The effect of genetic variations for interleukin-10 (IL-10) on the efficacy of immunosuppressive therapy in patients after kidney transplantation.

Kidney transplantation is the target method of treating chronic kidney disorders. It improves the comfort of patient life by eliminating the need for repeated dialysis. The aim of the study was to examine the correlation between tacrolimus (TAC) dose and genetic variation for interleukin-10 (IL-10) and its effect on the therapeutic outcome. In addition, the correlations between the IL-10 polymorphism andthe clinical and the biochemical parameters of TAC patients were also analyzed. The study included 209 subjects after kidney transplantation, who received TAC every 12 and 24 h. Drug concentrations in blood, selected morphological and biochemical parameters, and the genetic variation of IL-10 (-1082A > G) which may affect immunosuppressant dosage and risk of acute graft rejection were analyzed. Genetic analyses were performed using real-time PCR. No significant correlations between the clinical and the biochemical parameters and IL-10-1082A > G polymorphism for patients receiving TAC after kidney transplantation were found. The analysis of the correlation between TAC dose and IL-10 genetic variation for the -1082A > G polymorphism revealed that patients with the AA genotype required lower immunosuppressive drug doses (AA: 3.54 ± 2.38 mg/day vs AG: 6.18 ± 5.10 mg/day, GG: 4.44 ± 3.01 mg/day). Furthermore, frequencies of the genotypes for the IL-10 -1082A > G polymorphism were characterized by a significantly higher frequency of the AA genotype among TAC 24 as compared to TAC 12 patients. The results of the study indicated that the IL-10 -1082A > G polymorphism may in fact influence the TAC dose. The biochemical parameters of the renal profile in relation to the IL-10 genetic variations were not indicative of higher risk of acute rejection after transplantation.

Effect of Multidrug-Resistant 1 (MDR1) and CYP3A4*1B Polymorphisms on Cyclosporine-Based Immunosuppressive Therapy in Renal Transplant Patients.

BACKGROUND Immunosuppressive drugs such as cyclosporine A (CsA) are characterized by a narrow therapeutic range and high interindividual pharmacokinetic variations. Therefore, the effective monitoring of drug serum level is crucial for successful therapy. This variability can be caused by polymorphisms in genes encoding drug transporters and enzymes responsible for biotransformation. The aim of this study was to determine the relationship between CYP3A4*1B and MDR1 polymorphisms and dose requirements to achieve the target therapeutic range for CsA. MATERIAL AND METHODS The study group consisted of 184 patients after kidney transplantation who were treated with immunosuppressive therapy. The MDR1 3435C>T and CYP3A4*1B polymorphisms were determined by the real-time PCR using the LightCycler® 480 device (Roche Diagnostics). RESULTS Patients with the CYP3A4*1/*1 genotype received the lowest mean dose of CsA compared to CYP3A4*1/*1B, and had a higher average drug concentration in the blood. In the case of MDR1 3435C>T polymorphism, we observed that patients with the CC genotype received lower doses of CsA than patients with the CT and TT genotypes. Average drug concentration in the blood was comparable to individuals with different MDR-1 genotypes. Analysis of dependence between both polymorphisms and concentration/dose ratio showed no statistically significant differences. CONCLUSIONS The characterization of CYP3A4*1B and 3435C>T MDR1 polymorphism cannot provide useful guidance for individualizing CsA dosages in renal transplant patients by indicating the optimal dose of these drugs without exposing patients to possible adverse effects associated mainly with nephrotoxicity.

Analysis of common polymorphisms within NR1I2 and NR1I3 genes and tacrolimus dose-adjusted concentration in stable kidney transplant recipients.

