环孢素A减量联合骁悉治疗急性环孢素A肾中毒

目的：探讨环孢素A（CsA）对移植肾的早期毒性与其血清浓度的相关性及对急性CaA肾中毒的诊断与治疗。方法：回顾性地对12例肾移植术后发生CsA毒性反应患者的CsA服用量和全血CsA浓度进行分析，拟诊CsA肾毒性反应后联合应用骁悉（MMF）并减少CsA用量，观察肾功能恢复情况，结果：12例发生CsA肾中毒患者的CsA服用剂量均超过8mg/(kg.d)，其中8例（70％）血清CsA谷值浓度超过400μg/L(HPLC法），经过减少CsA用量并联合应用MMF，12例发生CsA肾中毒患者的肾功能都有不同程度的改善，结论：长时间服用CsA剂量过大是引起CsA肾毒性反应的主要原因，减少CsA用量是有效减少CsA对移植肾毒性的有效方法，改硫唑嘌呤为MMF可有效防止因CsA的低剂量而致的排斥反应。     

婴儿原位心脏移植术后早期的免疫抑制治疗一例

目的：总结婴儿原位心脏移植术后早期免疫抑制剂应用的临床经验。方法：为1例患难治性先天性心脏病的8个月龄婴儿施行原位心脏移植术，术后1个月内应用环孢素A（CsA），霉酚酸酯（MMF）及泼尼松预防急性排斥反应，1个月后停用泼尼松，仅用CsA和MMF，原则为小剂量用药。术后监测血CsA浓度、白细胞数及T淋巴细胞亚群，定期行超声心动图、心电图及X线胸片检查，结合临床症状与体征综合判断是否发生排斥反应，同时观察药物的不良反应。结果：受者顺利渡过围手术期，现已存活260d，未发生急性排斥反应及感染。术后1个月内血CsA浓度谷值（G0）维持在0．1664～0．2080μmol／L，2～3个月G，维持在0．1248～0．1664μmol／L，4～6个月G，维持在0．（1832～0．1248μmol／L，7～10个月G0维持在0．0666～0．0998μmol／L。未见药物不良反应。结论：婴儿原位心脏移植术后早期免疫抑制剂应根据婴儿免疫反应的特点，以1：3服给药为主，小剂量、不过多干预为原则。     

应用荧光偏振免疫法监测肾移植患者全血环孢素A浓度的临床评价

应用荧光偏振免疫法(FPIA)对274例肾移植术后患者行2312人次全血环孢素A(CsA)浓度测定。结果分析表明:(1)CsA在三联免疫抑制疗法中的理想治疗窗浓度范围是:术后第1、2、3和4～12个月全血CsA浓度分别为300～430、280～350、180～280和110～250ng/ml;(2)FPIA法具有快速、准确、操作简便,适于批量测定等优点。讨论了肝肾中毒、排斥反应、高危人群及合并用药与全血CsA浓度的关系。     

维拉帕米拮抗肾移植术后免疫抑制剂毒性作用的研究

目的　提高移植肾的远期存活率。　方法　采用特异性单克隆抗体放免方法对 4 4例肾移植术后 2周病人服用维拉帕米 (IPT) 2、3、4周后环孢素浓度及毒副作用进行分析 ,观察排斥反应发生率、环孢素A(CsA)谷值浓度 (C0 )、服用量及毒副反应、血压和心血管并发症、血生化等指标。同期 15例术后未使用维拉帕米者作为对照组。　结果　 4 4例病人服用IPT后与同期对照相比排斥反应发生率并未增加 ,服用IPT 2周后 ,CsA浓度增加 2 5 .5 % ,CsA用量减少 32 .6 % ,药费减少 30 .0 %。CsA毒副反应减轻。　结论　肾移植术后常规使用IPT可以提高CsA浓度 ,减少CsA用量 ,相应节省医疗开支     

