Urinary CXCL9 and CXCL10 Levels and Acute Renal Graft Rejection.

BACKGROUND: Monitoring of chemokines, CXCL9 and CXCL10, in serum may present a non-invasive detection method for rejection. OBJECTIVE: To investigate the relationship between urinary levels of CXCL9 and CXCL10 and graft function following renal transplantation. METHODS: 75 living-related donor renal transplant recipients were studied. Urinary levels of chemokines were collected pre-operatively, on post-operative 1st day, 7th day, 1st month, 3rd month, and at the time of rejection. Chemokines levels were assayed using and enzyme-linked immunosorbent assay. RESULTS: Clinical variables were monitored. 10 (15%) patients had biopsy-proven rejection during the follow-up period. The urinary CXCL9 level in those with rejection was significantly higher than that in those with non-rejection group at the 1st day (p<0.001), 7th day (p<0.001), and at the time of rejection (p=0.002). The urinary CXCL10 level was also significantly higher in those with rejection compared with non-rejection group at 1st day (p<0.001), 7th day (p<0.001), and at the time of rejection (p=0.001). Serum creatinine level was strongly correlated with the urinary CXCL9 and CXCL10 levels at the time of rejection (r=0.615, p=0.002; and r=0.519, p=0.022, respectively). Among those with T cell-mediated rejections the mean urinary CXCL10 level increased to as high as 258.12 ng/mL. CONCLUSION: Urinary CXCL9 and CXCL10 levels might have a predictive value for T cell-mediated rejection in early post-transplantation period. Measurement of urinary CXCL9 and CXCL10 levels could provide an additional tool for the diagnosis of rejection.

Effects of Rituximab on Atherosclerotic Biomarkers in Kidney Transplant Recipients.

INTRODUCTION: Cardiovascular disease is the leading cause of mortality in kidney transplant recipients. Rituximab is widely used in kidney transplantation for a variety of situations, and rituximab may inhibit some cytokines and antibodies that may play an active role in the atherosclerotic process. The aim of the study was to evaluate the efficacy of rituximab on atherosclerosis biomarkers in kidney transplant recipients. METHODS: All patients, 18 years of age and older, who underwent kidney transplantation and received at least 1 dose of 375 mg/m2 rituximab were considered for participation in this study. The primary study endpoint was the development of cardiovascular diseases after rituximab therapy. The secondary endpoint was the onset of cytomegalovirus (CMV) disease or biopsy-confirmed BK virus nephropathy. In addition, comparison of atherosclerosis biomarkers was performed between study and control groups. RESULTS: There were no cardiovascular events observed during follow up. Only 8 patients in the study group suffered from CMV disease during follow up. Serum interleukin 10 levels were significantly higher in the rituximab group compared with the control group, although anti-oxidized low-density lipoprotein levels were lower in the rituximab group compared with the control group, though this did not achieve statistical significance. DISCUSSION: Rituximab treatment may increase the risk of CMV reactivation and decrease lymphocyte counts and interleukin 10 levels; however, significant decreases in all atherosclerotic-related biomarkers have not been shown in our study.

Panel Reactive Antibody Responses Against Influenza Vaccination in Kidney Transplant Recipients.

INTRODUCTION: Seasonal influenza is an important cause of morbidity and mortality in the post-transplant period; therefore, the influenza vaccination has been recommended for all kidney transplant recipients before the influenza season. However, at least theoretically, the introduction of antigens via vaccines may trigger rejection attacks by causing an antibody response. In this study, we examined the development of de novo panel reactive antibody (PRA) development against the influenza vaccine in kidney transplant recipients. MATERIALS AND METHODS: Overall, 41 kidney transplant recipients who received the influenza vaccination and 50 kidney transplant recipients (study group) who refused to receive the influenza vaccination (control group) were enrolled in the study. Following basal biochemistry examination, the inactivated trivalent influenza vaccine was administered intramuscularly. Panel reactive antibodies were screened in all patients before and after vaccination on days 30 and 180. The primary outcome variable was development of de novo panel reactive antibodies. RESULTS: One patient in the study group developed de novo class I and II PRA at 6 months after vaccination (P > .05), while no antibody development was noted in the control group. Graft dysfunction or biopsy-confirmed rejection was not observed during the follow-up period in both groups. CONCLUSION: The influenza vaccination is generally effective and safe in solid organ transplant recipients. The vaccination procedure has the potential to trigger antibody development and occurrence of rejection. Therefore, vaccinated kidney transplant recipients should be monitored more carefully with regard to PRA; if the graft deteriorates, a rapid transplant biopsy should be performed.