OBJECTIVES: Several genetic factors were identified to be responsible for interidividual variability in tacrolimus (TAC) pharmacokinetics, with the predominant role of CYP3A5 and CYP3A4 polymorphisms. In this study, genetic variants of NR1I2 and NR1I3 nuclear receptors (responsible for the regulation of drug-metabolizing enzymes and transporters at the transcriptional level) were evaluated for their potential association with altered TAC concentrations. MATERIALS AND METHODS: Two hundred and forty White kidney transplant patients were genotyped for five single-nucleotide polymorphisms (rs3814055, rs6785049, rs2276707, rs2307424, and rs2307418) in NR1I2 and NR1I3 genes. Genetic data were analyzed in relation to TAC dose-adjusted trough concentration measured 6 months after transplantation (unadjusted and adjusted for patient's CYP3A5 expresser status). RESULTS: There were significant differences in TAC concentrations between patients with different NR1I2 rs3814055:C>T genotypes (mean values: 121.3 ng/ml mg/kg in major CC homozygotes, 169.6 ng/ml mg/kg in CT heterozygotes, and 186.0 ng/ml mg/kg in patients homozygous for the minor T allele) that remained significant after excluding CYP3A5 expressers from analysis. The TAC dose administered to minor T allele carriers (CT or TT genotype) was significantly lower (~22%) compared with CC homozygotes. For all the other loci analyzed, no significant associations were noted. CONCLUSION: Our results support the previous data on the functionality of NR1I2 rs3814055 single-nucleotide polymorphism that points to its association with interindividual differences in activity and inducibility of a broad range of drug-metabolizing enzymes and drug transporters.

Multiorgan transplantation from a deceased donor with intravascular diffuse large B-cell lymphoma: transmission of the disease and results of treatment.

This report presents the transplantation of two kidneys and the liver from a deceased donor with suspected autoimmune encephalomeningitis (ADEM). Due to an atypical post-transplantation clinical course, the transplanted kidneys were biopsied and this disclosed diffuse large B-cell (DLBC) lymphoma of the intravascular type in each kidney. The same malignancy was found in the postmortem donor brain examination. The renal allografts from the two recipients were removed: despite every effort, one patient died, while chemotherapy was successful in the second. No malignancy was observed in the liver transplant recipient, who received prophylactic chemotherapy. These cases highlight the occasional failure of organ donor disease screening and the consequent unforeseen complications.

Impact of PPARA and POR polymorphisms on tacrolimus pharmacokinetics and new-onset diabetes in kidney transplant recipients.

Recent efforts have been made to identify genetic markers of CYP3A4 enzymatic activity within genes encoding for regulatory elements. The aim of the current study was to investigate the impact of polymorphism of PPARA and POR genes on tacrolimus (TAC) dose-adjusted trough concentration and risk of new-onset diabetes after transplantation (NODAT). A total of 241 White kidney transplant patients were genotyped for three functional single nucleotide polymorphisms: rs1057868 (*28) in POR, rs4253728:G>A, and rs4823613:A>G in PPARA. No significant genotype-dependent differences in TAC dose-adjusted trough concentration were observed for either POR or PPARA variants. No significant differences in the incidence of NODAT were observed between patients stratified by PPARA and POR genotypes. The frequency of NODAT among PPARA rs4253728 AA homozygotes (42%) was higher compared with heterozygotes (22%) and GG homozygotes (19%), but the difference was not significant. Testing TAC-medicated renal transplant recipients for POR and PPARA variants seems to have limited clinical application.

CYP3A5 and CYP3A4, but not ABCB1 polymorphisms affect tacrolimus dose-adjusted trough concentrations in kidney transplant recipients.

