuppressive regimens. To evaluate whether FTO could be a candidate for targeted preventive intervention in the transplant setting, we investigated whether the common genetic variation, FTO rs9939609T>A, could affect weight gain and risk of cardiovascular complications in kidney transplantation. METHODS: In 198 kidney transplant recipients, FTO rs9939609 was investigated in association with body mass index (BMI)/obesity and with other clinical markers of posttransplant risk, then monitored up to 5 years after transplantation. Genotyping was performed using an allelic discrimination method on a real-time polymerase chain (PCR) system. Associations were analyzed using the chi-square test; differences between genotypes were examined with analysis of variance or Kruskal-Wallis test; tests for repeated measures and a general linear model analysis controlling for age and gender were also utilized. RESULTS: Allele and genotype frequencies of FTO rs9939609 in recipients (T/T, 29.8%; T/A, 49.0%; A/A, 21.2%; A, 45.7%; T, 54.3%) reflect those present in healthy Caucasian populations. In the face of pre-/posttransplant differences in total cholesterol, triglycerides, or fasting glucose, results did not show significant changes in these factors among genotypes either before or after transplantation. CONCLUSION: This study highlights a lack of association of FTO rs9939609T>A genotypes and posttransplant weight gain, plasma lipids, and fasting blood glucose in kidney transplantation.

Kidney Transplantation, Polymorphisms of IL-18, and Other Pro-Inflammatory Genes and Late Post-Transplant Outcome.

BACKGROUND: Functional polymorphisms of molecules involved in immune-mediated mechanisms of allograft rejection could be predictive of increased risk for early and late post-transplant complications. In the past years, the challenge for long-term graft survival in kidney recipients is the implementation of personalized approaches. In this study, effects of interleukin (IL)-18-137G/C (rs187238), -607C/A (rs1946518), and other pro-inflammatory cytokine gene polymorphisms (tumor necrosis factor [TNF]-α-308G/A, rs1800629, IL-6-174G/C, rs1800795, and interferon [IFN]-γ+874A/T, rs2430561) on the main post-transplant risk parameters and diseases (metabolic, cardiovascular, infective, and chronic allograft rejection) were assessed in kidney-transplanted patients. METHODS: One hundred seventy-nine transplanted patients were retrospectively analyzed for clinical and biochemical parameters and onset of post-transplant complications. Taqman allelic discrimination and PCR-SSP (polymerase chain reaction-sequence specific primers) techniques were used for genotyping. RESULTS: No predictive effects of allele and genotypes of IL-18-607C/A, TNF-α-308G/A, IL-6-174G/C, and IFN-γ+874A/T gene polymorphisms and onset of risk factors and late complications were evidenced. However, Kaplan-Meier analysis evidenced a weak effect of IL-18-137G/C genotypes on graft survival. CONCLUSIONS: Analyzing associations between some pro-inflammatory cytokine gene polymorphisms and onset of the most relevant risk factors and late complications of kidney transplant, results suggested a possible impact of IL-18-137G/C genotypes on graft survival, which deserves further studies.

A new proposal of surgical suture in case of spontaneous renal allograft rupture.

INTRODUCTION: Spontaneous kidney allograft rupture (KAR) is a rare but potentially life-threatening complication after kidney transplantation. It is associated with a high risk of graft loss and patient death. We report a new technique of surgical repair in case of KAR. CASE REPORT: A 53-year-old man transplanted due to diabetic nephropathy-related end-stage renal disease experienced a spontaneous KAR 10 days after KT. Immediate laparotomy revealed the presence of a 4-cm linear kidney fracture. Dexon 2-0 wires were used for the suture, stopping each wire with Hem-o-Loks on a cylinder of oxidized cellulose gauze, with the intent of avoiding the risk of tissue fracture caused by the suture itself. Bleeding was thus controlled. The patient experienced an uneventful course and was discharged on postoperative day 26. CONCLUSIONS: According to the recent literature, graft nephrectomy for KAR is no longer considered the standard surgical treatment. A new approach to rupture repair has been proposed, providing good rates of graft and patient survival.

Influence of cytotoxic T-lymphocyte antigen-4 polymorphisms on acute rejection onset of cadaveric renal transplants.

