Impact of Immunosuppressive Medication on the Risk of Renal Allograft Failure due to Recurrent Glomerulonephritis

Recurrent glomerulonephritis is a major problem in kidney transplantation but the role of immunosuppression in preventing this complication is not known. We used data from the United States Renal Data System to examine the effect of immunosuppressive medication on allograft failure due to recurrent glomerulonephritis for 41 272 patients undergoing kidney transplantation from 1990 to 2003. Ten-year incidence of graft loss due to recurrent glomerulonephritis was 2.6% (95% confidence interval [CI]: 2.3–2.8%). After adjusting for important covariates, the use of cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil, sirolimus or prednisone was not associated with graft failure due to recurrent glomerulonephritis. There was no difference between cyclosporine and tacrolimus or between azathioprine and mycophenolate mofetil in the risk of graft failure due to recurrent glomerulonephritis. However, any change in immunosuppression during follow-up was independently associated with graft loss due to recurrence (adjusted hazard ratio 1.30, 95% CI: 1.06–1.58, p = 0.01). In patients with a pretransplant diagnosis of glomerulonephritis, the risk of graft loss due to recurrence was not associated with any specific immunosuppressive medication. The selection of immunosuppression for kidney transplant recipients should not be made with the goal of reducing graft failure due to recurrent glomerulonephritis.     

New immunosuppressive therapies and surgical complications after renal transplantation

Background

To analyze the association between the principal immunosuppressive drugs (mycophenolate mofetil, calcineurin inhibitors and mammalian target of rapamycin [mTOR] inhibitors) used in the routine management of kidney transplant patients and the development of postoperative surgical complications.

Materials and Methods

We analyzed 415 kidney transplants, studying the influence of various immunosuppressive regimens on the main postoperative surgical complications.

Results

The mean follow-up for the entire group was 72.8 months (± 54.2 SD). Patients treated with myeophonolate mofetil (MMF) and cyclosporine (n = 121) experienced a higher frequency of wound eventration odds ratio [OR], 5.2; 95% confidence interval [CI], 1.2-23.5; P = .03) compared with azathioprine and cyclosporine (n = 71). Compared with transplant recipients treated with tacrolimus and MMF (n = 181), transplant recipients treated with cyclosporine and MMF (n = 121) had a significantly greater frequency of wound eventration (OR, 3.7; 95% CI, 1.5-9.5; P = .005), urologic (OR, 2; 95% CI; 1.02-3.9; P = .04), wound (OR; 2.2; 95% CI; 1.07-4.6; P = .03), late (OR, 1.7; 95% CI; 1.01-3.03; P = .04), and Clavien grade 3 surgical complications (OR; 1.9; 95% CI, 1.1-3.37; P = .01). Patients treated with mTOR inhibitors (n = 26) had higher rates of lymphocele (OR, 3.6; 95% CI, (1.1-11.4; P = .002) compared with those who received tacrolimus (n = 197).

Conclusions

New immunosuppressive drugs have improved short-term functional results; however, in some cases they seem to increase surgical complications rates.     

Reduced Incidence of Cytomegalovirus Infection in Kidney Transplant Recipients Receiving Everolimus and Reduced Tacrolimus Doses

This study compared the incidence of CMV infection/disease in de novo kidney transplant recipients receiving everolimus or mycophenolate and no CMV pharmacological prophylaxis. We randomized 288 patients to receive a single 3 mg/kg dose of antithymocyte globulin, tacrolimus, everolimus, and prednisone (r‐ATG/EVR, n = 85); basiliximab, tacrolimus, everolimus, and prednisone (BAS/EVR, n = 102); or basiliximab, tacrolimus, mycophenolate, and prednisone (BAS/MPS, n = 101). The primary end‐point was the incidence of first CMV infection/disease in the intention‐to‐treat population at 12 months. Patients treated with r‐ATG/EVR showed a 90% proportional reduction (4.7% vs. 37.6%, HR 0.10, 95% CI 0.037–0.29; p < 0.001), while those treated with BAS/EVR showed a 75% proportional reduction (10.8% vs. 37.6%, HR 0.25, 95% CI 0.13–0.48; p < 0.001) in the incidence of CMV infection/disease compared to BAS/MPS. There were no differences in the incidence of acute rejection (9.4 vs. 18.6 vs. 15.8%, p = 0.403), wound‐healing complications, delayed graft function, and proteinuria. Mean estimated glomerular filtration rate was lower in BAS/EVR (65.7 ± 21.8 vs. 60.6 ± 20.9 vs. 69.5 ± 21.5 ml/min, p = 0.021). In de novo kidney transplant recipients receiving no pharmacological CMV prophylaxis, reduced‐dose tacrolimus and everolimus was associated with a significant reduction in the incidence of CMV infection/disease compared to standard tacrolimus dose and mycophenolate ( ClinicalTrials.gov NCT01354301).     