BACKGROUND: Tacrolimus (TAC), acting as a calcineurin inhibitor, is an immunosuppressant widely used after kidney transplantation. TAC requires blood concentration monitoring due to large interindividual variability in its pharmacokinetics and a narrow therapeutic index. Since genetic factors are considered responsible for a part of the observed pharmacokinetic variability, hereby SNPs within the CYP3A4, CYP3A5 and ABCB1 genes in kidney transplant patients of Polish Caucasian origin were investigated. PATIENTS & METHODS: A total of 241 patients treated with TAC through the first year after kidney transplantation were genotyped for the presence of common SNPs: rs776746:A>G (CYP3A5*3), rs35599367:C>T (CYP3A4*22), rs2740574:A>G (CYP3A4*1B) and rs1045642:C>T (ABCB1 3435C>T) using TaqMan(®) assays. RESULTS: CYP3A5 expressers received significantly higher weight-adjusted TAC doses, and were characterized by markedly lower C0 and dose adjusted C0 values in the course of treatment. CYP3A4*1B was significantly associated with TAC pharmacokinetics in univariate analysis. Impact of the CYP3A4*22 allele was significant only at particular time points, that is, 3 months after transplantation, with marginal significance 6 months after transplantation. The ABCB1 genotype did not influence TAC pharmacokinetics. Multivariate analysis of all the studied loci demonstrated that only the CYP3A5*1 (starting from month 1) and CYP3A4*22 alleles (at 3 and 6 months) were independent predictors of TAC dose-adjusted C0. CONCLUSION: Our results confirm the impact of the CYP3A4*22 allele on TAC pharmacokinetics, as a second significant genetic factor (in addition to the CYP3A5*1 allele) influencing TAC dose-adjusted blood concentrations in kidney transplant recipients.

Analysis of common type 2 diabetes mellitus genetic risk factors in new-onset diabetes after transplantation in kidney transplant patients medicated with tacrolimus.

PURPOSE: New-onset diabetes after transplantation (NODAT) is a major complication after kidney transplantation. The risk factors for NODAT include the use of calcineurin inhibitors as part of the immunosuppressive regimen, among which tacrolimus has the most pronounced diabetogenic effect. Both NODAT and type 2 diabetes mellitus (T2DM) share several risk factors. Recent studies have identified a number of common genetic variants associated with increased risk of T2DM. Here we report the results of our study on the potential effect of single nucleotide polymorphisms (SNPs) previously associated with T2DM on the risk of NODAT in kidney transplant patients medicated with tacrolimus. METHODS: Seven SNPs in six genes known to increase the risk of T2DM in Caucasians were genotyped by means of TaqMan assays in 235 kidney transplant patients medicated with tacrolimus: rs4402960 and rs1470579 in IGF2BP2; rs1111875 in HHEX; rs10811661 upstream of CDKN2A/B; rs13266634 in SLC30A8; rs1801282 in PPARG; rs5215 in KCNJ11. The TCF7L2 rs7903146 SNP was also included in the multivariate analysis. RESULTS: None of the analyzed SNPs was significantly associated with the risk of NODAT. However, the IGF2BP2 rs4402960 T allele was present significantly more frequently among patients diagnosed with NODAT more than 2 weeks after transplantation (p = 0.048). Mean (± standard deviation) number of the analyzed alleles tended to be lower in patients without NODAT (6.19 ± 1.71) than in NODAT patients (6.58 ± 1.1.95; p = 0.09) and significantly lower compared to late-onset NODAT patients (7.03 ± 1.88; p = 0.018). Multivariate analysis confirmed the significance of 'diabetogenic' allele number in late-onset NODAT development [odds ratio (OR) 1.37, 95 % confidence interval (CI) 1.05-1.78; p = 0.017]. Additionally, individuals carrying >7 of the analyzed 'diabetogenic' alleles were at a significantly higher risk of NODAT (OR 2.17, 95 % CI 1.18-3.99; p = 0.015). CONCLUSIONS: Complex analysis of genotypes increasing the risk of diabetes may lead to the identification of NODAT susceptibility predictors.

Polymorphism of genes involved in purine metabolism (XDH, AOX1, MOCOS) in kidney transplant recipients receiving azathioprine.

