Enalapril/amlodipine combination in cyclosporine-treated renal transplant recipients: a prospective randomized trial

BACKGROUND: Most hypertensive renal transplant recipients require two or more antihypertensive medications to achieve blood pressure control. However, which medications must be combined is still a matter of debate. METHODS: A prospective randomized open-label blinded evaluation trial comparing the six-month effects of the amlodipine-enalapril combination (n = 32) vs. enalapril alone (n = 33) and vs. amlodipine alone (n = 34) on arterial pressure, renal function, albuminuria and tolerability. RESULTS: At six months, diastolic arterial pressure was more adequately controlled (i.e., <90 mmHg) in the combination group than in the amlodipine and enalapril groups (100% vs. 82.4% and 84.8%, respectively, p = 0.038). The same trend was observed for systolic arterial pressure (65.6% vs. 58.8% and 51.5%, NS). The six-month change in albuminuria was similar in the combination group and in the enalapril group (-64.7% vs. -59.5%); however, patients in the combination group exhibited a greater reduction in albuminuria than in the amlodipine group (-64.7% vs. -29.0%, p = 0.002). As compared with baseline values, serum creatinine and potassium remained unchanged in the combination group, whereas they increased by 9 +/- 12 micromol/L (p = 0.01) and by 0.2 +/- 0.4 mmol/L (p < 0.01), respectively, in the enalapril group. The cyclosporine trough levels remained unchanged in the combination group, but increased in the amlodipine group. CONCLUSION: Angiotensin-converting enzyme inhibitor (ACEI)-calcium-channel blocker (CCB) combination controls arterial pressure more adequately than ACEI alone or CCB alone, reduces albuminuria and may prevent the ACEI-induced initial rise in serum creatinine.     

Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study

BACKGROUND: Because humoral immunity is believed to play a pivotal role in the pathogenesis of IgA nephropathy (IgAN), a prospective placebo-controlled randomized study was started in patients with IgAN using mycophenolate mofetil (MMF). METHODS: A total of 34 patients with IgAN were treated with salt intake restriction, angiotensin-converting enzyme (ACE) inhibition and MMF 2 g per day (N= 21) or placebo (N= 13). After 36 months of follow-up clinical, biochemical, and radiologic data were analyzed using linear mixed models for longitudinal data and Kaplan-Meier survival analysis. RESULTS: Therapy had to be stopped prematurely in five patients. Two patients (MMF group) evolved to end-stage renal disease (ESRD). There was no difference between groups in the percentage of patients with a decrease of 25% or more in the inulin clearance or with a serum creatinine increase of 50% or more over 3 years. There was also no significant difference between groups in annualized rate of change of serum creatinine, computed by linear regression analysis. No significant difference was noted between groups for inulin clearance, serum creatinine, proteinuria, blood pressure, or other parameters of renal function. Hemoglobin and C-reactive protein were significantly lower in the MMF group compared with the placebo group. As a function of time, a significant decline in both groups was noted of proteinuria, parenchymal thickness of the kidneys and C3d. CONCLUSION: In patients with IgAN at risk for progressive disease, no beneficial effect of 3-year treatment with MMF 2 g per day could be demonstrated on renal function/outcome or proteinuria. However, larger randomized studies are needed to confirm or reject these results.     

Influence of diltiazem on renal function and rejection in renal allograft recipients receiving triple-drug immunosuppression: a randomized, double-blind, placebo-controlled study

In a prospective, randomized and placebocontrolled study weevaluated the influence of treatment with the calcium-channelblocker diltiazem on the course and results of cadaveric kidneytransplantation in 39 graft recipients. The grafts were reperfusedwith Euro-Collins solution containing diltiazem 20 mg/l. Allrecipients except those in chronic treatment with a calcium-channelblocker received preoperatively a bolus of diltiazem or placebo0.3 mg/kg and in all an infusion of diltiazem or placebo 3 mg/kg/24h was started preoperatively. After that, diltiazem or placebowas given orally for 3 months. Donors were not treated. Immunosuppressivetherapy consisted of prednisone, azathioprine and CsA. Therewere no significant differences between the groups concerningdonor or recipient characteristics, HLA-mismatching, and ischaemictime. Thrombosis leading to graft loss occurred in 3 recipients(diltiazem:2, placebo:1) and one graft was lost due to septicaemia(diltiazem). For the remaining 35 grafts no beneficial effectof treatment with diltiazem was found for the rate of delayedgraft function, the rate of rejections, time to first rejection,whole blood CsA concentration, or graft function. The CsA doseneeded to reach target whole blood concentration was significantlyless in the diltiazem group. In conclusion, our results do notindicate any beneficial effects of treatment with diltiazemin cadaveric kidney transplantation, except a reduction of costsbecause of a significant reduction of the CsA dosage.     

