J. Wyzgał

Long‐term results of treatment of chronic hepatitis B, C and D with interferon‐α in renal allograft recipients

Abstract The aim of this study was to evaluate the efficacy and safety of interferon‐a (IFN‐α) therapy of chronic hepatitis B, C and D (HBV, HCV and HDV, respectively) in renal transplant recipients. A group of 42 patients (30 males, 12 females, mean age 38 years) with documented viraemia and chronic active hepatitis (CAH) were studied, of whom 1 had HBV infection alone, 11 had HCV infection alone, 3 had HBV and HDV infection concomitantly, 12 had HBV and HCV infection concomitantly, and 2 had HBV, HCV and HDV infection concomitantly. Patients received 3 MU IFN‐α three times weekly for 6 months. After IFN‐α therapy, 18 patients (43 %) achieved normal alanine aminotransferase (ALT) activity and a partial response was observed in 12 (29%) patients. Two patients relapsed (one with HCV and one with HBV + HCV infection) immediately after the cessation of IFN‐α therapy. Repeated liver biopsy was performed in 16 patients after 6–24 months of therapy and revealed progression to cirrhosis in five patients, remission in two and stable disease in nine. None of the patients cleared HCV RNA, four patients cleared HBeAg (two also HDV), and one both HBV and HCV. Five patients died during IFN‐α therapy (one as a consequence of liver failure), and four died during the 6 months after therapy (two as a consequence of liver failure). During IFN‐α therapy renal allograft function remained stable in 31 patients and acute rejection episodes occurred in 7, of whom 5 lost their graft and all had experienced rejection episodes before. In 16 patients normalization of ALT continued during long‐term follow‐up (median 22 months, range 0–84 months). IFN‐α seemed to be moderately effective in the treatment of chronic HBV or HCV infections, but cannot be recommended for recipients infected with both HBV and HCV.

Rapamycin, unlike cyclosporine A, enhances suppressive functions of in vitro-induced CD4+CD25+ Tregs

BACKGROUND A growing body of data shows that CD4(+)CD25(+) regulatory T cells (Tregs) can induce transplantation tolerance by suppressing immune responses to allograft antigens. However, both the generation and the suppressive capacity of CD4(+)CD25(+) Tregs can be substantially affected by different immunosuppressive drugs used in clinical transplantation. The goal of this study was to compare the effects of cyclosporine A and rapamycin on the induction and suppressive functions of human CD4(+)CD25(+) Tregs in vitro. METHODS CD4(+)CD25(+) Tregs were induced in two-way mixed lymphocyte reaction (MLR) in the presence of rapamycin (Treg-Rapa) or cyclosporine A (Treg-CsA). Tregs were identified in MLR cultures by flow cytometry using anti-CD4, anti-CD25, anti-CTLA-4, anti-CD122, anti-GITR mAbs and ant-PE-FOXP3 staining sets. Suppressive capacity of induced Tregs was evaluated by their capability to inhibit anti-CD3 Ab-triggered proliferation of peripheral blood mononuclear cells (PBMCs), as measured by flow cytometry. The concentration of TGF-beta1 in culture supernatants was measured by enzyme-linked immunosorbent assay. RESULTS Although both rapamycin and cyclosporine A suppressed the induction of CD4(+)CD25(+) Tregs during MLRs, this effect was significantly more pronounced in cells cultured with cyclosporine. On the other hand, only rapamycin significantly decreased the percentage of CD4(+)CD25(+) Tregs which expressed GITR, a negative regulator of Tregs suppressive capacity. Importantly, Treg-Rapa, unlike Treg-CsA, displayed significant suppressive activity and were capable of inhibiting the proliferation of anti-CD3 Ab-activated PBMCs. This activity was likely mediated by TGF-beta1. CONCLUSIONS Rapamycin, unlike cyclosporine A, does not inhibit the function of CD4(+)CD25(+) Tregs. This implies that rapamycin could contribute to the development of transplantation tolerance by promoting the induction of functional CD4(+)CD25(+) Tregs. Moreover, our results suggest that rapamycin could be combined with functional Tregs.

Assessment of Health-Related Quality of Life of Patients after Kidney Transplantation in Comparison with Hemodialysis and Peritoneal Dialysis

BACKGROUND The quality of life may determine the efficacy of renal replacement therapy (RRT). The purpose of the study was to compare the health-related quality of life (HRQOL) of end-stage renal disease (ESRD) patients depending on RRT method. MATERIAL/METHODS The studies were conducted on 120 patients divided into 3 groups depending on RRT method: 30 peritoneal dialysis (PD) patients, 40 hemodialysis (HD) patients, and 47 post-kidney transplantation (KTx) patients. The following research tools were used: (1) Medical Outcomes Study 36 - the Short Form (SF-36 v.1); (2) Kidney Disease Quality of Life Short Form (KDQOL-SF™ v.1.3); and (3) disease history. The relevance level was p<0.05. RESULTS The evaluation of PCS by HD and PD patients is poorer compared to patients in the 3rd and 12th month after KTx (34.7 ± 7.4 vs. 37.51 ± 10.63 vs. 45.01 ± 9.43 vs. 45.55 ± 8.62; p<0.05; respectively). PCS statistically significantly correlated with the following: SBP (r=-0.54; p<0.05), DBP (r=-0.58; p<0.05), and creatinine concentration (r=0.46; p<0.05) in the 12(th) month after KTx. CONCLUSIONS HRQOL of ESRD patients differed depending on the RRT method: top values were shown by post-KTx patients, lower by PD patients, and the bottom ones by HD patients. Along with patient age, increased BP, and BMI, a drop in value of HRQOL in post-Tx or PD patients was observed. When choosing RTT method, patients may use the results of the evaluation of quality of life. A preferred lifestyle, and predominantly the work status and quality of social interaction, should decide the choice of treatment.