BACKGROUND: Xanthine dehydrogenase (XDH), aldehyde oxidase1 (AOX1), and molybdenum cofactor sulfurase (MOCOS) are enzymes involved in purine metabolism. The aim of this study was to investigate single nucleotide polymorphisms (SNPs) in XDH, AOX1, and MOCOS genes in relation to clinical parameters and risk of drug side effects in a cohort of kidney transplant recipients treated with azathioprine (AZA) as a part of standard immunosuppressive regimen. METHODS: One hundred fifty-six patients receiving AZA for the first year from the surgery were genotyped for the presence of common SNPs in the coding regions of XDH, AOX1, and MOCOS genes using TaqMan assays. RESULTS: AOX1 rs55754655 variant allele carriers received a higher mean AZA dose 3, 6, and 12 months after transplantation (P < 0.05). The patients inheriting rs594445 MOCOS minor allele required significantly lower doses of AZA for efficient treatment compared with wild-type heterozygotes at 3, 6, and 12 months from the transplantation (mean values: 1.39 versus 1.59, 1.38 versus 1.58, and 1.33 versus 1.53 mg·kg·24 h) and displayed lower mean RBC count at the time points evaluated. Multivariate analysis has shown that the effect of MOCOS rs594445 polymorphism is independent of other investigated gene variations and might influence AZA dosage, similarly to TPMT heterozygosity. The authors have not observed an association between any of the studied XDH SNPs and clinical parameters of AZA-treated patients. CONCLUSIONS: The results of this study should be regarded as preliminary. However, if the observed association between SNPs: AOX1 rs55754655, MOCOS rs594445, and AZA dose requirements would be positively confirmed in further independent studies, it could be introduced into clinical practice to individualize thiopurine treatment.

Association of transcription factor 7-like 2 (TCF7L2) gene polymorphism with posttransplant diabetes mellitus in kidney transplant patients medicated with tacrolimus.

New onset posttransplant diabetes mellitus (PTDM) has a high incidence after kidney transplantation in patients medicated with tacrolimus. PTDM can adversely affect patient and graft survival. The pathophysiology of PTDM closely mimics type 2 diabetes mellitus (T2DM). One of the possible genetic factors predisposing individuals to PTDM might be a polymorphism in the transcription factor 7-like 2 gene (TCF7L2). This polymorphism has previously been associated with increased risk of T2DM in the general population. Therefore, the present study aimed to evaluate TCF7L2 polymorphisms in PTDM in kidney transplant patients medicated with tacrolimus. Non-diabetic kidney transplant patients medicated with tacrolimus (n = 234) were genotyped for the presence of TCF7L2 gene variants (rs12255372 and rs7903146) using TaqMan probes. Of the 234 patients, 66 patients had developed PTDM and 168 had not. Frequencies of the studied single nucleotide polymorphisms (SNPs) did not differ significantly between the study groups. Moreover, haplotype analyses failed to detect any associations between TCF7L2 haplotypes and PTDM. However, in late-onset PTDM (developed later that 2 weeks from transplantation), frequencies of the rs7903146 TT genotype and T minor allele were significantly increased compared to non-PTDM controls (17.9% vs. 5.9%, p = 0.017, OR: 4.13, 95% CI: 1.19-14.33 for TT genotype, 39.3% vs. 25.9%, p = 0.038 for T allele). If the application of TCF7L2 rs7903146 SNPs as a marker for PTDM is confirmed by further independent studies, replacing tacrolimus with other immunosuppressants could be warranted in patients at high risk of PTDM, as diagnosed by TCF7L2 genotyping.

Kidney transplantation among identical twins: therapeutic dilemmas.

A case of the successful kidney transplantation among two homozygous twins is presented here. Prior to the familial kidney transplantation from the identical twins, the patient underwent peritoneal and haemodialyses as well as cadaveric kidney transplant from an unrelated donor. In this patient, vascular accessibility was poor and the second familial transplantation was performed urgently. Transplanted kidney function proved excellent; however, the issues of the best immunosuppressant to be selected are under consideration. Decision on the use or withdrawal of immunosuppressant drugs requires careful review of the disease status, concomitant disease and other factors influencing the final outcome.

Association of calpain-10 gene polymorphism and posttransplant diabetes mellitus in kidney transplant patients medicated with tacrolimus.