We retrospectively examined in cadaveric renal transplants the association between acute rejection episodes (ARE) and single nucleotide polymorphisms (SNPs) localized in the cytotoxic T-lymphocyte antigen (CTLA)-4 promoter, -1147T/C and -318C/T, in exon 1 +49A/G and within the 3' untranslated region (UTR) CT60G/A. Each one of these SNPs may influence the cell surface expression of the CTLA-4 molecule. Seventy-two cadaveric renal transplant recipients with at least 6 month's follow-up were genotyped for CTLA-4 dimorphisms using direct sequencing of specific polymerase chain reaction products. Allele frequencies in both groups of patients with or without acute rejection (ARE and non-ARE) did not show significant differences in various nucleotide positions. At the level of genotype frequency we first noted a positive association to acute rejection of G/G genotypes (ARE af = 14.7%, non-ARE af = 5.9%) for the +49 (cod. 17), which was associated with decreased expression of the CTLA-4 full-length molecule. In contrast, the AG genotype seemed to be protective (61.8% vs 32.4%, P = .028; odds ratio [OR] = 0.2961). Regarding the CT60G/A dimorphism, noteworthy was the identification of a significantly higher incidence of CT60 A/A genotype in ARE compared with non-ARE group (29.7% vs 8.6%; Yates P = .035; OR = 4.51). Such association of protective AA genotype with ARE, as observed also in autoimmunity, was associated with an increased level of sCTLA-4 induced by the polymorphism, which blocks B7-flCTLA-4 interactions, enhancing T-cell reactivity by preventing transduction of inhibitory signals. Considering the various polymorphic sites in the haplotype, we observed a significant increase in ARE among patients of the CTLA4 +49A/CT60A (HF = 51.5% vs 29.5%; P = .014; OR = 2.545) and a reduction among the +49A/CT60G (17.6% vs 33.8%; P = .04; OR = 0.4193) 2-loci haplotype, As regards the -1147/-318/+49/CT60 CTLA-4 4-loci haplotypes, we observed a significantly higher frequency of the CCAA haplotype in ARE patients comparison with those free of rejection (HF = 51.8% vs 31.1%, P = .046 OR = 2.363). These findings are consistent with those observed in allogeneic stem cell transplantation, wherein patients with CT60 AA showed a major incidence of graft-versus-host disease. An association of protective AA genotype with ARE, as observed also in autoimmunity was associated with an increased level of sCTLA-4 induced by this polymorphism, which blocking the B7-flCTLA-4 interaction, would enhance T-cell reactivity by preventing transduction of inhibitory signals.

Cytomegalovirus and gastric cancer after renal transplantation: a possible interplay.

We herein have described a case of de novo gastric cancer in a renal transplant recipient with a concomitant diagnosis of gastrointestinal cytomegalovirus (CMV) disease. We hypothesize that CMV, through causing an imbalance between cell proliferation and cell death, functions as the causative agent for the progression of the gastric tumor in this case after gastric colonization. To the best of our knowledge, this is the second such case ever reported of such kind and may represent a platform for investigations aimed at understanding the possible interplay between CMV and gastric cancer.

Management of kidney transplantation in a factor VII-deficient patient: case report.

Transplantation in patients with congenital bleeding disorders is a challenge requiring an integrated approach of various specialists. Renal transplantation, the most frequent type of solid organ transplantation, is rarely performed in individuals with congenital hemorrhagic disorders. We performed a renal transplantation in a 53-year-old man with end-stage renal disease and congenital coagulation factor VII deficiency, a rare bleeding disorder with a peculiar clinical picture requiring replacement therapy in surgical interventions. Perioperative bleeding was successfully prevented by administration of recombinant activated factor VII. Treatment schedule, administration rate, and long-term follow-up are reported in detail. Our report confirmed the feasibility and safety of recombinant activated factor VII in major surgical procedures like solid organ transplantations. Success requires evaluation of doses and therapeutic schedules as well as a multidisciplinary approach.

[Bio-ecological control of chronic liver disease and encephalopathy]. / Controllo bio-ecologico della cirrosi epatica e dell'encefalopatia.

