肾移植术后应用FK506抗排斥治疗的临床研究

目的　观察ＦＫ５０６ 在肾移植术后抗排斥治疗的效果及副作用。　方法　对肾移植术后单独应用环孢素Ａ（ＣｓＡ）５０ 例和术后应用ＦＫ５０６ ５０ 例（ 术后２４ 小时应用ＦＫ５０６ ４０ 例,ＣｓＡ 中毒后改ＦＫ５０６ １０ 例）患者进行比较。　结果　ＣｓＡ 组发生急性排斥反应（ＡＲ）９ 例,发生率为１８ ％ ,逆转８ 例（８８ ％） ,肾功能在２ ～２６ 天恢复正常３８ 例（７６ ％） ,肺部感染２ 例,泌尿系感染１ 例,肾中毒２例,肝中毒３ 例,高血糖２ 例,腹泻１ 例,摘肾１ 例。ＦＫ５０６ 组ＡＲ４ 例均逆转,肾功能２～１３ 天恢复正常４０ 例（８０％ ）,高血糖１４ 例（２８％ ）,肾中毒２ 例,肝中毒１ 例,腹泻２２ 例（４４％ ）,１ 例因肺部感染、高血糖难以控制仍改用ＣｓＡ。应用ＣｓＡ 肝中毒的１０ 例患者改用ＦＫ５０６ 后肝功能７ ～１６ 天全部恢复正常。　结论　肾移植术后应用ＦＫ５０６ 安全有效,排斥率明显降低,副作用小,但对长期存活的影响及并发症还需进一步观察。     

Male fertility in cyclosporine-treated renal transplant patients

Fertility and potential fertility were evaluated in 9 young men on cyclosporine A therapy following renal transplantation. Semen analysis was normal in most parameters in 8 patients as was testicular hormonal function. Of 4 men who had attempted to impregnate their wives 3 succeeded. Cyclosporine A does not seem to affect adversely fertility in men.     

A comparative study of FK506 granules and capsules in renal transplant recipients

Nine renal transplant recipients in stable systemic condition on FK506 capsules were converted to FK506 granules in order to investigate the safety, efficacy, and pharmacokinetics of the granular formulation of FK506. The study period for the administration of FK506 granules was 4 weeks, and in principle, the oral dose was the same as that of the FK506 capsules. Renal graft function remained stable and no rejection signs were noticed while the patients were taking the granules. The area under the blood concentration-time curve (AUC), the maximum blood level (C_max), and the time to reach C_max (T_max) after FK506 capsules and FK506 granules were, respectively, 93.1 ± 66.4 and 97.0 ± 89.1 ng · h/ml (P = 0.81), 12.7 ± 7.1 and 15.2 ± 11.7 ng/ml (P = 0.39), and 2.0 ± 1.7 and 1.3 ± 0.6 h (P = 0.29). The mean trough blood level during FK506 medication was 4.25 ± 3.42 and 4.02 ± 3.83 ng/ml, respectively, for the capsules and the granules. FK506 granules, a new formulation, showed an efficacy comparable to that of the FK506 capsular formulation. Received: 28 July 1997 Received after revision: 25 November 1997 Accepted: 14 January 1998     

Diabetes as a complication of tacrolimus (FK506) in pediatric renal transplant patients

Three cases of insulin-requiring diabetes mellitus associated with tacrolimus (FK506) therapy in pediatric renal transplant patients are presented. New-onset diabetes mellitus has been reported with tacrolimus therapy post liver and kidney transplants in up to 12% of adult patients, but is thought to be rare in pediatrics. Although insulin requirement with tacrolimus therapy has been occasionally reported in adolescent patients post liver transplant, only a single case in a pediatric kidney transplant recipient has been previously documented. These cases illustrate the significant diabetogenic effect of tacrolimus in pediatric renal transplant patients. As the use of tacrolimus becomes more prevalent in pediatric kidney transplantation, pediatric nephrologists should be aware of this potential complication.     

Pronounced renal vasoconstriction and systemic hypertension in renal transplant patients treated with cyclosporin A versus FK 506

This prospective study investigated hypertension and renal vasoconstriction developing during the 1st year after renal transplantation in patients randomly allocated to treatment with FK 506 (n = 28) or CyA (n = 13). Starting doses were 0.2–0.3 mg/kg per day for FK 506 and 5–8 mg/kg per day for CyA; doses were subsequently adjusted to trough levels (5–15 ng/ml for FK 506 and 100–150 ng/ml for CyA). We compared 24-h ambulatory blood pressure measurement, antihypertensive treatment, serum creatinine, and resistance index (RI), measured by Doppler ultrasound at the level of the interlobar artery. Until month 2 of treatment, FK 506-treated patients had a significantly lower RI (8 %) and better renal graft function, as evidenced by significantly lower serum creatinine values. Some 13 % of FK 506-treated patients, compared to 70 % of CyA-treated patients (P < 0.01), needed additional antihypertensive drugs after transplantation to keep blood pressure stable. FK 506 treatment, at the above-mentioned dosages, was associated with a significantly higher number of infections (urinary tract infection, pyelonephritis, and pneumonia). We conclude that CyA produces greater renal vasoconstriction and systemic hypertension than FK 506, as reflected in higher renal interlobar artery RI values and a greater need for antihypertensive treatment. After 2 months of treatment and a reduction in CyA trough levels, the renal effects (i. e., lower RI and lower creatinine values), but not the systemic hypertensive effects, disappear. Received: 25 March 1997 Received after revision: 25 September 1997 Accepted: 8 October 1997     