Sirolimus-associated hepatotoxicity in the kidney graft recipient

The aim of our paper was to describe hepatotoxicity of sirolimus (SRL) in a kidney graft recipient. We report the case of a 30‐year‐old male after kidney transplantation, treated with steroids, cyclosporin A and SRL, with steroid‐resistant acute rejection in anamnesis. At 16th month after transplantation, elevation of serum aminotransfereases was observed. After exclusion of common reasons of this condition, liver biopsy was performed. Nonspecific changes were observed, with probability of drug‐induced injury. SRL was changed to mycophenolate mofetil, which was followed by quick normalization of serum aminotransferase levels. Hepatoxicity is a rare complication of SRL therapy and may be connected with some diagnostic and/or therapeutic problems. Conversion to another immunosuppressant seems to be an appropriate procedure in this condition.

Impact of CYP3A4*1B and CYP3A5*3 polymorphisms on the pharmacokinetics of cyclosporine and sirolimus in renal transplant recipients

BACKGROUND Calcineurin inhibitor (cyclosporine, CsA) and mTOR inhibitors (sirolimus, SRL) - immunosuppressants used to prevent allograft rejection after renal transplantation - have a narrow therapeutic index and show considerable inter-individual pharmacokinetic differences. Differences in expression and activity of cytochrome P450 (CYP) 3A4 and 3A5 affect these pharmacokinetics; cytochrome activity differences are associated with CYP genetic polymorphisms. MATERIAL/METHODS This study evaluated the effects of polymorphisms in CYP3A4 and CYP3A5 on immunosuppressive drug-dose adjusted trough blood concentrations. One hundred renal transplant recipients were genotyped for CYP3A4*1B and CYP3A5*3 using PCR-RFLP. Blood concentrations of CsA and SRL were determined by EMIT and HPLC/UV, respectively. RESULTS The allelic frequencies of CYP3A4*1B and CYP3A5*3 in the study group were 2.5% and 96.5%, respectively. The mean cyclosporine dose in CYP3A4*1/*1B subjects was 455.04±128.68 mg/day vs. 261.68±64.72 mg/day in CYP3A4*1/*1 subjects (p<0.001). The mean cyclosporine dose-adjusted trough blood concentrations (ng/ml per mg/kg body weight) in CYP3A4*1/*1B subjects were lower than in the CYP3A4*1/*1 group (37.06±10.38 vs. 44.63±13.99; p<0.218). The mean cyclosporine dose in CYP3A5*1/*3 subjects was 400.65±164.97 mg/day vs. 263.52±64.39 mg/day in CYP3A5*3/*3 subjects (p<0.022). No association was detected between sirolimus trough blood concentration (C0) or dose requirement, and CYP3A4 or CYP3A5 genotype. CONCLUSIONS Genetic polymorphisms in CYP3A4 and CYP3A5 may underlie inter-individual differences in cyclosporine pharmacokinetics after renal transplantation. Patients with at least 1 functional CYP3A5*1 or CYP3A4*1B allele require significantly higher doses of cyclosporine to reach target drug levels compared to patients with the CYP3A4*1 or CYP3A5*3 alleles.

Posttransplantation diabetus mellitus under calcineurin inhibitor

BACKGROUND The development of postransplantation diabetes mellitus (PTDM) is a serious complication of kidney transplantation. PTDM has a major impact on quality of life decreasing rates of patient and graft survival. It is well known that some currently used immunosuppressants are diabetogenic. Greater diabetogenicity of FK-506 has been reported in multicenter trials. We initiated a study of conversion from tacrolimus (FK-506) to cyclosporine (CsA) among kidney allograft recipients presenting with PTDM to evaluate whether this maneuver would ameliorate a diabetic state. METHODS This analysis of 20 adult, renal allograft recipients presenting with PTDM assumed the need for insulin therapy or oral hypoglycemics before and after conversion of the immunosuppressive regimen. The criteria for evaluating the outcome were as follows: dose reduction of insulin or oral hypoglycemic agents, adequacy of glucose control, C-peptide levels, and insulin concentration. RESULTS During the follow-up, we observed an improvement in the control of blood glucose in the converted group. In 13 patients, satisfactory glucose control was obtained without insulin or any other agent. In 3 patients a significant dose reduction of required insulin was possible. In another 2 patients who were insulin-dependent, the switch to oral hypoglycemic treatment was clinically possible after conversion. After conversion we observed significantly lowered fasting blood glucose levels and increased C-peptide levels. CONCLUSIONS The conversion from a tacrolimus to a CsA-based immunosuppressive regimen resulted in better glucose metabolism. We demonstrated a positive effect of conversion on the diabetic state of patients with PTDM.