Effect of basiliximab on renal allograft rejection within 1 year after transplantation

Basiliximab is widely used in clinical practice for initial immunosuppressive treatment of renal transplant recipients, seeking to reduce the incidence of acute rejection episodes without adverse events. This retrospective study included 123 renal allograft recipients transplanted at a single center. All were followed for longer than 1 year after transplantation and treated with calcineurin inhibitor and steroid (methylprednisolone) for prophylactic immunosuppression, but basiliximab and mycophenolate mofetil were optional. We compared the outcomes of renal transplant recipients who were versus treated were not with basiliximab as initial immunosuppressive therapy. Basiliximab was used for initial immunosuppression in 42 patients. Their maintenance immunosuppressive treatment included triple (n = 44) or double (n = 79) regimens, including a calcineurin inhibitor (cyclosporine [n = 87] or tacrolimus [n = 36]), methylprednisolone with or without mycophenolate mofetil. Twenty-six (21.1%) patients had a rejection episode within 1 year after transplantation and 22 (17.9%) had infections. Within the first year after transplantation the patients who were treated with basiliximab showed fewer rejection episodes (n = 6, 14.3%) than the patients without this therapy (n = 20, 24.7%), which was not statistically significant (P = .245). However, basiliximab significantly affected the occurrence of rejection episodes among the double immunosuppressive regimen group (P = .006), but not the triple regimen group (P = .098) without an impact on infection episodes (P value of double, triple = .291, .414) within 1 year after transplantation. We concluded that basiliximab was more useful for the recipients treated with double immunosuppression with a calcineurin inhibitor and steroid than for those on a triple regimen including mycophenolate mofetil.     

Tacrolimus-induced alopecia in female kidney-pancreas transplant recipients

BACKGROUND: Immunosuppressive drugs given to solid organ transplant recipients may be responsible for cosmetic side effects which can endanger patient compliance. Cyclosporine is associated with hirsutism whereas tacrolimus has been associated with rare cases of alopecia. Since 1998, we have included tacrolimus within the immunosuppressive regimen following kidney-pancreas transplantation. The aim of this study was to evaluate the incidence of alopecia in this population and possible risk factors. METHODS: Between January 1, 1995 and October 31, 2003, 59 consecutive simultaneous kidney-pancreas (SPK) transplants were performed in 58 recipients (27 females and 31 males). The immunosuppressive regimen comprised corticosteroids, calcineurin inhibitor (cyclosporine, n=11; or tacrolimus, n=40) and a purine inhibitor (azathioprine or mycophenolate mofetil). RESULTS: Clinically significant alopecia occurred in 13 patients (28.9%) receiving tacrolimus versus none receiving cyclosporine (P<0.001). Of those who experienced alopecia, 11 were female and two were male (P=0.02). The mean delay between transplantation and alopecia was 422 days (range 100-1,567). Other causes of alopecia were excluded. Treatment of alopecia with topic minoxidil was successful in all cases but one, which required conversion from tacrolimus to cyclosporine. CONCLUSIONS: Alopecia is a frequent complication in women receiving tacrolimus therapy following SPK transplantation. Its pathogenesis is unknown. This cosmetic complication must be discussed with patients before transplantation to minimize the risk of noncompliance.     

