Results of liver transplantation in the Department of General, Transplant and Liver Surgery at the Medical University of Warsaw in patients with chronic hepatitis B and C viruses infection.

INTRODUCTION: Cirrhosis related to hepatitis C virus (HCV) and hepatitis B virus (HBV) infection is the most frequent indication for liver transplantation worldwide. Progress in prophylaxis of posttransplant HBV recurrence has led to major improvements in long-term outcomes of patients after liver transplantation. Conversely, impaired posttransplant survival of patients with HCV infection was reported in several studies, mainly due to recurrence of viral infection. The purpose of this study was to compare long-term results of liver transplantation between patients with HBV monoinfection, HCV monoinfection and HBV/HCV coinfection. MATERIAL AND METHODS: A total of 1090 liver transplantations were performed in the Department of General, Transplant and Liver Surgery in cooperation with the Department of Immunology, Internal Medicine, and Transplantology at the Transplantation Institute Medical University of Warsaw between December 1994 and May 2012. After exclusion of patients with cirrhosis of non-viral etiology, patients with malignant tumors, and patients with acute liver failure, the final study cohort comprised 209 patients with HBV (HBV+/HCV- subgroup; n = 56) or HCV (HBV-/HCV+ subgroup; n = 119) monoinfection or HBV/HCV coinfection (HBV+/HCV+; n = 34). These subgroups of patients were compared in terms of long-term results of transplantations, defined by 5-year patient and 5-year graft survival estimates. RESULTS: Overall and graft survival rates after 5-years for the whole study cohort were 74.5% and 72.6%, respectively. Five-year overall survival was 70.4% for patients within the HBV+/HCV- subgroup, 77.8% for patients within the HBV-/HCV+ subgroup, and 68.5% for patients within the HBV+/HCV+ subgroup. The corresponding rates of graft survival were 67.0%, 76.3%, and 68.5% for patients within the HBV+/HCV-, HBV-/ HCV+, and HBV+/HCV+ subgroups, respectively. Observed differences were non-significant, both in terms of overall (p = 0.472) and graft (p = 0.461) survival rates. CONCLUSIONS: Both overall and graft survival rates after liver transplantations performed in the Department of General, Transplant and Liver Surgery in cooperation with the Department of Immunology, Internal Medicine, and Transplantology at the Transplantation Institute Medical University of Warsaw in patients with HBV and HCV infection are comparable to those reported by other European and American centers. In contrast to other studies, obtained results do not confirm the negative impact of HCV infection on long-term outcomes of patients.

Tacrolimus-based, steroid-free regimens in renal transplantation: 3-year follow-up of the ATLAS trial.

BACKGROUND: Long-term use of corticosteroids is associated with considerable morbidity, including cardiovascular and metabolic adverse effects. METHODS: This study evaluated the long-term efficacy and safety of two steroid-free regimens compared with a triple immunosuppressive therapy in renal transplant recipients. This was a 3-year follow-up to a 6-month, open-label, randomized, multicenter study. RESULTS: Data from 3 years were available for 421 (93.3%) of 451 patients in the original intent-to-treat population (143 tacrolimus/basiliximab [Tac/Bas], 139 tacrolimus/mycophenolate mofetil [Tac/MMF], and 139 tacrolimus/MMF/steroids [triple therapy]). In the time interval from 6 months to 3 years after transplantation, the incidence of biopsy-proven acute rejection was low and similar (Tac/Bas, 2.1%; Tac/MMF, 2.2%; triple therapy, 2.2%); Most rejection episodes occurred during the first 6 months of the study. Graft survival was high (Kaplan-Meier estimates: 92.7%, 92.5%, and 92.5%), as was patient survival (93.1%, 96.4%, and 97.0%). There were 10 graft losses (n=2, 4, and 4) and 12 patient deaths (n=5, 2, and 5). Renal function was well preserved throughout the study and similar between groups. There was a trend toward improved cardiovascular risk factors in the Tac/Bas group, including reduced total and low-density lipoprotein cholesterol and lower new-onset insulin use. There were no between-group differences in the incidence or type of adverse events. CONCLUSION: Higher rates of acute rejection early in treatment were seen with the steroid-free regimens, but this did not translate into poorer long-term outcomes, such as graft and patient survival and renal function. A trend for a more favorable cardiovascular risk profile was observed for steroid-free immunosuppression with Tac/Bas.

