Krzysztof Mucha

Urine cytokines profile in renal transplant patients with asymptomatic bacteriuria.

Background. The role of asymptomatic bacteriuria in kidney transplant recipients is unknown. There is no clear evidence of its effect on transplanted kidney. Methods. We studied urine cytokines profile among kidney transplant recipients with bacteriuria found in screening examination. Urine cultures were collected in 269 patients with stable graft function and serum creatinine level <2 mg/dl, during their routine visits. Interleukin (IL)-6 and IL-8 levels were measured in urine samples from patients with asymptomatic bacteriuria, symptomatic urinary tract infection and patients without bacteriuria (control group). Changes in serum creatinine level in patients with asymptomatic bacteriuria and in the control group were observed during 12 months follow up. Results. Urinary tract infection (UTI) was diagnosed in five patients and asymptomatic bacteriuria in 22 patients. Urine IL-6 level was significantly higher in symptomatic UTI group (median 15.71 pg/mg) but there were no differences between group of patients with asymptomatic bacteriuria (3.92 pg/mg) and control group (2.54 pg/mg). Urine IL-8 level was higher in symptomatic UTI group (median 146.8 pg/mg) and was also significantly higher in asymptomatic bacteriuria group (33.49 pg/mg) in comparison to control group (2.97 pg/mg; P=0,0002). During 1-year follow up, incidence of UTI was higher in the asymptomatic bacteriuria group than in the control group but graft function was not different in both groups. Conclusions. Elevated urine IL-8 level in kidney transplant patients with asymptomatic bacteriuria may reflect impaired immune response to bacterial infection and occult inflammatory process in urinary tract.

Efficacy of rapamycin in patient with juvenile rheumatoid arthritis

Juvenile rheumatoid arthritis (JRA) is an immune‐mediated disease characterized by articular inflammation and subsequent tissue damage that may result in severe disability. Several combinations of drugs, including immunosuppressive agents have been used to control disease progression. Although there is no information available on rapamycin efficacy in JRA, it has demonstrated a potential to inhibit inflammatory processes observed in adult rheumatoid arthritis (RA). We present a 21 years old renal transplant recipient with JRA, primarily treated with tacrolimus and steroids, who achieved a long‐term disease remission after introduction of rapamycin. As long as pathogenesis of JRA and RA is similar, we conclude that rapamycin could be promising immunosuppressant for patients after renal transplantation suffering from both JRA and RA.

Interleukin 12 and indomethacin exert a synergistic, angiogenesis-dependent antitumor activity in mice

Nonsteroidal anti-inflammatory drugs have been shown to reduce the incidence and mortality from colorectal cancer. It has recently been demonstrated that these drugs are capable of suppressing the production of pro-angiogenic factors from tumor cells. The mechanisms of antitumor action of interleukin 12 include the enforced secretion of anti-angiogenic factors and stimulation of antitumor immunity. Therefore, we hypothesized that the combination of a model nonsteroidal anti-inflammatory drug--indomethacin and interleukin 12--would result in enhanced angiogenesis-dependent antitumor effects against a colon-26 carcinoma cells transplanted into syngeneic mice. As expected the combined administration of both agents simultaneously resulted in a strengthened antitumor activity that was manifested as a retardation of tumor growth and prolongation of mouse survival. Importantly some mice were completely cured after the combined treatment. As administration of interleukin 12 and indomethacin resulted in enhanced inhibition of angiogenesis it seems possible that prevention of new blood vessel formation is one of the mechanisms responsible for the observed antitumor effects.

Cytomegalovirus infection as a common complication following liver transplantation

The aim of our study was to assess the incidence course, influence on liver function, diagnostic methods, prophylaxis of, and cost treatment effectiveness of CMV infection among 123 consecutive liver transplant recipients. All patients received immunoglobulin and parenterall gancyclovir as prophylaxis. CMV IgM and IgG antibodies were determined using an ELISA method. Thirty seven patients (30.0%) developed CMV infection. Main indications for primary LTX were: immune liver disease (n = 22), viral hepatitis (n = 5), and other (n = 10). CMV infection occurred between the days 5 and 416. Ten patients (27.0%) developed more than one infection (52 infections in total). Asymptomatic CMV infection was diagnosed in six cases (16.2%), CMV syndrome in 11 cases (29.7%), and hepatitis in 35 cases. All patients were treated with gancyclovir and immunoglobulin (18 cases). The intensity of infection was mild or moderate. There was no case of pneumonia or neurological disease, nor the need to use foscarnet. The correlations between the incidence of CMV infection and acute rejection, tacrolimus versus cyclosporine regimens, dual versus triple immunosupressive schemes were not statistically significant, whereas anti-IL-2R-ab antibodies markedly reduced the incidence of CMV infection (P <.05). The values of CMV IgM significantly differred before/during infection (P <.001) and before/after infection (P <.05). In conclusion, prophylaxis and antiviral treatment result in a mild or moderate intensity of CMV infection with acceptable costs. Among immunosuppressive drugs, only anti-IL-2Rab was proved to significantly reduce the incidence of CMV.