西罗莫司替代钙调磷酸酶抑制剂治疗肾移植后慢性移植肾肾病

目的 探讨采用西罗莫司（SRL）替换钙调磷酸酶抑制剂（CNI）治疗肾移植术后慢性移植肾肾病（CAN）的有效性和安全性。方法 在42例肾移植术后发生CAN的患者中，有32例采用以环孢素A（CsA）为主的免疫抑制方案；10例采用以他克莫司（FK506）为主的免疫抑制方案。将患者的CsA或FK506替换为SRL，停用CNI 12h后口服SRL，SRL的初始剂量为4mg，然后改为2mg／d，以后根据SRL的血药谷值浓度调整其使用剂量，使其血药谷值浓度维持在5～8μg／L。药物替换前、后霉酚酸酯和激素的用量不变。所有患者均随访1年，观察血肌酐、肌酐清除率的变化并监测血常规、血糖、血脂、肝功能等指标。结果 SRL替换CNI治疗1年后，25例患者的移植肾功能明显改善，替换治疗3～20周后移植肾功能好转；10例患者的移植肾功能维持稳定；但7例患者的肾功能继续恶化。替换治疗后，患者血肌酐从替换前的（218±14）μmol／L降为（187±11）μmol／L，肌酐清除率从替换前的（0．83±0．03）ml／s升高为（0．90±0．03）ml／s，替换前后比较，差异有统计学意义（P〈0．05）。所有患者均未发生急性排斥反应和肿瘤等不良反应。结论 SRL替换CNI治疗慢性移植肾肾病是安全有效的，该方案的副作用主要是血脂增高。     

环孢素A药代动力学的个体差异对术后早期移植肾功能的影响

目的　探讨服用环孢素A(CsA)的肾移植受者药代动力学特性与术后早期移植肾急性排斥及CsA肾中毒的关系。方法　 4 7例肾移植受者术后服用CsA 6mg·kg-1·d-1,7d后留取服药即刻及服药后 1、2、3、4、5、6、8、10及 12h的血样 ,测定全血CsA浓度 ,计算各自的药代动力学参数。根据检测后 1个月内移植肾功能状况进行分组 ,回顾分析各组受者药代动力学指标的差异。结果　 4 7例肾移植受者中 ,观察期内共有 12例出现急性排斥反应 ,7例出现CsA肾中毒 ,其余 2 8例移植肾功能稳定。急性排斥组CsA吸收半衰期 (T1/2 (a) )、清除半衰期 (T1/2 (e) )、药物清除率 (CL/F)、达峰值时间 (Tmax)及浓度 时间曲线下面积 (AUC)与肾功能稳定组比较 ,差异有显著性 ;CsA肾中毒组的T1/2 (e) 、CL/F、Tmax及AUC与稳定组比较 ,差异均有显著性。结论　通过多点浓度进行CsA的药代动力学检测可以较准确反映肾移植受者的药物暴露剂量强度 ;CsA吸收清除较快的患者 ,容易出现急性排斥 ,而清除慢的患者存在并发CsA肾中毒的危险。     

他克莫司替代环孢素A治疗难治性排斥

目的：观察他克莫司（FK506）替代环孢素A（CsA)治疗肾移植后难治性急性排斥反应的有效性及安全性。方法：10例肾移植患者术后使用CsA,发生急性排斥反应后给予皮质激素冲击和单克隆抗体或抗胸腺细胞球蛋白,治疗无效后,停用CsA,开始给予FK506,服药1周后,根据血中FK506的浓度调整其用量,维持血中FK506的浓度为9－12ug/L。结果：10例患者中有9例急性排斥得到逆转,肾功能恢复正常,1例无效,随访50－350d,9例肾功能恢复者保持持续稳定,结论：FK506替代CsA治疗肾移植术后难治性急性排斥反应是安全,有效的。     

他克莫司治疗移植肾慢性排斥反应的疗效观察

目的：观察他克莫司（FK506）替代环孢素A（CsA)治疗移植肾慢性排斥反应的效果。方法：用FK506替代CsA治疗10例移植肾慢性排斥反应,FK506起始剂量为0．1－0．15mg.kg^-1d^-1,以后根据血中FK506的浓度加以调整,维持浓度在5－10ug/L,结果：6例治疗前血肌酐低于400umol/L的患者经肜FK506治疗后血肌酐水平较治疗前下降,高血压及肾功能不全症状明显改善,随访1年,病情稳定;但4例血肌酐超过400umol/L者治疗无效,结论：对于移植肾慢性排斥反应的早期,用FK506替代CsA治疗具有一定效果。     