Cyclosporine A Protects Against Primary Biliary Cirrhosis Recurrence After Liver Transplantation

Primary biliary cirrhosis (PBC) reoccurs in a proportion of patients following liver transplantation (LT). The aims of our study were to evaluate the risk factors associated with PBC recurrence and determine whether recurrent disease constitutes a negative predictor for survival. One hundred and eight patients receiving LT for end‐stage PBC were studied. Recurrent disease was diagnosed in 28 patients (26%). Probability of recurrent PBC at 5 years was 13% and 29% at 10 years with an overall incidence of 3.97 cases per 100 patient years. By univariate Cox analysis use of tacrolimus (HR 6.28, 95% CI, 2.44–16.11, p < 0.001) and mycophenolate mofetil (HR 5.21, 95% CI, 1.89–14.33, p = 0.001) were associated with higher risk of recurrence; whereas use of cyclosporine A (CsA) and azathioprine were associated with reduced risk of recurrence (HR 0.13, 95% CI 0.05–0.35, p < 0.001 and HR 0.27, 95% CI 0.11–0.64, p = 0.003, respectively). In the multivariate Cox analysis, only CsA was independently associated with protection against recurrence (HR 0.17, 95% CI 0.06–0.71, p = 0.02). Five‐year probability of survival was 83% and 96%, in patients without and with recurrence (log‐rank test, p = 0.3). Although PBC transplant recipients receiving CsA have a lower risk of disease recurrence, the development of recurrent PBC did not impact on long‐term patient survival.     

Association of hepatitis C with posttransplant diabetes in renal transplant patients on tacrolimus

Posttransplant diabetes mellitus (PTDM) remains a common complication of immunosuppression. Although multiple risk factors have been implicated, none have been clearly identified as predisposing to the increased PTDM frequency observed in patients on tacrolimus. Hepatitis C virus (HCV) has been associated with diabetes and is a significant renal transplant comorbidity. In this study, records of 427 kidney recipients who had no known diabetes before transplantation were retrospectively examined. A multivariate logistic regression model was fit with covariates that had unadjusted relationships with PTDM to examine the independent relationship of HCV and the odds of development of PTDM by 12 mo posttransplant. A potential interaction between HCV and the use of tacrolimus as maintenance therapy on the odds of the development of PTDM was examined. Overall, PTDM occurred more frequently in HCV(+) than HCV(-) patients (39.4% versus 9.8%; P = 0.0005). By multivariate logistic regression, HCV (adjusted odds ratio [OR], 5.58; 95% confidence interval [CI], 2.63 to 11.83; P = 0.0001), weight at transplantation (adjusted OR 1.028; 95% CI, 1.00 to 1.05; P = 0.001), and tacrolimus (adjusted OR, 2.85; 95% CI, 1.01 to 5.28; P = 0.047) were associated with PTDM. A significant interaction (P = 0.0001) was detected between HCV status and tacrolimus use for the odds of PTDM. Among the HCV(+) cohort, PTDM occurred more often in tacrolimus-treated than cyclosporine A-treated patients (57.8% versus 7.7%; P < 0.0001). PTDM rates in HCV(-) patients were similar between the two calcineurin inhibitors (10.0% versus 9.4%; P = 0.521, tacrolimus versus cyclosporine A). In conclusion, HCV is strongly associated with PTDM in renal transplant recipients and appears to account for the increased diabetogenicity observed with tacrolimus.     

Epidemiology and long-term outcomes of cytomegalovirus DNAemia and disease in pediatric solid organ transplant recipients

Despite prevention strategies, cytomegalovirus (CMV) remains a common infection in pediatric solid organ transplant recipients (SOTR). We sought to determine the frequency, associations with, and long-term outcomes of CMV DNAemia in pediatric SOTR. We performed a single-center retrospective cohort study, including 687 first time SOTR ≤21 years receiving universal prophylaxis from 2011 to 2018. Overall, 159 (23%) developed CMV DNAemia, the majority occurring after completing primary prophylaxis. CMV disease occurred in 33 (5%) SOTR, 25 (4%) with CMV syndrome and 10 (1%) with proven/probable tissue-invasive disease. CMV contributed to the death of three (0.4%) patients (all lung). High-risk (OR 6.86 [95% CI, 3.6–12.9]) and intermediate-risk (4.36 [2.3–8.2]) CMV status and lung transplantation (4.63 [2.33–9.2]) were associated with DNAemia on multivariable analysis. DNAemia was associated with rejection in liver transplant recipients (p < .01). DNAemia was not associated with an increase in graft failure, all-cause mortality, or other organ-specific poor outcomes. We report one of the lowest rates of CMV disease after SOTR, showing that universal prophylaxis is effective and should be continued. However, we observed CMV morbidity and mortality in a subset of patients, highlighting the need for research on optimal prevention strategies. This study was IRB approved.

