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.

For anti-HLA-specific donor antibodies detection by flow cytometry cytotoxic crossmatches comparison of methods.

Anti-HLA-specific donor antibodies induce rapid, irreversible destruction of the transplant (hyperacute rejection) that today happens rarely due to immunologic studies-prospective crossmatch-of patients awaiting the kidney graft. The usual approach for pretransplant donor/recipient evaluation is based on 2 methods: (1) the cytotoxic complement crossmatch (CDC) and (2) the flow cytometric crossmatch (FCX). The CDC crossmatch is positive when complement-fixing antibodies are present, an absolute contraindication to kidney transplantation. The more sensitive FCX-positive crossmatch detects low concentrations of unable to fix performed antibodies complement. It is an "index" of possible damage due to accelerated rejection. The target of our study was to develop a cytotoxic flow cytometry crossmatch (cFCX) that detected cytotoxic antibodies move sensitively than the traditional CDC method and also was less subjective and more standardized for interpretation studying sera from 23 patients; the cFCX showed the requested efficiency characteristics even in an emergency. In addition, the new method permited one to calculate a cutoff for positivity (average value of the negative control + 2 standard deviations), assuring an "objective" interpretation of the results that agreed with the CDC but was more sensitive and accurate allowing solution of ambiguous results for cases of "doubt"-positive CDC crossmatch. Furthermore, our aim was to correlate the effect of the strength of the anti-HLA antibodies determined by mean fluorescence intensity value of LabScreen Single Antigen beads with results of CDC, cFCX, and FCX methods.

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.

[Psychopathology, quality of life and social functioning in dialysis treatment and kidney transplantation patients]. / Psicopatologia, qualità di vita e funzionamento sociale in pazienti in trattamento dialitico e sottoposti a trapianto di rene.

OBJECTIVES: Psychiatric evaluation of organ transplant candidates is now routinely proposed also in Italy. This study purposed to assess the psychological status in patients on hemo-dialysis, peritoneal dialysis and renal transplantation; moreover other purpose is to investigate the possible differences among the three groups. MATERIALS AND METHODS: 157 subjects were consecutively enrolled, to the service of U.O. Trapianti d'Organo of San Salvatore Hospital in L'Aquila (Italy), between October 2007 and August 2009; 127 were in dialysis (80.9%), of which 101 were in hemodialysis (64.3%) (HD group) and 26 in peritoneal dialysis (16.6%) (PD group) and 30 (19.1%) Kidney transplant (PT group). The subjects were examined with clinical evaluation and through the following psychometric instruments: HAM-D, HAM-A, Jalowiec Coping Scale, STAI-Y1, STAI-Y2, DISS, SF-36. RESULTS: 30% out of our sample showed the presence of some psychopathological signs and symptoms, especially depression and anxiety. At HAM-D there were no differences between HD group (6.73; DS + 5.58) and PD group (5.27, DS + 5.63); the mean value at HAM-D in PT group was 4.4 (DS + 3.16) (p < 0.05). At HAM-A there were no differences between three groups. The HD group showed an higher value at STAI-Y1 (38.61; DS + 10.64) than PD (34.95; DS + 6.75) and PT (33.89; DS + 6.14) groups (p < 0.05). The quality of life (physical role, general health, vitality and role emotional) was lower in HD and PD groups, higher in group PT. The HD e PD groups showed a higher level of disability than PT group (p < 0.05). All subjects used "positive: coping styles. CONCLUSIONS: We consider essential to investigate the issues observed in this study, with the need to integrate psychosocial and functional needs assessment within a course of diagnosis and treatment for people who are undergoing dialysis procedures, or after waiting for a transplantation. Dialysis affects the quality of life, leading to limitations in activities and high level of disability. The PT group showed better quality of life and less impairment in functioning in the investigated areas. If the impact of psychological and/or psychiatric aid remains difficult to appraise, these results emphasize the impact of psychological status and the appropriateness of psychosocial support intervention on patients facing the transplant process or in dialysis treatments.

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.