[Application of intravenous immunoglobulin preparations (IVIGs) in organ transplantation]. / Zastosowanie dozylnych przeciwcial poliwalentnych (IVIG) w przeszczepianiu narzadów.

In clinical setting intravenous immunoglobulin preparations (IVIGs) are used for over thirty years. They were used initially as a substitutive treatment. Discovering of IVIG immunosuppressive properties has led to its use in the treatment of autoimmune diseases. Since then the range of indications in this group of diseases is becoming wider. With regard to IVIG's multidirectional influence exerted on the immune system it has also find its application in transplantology. In the article IVIG's mechanism of action, possible applications in transplantation and adverse effects are discussed.

Tacrolimus combined with two different corticosteroid-free regimens compared with a standard triple regimen in renal transplantation: one year observational results.

Side effects of steroid use have led to efforts to minimize their use in transplantation. Two corticosteroid-free regimens were compared with a triple immunosuppressive therapy. Data from the original intent-to-treat (ITT) population (153 tacrolimus/basiliximab [Tac/Bas], 151 tacrolimus/MMF [Tac/MMF], and 147 tacrolimus/MMF/steroids [control]) were analyzed in a 12-month follow-up. Percentage of graft survival were 92.8%, 95.4%, and 95.9% (KM estimates 89.9%, 95.3%, 95.9%), percentage of surviving patients were 98.7%, 98.0%, and 100% (KM estimates 95.9%, 92.8%, and 100%). During months 7-12, graft loss occurred in 3 Tac/Bas, 2 Tac/MMF, and zero control patients, patient deaths in 1 Tac/Bas, 2 Tac/MMF, and zero control, and biopsy-proven acute rejection episodes in 4 Tac/Bas, 3 Tac/MMF, and zero control. Mean serum creatinine at month 12 was 141.9 +/- 69.6 microM, 144.0 +/- 82.1 microM, and 134.5 +/- 71.2 microM (ns). New-onset insulin use in previously non-diabetic patients at month 12 was 1/138, 6/127, and 4/126. Patient and graft survival as well as renal function at 12 months were not different between patient groups, despite considerably higher rates of acute rejection occurring within the first six months after transplantation in both steroid-free patient groups. Tac/Bas therapy might offer benefits in terms of a trend for a more favorable cardiovascular risk profile.

Two corticosteroid-free regimens-tacrolimus monotherapy after basiliximab administration and tacrolimus/mycophenolate mofetil-in comparison with a standard triple regimen in renal transplantation: results of the Atlas study.

