Sequential monitoring of TIM-3 mRNA expression in blood and urine samples of renal transplant recipients.

BACKGROUND: T cell immunoglobulin and mucin domain 3 (TIM-3), as a co-inhibitory receptor expressed on Th1, Th17, CD8T, FoxP3 + Treg and innate immune cells, plays an important role in suppression of T cell-mediated immune responses, tolerance induction and T cell exhaustion. In this study, we evaluated sequential alterations of TIM-3 mRNA expression level in blood and urine samples of renal transplant recipients to predict approaching clinical episodes. METHODS: A total of 52 adult renal transplant recipients (31 male and 21 female) were enrolled in this study. All the patients received kidney transplant from living unrelated donors. TIM-3 mRNA expression in peripheral blood mononuclear cells (PBMCs) and urinary cells were quantified using Real Time TaqMan polymerase chain reaction (PCR) at 4 different time points (pre-transplantation, 2, 90 and 180 days post-transplantation). RESULT: TIM-3 mRNA expression level on days 2, 90 and 180 after transplantation was significantly higher in blood and urine samples of patients with graft dysfunction (GD) compared with patients with well-functioning graft (WFG). Our results also showed a high correlation between blood and urinary level of TIM-3 mRNA expression. The data from Receiver Operating Characteristic (ROC) Curve Analysis showed that blood and urinary TIM-3 mRNA expression level at month 3 and 6 could discriminate graft dysfunction (GD) from well-functioning graft (WFG) with high specificity and sensitivity. CONCLUSION: Our data suggested that serial monitoring of TIM-3 mRNA level in the blood and urine samples of renal transplant recipients could be a useful non-invasive biomarker for prediction and diagnosis of allograft dysfunction.

Association of programmed cell death 1 and programmed cell death 1 ligand gene polymorphisms with delayed graft function and acute rejection in kidney allograft recipients.

INTRODUCTION: The genetic variations of co-stimulatory molecules can affect the extent of T cell activity during T-cell mediated immunity, especially in transplant patients. This study aimed to investigate the association of programmed cell death 1 (PDCD1) and programmed cell death 1 ligand 1 (PDCD1LG1) gene polymorphisms with clinical outcome of kidney transplantation. MATERIALS AND METHODS: A total of 122 patients with a kidney transplant were included in this retrospective study. Patients were classified into two groups of biopsy-proven acute allograft rejection (AAR) and stable graft function (SGF) during the 5-year follow-up period. Four single nucleotide polymorphisms in PDCD1 and PDCD1LG1 were determined in the groups of patients as well as in 208 healthy control individuals. RESULTS: The frequencies of PD-1.3 (+7146 G>A), PD-1.9 (+7625 C>T), PD-L1 (8923 A>C), and PD-L1 (+6777 C>G) genotypes and alleles were not significantly different between the AAR and SGF groups. In comparison with healthy controls, PD-1.9 (+7625 C>T) genotype and T allele were significantly more frequent in all of the patients and in those with SGF. Overall, 27 of 122 kidney allograft recipients experienced delayed graft function, and a higher frequency of PD-1.9 (+7625 C>T) genotype and T allele was observed in this group versus those without delayed graft function. Similarly, a significant high frequency of this genotype was found among the AAR subgroup of patients with delayed graft function. CONCLUSIONS: Our results indicate that potentially functional genetic variation in PDCD1 can influence the outcome of kidney transplantation.

Dynamic changes of regulatory T cell and dendritic cell subsets in stable kidney transplant patients: a prospective analysis.

