Barbara Suwelack

Withdrawal of Cyclosporine or Tacrolimus After Addition of Mycophenolate Mofetil in Patients With Chronic Allograft Nephropathy

There has been a need for a prospective, randomized, controlled trial to determine whether the addition of mycophenolate mofetil (MMF) to a calcineurin inhibitor (CNI)‐based regimen or MMF addition followed by CNI withdrawal is an effective treatment for chronic allograft nephropathy (CAN). We conducted the first randomized, prospective study to compare the introduction of MMF with or without CNI withdrawal in long‐term transplant recipients with histologically proven CAN and deteriorating renal function. The primary endpoint was renal function as indicated by the slope of the inverse serum creatinine vs. time at 32 weeks after randomization. After an interim analysis found a greater‐than‐expected difference between groups in the slopes of the inverse serum‐creatinine, the study was stopped for ethical reasons. There were 20 patients in the MMF/CNI continuation and 19 patients in the MMF/CNI withdrawal groups (mean time post‐transplant 7 years). Renal function improved in the dual‐therapy compared with the triple‐therapy group (p = 0.002). Blood pressure decreased in the dual‐therapy group with a significant difference between groups at 35 weeks (p = 0.04). No acute rejections occurred. Long‐term patients with CAN experience a significant improvement in renal function and blood pressure when CNIs are replaced by MMF.

Preemptive treatment of Cytomegalovirus infection in kidney transplant recipients with letermovir: results of a Phase 2a study.

Cytomegalovirus (CMV) infection remains a significant cause of morbidity and mortality in transplant recipients. Letermovir (AIC246), is a novel anti‐HCMV drug in development, acting via a novel mechanism of action. In this proof‐of‐concept trial with first administration of letermovir to patients, 27 transplant recipients with active CMV replication were randomly assigned to a 14‐day oral treatment regimen of either letermovir 40 mg twice a day, letermovir 80 mg once a day, or local standard of care (SOC) in a multicenter, open‐label trial. Efficacy, safety, and limited pharmacokinetic parameters were assessed. All groups had a statistically significant decrease in CMV‐DNA copy number from baseline (40 mg BID: P = 0.031; 80 mg QD: P = 0.018; SOC: P = 0.001), and comparison of viral load reduction between treatment groups showed no statistically significant differences. Viral clearance was achieved for 6 of 12 patients (50%) in the letermovir groups versus two of seven SOC patients (28.6%). Letermovir treatment was generally well tolerated, no patient developed CMV disease during the trial. Both letermovir treatment regimens resulted in equally high trough level plasma concentrations. The efficacy, safety, and pharmacokinetics observed in these viremic transplant recipients indicate that letermovir is a promising new anti‐CMV drug.

The influence of immunosuppressive agents on BK virus risk following kidney transplantation, and implications for choice of regimen

The increasing incidence of BK-associated nephropathy following kidney transplantation has prompted an examination of strategies for risk reduction and management through immunosuppression manipulation. Evidence from retrospective and prospective studies suggests that BK viruria and viremia, and the need for BK virus treatment, are higher with tacrolimus than cyclosporine. Combined therapy with tacrolimus and mycophenolic acid may be associated with a particularly higher risk of BK infection, but data are conflicting as to whether mycophenolic acid per se is an independent risk factor. The incidence of BK-related events may be reduced in patients receiving mTOR inhibitors (everolimus or sirolimus) with cyclosporine vs a calcineurin inhibitor with mycophenolic acid. De novo immunosuppression regimens that avoid rabbit antithymocyte globulin and tacrolimus, particularly tacrolimus with mycophenolic acid, may be advantageous, whereas low-exposure cyclosporine with an mTOR inhibitor appears a favorable option. Routine screening for BK infection during the first 2 years posttransplant is recommended to allow preemptive modification of the immunosuppressive regimen. In patients at high risk of BK virus infection, appropriate de novo immunosuppression or very early conversion to an mTOR inhibitor to facilitate reduction or discontinuation of calcineurin inhibitors or antimetabolites should be considered. Extensive further research into optimal avoidance, screening, and treatment strategies is required.

Impact of failed allograft nephrectomy on initial function and graft survival after kidney retransplantation

The management of an asymptomatic failed renal graft remains controversial. The aim of our study was to explore the effect of failed allograft nephrectomy on kidney retransplantation by comparing the outcome of recipients who underwent graft nephrectomy prior to retransplantation with those who did not. Retrospective comparison of patients undergoing kidney retransplantation with (group A, n = 121) and without (group B, n = 45) preliminary nephrectomy was performed, including subgroup analysis with reference to patients with multiple (≥2) retransplantations and patients of the European Senior Program (ESP). Nephrectomy leads to increased panel reactive antibody (PRA) levels prior to retransplantation and is associated with significantly increased rates of primary nonfunction (PNF; P = 0.05) and acute rejection (P = 0.04). Overall graft survival after retransplantation was significantly worse in group A compared with group B (P = 0.03). Among the subgroups especially ESP patients showed a shorter graft survival after previous allograft nephrectomy. On the multivariate analysis, pretransplant graft nephrectomy and PRA >70% were independent and significant risk factors associated with graft loss after kidney retransplantation. Nephrectomy of the failed allograft was not beneficial for retransplant outcome in our series. Patients with failed graft nephrectomy tended to have a higher risk of PNF and acute rejection after retransplantation. The possibility that the graft nephrectomy has a negative impact on graft function and survival after retransplantation is worth studying further.