     

Trends in maintenance immunosuppressive drugs used in taiwanese kidney transplant recipients: an analysis of the national health insurance research database

Trends in maintenance immunosuppressive drugs used among Taiwanese kidney transplant recipients have not been reported before. We examined the National Health Insurance Research Database to analyze trends in maintenance immunosuppressive drugs used in Taiwanese kidney transplant recipients for the years 2002-2009. The new case number of kidney transplant recipients ranged from 302 to 673 per year. In 2009, 5276 kidney transplant recipients received immunosuppressive therapy. The 5-year renal graft survival rate of kidney transplant recipients was 93%. In 2009, the most common immunosuppressive therapy among Taiwanese kidney transplant recipients was a triple regimen that included tacrolimus, mycophenolate mofetil, and corticosteroid. There was a significant increase in the use of a tacrolimus-based regimen from 35.1%-58.2%, while the use of cyclosporine decreased from 62.2%-24.8% (P < .05). The percentage of calcineurin inhibitor-free regimen increased from 2.7%-17%. Moreover, the use of Rapamune dramatically increased from 8.2%-22.6% in 2002-2004. However, the percentage of kidney transplant recipients using Rapamune maintained 23 ± 1.6% in 2004-2009. The use of mycophenolic acid remained stable at about 74.9 ± 3.2% in 2002-2009. As predicted, the use of Imuran decreased from 6.9%-3.5%. In summary, although calcineurin inhibitors remained the mainstay of immunosuppressive drugs, these findings suggest a general trends toward individualized regimens and the use of calcineurin inhibitor-free and mammalian target of rapamycin inhibitors-based regimens in Taiwanese kidney transplant recipients.     

Risk of Colorectal Cancer After Solid Organ Transplantation in the United States

Solid organ transplant recipients have increased colorectal cancer (CRC) risk. We assessed CRC risk among transplant recipients and identified factors contributing to this association. The US transplant registry was linked to 15 population‐based cancer registries (1987–2010). We compared CRC risk in recipients to the general population by using standardized incidence ratios (SIRs) and identified CRC risk factors by using Poisson regression. Based on 790 cases of CRC among 224 098 transplant recipients, the recipients had elevated CRC risk (SIR 1.12, 95% confidence interval [CI] 1.04 to 1.20). The increase was driven by an excess of proximal colon cancer (SIR 1.69, 95% CI 1.53 to 1.87), while distal colon cancer was not increased (SIR 0.93, 95% CI 0.80 to 1.07), and rectal cancer was reduced (SIR 0.64, 95% CI 0.54 to 0.76). In multivariate analyses, CRC was increased markedly in lung recipients with cystic fibrosis (incidence rate ratio [IRR] 12.3, 95% CI 6.94 to 21.9, vs. kidney recipients). Liver recipients with primary sclerosing cholangitis and inflammatory bowel disease also had elevated CRC risk (IRR 5.32, 95% CI 3.73 to 7.58). Maintenance therapy with cyclosporine and azathioprine was associated with proximal colon cancer (IRR 1.53, 95% CI 1.05 to 2.23). Incidence was not elevated in a subgroup of kidney recipients treated with tacrolimus and mycophenolate mofetil, pointing to the relevance of the identified risk factors. Transplant recipients have increased proximal colon cancer risk, likely related to underlying medical conditions (cystic fibrosis and primary sclerosing cholangitis) and specific immunosuppressive regimens.     