Association Between HLA Antibodies and Different Sensitization Events in Renal Transplant Candidates.

BACKGROUND: Human leukocyte antigen (HLA) allo-immunization is caused by various events such as blood transfusions, pregnancies, or organ transplantations, which can lead to sensitization. In this retrospective study, we evaluated different sensitization models and their effects on panel-reactive antibody (PRA) profiles of renal transplantation candidates. METHODS: Anti-HLA class I/II antibody screening tests were performed in 906 renal transplantation candidates with the use of a microbead-based assay (Luminex). RESULTS: Two hundred ninety-seven (32.8%) of the patients were determined as positive in terms of PRA, and 609 (67.2%) were negative. Sensitized and non-sensitized patients were compared separately in terms of each sensitization type. The anti-HLA class I, II, and I+II positivity rates in patients sensitized only by blood transfusion were 13.1%, 6.3%, and 14.1%, the rates with pregnancy sensitization were 35.5%, 29%, and 45.2%, and rates with previous transplantation sensitization were 15.6%, 34.4%, and 38.9%, respectively. Prevalence of PRA positivity was significantly higher in patients with previous pregnancy than with transplantation and transfusion (odds ratio, 1.003; 95% confidence interval, 0.441-2.281; P = .031). The risk of developing HLA class I antibodies was higher in pregnancies (P < .001), and the risk of developing anti-HLA class II antibodies was higher in patients who had undergone a previous transplantation (P < .001). The rate of developing HLA-B antibodies in patients sensitized by pregnancy were significantly higher compared with sensitization after transfusion (P = .015), as was the rate of developing HLA-DQ antibodies in patients sensitized by previous transplantation compared with sensitization through pregnancy (P = .042). CONCLUSIONS: In patients who are waiting for kidney transplantation, sensitization by pregnancy and transplantation have a significant impact on development of HLA class I and class II antibodies.

Prevalence of Human Herpesvirus-8 and BK Polyoma Virus Infections in End-stage Renal Disease and the Influence of Renal Transplantation.

Viral infections lead to significant morbidity and mortality in kidney transplant recipients. We evaluated 49 kidney transplant recipients for human herpesvirus 8 (HHV-8) and BK polyomavirus infections in conjunction with data obtained from 43 donors. The seroprevalence of HHV-8 was 6.9% in donors and 12.2% in recipients. HHV-8 DNA was detected below the limit of quantification (<5000 copies/mL) in a recipient with HHV-8 seropositivity at the pretransplant period and was undetectable at month 3 after transplantation. Transient viruria with BK polyomavirus was recorded in 10.2% of recipients without viremia. Multiple factors contribute to viral reactivation, particularly immunosuppressive treatment. Reduction in maintenance immunosuppression seems beneficial in terms of viral reactivation. At our center, routine use of valganciclovir for antiviral prophylaxis may be effective for the prevention of HHV-8 reactivation.

Corrected Panel-Reactive Antibody Positivity Rates for Hypersensitized Patients in Turkish Population With Calculated Panel-Reactive Antibody Software.