Significance of delayed graft function in cyclosporine-treated recipients of cadaver kidney transplants

Many transplant teams are reluctant to initiate cyclosporine immunosuppression in recipients of cadaver kidney grafts with delayed graft function (DGF). The renal function of cadaver kidney grafts in cyclosporine-treated recipients was compared in 47 recipients with DGF and 57 without DGF. Regardless of initial renal function, all recipients received prednisone, azathioprine, and oral cyclosporine 5 mg/kg/day or its intravenous equivalent. All kidneys were flushed with ice-cold intracellular electrolyte solution and cold-stored for 15-54 hr (mean of 31 hr) prior to transplantation at our hospital between April 10, 1985 and November 30, 1986. Rejection crises were treated with high-dose steroids or OKT3. Cyclosporine was discontinued during courses of OKT3. Recipients with DGF had significantly higher one-month serum creatinine nadirs (2.6 +/- 1.8 mg/dl vs. 1.5 +/- 0.5 mg/dl). Actuarial graft survivals were not significantly different at one year (82.2 +/- 5.5% vs. 82.6 +/- 6.4%, all graft losses included). Mean serum creatinine levels at six months and twelve months after grafting were not significantly different (1.7 +/- 0.4 mg/dl vs. 1.8 +/- 1.2 mg/dl and 2.0 +/- 0.5 vs. 1.7 +/- 0.7 mg/dl, respectively). Delayed graft function following cadaver kidney transplantation does not adversely affect intermediate term function of kidney grafts flushed with intracellular electrolyte solution and cold-stored until transplantation when a low-dose cyclosporine induction protocol is used and cyclosporine is discontinued during OKT3 administration.     

Serum ferritin and survival of renal transplant recipients: a prospective 10-year cohort study

Increased serum ferritin is frequent in renal transplant recipients. This reflects iron overload due to blood transfusions given to treat renal anaemia. Previous studies suggested excess mortality in non-renal transplant recipients with iron overload. We hypothesized that serum ferritin levels above 1100 ng/ml may be associated with increased long-term mortality in renal transplant recipients. Twenty consecutive renal transplant recipients with high levels of serum ferritin and 20 renal transplant recipients with normal serum ferritin levels, matched for age and gender, were prospectively studied for 10 years. Nine patients (45%) with increased serum ferritin died during follow-up, compared to four controls (20%). Univariate and multivariate analysis identified multiple blood transfusions (>40 units) prior to transplantation as being associated with higher mortality in renal transplant recipients (risk ratio (RR): 3.1, confidence interval (CI): 1.1-9.2; P=0.03). These data suggest that serum ferritin levels above 1100 ng/ml due to multiple blood transfusions causing iron overload is a relevant factor that increases mortality.     

Antifungal prophylaxis in liver transplant recipients: a randomized placebo-controlled study

The aim of this study was to evaluate the efficacy of two antifungal prophylaxis regimens in liver transplant recipients. One hundred and twenty-nine consecutive recipients were randomized to receive sequential treatment with intravenous liposomal amphotericin B + oral itraconazole, intravenous fluconazole + oral itraconazole, or intravenous and oral placebo. Frequency and incidence of mycotic colonization, local and systemic infection of mycotic origin, causes of death, and possible risk factors for mycotic infection were evaluated. The incidence of mycotic colonization was higher in the placebo group ( P<0.01), but there was no significant difference in the incidence of infection between the three groups. Pre-transplant colonization, severity of liver disease, and graft rejection were all risk factors for the development of fungal infection. The routine use of antifungal prophylaxis for all liver transplant recipients does not seem to be justified.     