一项随机、前瞻性试验:单独环孢素与三联方案用于肾移植的比较

为了评价肾移植术后单独应用环孢素(CsA)是否优于其他免疫抑制方案,他们从1987.3～1989.8对151例肾移植受者随机分为单用CsA组(Ⅰ组,74例)和三联治疗组(Ⅱ组,77例)进行前瞻性试验。Ⅰ组免疫抑制方案:CsA5mg/kg.d静点,4天后按起始剂量15mg/kg.d口服,每3周递减2mg/kg.d,至大约5mg/kg.d时维持,保持CsA全血谷值浓度200～600ng/ml之间(RIA法),若发生2次以上急性排斥或血肌酐进行性升高者加用甲基强的松龙(MP),起始剂量按.8～16mg/d,以后8mg/d维持。Ⅱ组免疫抑制方案:术后头4天CsA按4mg/     

早期排斥对首次尸肾移植受者移植物的影响

导致肾移植术后第1年移植物丧失的最常见原因是急性排斥。然而,很少有人研究急性排斥对移植物后果及功能的影响。为此,他们从1987.6～1990.3对110例首次尸肾移植受者(年龄>10岁)随机分为三联组(Ⅰ组,53例)和四联组(Ⅱ组,57例)进行前瞻性分析。Ⅰ组免疫抑制方案:根据术后尿量,CsA3～4mg/kg.d青点,5天后按5mg/kg.db.i.d口服,头3个月保持CsA全血谷值浓度300～450ng/ml(RIA法),尔后保持100～250ng/ml。Ⅱ组起始应用ALG10mg/kg.d,当SCr<300μmol/L时按如上所     

Cyclosporine plasma levels in renal transplant patients. Association with renal toxicity and allograft rejection

In 69 renal allograft recipients the highest-tolerated dose was given with respect to clinical events but without respect to the CsA plasma level (CsA-PL). The CsA dose was gradually decreased during the first 6-12 months after transplantation, and in some patients even later. The CsA dose after 12 months was 5-8 mg/kg/day and after 18 months 4-6 mg/kg/day, resulting in CsA-PL of 85-140 ng/ml and less than 50-110 ng/ml, respectively. CsA side-effects were usually seen in patients with high CsA-PL, but they were also encountered at levels normally seen in patients without toxicity. In the individual patient, acute CsA nephrotoxicity was associated with a significant rise in CsA-PL. In patients with acute nephrotoxicity a reduction of the CsA dose (mean 24%) was necessary to regain satisfactory renal function. All patients with several consecutive CsA-PL above 1000 ng/ml had hepatotoxicity or nephrotoxicity, or both, associated with severe morbidity and mortality. No difference was found between CsA-PL during acute rejection and during good renal function. The percentage of CsA determinations resulting in plasma levels below 50 ng/ml (the limit of detection) increased with the time of therapy and constituted 22% of all CsA-PL after 6 months of therapy. No rejections were seen later than 5 months after transplantation despite the low CsA-PL in many long-term treated patients. Treatment with high doses of methylprednisolone increased CsA-PL by 223%. Trimethoprimsulphamethoxazole in CsA-treated patients caused increases in serum creatinine levels. Monitoring of trough CsA plasma levels is recommended as a complement to clinical judgment. To avoid most nephrotoxicity and hepatotoxicity we have decided to keep the CsA-PL below 500 ng/ml during the first month, below 250 ng/ml the second month after transplantation, and below 200 ng/ml the third month after transplantation--and in long-term treated patients we now keep the CsA-PL between less than 50 and 150 ng/ml.     

Is There a Therapeutic Range for Monitoring Plasma Cyclosporin in Renal Allograft Recipients?

