Improved renal function after conversion from tacrolimus/sirolimus to tacrolimus/mycophenolate mofetil in kidney transplant recipients

BACKGROUND: There is limited data on the potential nephrotoxicity of sirolimus (SRL) and tacrolimus (TAC) in combination. METHODS: We reviewed the course of 97 kidney transplant patients treated with SRL and reduced-dose TAC. Conversion from SRL to mycophenolate mofetil (MMF) was prescribed in a minority (n = 19) for various nonrenal side effects. We compared outcomes of converted patients to those remaining on TAC/SRL (n = 78). RESULTS: TAC levels were increased in converters (P = 0.009). Rejection rates were similar between groups over 18 months (21% vs. 16%, p = ns). Serum creatinine (Cr) and MDRD glomerular filtration rate (GFR) were similar between groups at nadir and six-months, but at 18 months the percent change from six-month Cr was +17% in non-converters vs. -10% in converters (P = 0.004 for the difference). The difference in GFR between groups at 18 months was also significant (P = 0.01). By multivariate analysis, only conversion to MMF was associated with a greater percent change in Cr from 6 to 18 months (P = 0.015). Conversion to MMF also correlated with higher GFR at 18 months independent of rejection, delayed graft function, and ethnicity. CONCLUSIONS: Conversion from TAC/SRL to TAC/MMF led to improved renal function despite increased TAC exposure after conversion.     

Proteinuria in cyclosporine-treated renal transplant recipients

Of 704 renal transplant recipients receiving long-term cyclosporine immunosuppression, 71 patients experienced proteinuria greater than 1 g/24 hr beyond the first month posttransplant. Eight patients displayed transient proteinuria, defined as lasting less than 3 months. In most cases this condition was attributed to biopsy-proved acute rejection. The transient proteinuria cohort experienced good graft outcome--namely, 87.5% one-year and 52.5% five-year actuarial graft survivals, which was similar to that observed in patients without proteinuria. In contrast, 52.4% of the 63 patients with nontransient proteinuria experienced graft loss within a median time of 6.1 months. The one- and five-year actuarial graft survivals in patients with nontransient proteinuria were 75.3% and 37.5%, respectively. Among the 63 patients with nontransient proteinuria, histopathologic diagnosis included chronic rejection in 19, transplant glomerulopathy in 14, acute rejection in 9, glomerulonephritis (GN) in 7 including 2 cases of membranous GN, and nonspecific interstitial fibrosis in 10 cases. Despite the overall poor prognosis for graft survival among the entire cohort of patients with nontransient proteinuria, the seven with allograft GN maintained prolonged graft function. They showed an 83.3% five-year actuarial graft survival versus 31.2% in patients with other causes of proteinuria (P = 0.043). These results suggest that posttransplant proteinuria in CsA-treated renal transplant recipients arises primarily as a consequence of allograft rejection and portends a poor graft outcome.     

Early post‐transplant conversion from tacrolimus to belatacept for prolonged delayed graft function improves renal function in kidney transplant recipients

Prolonged delayed graft function (DGF) in kidney transplant recipients imparts a risk of poor allograft function; tacrolimus may be detrimental in this setting. We conducted a retrospective single center analysis of the first 20 patients converted to belatacept for prolonged DGF as part of a clinical protocol as a novel treatment strategy to treat prolonged DGF. Prior to conversion, patients underwent an allograft biopsy to rule out rejection and confirm tubular injury. The primary outcome was the estimated glomerular filtration rate (eGFR) at 12 months post‐transplant; secondary outcome was the change in eGFR 30 days post‐belatacept conversion. At 1 year post‐transplant, the mean eGFR was 54.2 (SD 19.2) mL/min/1.73 m². The mean eGFR on the day of belatacept conversion was 16 (SD 12.7) mL/min/1.73 m² and rose to 43.1 (SD 15.8) mL/min/1.73 m² 30 days post‐conversion (P<.0001). The acute rejection rate was 20% with 100% patient survival at 12 months post‐transplant. There was one graft loss in the setting of an invasive Aspergillus infection that resulted in withdrawal of immunosuppression and transplant nephrectomy. Belatacept conversion for prolonged DGF is a novel treatment strategy that resulted in an improvement in eGFR. Additional follow‐up is warranted to confirm the long‐term benefits of this strategy.     