更昔洛韦预防肾移植术后巨细胞病毒感染的前瞻性随机对照研究

目的研究更昔洛韦对肾移植术后巨细胞病毒(CMV)感染的预防作用。方法选取2004年行首次肾移植的55例患者,所有患者术后均常规应用环孢素A+霉酚酸酯+激素的免疫抑制方案。将患者随机分为2组,A组27例,从肾移植术后第2周起静脉滴注更昔洛韦5mg.kg-1.d-1,共30d,预防CMV感染;B组28例,没有针对CMV感染进行预防性用药。所有患者肾移植术后均随访6个月,检测其血清中CMV-IgG、CMV-IgM及CMV-DNA的表达,统计肾移植术后6个月时CMV感染率、CMV病的患病率、CMV感染时间、CMV病临床缓解时间、急性排斥反应发生率以及药物不良反应等项目。结果A、B两组患者的CMV感染率分别为37%和25%,CMV患病率分别为22.2%和14.3%,两组相比,差异无统计学意义。A组术后发现CMV感染时间较B组明显延迟(P<0.05),且发生CMV病后的临床缓解时间较B组显著缩短(P<0.05)。A、B两组急性排斥反应发生率分别为11.1%和21.4%,两组比较,差异无统计学意义。1例患者应用更昔洛韦后发生白细胞数减少,经集落刺激因子治疗后恢复。结论肾移植术后静脉滴注更昔洛韦对降低CMV感染率及发病率无明显作用,但可明显延迟肾移植术后CMV感染的发生时间,并显著缩短CMV发病后的临床症状缓解时间。提示肾移植术后CMV感染的预防性用药可能需要更长的时间。     

Predictors of renal function improvement following tacrolimus conversion in cyclosporine-treated kidney transplant recipients

The objective of this study was to evaluate the relationship between variability of cyclosporine (CsA) absorption and tacrolimus (TAC) conversion seeking factors that predict improvement in allograft function after TAC conversion. We performed a retrospective study of 44 adult kidney transplant recipients undergoing conversion from CsA to TAC-based immunosuppression. Before TAC conversion, patients had complete, consecutive, 6 monthly C2 levels and a follow-up duration beyond 6 months after TAC conversion. The patients were divided into 2 groups: one (n=23) with low variability of CsA absorption and one (n=21) with high variability of CsA absorption. At TAC conversion, the estimated glomerular filtration rate (eGFR) was similar in both patient groups. Six months after TAC conversion, eGFR improved in both groups. Stepwise regression analysis revealed the DeltaSCr6 (change in serum creatinine level at 6 months) to be independently associated with the preconversion serum creatinine (SCr; P<.0001) and the percent coefficient of variation (%CV) of SCr (P=.0034). DeltaSCr6 was inversely associated with posttransplantation years (P=.0033), and 6-month TAC blood levels (P=.0053). The DeltaSCr6 was not associated with variability of oral CsA absorption. The cutoff value of baseline SCr at TAC conversion differentiated an increase in or reduction of SCr to be about 1.0 mg/dL. Our study of CsA-treated kidney transplant recipients who underwent TAC conversion showed that a preconversion SCr>1.0 mg/dL, a high variability of SCr, and early TAC conversion predicted greater short-term benefit on graft function.     

Hamstring graft tibial insertion preservation versus detachment in anterior cruciate ligament reconstruction: a prospective randomized comparative study

Background

Anterior cruciate ligament (ACL) reconstruction with hamstring graft (HG) is a commonly performed procedure. Despite the type of reconstruction chosen, the detached HG undergoes a remodeling process known as ligamentization. In order to shorten the ligamentization process, the maintenance of HG tibial insertion, aimed to spare the tendons vascular supply, has been postulated. The aim of this paper is to report the results of a prospective randomized study comparing clinical and MRI results between two different ACL reconstructive procedures with and without HG tibial insertion preservation.

Methods

Forty patients (mean age 27.5 ± 9.5 years) were enrolled and randomly divided into two groups. The study group underwent an ACL reconstruction using a distally inserted HG, while the control group underwent a technique encompassing HG tibial detachment. Subjective and objective IKDC score was administered preoperatively and at 3-, 6-, 12- and 24-month follow-up. Graft morphology was assessed through MRI evaluation performed at 6-month follow-up.

Results

Clinical results were excellent in both groups. Regarding MRI results, a better intra-articular graft morphology was observed in the study group (Tau = 0.313, p = 0.024). No differences in graft integration were noticed.

Conclusion

The main finding of this preliminary study is that preservation of the hamstring tibial insertion seems to enhance graft ligamentization with improved morphology of the intra-articular portion of the graft compared to a detachment of the hamstring tendons from the tibial side. Further well-designed studies with higher number of patients as well as more serial MRI evaluations are required to validate these preliminary findings.