肾移植受者应用他克莫司治疗窗浓度的探讨

目的　寻求适合国人肾移植受者他克莫司 (FK5 0 6 )理想治疗窗浓度范围。方法　应用微粒子酶免疫分析法测定 5 8例肾移植患者口服FK5 0 6后 12h的血药谷浓度 ,并观察排斥反应的发生及药物的肾毒性。结果　FK5 0 6的血药浓度 ,术后 1个月为 (13.0± 2 .1) μg/L ,2～ 3个月为 (9.4±1.6 ) μg/L ,3个月以后为 (6 .5± 1.3) μg/L ,比较各时期全血FK5 0 6谷浓度 ,差异均有极显著性 (P <0 .0 1) ;术后发生急性排斥反应 3例次 ,肾毒性 4例次。结论　FK5 0 6具有良好的免疫抑制效果 ,其治疗窗浓度范围 ,术后第 1个月为 11～ 15 μg/L ,第 2～ 3个月为 8～ 11μg/L ;第 3个月后为 5～ 8μg/L ,此浓度范围既能达到满意的免疫抑制效果 ,又能减少FK5 0 6的肾毒性     

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.     

Comparison of short and long-term renal function in liver transplant patients receiving cyclosporin or FK 506

Abstract Long-term renal function was compared in 49 liver recipients [25 patients received cyclosporin (CyA) and 24 patients received FK 5061 followed for a period of 1 year. Creatinine (CR) and glome-rular filtration rate (GFR) pre-transplantation (pre-Tx) and at 1, 3, 5, and 12 months post-Tx were recorded, as well as incidences of hyperkalemia, post-Tx hypertension, and insulin-dependent diabetes mellitus (IDDM) in the two groups. At 1 year post-Tx, the mean Cr had risen from baseline by 56% and 60% in the FK and CyA groups, respectively; the mean GFR had dropped by 32% in FK patients and by 27 % in CyA patients. Acute nephrotoxicity occurred in 1/25 CyA patients (217 required dialysis) and 9/26 FK patients (7/9 required dialysis; 211 were switched to CyA). None remained on dialysis at 3 months. Renal insufficiency persisted at 1 year in 7/16 patients with early toxicity (CyA, 4; FK, 3) and in 3 of the remaining 36 pts ( P < 0.001). Hyperkalemia occurred in 4/25 CyA, and in 12/24 FK patients ( P < 0.025), post-Tx hypertension occurred in 15 CyA, and 7 FK patients ( P < 0.05), and IDDM occurred in 4 CyA and 7 FK patients ( P = ns). FK 506 and CyA, thus, exerted similar chronic renal effects. Although acute renal insufficiency improved upon dose reduction, renal impairment was permanent in some cases.     

Interaction of cyclosporine and FK506 with diuretics in transplant patients

BACKGROUND: The calcineurin inhibitors cyclosporine and FK506 are widely used for immunosuppression in solid organ transplantation. One of the side effects of these agents is renal magnesium wasting. The site of action and molecular mechanism of this effect are not known. We hypothesized that agents such as diuretics that cause renal magnesium wasting through a similar action would not have an additive effect on magnesium deficiency with calcineurin inhibitors. METHODS: The records of 50 heart transplant patients on calcineurin inhibitors were reviewed to determine levels of serum magnesium and required replacement dose of magnesium, diuretic usage, and other laboratory values. RESULTS: Loop diuretics did not change either the magnesium level or magnesium replacement requirements in patients on calcineurin inhibitors. In contrast, the thiazide diuretic resulted in an increase in serum magnesium and a decrease in magnesium replacement. Results were similar when the cyclosporine or FK506 groups were evaluated alone. Patients taking FK506 had lower serum magnesium values and higher requirements for magnesium replacement compared with patients taking cyclosporine. CONCLUSION: We conclude that calcineurin inhibitors and loop diuretics have a similar site of action.     

Two-year follow-up study of the efficacy and safety of FK 506 in kidney transplant patients

Abstract We conducted a 2-year follow-up study of the efficacy and safety of FK 506 in 104 kidney transplant patients at 32 sites in Japan. The initial daily oral dose of FK 506 was 0.3 mg/kg, which was gradually reduced to 0.15 mg/kg by month 10 and remained stable thereafter. The mean trough level of FK 506 in whole blood and the mean serum creatinine level in year 2 were 7.9 ng/ml and 1.9 mg/dl, respectively. Patient and graft survival rates for all patients were 97% and 92%, respectively. Forty-ix patients (44%) experienced rejection episodes, and 84% of these episodes occurred within 3 months after transplantation. The principal adverse reactions to FK 506 therapy were hyperglycaemia, renal dysfunction and hyperkalaemia. Most of these events were dose-dependent, and disappeared or ameliorated following reduction of the FK 506 dose.