Per Fauchald

Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial

BACKGROUND Renal transplant recipients are at increased risk of premature cardiovascular disease. Although statins reduce cardiovascular risk in the general population, their efficacy and safety in renal transplant recipients have not been established. We investigated the effects of fluvastatin on cardiac and renal endpoints in this population. METHODS We did a multicentre, randomised, double-blind, placebo-controlled trial in 2102 renal transplant recipients with total cholesterol 4.0-9.0 mmol/L. We randomly assigned patients fluvastatin (n=1050) or placebo (n=1052) and follow up was for 5-6 years. The primary endpoint was the occurrence of a major adverse cardiac event, defined as cardiac death, non-fatal myocardial infarction (MI), or coronary intervention procedure. Secondary endpoints were individual cardiac events, combined cardiac death or non-fatal MI, cerebrovascular events, non-cardiovascular death, all-cause mortality, and graft loss or doubling of serum creatinine. Analysis was by intention to treat. FINDINGS After a mean follow-up of 5.1 years, fluvastatin lowered LDL cholesterol concentrations by 32%. Risk reduction with fluvastatin for the primary endpoint (risk ratio 0.83 [95% CI 0.64-1.06], p=0.139) was not significant, although there were fewer cardiac deaths or non-fatal MI (70 vs 104, 0.65 [0.48-0.88] p=0.005) in the fluvastatin group than in the placebo group. Coronary intervention procedures and other secondary endpoints did not differ significantly between groups. INTERPRETATION Although cardiac deaths and non-fatal MI seemed to be reduced, fluvastatin did not generally reduce rates of coronary intervention procedures or mortality. Overall effects of fluvastatin were similar to those of statins in other populations.

Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens

Abstract Background: Nonmelanoma skin cancer occurs frequently in organ transplant recipients, but the relative importance of different immunosuppressive therapy regimens is unclear. Objective: We studied the risk of skin cancer in the complete, single-center Norwegian cohort of kidney and heart transplant recipients (n = 2561). Methods: We determined cancer risk estimation by means of standardized incidence ratios and multivariate Cox regression. Results: Transplant recipients had an increased risk of cutaneous squamous cell carcinoma (SCC) (65-fold), malignant melanoma (3-fold), and Kaposis sarcoma (84-fold), and of lip SCC (20-fold), compared with the general population. After adjustment for age, kidney transplant recipients receiving cyclosporine, azathioprine, and prednisolone had a significantly (2.8 times) higher risk of cutaneous SCC relative to those receiving azathioprine and prednisolone. After adjustment for age and type of immunosuppressive regimen, heart transplant recipients had a significantly (2.9 times) higher risk than kidney transplant recipients. Conclusion: The risk of cutaneous SCC, malignant melanoma, Kaposis sarcoma, and lip SCC is increased in kidney and heart transplant recipients. The risk of posttransplant cutaneous SCC is related to the degree of immunosuppression caused by long-term immunosuppressive therapy. (J Am Acad Dermatol 1999;40:177-86.)

The Impact of Cytomegalovirus Infection and Disease on Rejection Episodes in Renal Allograft Recipients

Cytomegalovirus (CMV) infection and disease are potential risk factors for acute allograft rejection in renal transplant recipients. The present study specifically addresses this issue. From October 1994 to July 1997, 477 consecutive renal allograft recipients (397 first transplants and 80 retransplants) were included in the study. CMV infection (cytomegalovirus pp65 antigen in leukocytes) and disease (infection and clinical symptoms or signs of disease) were examined prospectively for 3 months. No CMV prophylaxis was given, and CMV disease was treated with intravenous (i.v.) ganciclovir. The retransplantation of four patients transplanted twice during the study and 22 patients receiving kidneys from human leucocyte antigen (HLA)‐identical siblings were excluded from statistical analysis. Rejections were evaluated clinically [277(61%)] and 173 (38%) also had a biopsy verified rejection. CMV infection occurred in 64% of the patients and 24% experienced CMV disease. In a multiple time‐dependent Cox analysis, CMV infection and CMV disease were independent significant predictors for clinical acute rejections, RR = 1.6 (1.1–2.5, p = 0.02) and RR = 2.5 (1.2–5.1, p = 0.01), respectively. Among 173 patients with biopsy verified rejection, 72% of the patients had tubulointerstitial rejection whereas 28% had a vascular rejection. CMV disease, but not CMV infection was a predictor of tubulointerstitial rejection, RR = 3.1 (1.1–9.3, p = 0.04). CMV infection and disease are independent risk factors for clinical acute rejection in kidney allograft recipients. CMV disease is an independent risk factor for biopsy verified acute tubulointerstitial rejection in kidney allograft recipients.