Sixty-two consecutive adult cadaveric renal allograft recipientshave been monitored by highperformance liquid chromatographyestimations of trough plasma cyclosporin (CsA) concentrationswithin 30 days of transplantation. The CsA estimations duringgraft rejection (mean $ 1 SD 218.6 $ 126.4 ng/ml) were not significantlydifferent from those obtained during stable renal function (232.3$ 172.8 ng/ml), whereas the estimations during episodes of nephrotoxicity(476.0$ 267.3 ng/ml) were significantly greater (P<0.001).During stable renal function 73.7% of estimations were withinthe therapeutic range of 100–350 ng/mI. However, 37.9%of estimations during nephrotoxicity and 76.7% of estimationsduring rejection episodes were also within this range. The therapeutic window for trough plasma CsA estimations isnot clearly defined. It seems that rejection episodes may occurat apparently adequate CsA concentrations, and although mostnephrotoxic episodes are associated with elevated concentrations,acute nephrotoxicity may occur at apparently therapeutic values.However, in this study, some patients at risk of nephrotoxicitywithin 30 days of transplantation were identified as early as7 days post-transplantation by the simple determination of themean trough CsA concentration for days 1–7.     

Effective long-term immunosuppression maintained by low cyclosporine levels in primary cadaveric renal transplant recipients

Nephrotoxicity and cost are the major problems in the use of cyclosporine (CsA) in renal transplantation. Thus, maintenance of CsA levels at the lower limits of the therapeutic range is desirable. The lowest CsA level effective in preventing rejection while avoiding nephrotoxicity has not been defined. We report on 44 primary cadaveric renal transplant recipients treated with a protocol that involved a progressive reduction in the trough CsA levels. CsA was initiated at an oral dose of 15 mg/kg, and this dose was adjusted to achieve serum trough levels, as measured by radioimmunoassay, of 150-200 ng/ml during the first month, 100-150 ng/ml during the second month, 75-100 ng/ml during the third month, and 50-75 ng/ml thereafter. Patient and graft survival at 18 months were 94% and 83.6%, respectively. The mean daily CsA doses were 6.7 +/- 3.1 mg/kg at 6 months, 5.5 +/- 3.2 mg/kg at 12 months, and 4.7 +/- 2.4 mg/kg at 18 months. Corresponding trough serum CsA levels were 94 +/- 59 ng/ml, 64 +/- 22 ng/ml, and 44 +/- 21 ng/ml at 6, 12, and 18 months, respectively. Mean serum creatinine concentrations were 1.8 +/- 0.6 mg/dl at 6 months, 1.7 +/- 0.5 mg/dl at 12 months, and 1.6 +/- 0.5 mg/dl at 18 months. The mean serum creatinine concentration at 18 months was not significantly different from that of 18 conventionally treated primary cadaveric renal transplant recipients (1.6 +/- 0.5 vs. 1.4 +/- 0.4 mg/dl, P = .31). A total of 67% of patients did not have any rejection episodes under this protocol, while 71% of patients never developed CsA nephrotoxicity. No patient was taken off CsA for progressive nephrotoxicity. We conclude that trough serum CsA levels of 50-75 ng/ml, as measured by radioimmunoassay, are sufficient to maintain effective immunosuppression in the long-term management of primary cadaveric renal transplant recipients. These values are much lower than previously recommended, and this approach ameliorates chronic CsA nephrotoxicity.     

Optimizing tacrolimus therapy in the maintenance of renal allografts: 12-month results