Superior vena cava syndrome due to thrombotic occlusion in a thrombophilic renal transplant recipient: a case report.

The case of a superior vena cava syndrome due to a central venous catheter thrombosis occurring in a second renal transplant patient is described. Imaging revealed thrombosis of the right internal jugular vein with extension along the confluence of the brachiocephalic veins and partial obstruction of the superior vena cava. Anticoagulant therapy with subcutaneous low-molecular-weight heparin was followed by warfarin administration. Despite adequate treatment, the symptomatology worsened because of thrombus organization. A workup revealed a complex prothrombotic underlying condition. Cardiothoracic surgeons were consulted, and an operative reconstruction of the superior vena cava using spiral vein bypass grafting was performed. In this report we describe the clinical presentation, diagnosis, and treatment of this case, with an emphasis on the role of thrombophilia.

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.

Fatal hemorrhage in two renal graft recipients with multi-drug resistant Pseudomonas aeruginosa infection.

Pseudomonas aeruginosa (PA) infections occurring after renal transplantation (RT) represent a potentially life-threatening complication. We present 2 cases of early death following RT in which PA was transmitted, possibly from the donor to the recipients, despite preoperative cultures that were negative. The donor had developed PA-related bilateral pneumonia while in the intensive care unit. However, after appropriate antibiotic therapy, no signs of infection were present at the time of organ retrieval and cultures were negative. Both recipients received a renal graft from the same donor and developed multi-drug resistant (MDR)-PA infections with bacterial phenotypes and resistances similar to the donor. The first recipient died 9 days after RT from rupture of a false aneurysm of the external iliac artery, caused by a fully thickened PA-related arteritis. The second recipient died postoperatively on day 10 after rupture of an aneurysm in the right vertebral artery. Our experience shows that MDR-PA infection early after RT may be a catastrophic event. Specific anti-PA antibiotic therapy in RT patients during the perioperative period is recommended in the case of PA infection in the donor, even after apparent successful therapy with negative cultures.

Evaluation of serum sCD30 in renal transplantation patients with and without acute rejection.

Despite new immunosuppressive approaches, acute rejection episodes (ARE) are still a major cause of early kidney dysfunction with a negative impact on long-term allograft survival. Noninvasive markers able to identify renal ARE earlier than creatinine measurement include sCD30. We sought to establish whether circulating levels of sCD30 in pretransplantation and posttransplantation periods were of clinical relevance to avoid graft damage. Quantitative detection of serum sCD30 was performed using an enzyme-linked immunosorbent assay. Our results demonstrated that the mean concentrations of sCD30 were significantly higher in the sera of renal transplant recipients with ARE (30.04 U/mL) and in uremic patients on the waiting list (37.7 U/mL) compared with healthy controls (HC; 9.44 U/mL), but not nonrejecting patients (12.01 U/mL). Statistical analysis revealed a strong association between high sCD30 levels in posttransplantation sera and ARE risk. This study suggested that sCD30 levels were a reliable predictor of ARE among deceased-donor kidney recipients.

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.

Scrotal herniation of the ureter: a rare late complication after renal transplantation.

Although late ureteral obstruction represents the most frequent urologic complication after renal transplantation, its etiology remains poorly understood. Benign prostatic hyperplasia (BPH) is the most common cause of urinary tract obstruction in the adult male population, but information regarding BPH epidemiology and its impact on clinical outcomes are lacking. We herein have described a case of ureteral herniation into the scrotum, secondary to concomitant upper and lower urinary tract obstruction: namely, BPH and ureterovesical junction stenosis causing massive urine retention and acute renal failure. The simultaneous presence of the 2 lesions rendered the diagnosis difficult. In addition, urine outflow responsible for bladder outlet obstruction resumed after transurethral resection of the prostate (TURP). The hydroureteronephrosis, which persisted after the TURP resolved only after positioning a double J stent, but renal function did not normalize. Attention must be paid to BPH in the differential diagnosis of urinary tract obstruction. Stenosis of the ureterovesical junction may occur very late after transplantation.