Minimal encephalopathy was originally associated with chronic liver disease but is increasingly associated with most other chronic diseases and particularly with diabetes and also chronic disorders in other organs: kidneys, lungs, thyroid and with obesity. It is increasingly with dramatically increased and more or less permanent increase in systemic inflammation, most likely a result of Western lifestyle. Frequent physical exercise and intake of foods rich in vitamins, antioxidants, fibres, lactic acid bacteria etc in combination with reduction in intake of refined and processed foods is known to reduce systemic inflammation and prevent chronic diseases. Some lactic acid bacteria, especially Lb paracasei, lb plantarum and pediococcus pentosaceus have proven effective to reduce inflammation and eliminate encephalopathy. Significant reduction in blood ammonia levels and endotoxin levels were reported in parallel to improvement of liver disease. Subsequent studies with other lactic acid bacteria seem to demonstrate suppression of inflammation and one study also provides evidence of clinical improvement.

A rare case of herpes simplex type 1 bronchopneumonia associated with cardiomegaly in renal transplantation.

INTRODUCTION: We report a rare case of herpes simplex virus (HSV) type 1B in patient with kidney transplant as a possible cause of patient death. CASE REPORT: A 32-year-old renal transplanted Caucasian man was referred for asthenia, fever, anemia, chest pain, cough, dyspnea, myalgias, peripheral edema, acute renal failure, diffuse cutaneus and mucous vesicles, and acute weight gain. The home therapy consisted of tacrolimus, sodic mycophenolate, and steroids. Laboratory data, bronchoscopy, and bronchial mucosal biopsy revealed HSV1B. We administered antiviral and antibiotic agents and reduced tacrolimus with clinical resolution. But after 10 days from discharge, the patient was admitted for acute cardiomegaly. So using ex adiuvantibus criteria we administered antiviral therapy with complete clinical improvement. CONCLUSION: According to the literature, posttransplant HSV1B infection is a rare but severe complication of kidney transplantation associated with poor graft survival and a high mortality. Only an early, accurate diagnosis with efficient treatment permitted resolution of the problem. Our report stresses the difficulty of HSV2B clinical diagnosis and treatment.

Kidney transplantation from older donors.

BACKGROUND: The use of kidneys from older donors has become generally accepted and increasingly common, despite the knowledge that donor age is a well-known risk factor for graft failure. AIM: To review our experience with the utilization of kidneys from donors older than 60 years. PATIENTS AND METHODS: Among two hundred eight patients, 32 (group A) received an organ obtained from a donor older than 60 years. The organs were age-matched with a maximum gap of 20 years between donors and recipients. Organs from older donors were assigned to recipients presenting a body mass index lower than that of the donor. The primary end point was patient and graft survival. Secondary endpoints were incidences of delayed graft function and of acute rejection episodes as well as renal function at 3 months and yearly. RESULTS: The two groups were comparable in terms of demographic features, indications for transplantation, comorbidities, as well as cold and warm ischemia times. The Mean lengths of follow up were 31.4 ± 20.3 months and 30.3 ± 20.1 months, respectively. Graft and patient survivals were comparable. Mean creatinine values at the study intervals were significantly lower among group B who received grafts from younger donors. The incidence of delayed graft function and acute rejection episodes were similar: 15.6% (5/32) versus 20.5% (36/176; P=0.35) and 15.6% (5/32) and 12.1% (21/167; P=0.136) in groups A and B, respectively. CONCLUSIONS: Donor age older than 60 years showed a negative impact on kidney function. Though, given the escalating disparity between organ supply and demand, this precious source of organs cannot be neglected. We need better ways to use the available organs.

Regenerative medicine applied to solid organ transplantation: where do we stand?