BACKGROUND: The determination of optimal tacrolimus (TAC) trough levels is needed to prevent adverse effects of calcineurin inhibitors. METHODS: Stable transplant recipients currently receiving cyclosporine (CsA) were assigned randomly (1:1:1) to continue CsA (target trough level of 50-250 ng/mL); or convert to "reduced" TAC (target trough level 3.0-5.9 ng/mL) or "standard" TAC (target trough level 6.0-8.9 ng/mL). RESULTS: At 12 months, there was a significant improvement in renal function in the reduced TAC versus CsA group with lower serum creatinine (P=0.004) and cystatin C (P<0.001), and higher estimated creatinine clearance (P=0.017). However, there were no statistically significant differences in any renal parameter in the standard TAC versus CsA group. Total and low-density lipoprotein cholesterol were significantly reduced in both TAC groups versus the CsA group (P<0.001). Patient and graft survival and episodes of biopsy-confirmed acute rejection were similar for all treatment groups, and no statistically significant differences were observed between groups in the incidence of new-onset diabetes or cardiac conditions, or in the prevalence of hyperglycemia, hypertension, or hyperlipidemia among patients who did not have these conditions at baseline. Alopecia developed more commonly among TAC-treated patients than CsA-treated patients (P<0.001). CONCLUSIONS: Compared with CsA continuation, conversion to reduced TAC target trough concentrations resulted in significantly improved renal function without increasing the risk of rejection. Conversion to TAC, regardless of target concentration, resulted in improved serum lipid profiles in kidney transplant recipients at 12 months.     

Impact of the variability of cyclosporin A trough levels on long-term renal allograft function.

BACKGROUND: Among renal allograft recipients, there is a considerable variability in cyclosporin A (CsA) trough levels. Some of the CsA metabolites are pharmacologically active. The variability of polyclonal CsA trough levels may contribute to the fact that long-term renal allograft survival is still not satisfactory. In a retrospective, single-centre study, we investigated the influence of the variability of polyclonal CsA trough levels on long-term renal allograft function. METHODS: Patients (n=381) received double immunosuppression consisting of CsA and methylprednisolone (MP). For each patient the CsA coefficient of variation (CCV) and the mean CsA trough level during the observation period (5 years) were calculated. Based on receiver operating characteristic (ROC) analysis, patients were divided into two groups: group I, CCV <28.05%, n=231; group II, CCV >28.05%, n=150. Additionally, patients were divided into three groups according to their mean CsA trough level: group A, <270 ng/ml, n=50; group B, 270-370 ng/ml, n=282; group C: >370 ng/ml, n=49. RESULTS: Compared to group I, patients in group II experienced a higher incidence of acute rejection episodes (40.7% vs 29.4%, P=0.02), reduced 5-year graft survival (81.1% vs 93.3%, P=0.002), and higher serum creatinine levels (1.7+/-1.2 mg/dl vs 1.4+/-0.5 mg/dl, P=0.03). In patients with low mean CsA trough levels, the incidence of acute rejection episodes was elevated (group A vs B, 50.0% vs 30.9%, P=0.008) and 5-year graft survival was reduced (group A vs B, 79.8% vs 89.5%, P=0.005). Multiple logistic regression analysis confirmed that the risk of graft failure within 5 years after transplantation was markedly elevated in group II (RR: 6.2, P=0.013) and in group A (RR: 8.9, P=0.008). Whereas the effect of CCV on 5-year graft survival was still evident in patients with normal or high mean CsA trough levels (>270 ng/ml, 81.9% vs 94.8%, P=0.0005), graft survival was independent from CCV in patients with low mean CsA trough levels (<270 ng/ml, 77.0% vs 81.7%, P=NS). CONCLUSIONS: Both, the intra-individual variability and the mean of polyclonal CsA trough levels influence long-term renal allograft survival. Targeting at sufficiently high mean CsA levels with a low intra-individual variability may help to further improve long-term renal allograft survival.     

Switching cyclosporine blood concentration monitoring from C0 to C2 in children late after liver transplantation

BACKGROUND: Measurement of cyclospoprine (CsA) blood levels at 2 hours after oral administration (C(2)) has been proposed as a better measurement of trough level (C(0)) due to reduced intrapatient variability, acute rejection rate and renal toxicity. The aim of the present study was to assess whether there was any advantage to conversion from C(0) to C(2) CsA blood level monitoring in children late after liver transplantation. We reviewed the data from 44 children more than 1 year after liver transplantation. We measured the daily dose of CsA and the C(0) level before switching versus the daily dose and C(2) level at 6 months after conversion, in addition to the alanine aminotransferase (ALT) activity, creatinine blood concentration, and episodes of acute rejection. RESULTS: Conversion from C(0) to C(2) monitoring was not associated with a significant change in mean daily dose of CsA, mean concentration of creatinine, ALT activity or occurrence of rejection episodes. CONCLUSION: Switching from C(0) to C(2) monitoring did not seem to proffer any benefits for children late after liver transplantation.     