BACKGROUND: The side effects associated with corticosteroids have led to efforts to minimize their use in renal transplant patients. In this study we compared two corticosteroid-free tacrolimus-based regimens with a standard triple therapy. METHODS: This was a 6-month, phase III, open-label, parallel-group, multicenter study. The total analysis set comprised 451 patients, randomized (1:1:1) to receive tacrolimus (Tac) monotherapy following basiliximab (Bas) administration (n=153), Tac/mycophenolate mofetil (MMF) (n=151), or, Tac/MMF/corticosteroids triple therapy as a control (n=147). RESULTS: The study was completed by 91.2% (triple therapy), 94.7% (Tac/MMF), and 82.4% (Bas/Tac) of patients. Patient baseline characteristics were similar in all groups. The incidences of biopsy-proven acute rejection were 8.2% (triple therapy), 30.5% (Tac/MMF), and 26.1% (Bas/Tac), p<0.001 (multiple test for comparison with triple therapy); Bas/Tac vs. Tac/MMF, p=ns. The incidences of corticosteroid-resistant acute rejection were 2.0%, 4.0%, and 5.2%, p=ns. Graft survival (95.9%, 96.7%, and 94.7%, p=ns) and patient survival (100%, 99.3%, and 99.3%, p=ns) were similar in all groups. Median serum creatinine at month 6 was 123.0 micromol/L (triple therapy), 134.7 micromol/L (Tac/MMF) and 135.8 micromol/L (Bas/Tac). The overall safety profiles were similar; differences (p<0.05) were reported for anaemia (24.5% vs. 12.6% vs. 14.5%), diarrhoea (12.9% vs. 17.9% vs. 5.9%), and leukopenia (7.5% vs. 18.5% vs. 5.9%) for the triple therapy, Tac/MMF, and Bas/Tac group, respectively. The incidences of new-onset diabetes mellitus were 4.6%, 7.1%, and 1.4%, respectively. CONCLUSION: Corticosteroid-free immunosuppression was feasible with the Bas/Tac and the Tac/MMF regimens. Both corticosteroid-free regimens were equally effective in preventing acute rejection, with the Bas/Tac therapy offering some safety benefits.

The comparison of treatment results of type 1 diabetes mellitus complicated by end-stage diabetic nephropathy in patients undergoing simultaneous pancreas and pre-emptive kidney transplantation (SPPkTx) and patients enrolled into the dialysis program--a cohort study.

OBJECTIVE: A cohort study was conducted to compare treatment of patients with type 1 diabetes mellitus and end-stage diabetic nephropathy. PATIENTS AND METHODS: 47 type 1 diabetic patients required renal replacement therapy in years: 2001-2005 were enrolled. Simultaneous pancreas and preemptive kidney transplant (sppktx) was performed in 18 (group I). Group II consisted of 29 patients who entered dialysis program. Survival rate for patients from both groups was estimated. Transplanted organ function was evaluated for group II. Lipid profile and its correlation with thickness of carotid media was assessed. Impact of sppktx on diabetic retinopathy was investigated. Cost and life quality were compared between groups. RESULTS: Two-year cumulative recipient survival rate for group I and II was 100% and 96%, respectively. One-year cumulative survival rate for transplanted pancreas was 88% and for kidney grafts 94%. In group I cholesterol and triglyceride level before transplantation were: 207 +/- 38 mg/dl and 133 +/- 65 mg/dl and decreased after transplantation to 155 +/- 20 mg/dl and 78 +/- 25 mg/dl, respectively (p < 0.05). No difference of carotid media thickness was observed between groups. Stabilization of retinopathy was observed in 91.6% non-blind recipients. During the first year of the follow-up the costs of transplantation doubled those of dialysis therapy but in the second year the costs of dialysis exceeded the costs required for transplanted patients. CONCLUSION: Despite of major surgery and introduction of immunosuppression in group I, results did not differ significantly between groups during a two-year follow-up. After sppktx, stabilization of the carotid media was slower than the normalization of lipids. At the second year, transplantation is less expensive than dialysis.

[Urine TGF-beta1 concentration in patients with type II diabetes mellitus--prognostic values]. / Stezenie TGF-beta 1 w moczu u pacjentów z cukrzyca typu 2--znaczenie prognostyczne.