New-onset, posttransplant diabetes mellitus (PTDM) has a high incidence after kidney transplantation in patients medicated with tacrolimus, and may adversely affect the patient and graft survival. The pathophysiology of PTDM closely mimics that of type II diabetes mellitus (T2DM). One of possible genetic factors predisposing to PTDM might be polymorphism in calpain-10 gene (CAPN10), previously associated with increased risk of T2DM in general population. Therefore, the present study was aimed at evaluation of CAPN10 gene polymorphisms in PTDM in kidney transplant patients medicated with tacrolimus. A total of 214 nondiabetic kidney transplant patients medicated with tacrolimus (56 patients with PTDM and 158 patients without PTDM were genotyped for the presence of CAPN10 gene variants (SNP-43: rs3792267:G>A, SNP-19: rs3842570 ins/del and SNP-63: rs5030952:C>T) using PCR-based assays. Frequency of SNP-63 minor allele was slightly increased in PTDM patients (P=0.056), and an association of SNP-63 heterozygosity and the risk of PTDM (odds ratios (OR)=2.45, P=0.023) was observed. An increased odds for PTDM development in patients carrying 1-1-2 haplotype (rs3792267:G-rs3842570:ins-rs5030952:T) compared to noncarriers was also noted (OR=2.35, P=0.026). Patients' higher body mass index and SNP-63 minor T allele carrier status were identified as independent PTDM risk factors, confirmed by multivariate regression analysis. This is the first study of CAPN10 polymorphism in relation to PTDM risk. However, the application of SNP-63 (rs5030952:C>T) as a marker of PTDM should be verified by further independent studies.

The effect of dialysis membrane type on plasma concentrations of pentosidine, a marker of carbonyl stress, in hemodialyzed patients.

INTRODUCTION: Advanced glycation end products (AGEs), which accumulate in plasma of hemodialyzed patients, participate in the development of complications associated with hemodialysis (HD). Carbonyl stress plays an essential role in the formation of AGEs, including pentosidine. OBJECTIVES: The aim of the study was to assess the effect of various low-flux dialysis membranes on plasma concentrations of total (P(tot)) and free (P(free)) pentosidine. PATIENTS AND METHODS: We examined 56 adult patients (aged 50 +/-13 years) on chronic HD. Plasma pentosidine concentrations were measured with high-performance liquid chromatography with fluorescence detection. Plasma proteins were subjected to acid hydrolysis or precipitation with trichloroacetic acid before measurement of P(tot) and P(free), respectively. RESULTS: Significantly lower concentrations of P(tot) were observed in patients dialyzed with polysulfone than non-polysulfone membranes before the HD session (22.0 +/-11.9 vs 34.4 +/-12.5 pmol/mg protein, respectively, p = 0.0008) and after the HD session (22.5 +/-12.9 vs 32.9 +/-12.0 pmol/mg protein, p = 0.004). Moreover, there was a strong inverse correlation between the percentage of HD sessions performed with polysulfone membranes during the last 3 months and P(tot) concentration before HD (Rs = -0.44, p = 0.0011) and after HD (Rs = -0.45, p = 0.00073). CONCLUSIONS: The results suggest that polysulfone membranes reduce carbonyl stress more effectively than modified or unmodified cellulose membranes in patients on chronic HD. Determination of plasma pentosidine in hemodialyzed patients may help in comparing the physicochemical and biological properties of dialysis membranes. It may also contribute to the development of optimal strategies for renal replacement therapy.

TPMT but not ITPA gene polymorphism influences the risk of azathioprine intolerance in renal transplant recipients.

PURPOSE: Thiopurine drugs have to be withdrawn in 10-30% of cases due to side effects, and it has been presented that genetic factors may be responsible for some of reported toxicity cases. Among polymorphic enzymes of thiopurines' metabolic pathway, thiopurine S-methyltransferase (TPMT) has been studied most extensively, and some recent studies point to inosine triphosphate pyrophosphohydrolase (ITPA) polymorphism as an additional toxicity risk factor. METHODS: The aim of the current study was to evaluate an association between TPMT and ITPA gene polymorphisms and drug intolerance in a cohort of 157 renal transplant recipients treated with azathioprine (AZA). Each subject was genotyped for the presence of variant TPMT (*2, *3A, *3B, and *3C) and ITPA (94C>A and IVS2+21A>C) alleles. RESULTS: Mean AZA dose, mean white-blood-cell count, and platelet count in the course of treatment were lower in carriers of variant TPMT alleles compared to patients with TPMT wild-type genotype. Leukocyte numbers fell below 4.0 x 10(9)/L in 41.2% of TPMT heterozygous renal transplant recipients, compared to only 18.0% of wild-type patients (P < 0.01). In contrast, ITPA genotype did not influence AZA dose, hematological parameters, or leucopenia risk. CONCLUSIONS: Our results suggest that routine genotyping of renal transplant recipients for TPMT variants may be useful in reducing the risk of AZA-related myelotoxicity, but there is not enough evidence to introduce ITPA testing into clinical practice.