Sustained improvement of renal graft function for two years in hypertensive renal transplant recipients treated with nifedipine as compared to lisinopril

BACKGROUND Treatment of posttransplant hypertension is still a matter of debate. Calcium antagonists may ameliorate renal side effects of cyclosporin. Angiotensin converting enzyme- (ACE) inhibitors may be more effective in sustaining renal function in native chronic renal disease. We prospectively compared the effect of controlled release nifedipine and lisinopril on long-term renal function in hypertensive kidney transplant patients treated with cyclosporin. METHODS A total of 154 renal transplant patients presenting with hypertension (diastolic blood pressure >or=95 mmHg) during the first 3 weeks after transplantation were randomised to receive double-blind nifedipine 30 mg or lisinopril 10 mg once daily. A total of 123 patients completed 1 year of treatment (69 nifedipine, 54 lisinopril) and 64 patients completed 2 years of double-blind treatment (39 nifedipine, 25 lisinopril). Baseline glomerular filtration rate was measured as 99 mTc-diethylene-triaminepentaacetate clearance in a stable phase 2 to 5 weeks after inclusion and repeated at 1 and 2 years. RESULTS Baseline glomerular filtration rates were similar (46+/-16 ml/min with nifedipine, 43+/-14 ml/min with lisinopril). The changes in glomerular filtration rates from baseline were statistically significant between the groups after 1 year (9.6 ml/min mean treatment difference (95% confidence interval [CI]s 5.5-13.7 ml/min, P=0.0001) and remained statistically significant also after 2 years (10.3 ml/min mean difference (95% CIs 4.0-16.6], P=0.0017). After 1 year glomerular filtration rates averaged 56+/-19 ml/min in the nifedipine group and 44+/-14 ml/min in the lisinopril group. CONCLUSIONS Both nifedipine and lisinopril were safe and effective in treatment of hypertension in renal transplant patients treated with cyclosporin. Patients receiving nifedipine but not lisinopril improved kidney transplant function over a period of 2 years.

Fluvastatin prevents cardiac death and myocardial infarction in renal transplant recipients: post-hoc subgroup analyses of the ALERT Study

Renal transplant recipients have a greatly increased risk of premature cardiovascular disease. The ALERT study was a multicenter, randomized, double‐blind, placebo‐controlled trial of fluvastatin (40–80 mg/day) in 2102 renal transplant recipients followed for 5–6 years. The main study used a composite cardiac end‐point including myocardial infarction, cardiac death and cardiac interventions. Although reduced by fluvastatin, this primary end‐point failed to achieve statistical significance thus precluding analysis of predefined subgroups. Therefore, in the present survival analysis, we used an alternative primary end‐point of cardiac death or definite nonfatal myocardial infarction (as used in other cardiac outcome trials) which was significantly reduced by Fluvastatin therapy and permits subgroup analysis. Fluvastatin reduced LDL‐cholesterol by 1 mmol/L compared with placebo, and the incidence of cardiac death or definite myocardial infarction was reduced from 104 to 70 events (RR 0.65; 95% CI 0.48, 0.88; p = 0.005). Fluvastatin use was associated with reduction in cardiac death or nonfatal myocardial infarction, which achieved statistical significance in many subgroups. The subgroups included patients at lower cardiovascular risk, who were younger, nondiabetic, nonsmokers and without pre‐existing CVD. These data support the early introduction of statins following renal transplantation.