INTRODUCTION: High rates of panel-reactive antibody (PRA) may decrease the chance of kidney transplantation and may result in long waiting periods before transplantation. The calculated PRA (cPRA) is performed based on unacceptable HLA antigens. These antigens are identified by a program that was created based on the antibodies that developed against the HLA antigens circulating in serum and on the risk of binding of these antibodies to antigens. The antigen profile of the population and antigen frequencies can be measured, and more realistic cPRA positivity rates may be obtained using this method. MATERIALS AND METHODS: We developed a program based on the HLA antigens of 494 blood donors in 2 European Federation for Immunogenetics-accredited Tissue Typing Laboratories in Turkey. Next-generation sequencing-based tissue typing (HLA-A, -B, -C, -DR, -DQ, 4 digits) of the samples was performed. The PRA screening test was performed on 380 patients who were waiting for organ transplant from a cadaver in Istanbul Faculty of Medicine. The single antigen bead assay testing was performed to identify the antibody profiles on 48 hypersensitized patients. RESULTS: The PRA testing results using the current methods were 44.6% ± 18.5%, and the cPRA rate was 86.2% ± 5.1%. The mean PRA positivity of the sensitized patients using the current methods was 44.6%; however, the rate was 86.2% using the cPRA. DISCUSSION: cPRA shows the rate of the rejected donors according to all unacceptable antigens. The need for a list of unacceptable antigens in place of the PRA positivity rate is a real change in the sensitization-dependent calculation as cPRA positivity rate. CONCLUSION: In principal, implementation of cPRA will encourage many centers and laboratories to adopt a standard measurement of sensitization in Turkey. It will increase the chances of better donor match, particularly for hypersensitized patients, by the creation of an unacceptable mismatch program using cPRA software.

Tac-MMF Versus CsA-MMF/CsA-AZA-Based Regimens in Development of De Novo Complement-Binding Anti-HLA Antibodies After Kidney Transplantation.

BACKGROUND: Immunosuppressive regimens with tacrolimus or cyclosporine A (CsA) were compared for graft-related outcomes in conjunction with complement-binding de novo donor-specific antibodies (DSAs). METHODS: Non-sensitized adult patients without rejection episodes within 3 months after transplantation were screened for the presence of de novo DSAs and C1q binding. Clinical and biopsy data were retrospectively obtained. RESULTS: The analysis included 118 patients (68 tacrolimus, 50 CsA), with mean age and follow-up of 36.1 ± 11.4 and 7.2 ± 4.8 years, respectively. As compared with tacrolimus, the CsA group had higher rates of both class II DSAs and C1q-binding DSAs (20% vs 4.4%, P = .008, and 18% vs 0%, P = .003, respectively). Rates of chronic antibody-mediated rejection (cAMR), proteinuria >500 mg/g, and levels of creatinine both at last visits were also higher in the CsA group (20% vs 0%, P = .002, 30% vs 5.9%, P = .005, 1.67 ± 1.31 vs 1.18 ± 0.45 mg/dL, P = .019, respectively).Class II DSAs and C1q-binding class II DSAs were significantly correlated with the clinical outcomes (creatinine levels, proteinuria, and cAMR). CONCLUSIONS: Compared with tacrolimus, CsA appears to pose a higher risk for the development of de novo anti-HLA antibodies with C1q-binding properties and, consequently, adverse graft-related outcomes.

Evaluation of TH17 and TH1 Immune Response Profile in Patients After Renal Transplant.

BACKGROUND: Renal transplantation (RT) is the best treatment option for patients with end-stage renal disease (ESRD) because it improves both quality of life and survival. However, allograft rejection remains the most important barrier to successful transplantation. Underlying immunologic mechanisms should be understood to develop appropriate treatment strategies. METHODS: In this prospective study, we followed renal transplant recipients for 6 months. The study population comprised 50 recipients of renal transplants, and these were divided into 2 groups: 44 patients with stable graft function (SGF) and 6 patients with rejection (RX). Peripheral blood samples were drawn from patients on the pre-RT day, at post-RT day 7, month 1, and month 6, and on the day of rejection for analysis of the percentages of cytokines interleukin (IL) 17 and interferon (IFN) γ with the use of flow cytometry and enzyme-linked immunosorbent assay. RESULTS: The percentages of intracellular IFN-γ were not significant in the group with RX compared with SGF. Levels of intracellular IL-17 obtained at the 6th month after RT were significantly higher in the RX group than in the SGF group. Plasma levels of pre-RT IL-17 were also higher in the RX group; therefore, it may be a predictive biomarker of acute rejection of renal transplants. CONCLUSIONS: The present study provides information about pre-RT and post-RT cytokine profiles of Turkish patients with ESRD. We consider cytokine analysis to be a valuable biomarker panel in the prevention of rejection and in assisting with new treatment strategies for patients undergoing renal transplant.