The objective of regenerative medicine (RM) and Tissue Engineering (TE) is to create living functional tissues to repair or replace tissues or organ functions. This field holds the promise of regenerating damaged tissues and organs in the body. It has the potential to solve the problems of organ shortage and of toxicities deriving from life-long immunosuppression. In fact, cells in the regenerated organ would match those of the patient, from whom they would normally be derived. In the past decade, RM/TE has achieved striking results which are of interest to the transplant community. However, major roadblocks on the avenue to full success include the need for a deeper understanding of cell biology and of interactions with the extracellular matrix. We are presently not able to grow and expand cells indefinitely and safely in various scenarios where RM/TE may be indicated. The production of adequately vascularized scaffolds to optimize nutrients and oxygen delivery, assessment of the viability and function of the cells in the bioengineered construct, and the costs remain areas of scientific research.

Surgical antibiotic prophylaxis after renal transplantation: time to reconsider.

The optimal regimen for perioperative antibiotic prophylaxis after renal transplantation remains to be determined. Worldwide, it seems there is a trend toward decreased use of prophylaxis from the first 48 hours to several days after surgery. However, bacterial strains resistant to common antibiotic agents arise even if only a single dose of a molecule is administered at any time. Inasmuch as infections currently are the primary cause of hospitalization after renal transplantation, it is desirable to not favor selection of resistant strains that may not be treated appropriately in the event of onset of infection. Therefore, antibiotic therapy, whether for therapeutic or prophylactic purposes, should be administered based exclusively on clinical evidence. Because systemic antibiotic prophylaxis is not effective against infections of the urinary tract, the objective of perioperative antibiotic prophylaxis should be to prevent infection of the surgical wound. In this case, administration of a single dose of an antibiotic agent (1-shot regimen) at the induction of anesthesia is effective and safe. For these reasons, it is urgent that new guidelines be defined for perioperative antibiotic prophylaxis. Multicenter prospective randomized trials comparing 1-shot vs multiple-dose regimens should be performed to establish the optimal regimen.

A rare case of colic thrombotic microangiopathy in renal transplantation.

INTRODUCTION: We report a case of thrombotic microangiopathy (TM) in patient with UC and kidney transplantation. CASE REPORT: A 59-year-old Caucasian may with a renal transplant, with atrial fibrillation and ulcerative colitis (UC), was referred for asthenia, fever (38 degrees C), anemia, colicky pain, and bloody diarrhea. The maintenance therapy consisted of CSA, sodium mycophenolate, steroids, ticlopidine, and mesalazine. Laboratory data, colonscopy, and colic mucosal biopsy revealed de novo colic TM. We administered antibiotics and antishock therapy, reducing CSA, withdrawing ticlopedine and maintaining mesalazine with the resolution of the problem. CONCLUSION: Posttransplantation TM is an uncommon but severe complication of kidney transplantation associated with reduced graft survival and a high risk for death. Only an early, accurate diagnosis with optimal treatment permits resolution of the problem.

HLA-G 14-bp insertion/deletion polymorphism in kidney transplant patients with metabolic complications.

HLA-G, a nonclassical HLA molecule with limited polymorphism has immunomodulating/tolerogenic properties. The most common polymorphism of HLA-G is a deletion/insertion of 14 bp, located at the 3'UTR region of the gene (exon 8). This polymorphism is associated with modifications of mRNA stability that can lead to variations of membrane versus soluble HLA-G expression. HLA-G may be involved in the clinical outcomes of transplantation, as evidenced by studies in hematopoietic cell transplantation. We evaluated the possible prognostic importance of 14-bp polymorphisms of HLA-G among kidney transplantation patients. Using polymerase chain reaction amplification we genotyped 124 patients (mean organ survival: 878.95 +/- 595.12 days; range = 1-2565) and 98 control individuals representative of the Italian population. Products were visualized by electrophoresis on agarose gels. The results showed no differences between patients and controls. Twenty-nine patients with acute or chronic rejection or in whom clinical conditions required the use of steroid bolus treatments also showed no association with HLA-G 14-bp genotypes or alleles. The subset of patients with dyslipidemia during follow-up showed a significant decrease among the HLA-G-14/-14 genotype, compared with heterozygous (+14/-14) and nondeleted homozygous (+14/+14) genotype patients (P(c) = .03). These preliminary data showed that HLA-G 14-bp genotypes, although not predictive of rejection, may be useful to identify individuals at risk for the development of posttransplant complications.