Consistent absorption of cyclosporine from a microemulsion formulation assessed in stable renal transplant recipients over a one-year study period.

To evaluate the pharmacokinetic properties of the new microemulsion formulation of cyclosporine (Sandimmun Neoral), a double-blind, prospective study in stable renal transplant recipients was performed. The patients were randomized on a 4:1 basis either to receive Sandimmun Neoral (n = 45) or continue on regular Sandimmun (n = 12). Before randomization, a steady-state pharmacokinetic profile study was performed in all patients while they were still on regular Sandimmun. Pharmacokinetic assessments were then performed after 8 and 12 weeks and after 1 year. A milligram-to-milligram dose conversion was shown to be adequate to maintain the patients within a predefined target therapeutic window. Changes in pharmacokinetic parameters after conversion to Sandimmun Neoral were consistent with an increased rate and extent of cyclosporine absorption from the Neoral formulation. This was reflected by a shorter time to reach peak concentration and also by a mean increase in peak concentration by 67%, and an overall mean increase in drug exposure (area under the curve) by 34%. These findings were also confirmed 1 year after conversion. Furthermore, significantly reduced intraindividual variability in pharmacokinetic parameters was found, as well as improvements in the correlation between trough concentrations and area under the curve after conversion to Sandimmun Neoral. In conclusion, our results indicate an improved and consistent absorption of cyclosporine from the Neoral formulation, which should make clinical management easier and safer.

Reduction of left ventricular mass by lisinopril and nifedipine in hypertensive renal transplant recipients: a prospective randomized double-blind study.

Background. Cardiovascular disease is the dominant cause of death in renal transplant recipients. Left ventricular hypertrophy (LVH) is a known risk factor. After renal transplantation, persistent hypertension is an important determinant for the further evolution of LVH. The aim of the present study was to compare the effect of an angiotensin converting enzyme (ACE) inhibitor (lisinopril) with a calcium channel blocker (CCB) (controlled release nifedipine) in treatment of posttransplant hypertension focusing on changes in LVH. Methods. One hundred fifty-four renal transplant recipients presenting with hypertension (diastolic BP≥95 mmHg) during the first 3 weeks after transplantation were randomized to receive double-blind 30 mg nifedipine or 10 mg lisinopril once daily. Results. One hundred twenty-three patients completed 1 year of treatment. Good quality echocardiographic data were available in 116 recipients (62 nifedipine/54 lisinopril) 2 and 12 months posttransplant. Blood pressure was equally well controlled in the two groups throughout the study (mean systolic/diastolic±SD after 1 year: 140±16/87±8 mmHg with nifedipine and 136±17/85±8 mmHg with lisinopril). Left ventricular mass index was reduced by 15% (P <0.001) in both groups (from 153±43 to 131±38 g/m2 with nifedipine and from 142±35 to 121±34 g/m2 with lisinopril). There were no statistically significant differences between the two treatment groups at baseline or at follow-up. Conclusions. In hypertensive renal transplant recipients with well-controlled blood pressure, there is a regression of left ventricular mass after renal transplantation. The regression of left ventricular mass index is observed to a similar extent in patients treated with lisinopril or nifedipine.

Unrelated living donors in 141 kidney transplantations: a one-center study.

BACKGROUND Kidney transplantation is the optimal treatment for the majority of patients with end-stage renal disease. However, the shortage of kidneys for transplantation is a global problem, and any attempt to improve the donor situation would be of benefit to the growing number of patients on transplant waiting lists. PATIENTS AND METHODS Since 1984, we have transplanted 141 kidneys from genetically unrelated living donors. Donors were most often spouses and were accepted regardless of HLA match grade. Preemptive transplantation was performed in 39% of the patients. Standard triple-drug immunosuppression with prednisolone, cyclosporine, and azathioprine was used. The patients were followed from 6 months to 13 years. RESULTS The incidence of acute rejection during the first 3 months after transplantation was higher in recipients of grafts from unrelated donors than in recipients of grafts from related living donors or cadaveric donors. However, unrelated living donor grafts survived significantly better than did cadaveric grafts (P < 0.02) and had a survival rate similar to that of living-related donor grafts mismatched for one or both HLA haplotypes. The perioperative complication rate for the donor was low. CONCLUSION We consider unrelated living donors an excellent source for alleviating the shortage of donor kidneys.