Long-term beneficial effect of tacrolimus conversion on renal transplant recipients

OBJECTIVE: Acute rejection, chronic allograft nephropathy, and cyclosporine (CsA) toxicity remain serious problems for renal transplant recipients and may lead to graft loss. We retrospectively analyzed 34 patients whose biopsies revealed acute and/or chronic allograft rejection, or CsA nephrotoxicity, and who converted from CsA to tacrolimus. PATIENTS AND METHODS: From July 1996 through September 2003, CsA was converted to tacrolimus in 34 renal transplant recipients (26 male, 8 female) with renal biopsy at our hospital. Blood pressure and serum creatinine levels were checked monthly and serum cholesterol, triglyceride, and glutamic-pyruvic transaminase (GPT) levels were checked every three months. RESULTS: A consistently stable and better function after conversion was obtained in a significant portion (24, 71%) of patients. A statistically significant decline in serum creatinine and an improvement in the glomerular filtration rate were found at 3 m, 6 m, 12 m, 36 m, and 72 m after tacrolimus conversion. In 85.7% (12/14) of patients with acute rejection and in 35.7% (5/14) of patients with chronic allograft nephropathy (concomitant with acute rejection in 5), improved or stabilized graft function was noted. In addition, the systolic blood pressure and diastolic BP dropped significantly (P<0.05), while there was no significant change in cholesterol, triglyceride, and GPT levels. CONCLUSION: The beneficial effect of tacrolimus conversion on patients with acute rejection, chronic allograft nephropathy, or CsA nephrotoxicity was demonstrated in long-term follow up. The improvement in both renal function and blood pressure may be of paramount importance in reducing long-term cardiovascular morbidity and mortality.     

Kidney function in cyclosporine-treated paediatric pulmonary transplant recipients

BACKGROUND: Lung or heart-lung transplantation is a useful therapy in life-threatening pulmonary disorders during childhood. Cyclosporine A is a major immunosuppressive treatment but has a number of adverse effects including nephrotoxicity. There have been no reports on the long-term evolution of renal function in a large series of paediatric pulmonary transplantation recipients. METHODS: We examined 19 patients followed up for at least 3 years after pulmonary transplantation. The mean time of follow-up was 5.36 years. Kidney function was evaluated by calculation of glomerular filtration rate (GFR) according the Schwartz formula. RESULTS: The GFR was normal before transplantation in all patients. The short-term evolution of GFR was marked by a significant drop during the first and until the 6th month. Then, regardless of the level reached at the end of the 6th month, the GFR remained stable in all patients except one until the end of follow-up. At the end of follow-up, 31% had normal GFR, 57% had mild chronic renal failure, and 5% had advanced renal failure. Hypertension was frequent and associated with renal failure. CONCLUSIONS: Paediatric pulmonary recipients showed evidence of long-term cyclosporine A-associated nephrotoxicity. Most of this toxicity occurred during the first 6 months.     

稳定期肾移植受者将他克莫司普通剂型转换为缓释剂型对移植肾功能的影响

目的观察稳定期肾移植受者由普通剂型他克莫司(Tac)转换为缓释剂型Tac后对移植肾功能的影响。方法回顾性分析山西省第二人民医院2011年12月至2019年6月由普通剂型Tac转换为缓释剂型Tac的83例稳定期肾移植受者,随访12~36个月,同时匹配83例继续服用普通剂型Tac的稳定期肾移植受者作为对照组。观察稳定期肾移植受者由普通剂型Tac转换为缓释剂型Tac后肾功能、谷值浓度个体内变异度(IPV)及依从性的变化、排斥反应的发生率及移植肾和移植受者的存活率。结果普通剂型Tac转换为缓释剂型Tac时间为移植后(42.76±30.50)个月,转换后24个月血清肌酐(SCr)明显低于转换前(P=0.013),估算肾小球滤过率(eGFR)明显高于转换前(P=0.005)。试验组较对照组在转换后36个月SCr明显降低(P=0.017),eGFR明显增高(P=0.038)。试验组转换前免疫抑制剂治疗障碍量表(ITBS)得分为(20.23±2.89)分,转换后为(17.63±3.08)分(P=0.000);Tac每日剂量转换前是(2.09±0.84)mg,转换后为(2.10±0.83)mg;Tac谷值浓度转换前为(7.22±2.84)ng/mL,转换后显著降低,人/肾均健康存活。结论稳定期肾移植受者由普通剂型Tac转换为缓释剂型Tac肾功能保持稳定且较普通剂型Tac相对更好,依从性明显改善,谷值浓度个体内变异度明显降低,长期服用的临床疗效和安全性良好。     