Long-Term Outcomes of CMV Disease Treatment with Valganciclovir Versus IV Ganciclovir in Solid Organ Transplant Recipients

Though an important cause of morbidity and mortality in solid organ transplantation (SOT), the long-term outcomes of cytomegalovirus (CMV) disease treatment have not been well studied. In a randomized trial, 321 SOT recipients with CMV disease were followed 1 year after treatment with either twice daily intravenous ganciclovir or oral valganciclovir (for 21 days) followed by once daily valganciclovir until day 49 in all patients. Clinical and viral eradication of CMV disease was similar between groups. Clinical recurrence beyond day 49 was found in 15.1% and virological recurrence in 30.0%, no difference between groups (p > 0.77). In a multivariable logistic regression analysis, the only independent predictor for recurrence was failure to eradicate DNAemia by day 21 (clinical: OR 3.9 [1.3–11.3], p = 0.012; virological: OR 5.6 [2.5–12.6], p < 0.0001). Eight patients developed ganciclovir resistance, with no difference between groups (p = 0.62). Twenty patients (valganciclovir: 11, ganciclovir: 9, p = 0.82) died, 12 due to infections, two involving CMV disease. There were no differences in long-term outcomes between treatment arms, further supporting the use of oral valganciclovir for treatment of CMV disease. Persistent DNAemia at day 21, CMV IgG serostatus and development of resistance may be relevant factors for further individualization of treatment.     

Cyclosporine versus Tacrolimus Treated Liver Transplant Recipients with Chronic Hepatitis C: Outcomes Analysis of the UNOS/OPTN Database

Recurrent hepatitis C virus (HCV) remains a problematic cause of morbidity and mortality for liver transplant patients. Immunosuppression including calcineurin‐inhibitors has been implicated in the acceleration of recurrent HCV. Recent studies suggest that outcomes may be better with cyclosporine (CSA‐ME) compared to tacrolimus (TAC), but the data are inconclusive. We retrospectively analyzed data received from the United Network for Organ Sharing on 8809 chronic HCV liver transplant recipients receiving either cyclosporine microemulsion (CSA‐ME) or tacrolimus (TAC) as maintenance immunosuppression prior to discharge. We analyzed patient death, graft failure, failure due recurrent disease and acute cellular rejection (ACR) for CSA‐ME versus TAC treated patients. Three‐year unadjusted patient and graft survival rates were 76.8% and 71.5%, respectively, in the CSA‐ME group versus 79.9% and 75.0% in the TAC group. Propensity score‐adjusted results suggest CSA‐ME treated patients are at increased risk of patient death and graft failure [Hazards ratio (HR) = 1.17; 95% CI = 1.01–1.36 and HR = 1.19; 95% CI = 1.04–1.35, respectively] and biopsy‐confirmed AR (HR = 2.03; 95% CI = 1.54–2.67) compared to TAC treated patients. These results provide evidence to reconsider the targeted administration of CSA‐ME to HCV‐infected liver transplant recipients.     

Conversion from calcineurin inhibitors to mycophenolate mofetil in liver transplant recipients with diabetes mellitus

Diabetes mellitus, a frequent metabolic complication in liver transplant recipients, may be produced by the diabetogenic effect of calcineurin inhibitors cyclosporine and tacrolimus. The aim of this study was to investigate the safety and metabolic effects of a gradual switch from cyclosporine or tacrolimus to mycophenolate mofetil among 12 diabetic liver transplant recipients. One patient was withdrawn from the study due to gastrointestinal side effects. Of the 11 remaining patients, cyclosporine or tacrolimus was completely withdrawn in five patients. Two patients developed suspected acute rejection episodes that were controlled by increasing the tacrolimus dosage. Glycosylated hemoglobin A1C and C-peptide levels were significantly lower at 3 and 6 months after the initiation of mycophenolate mofetil (P<.03 in all cases). Furthermore, urea and uric acid levels were significantly reduced after the change of treatment. In conclusion, a switch from cyclosporine/tacrolimus to mycophenolate mofetil may produce beneficial metabolic effects in diabetic liver transplant recipients, but poses a risk of graft rejection.     