Individualized T cell monitored administration of ATG versus OKT3 in steroid‐resistant kidney graft rejection

Abstract: Acute steroid‐resistant rejection episodes are recommended to be treated with set doses of anti‐thymocyte globulin (ATG) or anti‐CD3 monoclonal antibody (OKT3). Individualized T cell monitoring has been proposed as a tool for dose finding. A randomized study comparing the efficacy and safety of ATG (n = 27) with OKT3 (n = 28) in the treatment of biopsy verified acute steroid‐resistant rejection (ASRR) when both drugs were administered on the basis of daily individualized T cell measurements. A drop to below 50 cells/mm3 CD2+ T cells was considered adequate and used to guide the dose of ATG/OKT3. Demographic, clinical and histopathological severities of rejections were equal in the two groups. During the 10 days of T cell monitoring and antibody treatment, 13 patients were in need of dialysis (ATG = 7/OKT3 = 6). Two grafts did not respond to antibody treatment and were lost due to rejection (ATG = 1/OKT3 = 1). There were 26 biopsy verified re‐rejections (ATG = 12/OKT3 = 14) within the first 3 months following antibody treatment. Mean serum creatinine (μmol/L) was similar in the two groups (ATG/OKT3: before rejection 157 ± 72/151 ± 88, at start of antibody treatment 308 ± 125/330 ± 94, end of antibody treatment 254 ± 122/246 ± 144 and at follow‐up after a mean of 32 months 166 ± 55 (n = 24)/164 ± 57(n = 23)). To keep the T cell count below 50 cells/mm3, average dose ATG given was 354 ± 151 mg (2.3 administrations, range 1–4) and average OKT3 was 32.5 ± 6.8 mg in 10 doses. In conclusion, individualized T cell monitored administration of ATG and OKT3 is safe and seems as effective as a standard set dose in treatment of ASRR. Tailoring the dose for each individual patient lowers the cost.

Calcineurin Inhibitor Avoidance with Daclizumab, Mycophenolate Mofetil, and Prednisolone in Dr-matched de Novo Kidney Transplant Recipients

Background. Calcineurin inhibitor (CNI)–free regimens posttransplantation have been claimed to conserve graft function in addition to reduce the risk factors for cardiovascular and malignant disease in renal transplant recipients. Methods. The primary aim of this prospective, open-label, randomized, parallel-group, single-center study was to compare the effect of complete CNI-avoidance posttransplant (daclizumab + mycophenolate mofetil + prednisolone: Dac-group, n=27) with the standard CNI-based immunosuppressive protocol at our transplant unit (cyclosporine A + mycophenolate mofetil + prednisolone: CsA-group, n=27) on renal function (glomerular filtration rate [GFR] determined as plasma clearance of 51Cr-EDTA) in a selected low immunogenic risk population (DR-matched, PRA-negative de novo cadaveric transplant recipients). Results. There were no significant difference in GFR at week 10 (P=0.61), but GFR was significantly (P=0.029) lower in the Dac-group (52±20 ml/min) at month 12 than in the CsA-group (69±29 ml/min). One-year patient and graft survival did not differ between the two groups. Overall acute rejection rate was 70.4% (19/27) in the Dac-group and 29.6% (8/27) in the CsA-group (P=0.006). Conclusions. The strategy to select DR-matched, PRA-negative de novo cadaveric transplant recipients for a CNI-avoidance protocol was not successful. The incidence of acute rejection was unacceptable high even though anti-CD25 antibody induction as well as initial higher mycophenolate mofetil doses (3 g/day) were applied, and renal function was significantly lower in the CNI-avoidance patients at 1 year. Other strategies need to be examined for avoidance of CNIs in the early posttransplant period.