Effect of a 3-year therapy with the 3-hydroxy-3-methylglutaryl coenzyme a reductase-inhibitor fluvastatin on endothelial function and distensibility of large arteries in hypercholesterolemic renal transplant recipient

BACKGROUND In patients after renal transplantation functional arterial vessel wall properties are impaired. Whether 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have a sustained effect on endothelial function and arterial distensibility in patients after renal transplantation is not clear. The authors studied the effects of a long-term therapy with fluvastatin on large artery distensibility and flow-mediated vasodilation (FMD) in hypercholesterolemic patients after renal transplantation in a prospective, blinded, and randomized trial. METHODS Twenty-six patients who had undergone renal transplantation were assigned randomly to either fluvastatin, 40 mg/d (n = 13) or placebo (n = 13) and underwent follow-up for 3 years. At baseline and after 6, 12, and 36 months of treatment, carotid and brachial artery distensibility, endothelium-dependent FMD, and nitroglycerine-induced vasodilation (NMD) of the brachial artery were measured by a echo-tracking device. RESULTS A significant decrease in total and low-density cholesterol was observed after 6, 12, and 36 months in patients treated with fluvastatin but not in the placebo group. FMD increased with fluvastatin from 4.6 +/- 2% to 12.4 +/- 2% after 12 months; this improvement was sustained with 13.4 +/- 3% after 36 months (P < 0.05). However, placebo did not alter FMD (P < 0.001 for trend difference between groups by analysis of covariance). Endothelium-independent NMD was similar in both groups at baseline and during therapy. Neither carotid nor brachial artery distensibility coefficients were altered by either treatment. CONCLUSION HMG-CoA reductase inhibitor therapy over 3 years results in a significant and sustained improvement of endothelial function in hypercholesterolemic patients after renal transplantation. However, this is not accompanied by a beneficial effect on impaired large artery distensibility even after long-term therapy with fluvastatin.

Renal, efficacy and safety outcomes following late conversion of kidney transplant patients from calcineurin inhibitor therapy to everolimus: the randomized APOLLO study.

AIMS The primary objective of this trial was to demonstrate, based on the estimated glomerular filtration rate (eGFR), superior renal function at month 12 after conversion of maintenance kidney transplant patients from calcineurin inhibitor (CNI) therapy to everolimus, compared to continuing a standard CNI regimen. MATERIALS AND METHODS APOLLO was an open-label, 12-month, prospective, multicenter study in which 93 maintenance kidney transplant patients were randomized to convert from CNI to everolimus (n = 46) or remain on standard CNI-based immunosuppression (n = 47). The primary efficacy variable was eGFR (Nankivell formula) 12 months after randomization. The study was terminated prematurely due to slow recruitment and was thus underpowered. RESULTS Mean time post-transplant was 83.5 months with everolimus and 70.1 months with CNI. Adjusted values for eGFR (Nankivell) at month 12 were 61.6 (95% CI 58.1, 65.1) mL/ min/1.73 m² with everolimus and 58.8 (95% CI 55.2, 62.3) mL/min/1.73 m² with CNI, a difference of 2.8 (95% CI -1.0, 6.7) mL/ min/1.73 m² (p = 0.145) i.e., the primary objective was not met. Using the modification of diet in renal disease (MDRD) formula, adjusted eGFR at month 12 was significantly higher with everolimus (p = 0.030). In the subpopulation who remained on the study drug (n = 52), the difference in the adjusted change from randomization was 6.6 (95% CI 1.5, 11.6) mL/min/1.73 m² (p = 0.013) in favor of everolimus. There was no biopsyproven acute rejection and no graft losses. Adverse events led to discontinuation of everolimus and CNI in 32.6% and 10.6% of patients, respectively. CONCLUSIONS Conversion from CNI to everolimus to preserve renal function can be considered several years after kidney transplantation and does not compromise immunosuppressive efficacy.

Blood pressure, antihypertensive treatment, and graft survival in kidney transplant patients.