The Immunobiogram,a novel in vitro diagnostic test to measure the pharmacodynamic response to immunosuppressive therapy in kidney transplant patients

BackgroundDiagnostic tools to measure the response to individual immunosuppressive drugs for transplant patients are currently lacking. We previously developed the blood-based Immunobiogram bioassay for in-vitro characterization of the pharmacodynamic response of patients' own immune cells to a range of immunosuppressants. We used Immunobiogram to examine the association between patients' sensitivity to their prescribed immunosuppressants and clinical outcome.MethodsWe conducted an international, multicenter, observational study in a kidney transplant population undergoing maintenance immunosuppressive therapy. Patients were selected by clinical course poor [PCC] N = 53 (with renal dysfunction, and rejection signs in biopsy or/and an increase in DSA strength in last 12 months) versus good [GCC] N = 50 (with stable renal function and treatment, no rejection and no DSA titers). Immunobiogram dose-response curve parameters were compared between both subgroups in patients treated with mycophenolate, tacrolimus, corticosteroids, cyclosporine A or everolimus. Parameters for which significant inter-group differences were observed were further analyzed by univariate and subsequent multivariate logistic regression.ResultsClinical outcome was associated with following parameters: area over the curve (AOC) and 25% (ID25) and 50% (ID50) inhibitory response in mycophenolate, tacrolimus, and corticosteroid-treated subgroups, respectively. These statistically significant associations persisted in mycophenolate (OR 0.003, CI95% <0.001–0.258; p = 0.01) and tacrolimus (OR < 0.0001, CI95% <0.00001–0.202; p = 0.016) subgroups after adjusting for concomitant corticosteroid treatment, and in corticosteroid subgroup after adjusting for concomitant mycophenolate or tacrolimus treatment (OR 0.003; CI95% <0.0001–0.499; p = 0.026).ConclusionsOur results highlight the potential of Immunobiogram as a tool to test the pharmacodynamic response to individual immunosuppressive drugs.     

Safety and efficacy of pravastatin therapy for the prevention of hyperlipidemia in pediatric and adolescent cardiac transplant recipients.

BACKGROUND: Hyperlipidemia is common after cardiac transplantation and it is a risk factor for post-transplantation coronary artery disease. Immunosuppression with corticosteroids and cyclosporine has been associated with hyperlipidemia. Pravastatin, a HMG-CoA reductase inhibitor, has been shown to be effective and safe for cholesterol reduction in adult heart transplant recipients. To our knowledge the safety and efficacy of pravastatin therapy in pediatric and adolescent heart transplant populations have not been previously analyzed. Therefore, we evaluated lipid profiles, liver transaminases, rejection data, and possible side effects in pediatric and adolescent cardiac transplant recipients treated with pravastatin. METHODS: The study group consisted of 40 cardiac transplant recipients 10 to 21 years old (mean age 16.9 years). Twenty-two patients received pravastatin in addition to an immunosuppressive regimen of either cyclosporine or tacrolimus, azathioprine or mycophenolate mofetil, and prednisone. Serial determinations of total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein, and triglycerides were available for all pravastatin-treated patients. Pre-treatment lipid values and hepatic transaminases were compared with those measured after therapy with pravastatin. Comparison of pravastatin-induced lipid reduction between groups treated with cyclosporine vs tacrolimus was also made. RESULTS: Patients receiving pravastatin experienced a mean 32 mg/dl decrease in TC (p < 0.005) and a mean 31 mg/dl decrease in LDL (p < 0.005), regardless of their immunosuppressive regimen. No statistical differences occurred in the magnitude of mean lipid reduction induced by pravastatin between the groups treated with cyclosporine vs tacrolimus. No significant changes in hepatic transaminase levels were noted, and no clinical evidence of pravastatin-induced myositis occurred in any subjects. CONCLUSION: Pravastatin therapy is effective and safe when used in pediatric and adolescent cardiac transplant recipients. Although the pravastatin-induced reduction in TC and LDL was more pronounced in patients receiving cyclosporine, the reduction was not statistically different from that in the tacrolimus group. No evidence of hepatic dysfunction or rhabdomyolysis in patients treated with pravastatin was noted. Long-term studies are required to evaluate the effect of pravastatin therapy on the incidence of accelerated coronary atherosclerosis in this population.     