Different profile of gene expression of cytokines in peripheral blood mononuclear cells of transplant recipients treated with m-TOR inhibitor and calcineurin inhibitor.

AIMS To determine how sirolimus (SRL), in comparison to calcineurin inhibitors (CNI), influences gene expression of cytokines: interleukin 1beta, tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), and interleukin 10 (IL-10) in peripheral blood mononuclear cells (PBMC) of transplant recipients. MATERIAL AND METHODS Twenty-two patients (13 kidney and 9 liver transplant recipients), in which: CNI was replaced by SRL (n=11); SRL was added to CNI (n=7); or SRL was replaced by CNI (n=4), were recruited. PBMC were obtained before and after modification of immunosuppression. Real-time polymerase chain reaction was used for quantitative assessment of expression of investigated genes. RESULTS During therapy with SRL either with, or without CNI (SRL+/-CNI), the pro-inflammatory genes expression was increased, and IL-10 gene expression was decreased, in comparison to treatment with CNI. In subgroup of patients with malignancy as the reason of liver transplantation, gene expression of TNF-alpha and IFN-gamma was higher when SRL+/-CNI was used in comparison to treatment with CNI. Patients with viral infection receiving SRL+/-CNI had higher expression of pro-inflammatory genes than during therapy with CNI. CONCLUSIONS Transplant recipients during therapy with SRL+/-CNI have increased gene expression of Th1 cytokines, and decreased gene expression of Th2 cytokine, IL-10, in PBMC, compared to treatment with CNI. Our data may influence management of transplant recipients.

Expression of FasL gene in T cells of renal allograft recipients

FasL molecule expressed on activated T cells induces apoptosis in Fas-expressing cells. It is possible that apoptosis induced by FasL is involved in the process of allograft destruction brought about by infiltrating T cells. The aim of our study was to evaluate expression of FasL gene in peripheral blood T cells of renal allograft recipients (RAR). We have studied 25 patients: 16 with uneventful stable course (RAR-S) and nine during biopsy proven chronic rejection (RAR-CH). The relative expression of FasL mRNA compared with that of beta-actin was established by semi-quantitative RT-PCR. We have found that FasL gene expression was significantly increased in T cells of RAR-CH compared to RAR-S (P<0.01). Our results suggest that T cell expression of FasL gene is increased during chronic rejection. Therefore, this phenomenon may pay a role in allograft injury associated with that process. Further studies are needed to unravel possible clinical consequences of observed differences in T cell expression of FasL.

Contribution of volume overload to the arterial stiffness of hemodialysis patients

Abstract Arterial stiffness is evaluated with the measurement of pulse wave velocity (PWV), while overhydration (OH) and nutritional status are evaluated with bioimpedance spectroscopy (BIS). In this study, we investigated the effect of a single dialysis session on arterial stiffness, hydration status, and laboratory parameters. The observational, cross-sectional, cohort study included 71 HD patients with mean age 64 ± 16 yrs. A Complior device was used to perform PWV measurements. The patients were examined immediately before and 15 min after a mid-week hemodialysis session. Body fluids and nutritional status were studied using a Body Composition Monitor (BCM), Fresenius Medical Care. Clinical and laboratory data were also analyzed. Multivariate regression analysis of PWV before HD showed that an OH increase of 1 L relate to a PWV parameter rise before HD of 0.523 m/s. Multivariate regression analysis of PWV after HD showed that a rise of central SBP after HD of 10 mmHg relate to a PWV increase after HD of 0.707 m/s. Our data indicate that hydration status and blood pressure may be major determinants of PWV in HD patients.

The adequacy of transplantation education in the ESRD population in Poland

BACKGROUND Education of patients with chronic kidney disease is one of the most important challenges in nephrology and transplant nursing. The increase in the number of kidney transplants depends on the prevalence of knowledge about family transplantation and quality of the coordination of dialysis patients. The aim of the article was to evaluate the knowledge of patients treated by renal replacement therapy, concerning family graft and principles of qualification for kidney transplantation. MATERIAL/METHODS The study included 120 patients from 5 out of 10 dialysis departments in Warsaw. We used a questionnaire designed by the author of the paper. RESULTS It was shown that 18% of interviewees were not aware of the possibility of family graft and 40% of respondents had not consulted their family about it; some said that even if it were possible, they would not make use of this form of treatment. Up to 87% of respondents see the need to organize special educational meetings. CONCLUSIONS The level of knowledge of patients on dialysis concerning family transplantation and rules of qualification for kidney transplantation appeared to be insufficient. Increasing the number of living donors depends largely on the professional training of the patient and his family. The results suggest that the amount of time spent by clinical staff on educating patients is insufficient. It seems that in order to increase the awareness of health issues among patients, a multi-centre education program should be implemented for patients with chronic kidney disease.