INTRODUCTION: We aimed to identify immune status of the stable kidney allografts from the point of some cellular changes that may occur after transplantation. MATERIALS AND METHODS: This study considered 57 patients with no rejection during the 6 months after transplantation. Flow cytometric frequencies of circulatory CD4+CD25+FoxP3+ and CD8+CD28- regulatory T cells (Treg) as well as myeloid dendritic cells type 1 (MDC1) and type 2 (MDC2) and plasmacytoid dendritic cells (PDC) were measured before transplantation and 2 weeks and 1, 3, and 6 months after transplantation. Using adjusted model of repeated measure analysis, we assessed the influence of different parameters on different cell subsets. RESULTS: The mean number of Tregs and PDCs decreased 2 weeks after transplantation and then increased as they reached their values before transplantation within a few months after transplantation. The mean MDC1s increased during 2 weeks and then decreased to its before-transplantation values within 6 months. The frequency of Tregs (r = 0.90) and MDC1s (r = 0.75) at month 3 could strongly predict their frequencies at month 6. Different variables including family relationship between donor and recipient, glomerular filtration rate, and human leukocyte antigen antibody mismatch did not change the frequency of different cell subsets during the time. CONCLUSIONS: The dynamism and circulatory changes in the frequency of Tregs and PDCs are opposite to MDCs after kidney transplantation. We describe these changes in a group of patients with stable graft; however, our study does not render any idea in patients with unstable or rejecting grafts.

Comparison of the Th1, IFN-γ secreting cells and FoxP3 expression between patients with stable graft function and acute rejection post kidney transplantation.

There are limited clinical investigations identifying the percentage of T helper 1 (Th1) and T regulatory (Treg) cells in stable as well as rejected kidney allografts, a concept which needs to be more studied. The aim of our study was to compare the percentage of CD4+ IFN-γ+ cells, the number of IFN-γ secreting cells and the amount of FoxP3 expression in patients with or without stable graft function, to determine the roles of these immunological factors in stable and rejected renal allografts. In this prospective study, 3 months after transplantation 30 patients who received renal transplants from unrelated living donors were enrolled and divided into two groups, 20 patients with stable graft function and 10 patients with biopsy proven acute rejection. The percentage of Th1 CD4+ IFN-γ+ cells was determined on PBMC by flow cytometry and the number of IFN-γ secreting cells by ELISPOT method. Furthermore, FoxP3 expression of PBMCs was measured by Real Time PCR method. The results of these assessments in both groups were statistically analyzed by SPSS 14.0. Our results showed that the percentage of Th1 CD4+ IFN-γ+ cells and the number of IFN-γ secreting cells were significantly higher in the patients with acute rejection in comparison to the stable graft function group (p<0.001). In addition, the level of FoxP3 gene expression was higher in the group with stable graft compared to the acute rejection group. The higher percentage of CD4+ IFN-γ+Th1 subset and number of IFN-γ secreting cells and also the lower expression of Foxp3 could prone the patients to acute rejection episode post transplantation. By these preliminary data, it is suggested that monitoring of Th1 cells post transplantation, as an immunologic marker could predict the possibility of rejection episodes.

Incidence of malignancy after living kidney transplantation: a multicenter study from iran.

Malignancy is a common complication after renal transplantation. However, limited data are available on post-transplant malignancy in living kidney transplantation. Therefore, we made a plan to evaluate the incidence and types of malignancies, association with the main risk factors and patient survival in a large population of living kidney transplantation. We conducted a large retrospective multicenter study on 12525 renal recipients, accounting for up to 59% of all kidney transplantation in Iran during 22 years follow up period. All information was collected from observation of individual notes or computerized records for transplant patients. Two hundred and sixty-six biopsy-proven malignancies were collected from 16 Transplant Centers in Iran; 26 different type of malignancy categorized in 5 groups were detected. The mean age of patients was 46.2±12.9 years, mean age at tumor diagnosis was 50.8±13.2 years and average time between transplantation and detection of malignancy was 50.0±48.4 months. Overall tumor incidence in recipients was 2%. Kaposis' sarcoma was the most common type of tumor. The overall mean survival time was 117.1 months (95% CI: 104.9-129.3). In multivariate analysis, the only independent risk factor associated with mortality was type of malignancy. This study revealed the lowest malignancy incidence in living unrelated kidney transplantation.