Relevance of Flow Cytometric Auto-Crossmatch to the Post-transplant Course of Kidney Transplant Recipients.

INTRODUCTION: The crossmatch test is essential prior to kidney transplantation (tx) to confirm compatibility between the donor and the recipient. However, its results can be misleading due to "undetectable antibodies" in the recipient's serum. To establish if undetectable autoantibodies are responsible for a positive result, an auto-crossmatch test can be performed. In this study, we aim to determine the long-term prognostic value of auto-flow cytometric auto-crossmatch (FCXM) test on kidney survival in kidney tx recipients. MATERIALS AND METHODS: The primary outcome variable was reduced renal function. Secondary endpoints were incidence of biopsy-confirmed chronic antibody-mediated rejection (CAMR) and recurrent glomerulonephritis (GN). RESULTS: There were no differences regarding initial serum creatinine levels between the study and control groups (P = .441). Patients who had positive auto-B FCXM had a significantly reduced renal function compared with the control group (P = .016). Four patients developed biopsy-confirmed CAMR in the study group and 1 patient in the control group (P = .047). Five patients had biopsy-confirmed recurrent GN in the GN study group, and only 1 patient had recurrent GN in the GN control group (P = .026). DISCUSSION: Kidney transplant recipients with positive auto-FCXM test had significantly reduced renal function and a higher incidence of recurrent GN and CAMR compared with the control group. The findings of this study suggest a potential role of auto-antibody causing positive auto-FCXM test result, meanwhile increasing the risk of CAMR, recurrent GN, and new-onset diabetes after tx.

Influence of Proton Pump Inhibitors on Mycophenolic Acid Pharmacokinetics in Patients With Renal Transplantation and the Relationship With Cytochrome 2C19 Gene Polymorphism.

BACKGROUND: Most patients have serious digestive complications after renal transplantation. Therefore, it is important to protect gastrointestinal function to improve the survival rate of transplant patients. Proton pump inhibitors (PPIs) such as lansoprazole and rabeprazole are widely administered to renal transplant patients with mycophenolic acid (MPA) in the perioperative period. PPIs are metabolized by cytochrome (CYP) 2C19 enzymes. Mycophenolate sodium (MYF) and mycophenolate mofetil (MMF) have been used in immunosuppression. Clinically relevant drug-drug interactions have been described between immunosuppressive drugs. In the present study, we investigated the drug interaction between MPA and lansoparazole or rabeprazole and the impact of CYP2C19 polymorphisms on these drug interactions after renal transplantation. MATERIALS AND METHODS: A total of 125 renal transplant patients taking MPA derivatives between 2012 and 2016 were included in this study. The 125 patients were divided into 6 groups: MMF/tacrolimus/steroid together with lansoprazole or rabeprazole; MYF/tacrolimus/steroid together with lansoprazole or rabeprazole and without PPI. The single nucleotide polymorphisms of CYP2C19 were determined by the polymerase chain reaction-restriction fragment length polymorphism. Plasma concentrations of MPA were measured by cloned enzyme donor immunoassay. Clinical parameters such as incidence of delayed graft function and acute rejection, the rate of change of serum creatinine, toxicity, and gastrointestinal adverse effects were analyzed retrospectively. RESULTS: The mean concentrations of MPA in the MYF group were higher than those in the MMF group. The mean dose-adjusted blood concentration of MPA coadministered with lansoprazole was lower than that of MPA with rabeprazole or without PPI in MMF and MYF groups (P < .05). In patients with the CYP2C19*2/*2 genotype, the mean concentrations of MMF with lansoprazole were significantly lower than those with rabeprazole with MMF or without PPI (P < .05). Gastrointestinal side effects were significantly higher in MMF with lansoprazole group than in MYF with lansoprazole group (P < .05). However, no differences were found according to genotype distribution in all groups (P > .05). CONCLUSION: Polymorphisms in CYP2C19 are related to the metabolic oxidation of drugs to varying degrees. Both genetic and clinical factors in pharmacokinetics may help to make further progress toward individualized therapy to yield maximum efficacy with minimal side effects.