A controlled trial of steroids in cyclosporine-treated renal transplant recipients

In a randomized controlled clinical trial, 117 recipients of a kidney transplant were treated with cyclosporine (15-17 mg/kg/day) either alone or with prednisolone 0.3 mg/kg/day in addition. There were no exclusions and all patients have been followed-up from 14 to 39 months. No differences in the survival of the patients or their transplants were seen between the two groups. Actual survival of first cadaver grafts was 73% at one year in the group receiving cyclosporine alone and 76% in the group with added steroids. Survival of second or third grafts in the steroid group was somewhat worse but not significantly so. All 6 recipients of living-donor grafts are currently alive with good function. Infective complications were significantly less common in the group not receiving routine steroids, and these patients were also at less risk of developing a changed facial appearance. However, half the patients in this group have subsequently required steroids because of previous rejections, and cyclosporine nephrotoxicity has been significantly more common. Nonetheless, we have found no overall advantage in combining cyclosporine with low-dose maintenance prednisolone, and we advise that patients undergoing renal transplantation receive cyclosporine alone in the first instance.     

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.     

Delayed acute rejection episodes in cyclosporine-treated renal transplant recipients.

Of 109 cyclosporine-treated cadaveric renal allograft recipients, 45 were free of acute rejection in the first 4 weeks after transplantation. Eleven of 45 (24%) subsequently had delayed, biopsy-proven first rejection episodes 34-61 days after grafting, often after discharge from the hospital. Delayed rejectors had significantly higher plasma creatinine levels at all times during the first posttransplant month than 34 nonrejectors. Trough serum cyclosporine levels were similar in the two groups, although by the 4th week oral cyclosporine dose was significantly lower in the delayed rejection group. Two-thirds of those patients who had serum creatinine levels greater than or equal to 260 mumol/l at 2 weeks and greater than or equal to 225 mumol/l at 3 weeks had a delayed acute rejection episode. Renal transplant recipients treated with cyclosporine who have serum creatinine levels at or above these levels should be aggressively worked up and closely followed for the development of delayed acute rejection.     

Neoral-to-Gengraf conversion in renal transplant recipients

OBJECTIVE: Our objective was to evaluate the safety, efficacy, and need for dosage adjustments when patients taking the Neoral formulation of cyclosporine are converted to the generic formulation, Gengraf. METHODS: From September 2001 through January 2002, patients receiving follow-up care in the renal transplant clinic at the VA Tennessee Valley Healthcare System were converted from Neoral to Gengraf based on a 1:1 dosing equivalency. Steady-state cyclosporine trough concentrations were obtained both prior to and following Neoral-to-Gengraf conversions. Patients were also monitored for changes in serum creatinine, hospitalization, cyclosporine toxicity, graft rejection, and need for further adjustment in cyclosporine regimen. RESULTS: Forty-one patients were included in data analysis. There were no differences in cyclosporine concentrations (P =.0853) or serum creatinine (P =.4469) following conversion to Gengraf. There were no reports of cyclosporine toxicity, no episodes of graft rejection, and no need for further dose adjustment related to the generic conversion. CONCLUSIONS: Neoral and Gengraf are therapeutically equivalent cyclosporine formulations, such that renal transplant recipients maintained on Neoral can be safely and effectively converted to the Gengraf formulation based on a 1:1 conversion ratio. The use of Gengraf over Neoral within the Veterans Affairs Healthcare System offers a reduced cost alternative but maintains equal efficacy and outcomes.