Type 2 diabetes mellitus is a social and civilization-related disease that leads to various micro- and macroangiopathic complications, including diabetic nephropathy. At present, the most sensitive and non-invasive indicator of the progression of diabetic nephropathy is microalbuminuria. Morphological features such as accumulation of extracellular matrix proteins, thickening of glomerules' basement membranes are prior to microalbuminuria. The aim of our clinical study was to establish whether urine and serum TGF beta 1 levels may be significant in prognosing and evaluating a risk for developing diabetic nephropathy. The trial was carried out in 68 patients with type 2 diabetes mellitus and a group of 10 healthy subjects served as control. Urine and serum TGF beta 1 concentrations were evaluated, as well as basic laboratory parameters. After one-year-observation serum creatinine level and microalbuminuria value were investigated in 60 patients with type 2 diabetes mellitus. In patients with type 2 diabetes mellitus both urine and serum TGF beta 1 concentration were elevated. After one-year-observation of patients with type 2 diabetes mellitus it was established that the increase of serum creatinine concentration and that of microalbuminuria value were higher in those patients, whose initial TGF beta 1 levels exceeded normal values. A positive correlation between urine TGF beta 1 level and the progression of renal failure measured by the increase of serum creatinine level was observed. In conclusion, our findings indicate that urine TGF beta 1 level may be a good prognostic factor of the development of diabetic nephropathy in the course of diabetes mellitus.

[New immune suppressants: topical immunomodulatory agents]. / Nowe leki immunosupresyjne: leki immunomodulujace do stosowania zewnetrznego.

Chronic antiinflammatory treatment is required in autoimmunologic dermatoses. Tacrolimus ointment (Protopic) an inhibitor of calcineurin, is the first topical nonsteroidal immunosuppressant for the last 50 years. Pimecrolimus (ASM 981), a newer calcineurin inhibitor developed for atopic dermatitis treatment has the same mode of action and altered skin penetration profile as takrolimus. Their structure, mechanism of immunosuppressive action, efficacy and safety in atopic dermatitis and other inflammatory dermatitides was described in this article. The attention was paid to systemic and in topical treatment, their intact and injured skin penetration profile, optimal doses, costs and perspectives of broad use of these drugs in dermatology were described.

[Treatment of diabetes mellitus in patients after renal transplantation]. / Problemy leczenia cukrzycy u chorych po zabiegu przeszczepienia nerki.

Diabetes mellitus (DM) is the most common metabolic disease, an independent risk factor of coronary disease, and shortens lifetime in all populations of patients, including kidney transplant recipients. Patients after kidney transplantation are exceptionally predisposed to develop or to exacerbate the preexisting DM. Age, DM in family, CMV infections, genetic factor (HLA A26 and B27), immunosuppressive treatment with steroids or calcineurin inhibitors belong to the major risk factors of diabetes. We analyzed 1300 renal transplant recipients in our center. Out of them 153 suffered from DM. DM de novo revealed 80 pts. Mean age in type I pts was 44.88 years and in type II pts was 57.27 years. De novo diabetics were 56.41 years old in average. CMV infection, potentially pathogenic in development of DM de novo, coexisted in 7.5% of these cases as frequently as in whole TPN population. Most frequently detected HLA antigens were: A2, B8 and DR5. Use of cyclosporine and tacrolimus promoted incidence of DM. We conclude, that low percentage of de novo DM in patients after renal transplantation may result from flexibility in administration of immunosuppressive regimens. Cyclosporine and tacrolimus treatment was switched to sirolimus or mycophenolate mofetil when the glucose intolerance was detected to prevent development of DM.

[Cytokines in noninvasive diagnostics of diabetic nephropathy progression]. / Cytokiny w nieinwazyjnej diagnostyce nefropatii cukrzycowej.

Diabetic nephropathy is major long-term complication of diabetes mellitus a social and civilization-related disease. At present, the most sensitive and non-invasive indicator of the progression of diabetic nephropathy is microalbuminuria. Morphological features such as accumulation of extracellular matrix proteins, thickening of glomerules' basement membranes are prior to microalbuminuria. The aim of our clinical study was to establish whether urine and serum TGF-beta 1 and IL-6 levels may be significant in prognosing and evaluating a risk for developing diabetic nephropathy. The trial was carried out in 68 patients with type II diabetes mellitus and a group of 10 healthy subjects served as control. Urine and serum TGF-beta 1 concentrations were evaluated, as well as, basic laboratory parameters. After one-year-observation serum creatinine level and microalbuminuria value were investigated in 60 patients with type II diabetes mellitus. In patients with type II diabetes mellitus both urine and serum TGF-beta 1 and IL-6 were elevated. After one-year-observation of patients with type II diabetes mellitus it was established that the increase of serum creatinine concentrations values were higher in those patients, whose initial TGF-beta 1 levels exceeded normal values. A positive correlation between urine TGF-beta 1 level and the progression of renal failure measured by the increase of serum creatinine level was observed. In conclusion, our findings indicate that urine TGF-beta 1 and IL-6 levels may be a good prognostic factor of the development of diabetic nephropathy in the course of diabetes mellitus.