A Novel Biomarker for Post-Transplant Recurrent IgA Nephropathy.

BACKGROUND: The serum levels of galactose-deficient immunoglobulin (Ig)A1 (Gd-IgA1) represent the most promising candidate biomarker for IgA nephropathy (IgAN). The aim of this study was to evaluate the serum levels of Gd-IgA1 as a novel noninvasive biomarker for post-transplant IgAN recurrence. METHODS: Serum Gd-IgA1 levels of 18 patients with recurrent IgAN were compared with control renal transplant recipients (n = 23) with non-recurrent IgAN and control non-transplant IgAN patients (n = 44) and healthy relatives (n = 11). Serum Gd-IgA1 levels of patients were measured with the use of KM55 enzyme-linked immunosorbent assay (ELISA). The effects of serum Gd-IgA1 concentrations on IgAN recurrence, post-transplant events, and graft survival were evaluated. RESULTS: All recurrent IgAN patients presented with renal dysfunction (mean serum creatinine, 1.62 ± 0.39 mg/dL) and detectable proteinuria at the time of diagnosis. Serum Gd-IgA1 levels of recurrent IgAN patients (8735 ± 10854 ng/mL [log10: 3.71 ± 0.45]) were significantly higher than those of non-recurrent IgAN patients (4790 ± 6089 ng/µL [log10: 3.31 ± 0.64]) (P = .027). Serum Gd-IgA1 levels of non-transplant IgAN patients were significantly higher (8791 ± 8700 ng/µL [log10: 3.79 ± 0.36]) than those of non-recurrent IgAN patients (4790 ± 6089 ng/µL [log10: 3.31 ± 0.64]) and healthy relatives (2615 ± 1611 ng/µL [log10: 3.34 ± 0.27]) (P < .001 and P = .021, respectively). Receiver-operating characteristic curve analysis revealed that the area under the curve for recurrence of IgAN was 0.69 (0.53-0.85) for serum Gd-IgA1 (P = .038). Biopsy-confirmed allograft rejection rates were similar in the recurrent IgAN group [3 (17%)] compared with the non-recurrent IgAN [6 (26%)] group (P = .47). Graft failure rate was not also significantly different in the recurrent IgAN group [4 (22.2%)] compared with the non-recurrent IgAN group [2 (8.7%)] (P = .224). CONCLUSIONS: This novel lectin-independent Gd-IgA1 ELISA that can detect serum Gd-IgA1 in patients with recurrent IgAN can be used as a biomarker for diagnosis and activity assessment of post-transplant recurrent IgAN.

Acquired Acrodermatitis Enteropathica Syndrome in a Kidney Transplant Receipt: A Case Report.

Acrodermatitis enteropathica syndrome (AE) is a clinical entity that results in severe zinc deficiency. It can be genetic or acquired. Acquired AE has been reported in patients with chronic liver disease, malabsorption syndrome, sickle cell anemia, and chronic renal failure. We present a kidney transplant recipient with skin rash and watery diarrhea. The patient had low serum zinc levels, which quickly resolved after zinc supplementation. Skin biopsy showed cytoplasmic pallor and vacuolization and ballooning degeneration of keratinocytes within the superficial epidermis, which may have led to confluent necrosis of keratinocytes. Large amounts of keratinosome-derived lamellae were found in the intercellular spaces in the keratinized area, probably related to disturbance of keratinosome metabolism due to zinc deficiency.

Comparative Analysis of Outcomes of Kidney Transplantation in Patients With AA Amyloidosis and Chronic Glomerulonephritis.