Laparoscopic live-donor nephrectomy with retroperitoneoscopic access - first case experience.

BACKGROUND: Despite observed huge progress in understanding the immunological basis of transplantation and the development of new immunosuppressive agents that have significantly improved both -- the patient and graft survival, still the kidney donation from live volunteers remains the most consistent factor which affects the long-term survival. The conventional, open method of donor nephrectomy is associated with significant surgical trauma. The laparoscopic live-donor nephrectomy (LDN) is the alternative for open approach. CASE REPORT: We present our experience of the case of laparoscopic removal of the kidney from a living donor. We applied retroperitoneoscopic access, the operation time was 210 minutes. Kidney was implanted shortly after LDN and its immediate function was observed. We have observed no serious postoperative complications either in donor or recipient. CONCLUSIONS: We hope that this successful initial case of LDN will have a positive effect on cooperation between transplantologists and urologists, and on rate of kidney donation in Poland.

Autosomal dominant polycystic kidney disease is not a risk factor for post-transplant diabetes mellitus. Matched-pair design multicenter study.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) is a relatively common complication of kidney transplantation. The aim of our work was to compare the incidence of PTDM in kidney transplant recipients with and without autosomal dominant polycystic kidney disease (ADPKD) in a matched-pair design study. METHODS: In total, 98 pairs of graft recipients, all of Caucasian origin and who received a kidney from the same cadaveric donor, were included in the study. The following clinical data were collected for statistical analysis: age, body mass index (BMI) before transplant, length and type of dialysis treatment, residual diuresis, and cold and warm graft ischemia time. Diabetes was diagnosed based on American Diabetes Association (ADA) criteria. RESULTS: Incidence of PTDM was 19.4% in the ADPKD group and 18.4% in the non-ADPKD group, with no significant differences between groups. Multivariate logistic regression analysis of the PTDM risk in the ADPKD group including age, gender, BMI, and dialysis time as independent variables indicated that only higher residual diuresis is a significant independent risk factor (OR = 5.64 per every L/24 h, 95% CI = 1.31-24.33, p = 0.017). Similarly, logistic regression analysis adjusted for age and gender in the non-ADPKD group has shown that significant independent risk factors are BMI (OR = 1.30 per every kg/m(2), 95% CI = 1.06-1.59, p = 0.0094), longer dialysis time prior to transplant (OR = 1.036 per each month, 95% CI = 1.004-1.070, p = 0.025), and a history of arterial hypertension (OR = 9.09, 95% CI = 1.20-68.66, p = 0.030). CONCLUSIONS: In this paired analysis, our results suggest that diagnosis of ADPKD does not increase risk of PTDM.

Impact of posttransplant diabetes mellitus on graft function in autosomal dominant polycystic kidney disease patients after kidney transplantation.