[Noninvasive monitoring of chronic glomerulonephritides progression]. / Nieinwazyjne monitorowanie progresji przewleklych klebuszkowych zapalen nerek.

Progression to end-stage renal failure is the final common pathway of many forms of glomerular diseases, independent of the type of initial insult. Tubulointerstitial fibrosis is tis near invariable finding and significant prognostic feature. We have reviewed immunological (cytokines, inflammatory cells) and nonimmunological factors (extracellular matrix proteins and proteolytic enzymes), being involved in mechanisms leading from glomerular disease to tubulointerstitial scarring, from the point of view of potential clinical usefulness of measuring its urine activities and levels to noninvasive diagnostic of kidney diseases.

[Expression of mRNA for growth factors and cytokines in the renal artery wall of chronically rejected renal allograft]. / Ekspresja mRNA czynników wzrostu i cytokin w scianie tetnicy nerkowej przeszczepionej nerki w okresie przewleklego odrzucania.

The vascular hallmark of chronic rejection (CR), as well as of atherosclerosis, is initial hyperplasia. It results from migration and proliferation of vascular smooth muscle cell and increased deposition of extracellular matrix proteins. A possible mechanism responsible for formation of neointima is the release of growth factors and cytokines, such as: transforming growth factor beta (TGF-beta), tumour necrosis factor alfa (TNF-alpha), interleukin 1 (IL-1) and interleukin 6 (IL-6). The expression of these factors in the renal artery wall of chronically rejected allografts was quantified. The renal artery samples were obtained from patients with chronic renal allograft rejection, undergoing graftectomy (n = 11) and patients with autosomal dominant polycystic kidney disease (ADPKD), undergoing nephrectomy (n = 4). Total RNA was isolated and the expression of mRNA for TGF-beta, TNF-alpha, IL-1 and IL-6 was measured using a real time PCR. In patients with CR the expression levels of TGF-beta, TNF-alpha and IL-1 mRNA were higher than in control group. No difference between groups was detected for IL-6. In both groups a correlation was detected between age and TGF-beta expression. The increased expression of TGF-beta, TNF-alpha and IL-1 may be a key factor in the neointimal formation and pathogenesis of CR. The increase in the TGF-b expression with age might be a protective mechanism in atherosclerosis.

[Effect of immunosuppressive treatment on diurnal profile of blood pressure]. / Wplyw leczenia immunosupresyjnego na dobowy profil cisnienia tetniczego krwi.

Prevalence of arterial hypertension suddenly rose in patients after renal transplantation since cyclosporine A was introduced. Arterial hypertension is now diagnosed in 67-90% of patients after renal transplantation. It has not only negative effect on cardiovascular system but also shortens survival of renal graft. Ambulatory blood pressure monitoring (ABPM) enables evaluation of diumal profile of BP and efficacy of treatment. This diagnostic tool is very useful in the management of these patients. Nocturnal hypertension was 2.5 times more frequent than daytime elevation of BP in the group of 58 consecutive renal transplant patients treated with calcineurin inhibitors who were assessed by ABPM at our department. Lack of nocturnal dip of BP was observed in most of the patients. Conversion from calcineurin inhibitors (cyclosporine A, tacrolimus) to sirolimus or mycophenolate mofetil may improve BP profile in this group of patients.