BACKGROUND: Amyloid A (AA) amyloidosis is a multisystemic, progressive, and severe disease. Renal involvement is a prominent feature of the disease, and the outcome of patients on dialysis is poor. We aimed to analyze the outcomes of kidney transplantation in patients with AA amyloidosis in comparison with chronic glomerulonephritis (CGN). METHODS: Charts of patients who underwent kidney transplantation between 1988 and 2012 were reviewed; 41 patients with AA amyloidosis were identified, and 41 age- and sex-matched control patients with chronic CGN were included. Baseline characteristics, immunosuppressive regimens, and transplantation-related outcomes were retrieved using a standardized form. RESULTS: The mean follow-up period was 70.9 ± 44.9 months. The 10-year patient survival was found to be significantly worse in the AA amyloidosis group (62.5%) compared to CGN group (100%) (P = .008). During the follow-up period, three of the 41 patients (9.7%) died of sepsis and one patient died of cardiac complications in the amyloidosis group, whereas there was no patients were lost in the CGN group. The first-year, fifth-year, and tenth-year mean graft survival rates, acute and chronic rejections, and mean creatinine levels at last visits were not significantly different between the groups. Proteinuria >1 g/d, cytomegalovirus and tuberculosis infections, and rhabdomyolysis were recorded at a significantly higher rate in patients with amyloidosis. CONCLUSION: As compared to patients with CGN, patients with AA amyloidosis had a lower patient survival; equal graft survival and rejection rates; and higher risks of developing proteinuria, cytomegalovirus and tuberculosis infections, and rhabdomyolysis.

Effect of Donor Nephrectomy Technique on Recipient Lymphatic Drainage.

AIM: We sought to evaluate the postoperative recipient lymphatic drainage depending on open donor nephrectomy (ODN) or laparoscopic (LDN) techniques. METHOD: Between March 2012 and August 2014, 58 patients underwent renal transplantation from living-related donors. Thirty donors underwent ODN (group 1), and 28 LDN (group 2). Operations were performed by the same surgeons. Both cranial and caudal drainage catheters for lymphatic leakage were placed preoperatively and all the recipients received tacrolimus, mycophenolate mofetil, and steroid as immunosuppressive regimen. None of the patients had coagulation abnormalities. RESULTS: All grafts were functioning during the early postoperative period and diuresis was ensured. No difference was observed on early postoperative period regarding to acute rejection (P = .329) or infection (P = .546). No difference was seen concerning mycophenolate mofetil and mycophenolate sodium regimens among the 2 groups (P = .227). In groups 1 and 2, the cranial drainage catheters were not taken out until postoperative days 5.5 ± 2.5 (range, 0-11) and 6.4 ± 3.8 (range, 0-14) and the caudal catheters stayed in place until days 8.8 ± 3.5 (range, 1-16) and 9.9 ± 5.9 (range, 3-22), respectively. No difference was found when comparing the cranial (P = .308) and caudal (P = .426) drainage periods. However, during clinical acute rejection episodes the cranial drainage period was longer in group 1 (P = .003). Three patients developed lymphoceles, 1 requiring drainage, in group 2. CONCLUSIONS: There seems to be no difference in recipient lymphatic drainage by donor nephrectomy technique. A laparoscopic procedure may be advantageous owing to shorter lymphatic drainage during clinical acute rejection episodes.

Renal transplantation in a patient with chronic granulomatous disease: case report.

Chronic granulomatous disease (CGD) is a genetic disease caused by structural mutations in the enzyme NADPH oxidase that results in severe immunodeficiency. End-stage renal disease occurs in this patient population and is attributed to various factors, including infections, amyloidosis, and nephrotoxic anti-infective agents. In this report, we present our experience in transplantation for a patient with CGD complicated by isolated hepatic tuberculosis abscess. The course of the case demonstrates the absolute requirements for a multidisciplinary and compulsive approach before, during, and after transplantation. This case report also highlights the unexpectedly benign effects of immunosuppressive therapy in this patient population.

The effect of anti-human leukocyte antigen, anti-major histocompatibility complex class 1 chain-related antigen a, and anti-glutathione transferase-T1 antibodies on the long-term survival of renal allograft.