Safety and Efficacy of Steroid-Free Immunosuppression with Tacrolimus and Daclizumab in Liver Transplant Recipients: 6-Year Follow-up in a Single Center

BACKGROUND Avoidance of steroid therapy after solid-organ transplantation has become a major challenge. Corticosteroid (CS)-free maintenance immunosuppression not only eliminates the well-known adverse effects but also may improve long-term outcome. OBJECTIVE To investigate whether a CS-free regimen of tacrolimus (Tac) in combination with daclizumab (Dac) induction therapy provides adequate coverage after orthotopic liver transplantation. PATIENTS AND METHODS This 6-year, single-center, retrospective study included 25 liver transplant recipients randomized to a Tac/CS regimen (n = 18) vs a Tac/Dac regimen (n = 7) according to the protocol of the MASTER (Monoclonal Antibodies vs STERoids) Study. RESULTS No significant difference was observed in patient and graft survival between treatment arms: 94.4% in the Tac/CS group vs 71.4% in the Tac/Dac group. The incidence of biopsy-proved acute rejection episodes was 23.5% in the Tac/CS group vs 14.3% in the Tac/Dac group (P = NS). Total duration of hospitalization did not differ significantly between groups: 46.5 days in the Tac/CS group vs 73.9 days in the Tac/Dac group. Liver function as estimated using serum alanine aminotransferase and aspartate aminotransferase activity and bilirubin concentration, was not significantly different between the groups during 5 years posttransplantation. However, after 6 years, alanine aminotransferase activity was significantly greater in the Tac/Dac group compared with the Tac/CS group. CONCLUSIONS A CS-free regimen of Tac/Dac is as effective as Tac/Cs in achieving good patient and graft survival. However, no substantial benefits insofar as the safety of Tac/Dac therapy were evident during long-term follow-up.

Leflunomide as a rescue treatment in ganciclovir-resistant cytomegalovirus infection in a seronegative renal transplant recipient – a case report

BACKGROUND Cytomegalovirus (CMV) infection is a frequent complication of immunosuppressive treatment after solid organ and bone marrow transplantation. Prophylaxis and treatment with ganciclovir is successful in most cases, but frequency of infections with ganciclovir-resistant CMV mutants has grown in recent years. Leflunomide, an immunosuppressive drug used in rheumatic diseases and which also exerts antiviral activity, could be a useful treatment option in such cases. CASE REPORT A 60-year-old, CMV-seronegative patient received a kidney graft from a CMV-seropositive donor. The post-transplant period was complicated by 2 episodes of biopsy-proven graft rejection treated with steroid pulses. CMV viremia was diagnosed 4 weeks after transplantation. The patient received treatment with intravenous ganciclovir and anti-CMV immunoglobulins with consecutive oral valganciclovir therapy. He was admitted to our hospital 6 months after transplantation, with symptoms of CMV infection confirmed by high viral load in his blood. Treatment with double-dose ganciclovir and anti-CMV immunoglobulins did not decrease CMV viremia, so we diagnosed ganciclovir-resistant CMV infection. We decided to discontinue mycophenolic acid treatment and start leflunomide 20 mg BID. This therapy led to rapid decrease and final disappearance of CMV viremia. Kidney graft function remained stable during leflunomide treatment. Seroconversion in both IgM and IgG anti-CMV classes was observed. CONCLUSIONS Treatment with leflunomide is a reasonable option in ganciclovir-resistant infection in kidney transplant recipients, providing effective viral elimination and reconstitution of adaptive anti-CMV immunity without excess risk of graft rejection.

Primary biliary cirrhosis in the era of liver transplantation.

Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver, characterized by the presence of antimitochondrial antibodies (AMA) and progressive immune-mediated destruction of biliary ductules, which lead to cirrhosis. Theories of the PBC etiopathogenesis assume that the disease develops secondarily as an improper immunological reaction to undefined environmental and/or infectious factors in genetically predisposed individuals. Ursodeoxycholic acid (UDCA) is the only drug recommended to treat PBC; it delays the progression of liver disease, but remains only a symptomatic treatment. In the advanced stage of PBC, the treatment of choice is liver transplantation (LTx). Nowadays, PBC is the third indication for LTx, after viral-related and alcoholic liver cirrhosis. Unfortunately, PBC recurs in 21-37% of patients at 10 years after LTx, and in 43% at 15 years after LTx, with the median time to recurrence of 3-5.5 years. Diagnosis of recurrent PBC (rPBC) is based on the liver histopathology. Although various risk factors of rPBC have been investigated, the cause of the recurrence is not clear. There is no specific treatment of rPBC. Together with immunosuppression after LTx, UDCA remains the treatment of choice. New diagnostic technologies (e.g., genomics, proteomics, cell-based therapy, and clinical study of the rPBC patients) may be helpful in understanding the pathogenesis of PBC and the development of new treatment modalities.

Pregnancy Outcomes Among Female Recipients After Liver Transplantation: Further Experience

INTRODUCTION Liver transplantations give female recipients an ability to carry pregnancies successfully. However, solid organ transplantations exacerbate the pregnancy including maternal and neonatal outcomes. The aim of our study was to evaluate and identify the obstetric outcomes in women with a prior liver transplantation. METHODS We analyzed all pregnant woman who had undergone a prior liver transplantation and afterward delivered from 2001 to 2011. Complete data were assessed in 39 deliveries and 40 live births. Three women were pregnant twice after liver transplantation. RESULTS The mean gestational age at birth measured 37.2±2.2 weeks. The most common obstetric complications were premature labor (12/39,30.8%), hypertension (10/39, 25.6%), and symptomatic urinary tract infections (7/39, 18%). Other complications were pregestational diabetes (n=1), cholestasis (n=3), and of severe anemia treated with blood transfusions (n=2). The mean time from organ transplantation to delivery was 67.6±47.2 months. Acute graft rejections occurred among pregnant women 7.7% (3/39) of studied. Only 8 (20.5%) deliveries were finished vaginally. Infants small for gestational age were diagnosed in 20% (8/40). One case displayed a congenital urinary tract malformation. None of the neonates died neonatally. CONCLUSIONS Pregnancies are possible after liver transplantation and likely end with successful maternal and newborn outcomes. Some cases experience an increased risk of obstetric complications. Therefore, posttransplant pregnancies must be regularly monitored with a multidisciplinary approach.

36-Month follow-up of 75 renal allograft recipients treated with steroids, tacrolimus, and azathioprine or mycophenolate mofetil

OBJECTIVES The aim of this retrospective study was to assess the incidence of acute rejection episodes (AR), diabetes mellitus (DM), and serum creatinine (SCr) among renal transplant recipients treated with tacrolimus (Tac), steroids (S), and mycophenolate mofetil (MMF) or azathioprine (Aza). METHODS Seventy-five renal allograft recipients enrolled in the COSTAMP study were followed for a period of 3 years. Patients were randomized to receive either Tac and MMF (n = 41) or Tac and Aza (n = 34) concomitantly with steroids. Follow-up assessments were performed at 3, 6, 12, 24, and 36 months. RESULTS Patient survival at month 36 was 91.18% in the Tac/Aza/S group and 97.56% in the Tac/MMF/S group. Graft survival at month 36 was 82.35% and 85.37%, respectively. During the study period, 22 cases of biopsy-proven AR were diagnosed in 17 patients (22.6%). After 36 months the total number of AR was 11 in the Aza-treated group (32.4%) and 11 in the MMF-treated group (26.8%). DM was diagnosed de novo in 17 individuals (22.6%). During 36 months, 10 patients from Aza-treated group (29.4%) and seven from MMF-treated group developed DM (17.1%). Serum creatinine values were not significantly different in both arms of the study. Comparison of arterial blood pressure and total cholesterol revealed no significant changes in any of the studied groups. CONCLUSIONS We conclude that combinations of steroids, tacrolimus, and azathioprine or MMF provide good results with regard to renal function.

The impact of experience of a transplantation center on the outcomes of orthotopic liver transplantation

The so-called learning factor has been disregarded for many years in analyzing the causes of surgical complications and post-operative mortality; it is also the case for OLT. In our center until April 2003, 209 OLT were performed in 196 patients. We evaluated the impact of experience of the transplantation team on the outcomes of liver transplantation. Thirty-four patients died (mortality rate, 16%) and 1-year survival rate, 64%. Mortality rates varied during different periods of observation due to increasing experience of the transplantation team. The causes of mortality were assessed for a series of 34 patients: it was 75% at the beginning of transplantation procedures while recent deaths have not recently exceeded 10% of cases.