A systematic review of two different trimetoprim-sulfamethoxazole regimens used to prevent Pneumocystis jirovecii and no prophylaxis at all in transplant recipients: appraising the evidence.

BACKGROUND: The aim of this study was to clarify the potential advantages of a low-dose regimen of trimethoprim-sulfamethoxazole prophylaxis to prevent Pneumocystis jirovecii pneumonia (PJP) in transplant recipients (80/400 mg/d every day or 160/800 mg/d every other day) with those obtained from the full-dose prophylaxis (160/800 mg/d every day) or no prophylaxis. METHODS: Prospectively randomized and retrospectively case controlled studies were selected. RESULTS: Four studies matched the inclusion criteria-2 randomized and 2 case controls-for a total of 570 patients. The pneumonia incidence was 0% after full-dose prophylaxis (0/181), 1% after the low-dose regimen (1/105), and 11% with no prophylaxis (31/284). Pneumonia occurrences were significant lower between the full-dose prophylaxis versus the no prophylaxis group (0% vs 11%; P < .001), and between the low-dose and no prophylaxis groups (1% vs 11%; P < .001). There was no difference between patients receiving the full-dose prophylaxis versus the low-dose regimen (0% vs 1%; P = NS). CONCLUSIONS: The low-dose gives similar results as the full-dose regimen for the prevention of PJP and seems a feasible, safe option for transplanted patients.

Clinical operational tolerance after solid organ transplantation.

Clinical operational tolerance (COT) is a clinical condition obtainable with difficulty after solid organ transplantation (SOT). It is characterized by perfectly normal graft function in the total absence of maintenance immunosuppression. Major benefits deriving from the onset of COT are the reduction of risk for immunosuppression-related side effects and the improved quality of life. Currently, COT can be safely achieved in stable liver transplant recipients; it remains a challenge after renal transplantation. Only 1 case of COT has been reported after lung transplantation; no cases have been described after other types of SOT. Overall, mechanisms of COT are unclear and strategies to induce COT cannot be applied on a regular base to a large cohort of SOT recipients. Due to the failure of molecularly based tolerogenic protocols, great hope relies in the adoption of cell-based strategies.

Incidence of urinary tract infections caused by germs resistant to antibiotics commonly used after renal transplantation.

BACKGROUND: The inadequate utilization of antibiotics is responsible for the development of urinary tract infections (UTI) after renal transplantation (RT), through the induction of resistance to the antibiotics themselves. The purpose of this study was to evaluate the incidence of resistance to cefotaxime (CEF) and trimethoprim/sulfamethoxazole (TMP-SMX), routinely used for surgical perioperative prophylaxis and prevention of Pneumocystis carinii, respectively. MATERIALS AND METHODS: We enrolled all adult patients having received an RT from 2001 to 2006 and having a minimum follow-up of 6 months. Urine cultures (UC) were routinely performed at every outpatient clinic control and whenever required by the onset of significant clinical signs/symptoms. UTI was diagnosed by the presence of a positive UC. The endpoint of the study was the emergence of bacterial strains resistant to either CEF or TMP/SMX. RESULTS: We recorded 169 UTI in 76 patients (38 men/38 women, 33%) over a mean follow-up of 779.9+/-523.3 days. Thirty-nine patients (51%) developed more than 1 UTI episode. When gram-negative bacteria were considered, 102/144 (70.8%) tests showed resistance to TMP/SMX, while data were available in about only 7 gram-positive infections (5/7, 71%). CEF was tested less frequently with 21/43 (49%) germs resistant to this molecule. CONCLUSIONS: The onset of bacterial resistance to either TMP/SMX or CEF is frequent after RT. A wiser stricter utilization of antibiotics is mandatory. Standard antibiotic protocols should be revised.

De novo autoimmune hepatitis following liver transplantation: a case report.

De novo autoimmune hepatitis (AIH), a rare disorder first described in 1998, appears in patients with liver transplants due to autoimmune and nonautoimmune etiologies. De novo AIH occurs in 2.5% to 3.4% of allografts; children seem to have a predilection for this syndrome. We have present herein a case of a liver allograft recipient who developed chronic hepatitis associated with autoimmune features outlining the clinical course, liver histology, and response to treatment.