Whether the use of angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker inhibitor (ACEI/ARB) is beneficial in renal transplant recipients remains controversial. In this retrospective study on 505 renal transplant recipients, we analyzed blood pressure and graft survival according to antihypertensive treatment with ACE‐I/ARB and/or calcium channel blockers (CCB) over a period of 10 years. Patients were stratified according to their blood pressure 1 year after transplantation [controlled (≤130/80 mmHg; CTR, 181 patients) and noncontrolled (>130/80 mmHg; non‐CTR, 324 patients)] and according to antihypertensive treatment (ACE‐I/ARB and/or CCB taken for at least 2 years). One year after transplantation, 88.4% of CTR and 96.6% of non‐CTR received antihypertensive treatment (P < 0.05). Graft survival was longer in CTR than in non‐CTR (P < 0.05). Importantly, graft survival was longer in patients who received long‐term treatment with ACEI/ARB, CCB, or a combination of ACEI/ARB and CCB (P < 0.001). The beneficial effect of ACEI/ARB therapy was more pronounced in non‐CTR compared with that of CTR. We conclude that blood pressure control is a key target for long‐term graft survival in renal transplant patients. Long‐term ACEI/ARB and CCB therapy is beneficial for graft survival, especially in patients with diabetes and/or albuminuria.

Comparison of quinapril versus atenolol: effects on blood pressure and cardiac mass after renal transplantation

Based on epidemiologic facts on elevated cardiovascular mortality in renal allograft recipients, an echocardiographic 2-year follow-up in hypertensive renal allograft recipients was conducted. This study provides evidence that, in contrast to atenolol, quinapril, independent of blood pressure reduction, reduces left ventricular hypertrophy and improves left ventricular diastolic function in this population.

Relationship of hepatitis B or C virus prevalences, risk factors, and outcomes in renal transplant recipients: analysis of German data.

BACKGROUND Chronic liver disease resulting from hepatitis B (HBV) and hepatitis C (HCV) virus infections is still a major concern in kidney recipients. Our aim was to evaluate the prevalences, risk factors, and impact of HBV and HCV infections in adult renal transplant recipients in Germany. MATERIALS AND METHODS Data were collected on 1633 kidney recipients transplanted between 1989 and 2002 at the 21 German renal transplant centers participating in MOST, the prospective Multinational Observational Study in Transplantation. Subgroup analyses compared HBV- and HCV-positive patients vs those with HBV/HCV-negative serology at the time of transplantation. RESULTS The prevalences of 4.4% (n = 72) for HBV and 5.8% (n = 94) for HCV showed a marked decline over the last 15 years. Retransplantations were significantly more common among HBV+ (29%) and HCV+ (36%) than HBV-/HCV- patients (12%). HCV+ patients experienced significantly longer dialysis times and received significantly more pretransplantation blood transfusions. Between all groups, no significant differences were observed in acute rejection rate at 12 months or in renal graft function up to 5 years posttransplantation (mean glomerular filtration rate: HBV+, 57.3 mL/min; HCV+, 58.5 mL/min; HBV-/HCV-, 59 mL/min). No progressive elevations in liver enzymes and bilirubin were noted during the 5-year observation period. CONCLUSIONS HBV and HCV infections currently have a low prevalence among German kidney graft recipients. Long dialysis times, blood transfusions, and retransplantations were identified as risk factors for hepatitis infections. At 5 years posttransplantation, kidney and liver functions did not differ significantly between HBV+ and HCV+ vs HBV-/HCV- renal transplant recipients.

Sympathetic nerve activity in renal transplant patients before and after withdrawal of cyclosporine.

Background It has been suggested that the increase in blood pressure observed in transplant patients treated with cyclosporine is mediated by cyclosporine-induced sympathoexcitation. However, the chronic effects of cyclosporine on sympathetic outflow in renal transplant patients have not been investigated. Therefore we studied sympathetic nerve activity and blood pressure before and 6 months after the withdrawal of cyclosporine in renal transplant patients. Methods Twenty-four renal transplant patients with histologically confirmed chronic allograft nephropathy (age 48 ± 3 years, 60 ± 10 months after transplantation) were included in the prospective study and randomly assigned to either withdrawal (n = 12) or continuation (n = 12) of cyclosporine. Both groups received mycophenolate mofetil and prednisolone as additional immunosuppressants. At entry and 6 months later blood pressure, muscle sympathetic nerve activity (MSNA), and plasma norepinephrine were measured. To assess the potential influence of the diseased native kidneys, three renal transplant patients who had their native kidneys removed were studied before and after cyclosporine withdrawal. Results Mean arterial pressure decreased significantly in the cyclosporine-withdrawal group (95 ± 4 versus 105 ± 4 mmHg 6 versus 0 months, P < 0.05) but not in the cyclosporine-continuation group (103 ± 3 versus 105 ± 4 mmHg, NS). However, plasma norepinephrine and MSNA did not change significantly in either group (MSNA 43 ± 4 versus 44 ± 3 and 38 ± 5 versus 39 ± 4 bursts/min in the cyclosporine-withdrawal and cyclosporine-continuation groups, NS). Graft function remained stable in both groups and in transplant patients who had their native kidneys removed MSNA did not decrease after cyclosporine withdrawal. Conclusion The withdrawal of cyclosporine in renal transplant patients, receiving relatively low doses of cyclosporine, resulted in a substantial decrease in blood pressure. However, MSNA and norepinephrine did not change. This suggests that cyclosporine treatment does not cause chronic sympathetic activation that could explain the cyclosporine-induced blood pressure elevation in renal transplant patients.