BACKGROUND: One of the most important mechanisms of allograft rejection is the production of donor-specific antibodies (DSA). Anti-major histocompatibility complex class-I chain-related antigen A (MICA) and anti-glutathione S transferase-T1 (GSTT1) antibodies cause graft dysfunction and reduce graft survival. The aim of this study was to examine the effects of anti-human leukocyte antigen class I-II, anti-MICA, and anti-GSTT1 antibodies in development of antibody-mediated rejection. METHODS: Among the 32 renal transplant patients included in this study 65% experienced antibody-mediated rejection (AMR; chronic active AMR [CAMR], n = 17; acute AMR [AAMR], n = 4) and 35%, ACR. The anti-HLA class I-II and anti-MICA antibodies were determined by using LUMINEX, anti-GSTT1 antibodies by enzyme-linked immunosorbent assay. GSTT1 genotyping of patients and donors was performed by polymerase chain reaction. RESULTS: Antibody was detected in 19 of 21 patients undergoing antibody-mediated rejection (90%). We detected anti-GSTT1 in 4, anti-MICA in 8, anti-HLA class I in 5, and anti-HLA class II in 9 patients with CAMR (P = .007). If the patients were divided into 2 groups according to being C4d(+) and C4d(-) both anti-HLA class I and class II antibodies were found significantly more frequently among the C4d(+) group (P = .019, P = .024). No difference was determined between AMR and ACR groups in terms of anti-GSTT1 and anti-MICA antibodies. CONCLUSIONS: In this study, we observed the role of anti-HLA class II antibodies in the development of CAMR and in long-term allograft survival. It is observed that anti-MICA and anti-GSTT1 antibodies showed no effect on rejection mechanisms.

Effect of MDR1 polymorphisms on the blood concentrations of tacrolimus in Turkish renal transplant patients.

BACKGROUND: Tacrolimus, a calcineurin inhibitör, is prescribed to prevent allograft rejection in renal transplantation. Tacrolimus not only has a narrow therapeutic index, but also shows significant interindividual differences. The absorption and metabolism of this drug are affected by multidrug resistance (MDR) 1 gene polymorphisms that correlated with single-nucleotide polymorphisms (SNPs) affecting in vivo P-glycoprotein activity. This study investigated associations of MDR1 gene C3435T polymorphism with tacrolimus blood concentrations and dose requirements as well as acute rejection episodes among Turkish renal transplant patients. METHODS: One hundred living-donor transplant recipients and 150 healthy control subjects underwent C3435T genotyping using polymerase chain reaction-restriction fragment length polymorphism. Blood concentrations of tacrolimus were determined with the cloned enzyme donor immunoassay. RESULTS: The CC, CT, and TT genotype frequencies among patients were, respectively, 44.0%, 33.0%, and 23.0% versus 36.7%, 43.3%, and 20.0% among control subjects. There was no significant difference between (P = .061; P = .102; P = .211; respectively). The ratio of blood concentration to dose of tacrolimus for patients with mutant homozygous 3435 TT genotype was higher than that of wild-type 3435 CC genotype homozygous individuals. The doses for these patients were lower at 1, 3, and 12 months (P = .048; P = .03; P = .041, respectively). There were no significant differences between the groups regarding coprescription of drugs that affect tacrolimus concentrations, such as diltiazem. Acute rejection episodes were not associated with the CC vs CT or TT genotypes: odds ratio (OR), 0.517 (95% confidence interval [CI], 0.190-1.407; P = .192); OR 1.558 (95% CI, 0.587-4.136; P = .372); OR 1.346; (95% CI, 0.456-3.968; P = .590), respectively. CONCLUSIONS: Determination of MDR1 polymorphism may help to achieve target of tacrolimus blood concentrations.

Human leukocyte antigen and major histocompatibility complex class I-related chain A antibodies after kidney transplantation in Turkish renal transplant recipients.