INTRODUCTION: Posttransplant diabetes mellitus (PTDM) remains the significant clinical problem and impairs the quality of life of renal transplant recipients. Negative influence of PTDM on graft function is associated with chronic allograft nephropathy, systemic infectious complications, recurrent infections or urinary tract infections. Some earlier studies suggest that patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD) are at special risk of developing PTDM. The aim of our study was to assess the influence of PTDM on graft function in recipients with ADPKD and other causes of renal failure during 12-month follow-up. Another aim of the study was to answer the question if the etiology of renal failure (ADPKD vs non-ADPKD) and the development of PTDM were independent predictors of graft function and if there was a significant interaction between them. MATERIAL AND METHODS: 98 pairs of kidney recipients from the same cadaveric donor were included into the study, with the ADPKD-related renal failure in one of the recipients, and different reasons for transplant in the other, with exclusion of the diabetic nephropathy. Diabetes was diagnosed according to American Diabetes Association (ADA) criteria. For statistical analysis the following parameters were included: age, sex, development ofposttransplant complications such as: PTDM, acute tubular necrosis (ATN) and early graft rejection, the presence of surgical and infectious complications (urinary tract infections excluded) and urinary tract infections as well as kidney function parameters such as serum urea, creatinine and uric acid concentrations 3, 6 and 12 months after transplantation. RESULTS: At the time of transplantation ADPKD patients were significantly older than non ADPKD patients (median 49.5 vs 45.3 years, p < 0.00008). There was no significant difference in incidence of PTDM between the study groups (19% in the ADPKD group and 18% in non-ADPKD group, p = 1.0). In ADPKD group no significant differences in serum urea, creatinine and uric acid following transplant were found between PTDM and non-PTDM subgroups. In non-ADPKD group, 3 and 6 months after transplantation, serum urea concentrations (77.5 mg/dL vs 54.0 mg/dL, p = 0.007 and 77.0 mg/dL vs 56.7 mg/dL, p = 0.016) and uric acid concentrations (7.7 mg/dL vs 6.8 mg/dL, p = 0.001 and 7.3 mg/dL vs 6.2 mg/dL, p = 0.034) were significantly higher in PTDM than in non-PTDM subgroup. Serum creatinine concentration was significantly higher in PTDM group 12 months following transplant (1.87 mg/dL vs 1.5 mg/dL, p = 0.035), with borderline significance 6 months following transplant (1.77 mg/dL vs 1.5 mg/dL, p = 0.057). In PTDM subgroup of ADPKD patients the percentage of infectious complications was slightly higher than in non-PTDM subgroup, but the difference was not statistically significant (37% vs 18%, p = 0.12), urinary tract infections were significantly more prevalent in PTDM subgroup (47% vs 18%, p = 0.013). In multivariate analysis no significant influence of ADPKD on any of the parameters of graft function was found. Significant interaction between ADPKD and PTDM presence for their influence on parameters of graft function was not found either what suggests that PTDM had a similar negative effect on these parameters in both ADPKD and non-ADPKD patients. CONCLUSIONS: 1. PTDM has negative influence on graft function independently of ADPKD diagnosis. 2. PTDM presence in ADPKD group significantly predisposes to urinary tract infections.

The impact of thiopurine s-methyltransferase polymorphism on azathioprine-induced myelotoxicity in renal transplant recipients.

Thiopurine S-methyltransferase (TPMT) is an enzyme that catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine, 6-thioguanine, and azathioprine. TPMT activity exhibits an interindividual variability, mainly as a result of genetic polymorphism. Patients with intermediate or deficient TMPT activity are at risk for toxicity after receiving standard doses of thiopurine drugs. It has previously been reported that 3 variant alleles: TPMT*2, *3A, and *3C are responsible for over 95% cases of low enzyme activity. The purpose of this study was to explore the association between these polymorphisms and the occurrence of azathioprine adverse effects in 112 renal transplant recipients undergoing triple immunosuppressive therapy including azathioprine, cyclosporine, and prednisone. TPMT genetic polymorphism was determined using PCR-RFLP and allele-specific PCR methods. Azathioprine dose, leukocyte, erythrocyte, and platelet counts, graft rejection episodes, as well as cyclosporine levels were analyzed throughout the first year after organ transplantation. We found the frequency of leukopenia episodes (WBC < 4.0 x 10(9)/L) significantly higher in heterozygous patients (53.8%) compared with those with TPMT wild-type genotype (23.5%). One patient, who was a compound homozygote (3A/*3C), experienced severe azathioprine-related myelotoxicity each time after receiving the standard drug dose. Our results suggest that polymorphisms in TPMT gene may be responsible for approximately 12.5% of all leukopenia episodes in renal transplant recipients treated with azathioprine. Genotyping for the major TPMT variant alleles may be a valuable tool in preventing AZA toxicity and optimization of immunosuppressive therapy.