Two decades of experience in mucormycosis after kidney transplantation.

BACKGROUND: Invasive mucormycosis is a very rare infection after kidney transplantation. Here, we report 25 renal transplant recipients with mucormycosis; to our knowledge, this is the largest reported population of mucormycosis in these patients. MATERIAL/METHODS: In a retrospective study, we collected all kidney transplants with mucormycosis from 9 Transplant Centers of Iran from 1990 to 2010. The definitive diagnosis of mucormycosis was established by obtaining a biopsy specimen of the involved tissue. RESULTS: The most form of disease was rhino-cerebral (n =13), followed by pulmonary (n=7). Overall mortality rate was 52% (n=13), particularly in recipients with pulmonary infection (100%); however, the mortality rate in rhino-cerebral form of disease was low (30.8%). There was no statistically significant difference in mortality rate between male and female (P=0.8). In addition, no significant differences were seen in mortality rate with age of patients (p=0.8) and time of diagnosis since transplantation (p=0.3). Pulmonary infection was more seen in recipients received azathioprine compared to those on mycophenolate mofetil (p=0.006). CONCLUSIONS: Mucormycosis after renal transplantation has a poor prognosis, particularly patients with pulmonary involvement.

Skin cancer after renal transplantation: Results of a multicenter study in Iran.

BACKGROUND: Incidence and risk factors for skin tumors following renal transplantation can vary geographically; therefore, a retrospective study was performed to determine the incidence of and potential risk factors for skin cancer at 14 Transplant Centers in Iran between 1984 and 2008. MATERIAL/METHODS: We enrolled 11,255 kidney transplant recipients who were examined for all skin tumors. All skin cancers were established by histological examination. The data collection included the patient's age and sex, immunosuppressive regimen before and after diagnosis of tumor, rejection episodes, post-transplant latency period, other concurrent neoplastic problems, renal allograft function and outcome. RESULTS: One hundred and twenty-eight (1.14%) renal recipients had skin tumor, representing half of all post-transplant malignancies (128 out of 245 cases). Kaposi's sarcoma was the most common post-transplant cancer compared with other skin tumors. Male recipients had more tumors than did females (P=0.04); the male-to-female ratio in the affected patients was 2.5:1. The age at transplantation of patients with skin tumor was higher compared to RTRs without skin tumor (47±11 vs. 38±15 years, P=0.000), and individuals older than 45 years were at higher risk (odds ratio=3.8, 95%CI 2.6-5.5) of skin cancers. Patients consuming azathioprine were at risk more of skin cancer compared with those were on MMF (odds ratio =2.9, 95%, CI 2.0-4.2). The overall mortality was low (7.8%) in cases with skin cancer. CONCLUSIONS: This study showed that male sex, increased age, prolonged immunosuppression and azathioprine increased the risk of skin tumors after renal transplantation.

Kaposi's sarcoma following living donor kidney transplantation: review of 7,939 recipients.

INTRODUCTION: Kaposi's sarcoma (KS) is one of the most common tumors to occur in kidney recipients, especially in the Middle East countries. Limited data with adequate sample size exist about the development of KS in living kidney recipients. METHODS: Therefore, we made a plan for a multicenter study, accounting for up to 36% (n = 7,939) of all kidney transplantation in Iran, to determine the incidence of KS after kidney transplantation between 1984 and 2007. RESULTS: Fifty-five (0.69%) recipients who developed KS after kidney transplantation were retrospectively evaluated with a median follow-up of 24 (1-180) months. KS occurred more often in older age when compared to patients without KS (49 +/- 12 vs. 38 +/- 15 years, P = 0.000). KS was frequently found during the first 2 years after transplantation (72.7%). Skin involvement was universal. Furthermore, overall mortality rate was 18%, and it was higher in patients with visceral involvement compared to those with mucocutaneous lesions (P = 0.01). However, KS had no adverse affect on patient and graft survival rates compared to those without KS. Forty-four patients with limited mucocutaneous disease and four with visceral disease responded to withdrawal or reduction of immunosuppression with or without other treatment modalities. Renal function was preserved when immunosuppression was reduced instead of withdrawn in patients with and without visceral involvement (P = 0.001 and 0.008, respectively). CONCLUSION: The high incidence of KS in this large population studied, as compared to that reported in other transplant patient groups, suggests that genetic predisposition may play a pathogenetic role.