     

Evaluation of daclizumab to reduce delayed graft function in non-heart-beating renal transplantation: a prospective, randomized trial

Daclizumab (DZB), an interleukin-2 receptor blocker, has been shown to reduce the rate of acute rejection, while non-heart-beating kidney recipients have high rates of delayed graft function that may be prolonged by high levels of calcineurin inhibitors. This study assessed whether DZB could safely replace calcineurin inhibitors in the immediate postoperative period and promote recovery from ischemic acute tubular necrosis. Patients were randomized into one of two groups: DZB induction and daily mycophenolate mofetil (MMF; 2 g) with steroids (20 mg prednisone) or standard triple therapy with tacrolimus, MMF, and prednisone. Patients in the DZB arm were converted to the control arm when either the serum creatinine dropped to <350 micromol/L or there was biopsy evidence of acute rejection. Over 2 years, Leicester and Newcastle non-heart-beating donor (NHBD) centers recruited 51 patients. There was one patient death in the DZB arm, during the study period, after a nonfunctioning graft was removed. A total of two (8%) grafts in the DZB arm and three (11.5%) grafts in the control arm failed to function. The overall rate of immediate function improved from around 5% (pre-2001) to 28%. There were no significant differences in the incidence of acute rejection or graft function (GFR) at 3 months. Machine-perfused kidneys in DZB-treated recipients had the highest rates of immediate function (53%, P = .015). We found that a calcineurin-sparing regime is safe and may be beneficial for recipients of machine-perfused grafts damaged by warm ischemia.     

The effects of dietary supplementation with fish oil on renal function in cyclosporine-treated renal transplant recipients

The effect of a daily supplementation of 6 g fish oil (30% C20:5 omega-3 (EPA) and 20% C22:6 omega-3 for three months on renal function variables was investigated in a placebo-controlled (6 g corn oil, 50% C18:2 omega-6) prospective, randomized, double-blind study in stable cyclosporine-treated renal transplant recipients, at least nine months after grafting. Ten patients ingested placebo capsules and eleven patients fish oil. When measuring glomerular filtration rate and effective renal plasma flow (ERPF) before (baseline [BL]) and after 3 months of oil ingestion nothing changed in the placebo-treated group: GFR-BL = 64.5 GFR-3 months = 60 ml/min/1.73m2 (NS; median, Wilcoxon test) ERPF BL = 229.5 and ERPF-3 months = 242.5 ml/min/1.73m2 (NS). In the fish oil-treated group GFR rose by 20.3% from GFR-BL = 56 to GFR-3 months = 68 ml/min/1.73m2 and ERPF by 16.4% from ERPF-BL 218 to ERPF-3 months = 245 ml/min/1.73m2, (P less than 0.01). In the placebo-treated group mean arterial pressure and calculated total renal vascular resistance (TRVR) did not change: MAP-BL = 106 mmHg and MAP-3 months = 109 mmHg, TRVR being 20856 dyne.sec/cm5 and 19862 dyne/sec/cm5, respectively (NS). In the fish oil-treated group MAP and TRVR fell by 8.6% and 21.1%, respectively: MAP-BL = 106 mmHg and MAP-3 months = 98 mmHg (P less than 0.01), TRVR-BL = 21952 dyne/sec/cm5 and TRVR-3 months = 17087 dyne/sec/cm5 (P less than 0.01). According to these results fish oil supplementation has considerable effects on renal function and blood pressure in stable CsA-treated renal transplant recipients.     

Steroid withdrawal in living donor renal transplant recipients using tacrolimus and cyclosporine: a randomized prospective study.

Steroids have been a mainstay of immunosuppressive regimens in renal transplantation despite their adverse effects. The introduction of new immunosuppressant has improved the survival rates and prompted trials of steroid withdrawal. We conducted a randomized prospective study to compare steroid withdrawal at 6 months post-transplant between tacrolimus + mycophenolate mofetil (MMF) (FK group) versus cyclosporine A + MMF (CsA group). Steroid was withdrawn at 6 months post-transplant under the condition of no rejection episode proven by biopsy and maintenance of serum creatinine level <2.0 mg/dl. Fourteen recipients were excluded because of acute rejection within 6 months or protocol violation. Steroid could be tapered off in 62 in FK group and 55 in CsA. Three cases in FK group and five in CsA had acute rejection within another 6 months after steroid withdrawal (P > 0.05). At 12 months, the incidence of post-transplant diabetes was 18.6% vs. 8.0% in FK and CsA group. And hypercholesterolemia was presented in 8.5% vs. 2.0%, hypertension in 47.5% vs. 56.0%, and serum creatinine level 1.18 +/- 0.24 mg/dl vs. 1.18 +/- 0.20 mg/dl, respectively (P > 0.05). Steroid withdrawal may be carried out successfully using both FK and CsA with MMF, but long-term follow-up is necessary.