BACKGROUND: This study was designed to determine whether human leukocyte antigen (HLA) and major histocompatibility complex class I chain-related A (MICA) antibody (Ab) production during the first 6 months posttransplantation correlated with long-term graft survival and rejection rate. The study group included 147 first transplantations from either living related (LRDs) or deceased donors (DDs) who were divided into two subgroups: rejection (RG, n = 28) and nonrejection (NRG, n = 119). Serum samples (n = 441) collected from each patient on posttransplant days 30, 90, and 180 were tested for HLA and MICA Ab using the Luminex technique. RESULTS: Among 82 Ab-positive patients (55.8%), 40 had both HLA and MICA, 33 only HLA, and 9 only MICA Ab in the posttransplant period. The rates of HLA class I, class II, or both Ab positivities were greater in the RG than the NRG (P = .011, .037, and .0275, respectively). At 180 days posttransplant, 64.3% of patients in the RG had Ab and 41.2% in the NRG (P = .0349). The data for the LRD (n = 116) group were similar to those for the entire group; whereas there was no significant difference in Ab positivity between RG and NRG patients who received organs from DDs. There was no significant difference with respect to HLA class II and/or MICA Ab positivity between RG and NRG among patients who lacked HLA class I Ab. DISCUSSION: We confirmed that HLA and MICA Ab may be harmful posttransplant, promoting rejection processes and representing an important cause of graft failure. HLA class II and MICA Ab positivities were only important predictors of graft failure when present together with HLA class I positivity. Patients who developed HLA alone or both HLA and MICA Ab rejected their grafts more frequently than Ab-negative recipients.

The effect of glutathion S-transferase polymoprhisms and anti-GSTT1 antibodies on allograft functions in recipients of renal transplant.

The balance between oxidative stress and anti-oxidant defense systems after renal transplantation may explain the development and progression of allograft dysfunction. Glutathione S-transferase (GST) decreases the damage from oxidative stress. In contrast, recipient antibodies against GSTT1 expressed on the graft are believed to cause its dysfunction. The aim of our research was to study the probable relationship to rejection between GST gene polymorphisms and anti-GSTT1 antibodies. We included 122 patients transplantations from living donors and 51 healthy individuals as controls group in our study. The patient groups were comprised of 57 patients who did and 65 who did not experienced rejection episode. Polymerase chain reactions were used to detect GSTM1 and GSTT1 polymorphisms, whereas PCR-RFLP (restriction fragment length polymorphism), for GSTP1 polymorphism. An enzyme-linked immunosorbent assay method was used for anti-GSTT1 antibody scans. There was no significant difference between the groups for allele and genotype frequencies of GSTT1, GSTM1, GSTP1 polymorphisms of the recipients, donors, and controls. Within the rejection group the frequency of patients with the GSTM1 null genotype was higher among subjects prescribed cyclosporine A versus tacrolimus (P = .029). Among the entire patient group, 46 subjects with GSTT1 null genotype were scanned for anti-GSTT1 antibody which was detected in 5 of 8 patients with an acute rejection episode (P = .04). Anti-GSTT1 antibody was observed more frequently albeit not significantly, among the cyclosporine versus tacrolimus patient group (P = .16). This study suggested that GSTM1 genotype may be important for cyclosporine detoxification and for allograft outcomes due to drug nephrotoxicity. After transplantation, antigens distinct from the HLA system such as GSTT1 protein may also be targets for alloimmune responses.

Long-term prognostic value of coronary flow velocity reserve in renal transplant recipients.

BACKGROUND: In this prospective study, we sought to investigate the long-term prognostic value of coronary flow reserve (CFR) and carotid intima media thickness (IMT) estimates in renal transplant recipients without known coronary artery disease. METHODS: The 20 renal transplant recipients included in this study underwent CFR recordings performed by trans-thoracic Doppler echocardiography (TTDE) and carotid IMT measured by carotid Doppler ultrasonography. RESULTS: During a 3-year follow-up only one patient experienced a cardiac event. The baseline CFR and carotid IMT values of the patients were 1.77 ± 0.47 and 0.67 ± 0.15 mm, respectively. After 3 years of follow-up, there were no significant differences compared with baseline measurements with regard to CFR and IMT values. CFR values at the third year of follow-up showed significant correlation with age as well as IMT at baseline and at the third year. Upon multivariate analysis, baseline carotid IMT (ß = -0.562; P = .05) was a significant independent predictor of CFR at the third year. CONCLUSION: Carotid IMT showed a greater predictive value for impaired CFR in renal transplant recipients. CFR was not an independent predictor for cardiovascular events among renal transplant recipients within the first 3 years of follow-up measurements.