Lymphoma after living donor kidney transplantation: an Iranian multicenter experience.

INTRODUCTION: Post-transplant lymphoproliferative disorders (PTLD) are well-recognized complications in solid organ recipients. Limited data exist about the development of PTLDs in living kidney recipients. This study deals with a multicenter nationwide experience with kidney recipients from living donors. METHODS: We reviewed data of PTLD patients from a total population of 6,500 patients transplanted at three different transplant centers in Iran from 1984 to 2006. We also compared their data with 2,250 normal kidney recipients of Baqiyatallah Transplant Center. Data were analyzed to determine potential correlates with the occurrence of PTLD and patient outcome. RESULTS: Overall, 31 patients were diagnosed as having post-transplant lymphomas. The incidence of PTLD in our kidney transplant population comprised 0.47%. Sixteen (53%) PTLD patients were females, whereas 15 (47%) were males. The mean ages at transplantation and diagnosis were 37.1 and 41.9, respectively. Twelve (63%) patients died, and seven are alive. All deaths occurred within the 1st year after PTLD diagnosis. The mean time period from transplantation to diagnosis of PTLD was 64 (0.7-173) months. Localization of PTLD in the brain associated the worst outcome. Compared to non-PTLD patients, PTLD patients were significantly female predominated (51.6% vs. 32.2%; P = 0.03) and had lower age at transplantation (36.9 years vs. 42.9 years, respectively; P = 0.01). Patients under immunosuppressive regimens containing azathioprine were at higher risk for acquiring PTLDs compared to those with a MMF-containing regimen. CONCLUSION: PTLD is a major threat to kidney transplant recipients. Immunosuppressive agents have a significant role in developing the disease. Early detection of the disease and using more safe immunosuppresants may have beneficial effects on patient outcomes and incidence of the disease.

Posttransplant lymphoproliferative disorders in kidney transplant recipients: an Iranian multicenter experience.

INTRODUCTION: Limited data with adequate sample size exist on the development of posttransplant lymphoproliferative disorder (PTLD) in living donor kidney recipients. We conducted a retrospective cohort study on the data of 10 transplant centers to identify the incidence of PTLD in Iran. MATERIALS AND METHODS: Data of 9917 kidney transplant recipients who received their kidneys between 1984 and 2008 were reviewed. Fifty-one recipients (0.5%) who developed PTLD were evaluated with a median follow-up of 47.5 months (range, 1 to 211) months. RESULTS: Patients with PTLD represented 24% of all posttransplant malignancies (51 out of 211 cases). There was no relationship between PTLD and sex (P = .20). There were no statistically significance differences considering the age at transplantation between patients with and without PTLD. The late-onset PTLD (70.6%) occurred more frequently compared to the early form. There was no signification relationship between early-onset and late-onset groups in terms of clinical course and outcome. In patients who received azathioprine, PTLD was more frequent when compared to those who received mycophenolate mofetil (P < .001). The lymph nodes were the predominantly involved site (35.3%), followed by the gastrointestinal tract, brain, kidney allograft, lung, ovary, vertebrae, and palatine. Age at diagnosis and the time from transplantation to diagnosis were comparable for various involvement sites of PTLDs. The overall mortality in this series of patients was 51.0%. CONCLUSIONS: Posttransplant lymphoproliferative disorder is a rare but devastating complication and long-term prognosis can be improved with early recognition and appropriate therapy.