Comparative study of the cellular pharmacodynamics of tacrolimus in renal transplant recipients treated with and without basiliximab

Basiliximab is a recently developed immunosuppressive agent for the prevention of acute allograft rejection in renal transplant recipients. The combination use of basiliximab and a calcineurin inhibitor was suggested to be more effective in comparison to immunosuppressive therapy using calcineurin inhibitor without basiliximab. Cyclosporine has been generally administered with basiliximab for renal transplant recipients. However, in cases of tacrolimus-based immunosuppressive regimen, the clinical efficacy and safety of combined use of tacrolimus and basiliximab remains to be elucidated. This study evaluated the tacrolimus pharmacological efficacy using a lymphocyte immunosuppressant sensitivity test (LIST) with MTT assay procedures in 16 cases of renal transplant recipients treated by tacrolimus without basiliximab and in 13 cases treated by tacrolimus in combination with basiliximab. The rate of acute rejection episodes in the recipients treated with tacrolimus plus basiliximab was 1/13 (7.7%), whereas the rate in the recipients treated with tacrolimus without basiliximab was 6/16 (37.5%). The recipients were divided into two groups according to their peripheral blood mononuclear cell (PBMC) sensitivity to tacrolimus [i.e., including a tacrolimus high sensitivity group (IC(50) <1.0 ng/ml) and a low sensitivity group (IC(50) >1.0 ng/ml). In the recipients treated with tacrolimus without basiliximab, the rate of acute rejection episodes in the tacrolimus high sensitivity group was 1/10 (10.0%), which was significantly lower than the rate in the low sensitivity group of 5/6 (83.3%; p = 0.008). The incidence of cytomegalovirus infection was not significantly different between the tacrolimus high and the low sensitivity groups of the recipients treated with tacrolimus with and without basiliximab. Therefore, in the case of selected tacrolimus-based immunosuppressive therapy for renal transplant recipients, the tacrolimus pharmacological efficacy should be evaluated using LIST at a time just before the transplant procedure in order to accurately predict allograft rejection. The data also suggested that low tacrolimus sensitivity recipients should be treated with tacrolimus-based immunosuppressive therapy in combination with basiliximab.     

Immunosuppression with calcineurin inhibitors with respect to the outcome of HCV recurrence after liver transplantation: results of a meta-analysis.

A controversy exists over whether the outcome of a hepatitis C virus (HCV)-infection-related liver transplant differs based on the calcineurin inhibitor (CNI) used. We have performed a systematic review and a subsequent meta-analysis evaluating tacrolimus (Tac)-based vs. cyclosporine A-based immunosuppression in HCV-infected liver transplant recipients. Searches were conducted to locate randomized controlled trials comparing Tac vs. cyclosporine A. Data on HCV liver transplant recipients were obtained, independently of whether the study was specifically designed for patients with this disease or not. A fixed effects model was used for statistical pooling of the relative risks (RR) for the different outcomes. A total of 5 articles (366 patients) fulfilled the inclusion criteria. Statistically significant differences between Tac-based vs. cyclosporine A-based therapies were not found for mortality (P = 0.11; RR = 0.72; 95% confidence interval [CI], 0.49-1.08), graft survival (P = 0.37; RR = 0.86; 95% CI, 0.61-1.21), biopsy-proven acute rejection (P = 0.65; RR = 0.91; 95% CI, 0.61-1.36), corticoresistant acute rejection (P = 0.26; RR = 2.25; 95% CI, 0.55-9.29), and fibrosing cholestatic hepatitis (P = 0.92; RR = 0.96; 95% CI, 0.41-2.26). In 1 study, no differences were detected regarding severe fibrosis at 1 yr. In conclusion, patient and graft survivals in HCV-positive liver transplant patients are similar independently of the CNI selected as basic immunosuppressant. Unfortunately, data on the severity of recurrence and effect on viremia are scarce. Well-designed randomized prospective studies are needed to determine whether there are differences between the 2 CNIs regarding these specific variables.     

Improvement in 3-month patient-reported gastrointestinal symptoms after conversion from mycophenolate mofetil to enteric-coated mycophenolate sodium in renal transplant patients

BACKGROUND: The benefit of conversion from mycophenolate mofetil (MMF) to enteric-coated mycophenolate sodium (EC-MPS) in terms of gastrointestinal symptom burden has been evaluated previously using patient-reported outcomes. However, data are lacking concerning the sustained effect of conversion over time, and the potential impact of concomitant calcineurin inhibitor. METHODS: In this 3-month, prospective, multicenter, longitudinal, open-label trial, MMF-treated renal transplant patients with gastrointestinal symptoms receiving cyclosporine or tacrolimus were converted to equimolar doses of EC-MPS. Change in gastrointestinal symptom burden was evaluated using a validated Gastrointestinal Symptom Rating Scale (GSRS). RESULTS: A significant improvement in GSRS score was observed from baseline (2.61, 95% CI 2.54-2.68) to month 1 (1.87, 95% CI 1.81-1.93) after conversion to EC-MPS and was sustained to month 3 (1.81, 95% CI 1.74-188; both P<0.0001 versus baseline). The mean change in overall GSRS score from baseline to month 1 was -0.74 overall (cyclosporine: -0.73 and tacrolimus: -0.74; all P<0.0001 versus baseline), with a slight further improvement (-0.79) at month 3 (cyclosporine: -0.82 and tacrolimus: -0.78; all P<0.0001 versus baseline). A significant improvement in GSRS subscale scores was also observed in the total population regardless of calcineurin inhibitor at month 1, sustained to month 3 (all P<0.0001 versus baseline). The improvement in GSRS score postconversion was similar in African-American and non-African-American patients, and in diabetic and nondiabetic patients. CONCLUSIONS: This exploratory study in 728 patients demonstrates that following conversion from MMF to EC-MPS, regardless of concomitant calcineurin inhibitor, GSRS is improved and sustained over 3 months.     

Impact of Everolimus and Low‐Dose Cyclosporin on Cytomegalovirus Replication and Disease in Pediatric Renal Transplantation

In order to investigate the hypothesis that the mammalian target of rapamycin inhibitor everolimus (EVR) shows anticytomegalovirus (CMV) activity in pediatric patients, we analyzed the impact of EVR‐based immunosuppressive therapy on CMV replication and disease in a large cohort (n = 301) of pediatric kidney allograft recipients. The EVR cohort (n = 59), who also received low‐dose cyclosporin, was compared with a control cohort (n = 242), who was administered standard‐dose cyclosporin or tacrolimus and an antimetabolite, mostly mycophenolate mofetil (91.7%). Multivariate analysis revealed an 83% lower risk of CMV replication in the EVR cohort than in the control cohort (p = 0.005). In CMV high‐risk (donor+/recipient?) patients (n = 88), the EVR‐based regimen was associated with a significantly lower rate of CMV disease (0% vs. 14.3%, p = 0.046) than the standard regimen. In patients who had received chemoprophylaxis with (val‐)ganciclovir (n = 63), the CMV‐free survival rates at 1 year and 3 years posttransplant (100%) were significantly (p = 0.015) higher in the EVR cohort (n = 15) than in the control cohort (n = 48; 1 year, 75.0%; 3 years, 63.3%). Our data suggest that in pediatric patients at high risk of CMV, an EVR‐based immunosuppressive regimen is associated with a lower risk of CMV disease than a standard‐dose calcineurin inhibitor–based regimen.     

Early Conversion From Calcineurin Inhibitor‐ to Everolimus‐Based Therapy Following Kidney Transplantation: Results of the Randomized ELEVATE Trial

In a 24‐month, multicenter, open‐label, randomized trial, 715 de novo kidney transplant recipients were randomized at 10–14 weeks to convert to everolimus (n = 359) or remain on standard calcineurin inhibitor (CNI) therapy (n = 356; 231 tacrolimus; 125 cyclosporine), all with mycophenolic acid and steroids. The primary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, was similar for everolimus versus CNI: mean (standard error) 0.3(1.5) mL/min/1.73² versus ?1.5(1.5) mL/min/1.73² (p = 0.116). Biopsy‐proven acute rejection (BPAR) at month 12 was more frequent under everolimus versus CNI overall (9.7% vs. 4.8%, p = 0.014) and versus tacrolimus‐treated patients (2.6%, p < 0.001) but similar to cyclosporine‐treated patients (8.8%, p = 0.755). Reporting on de novo donor‐specific antibodies (DSA) was limited but suggested more frequent anti‐HLA Class I DSA under everolimus. Change in left ventricular mass index was similar. Discontinuation due to adverse events was more frequent with everolimus (23.6%) versus CNI (8.4%). In conclusion, conversion to everolimus at 10–14 weeks posttransplant was associated with renal function similar to that with standard therapy overall. Rates of BPAR were low in all groups, but lower with tacrolimus than everolimus.