Everolimus and reduced cyclosporine trough levels in maintenance heart transplant recipients

BACKGROUND: Long-term survival of patients after oHTX significantly increased over the last years, but CAV and chronic renal failure due to nephrotoxic side-effects of CNIs still remain unsolved problems. Everolimus has shown to reduce acute cellular rejection and may allow CsA dosage reduction. In this study the effectiveness of Everolimus in combination with CsA dosage reduction in maintenance oHTX immunosuppression and the influence on renal function was tested. METHODS: 37 patients (30 male, 7 female) after oHTX were divided into group A (n = 20) receiving Everolimus in combination with CsA and prednisolone and group B (n = 17) under standard immunosuppression with CsA, MMF and prednisolone. Patients received 1.0 mg to 1.5 mg Everolimus per day and target Everolimus trough levels were between 3 and 8 ng/ml. Death, safety, side effects, BPAR, trough levels, and routine laboratory values especially creatinine levels were monitored over a follow-up period of 8 months retrospectively and statistically evaluated. RESULTS: A significant reduction of CsA dosage (p < 0.001) and a significant CsA trough level reduction (p < 0.001) to a median CsA trough level of 68.5 ng/ml were achieved in group A. Mean Everolimus trough levels were reached within 1 week and 2 months. Renal function was stable in both groups. No statistical differences in BPAR, hospitalization rates or triglyceride levels were observed. Cholesterol levels significantly increased in group B (p = 0.024). CONCLUSION: CsA trough levels and dosage can be significantly reduced in combination with Everolimus without higher rejection rates and with stable kidney function in oHTX patients.     

In renal transplantation blood cyclosporine levels soon after surgery act as a major determinant of rejection: insights from the MY.S.S. trial

BACKGROUND: Target organs express antigens recognized directly by antigen-specific T cells, and their recognition is crucial to precipitate rejection. Then, the earliest T-cell activation is inhibited by cyclosporine A (CsA), the lowest would be the risk of rejection. Here, we aimed to assess this possibility in a large cohort of de novo kidney transplant recipients participating in an ongoing clinical trial, the Mycophenolate Steroid-Sparing (MY.S.S.) Trial. METHODS: Three-hundred-thirty-four patients entered the prospective, multicenter MY.S.S. trial. The main aim of the study was to assess the predictive value of serial evaluation of blood CsA trough concentration (C0) and 2-hour postdose drug (C2) levels alone or in combination, and to identify which is the critical posttransplant measurement to target CsA therapy in order to minimize the risk of acute rejection. A very large number of CsA trough (N= 2236) and C2 (N= 2128) measurements during the first 6 months postsurgery were available for analysis. Patients with delayed graft function were excluded. RESULTS: CsA trough levels measured at day 2 posttransplant were the strongest predictor of acute graft rejection over 6-month follow-up. Levels within 300 to 440 ng/mL were associated with the lowest risk of rejection, while for levels lower than 300 ng/mL, the risk of acute rejection was more than doubled. Higher levels failed to provide any further protection from graft rejection. CsA trough values predicted allograft rejection with an accuracy of 74%, while C2 levels considered alone had no predictive values at all. CONCLUSION: Findings that among serial daily measurements posttransplant those taken as early as at day 2 have by far the highest capacity to predict rejection episodes, underline the need of targeting CsA therapy very early posttransplant with the goal to modulate early enough T-cell activation at the interface between the recipient's blood and the graft where alloimmune response actually initiates.     

Effect of renal allograft dysfunction upon cyclosporine trough levels in host blood

Cyclosporine (CsA) dose adjustment after renal transplantation is generally based on serum, plasma, or whole-blood trough level values. In the face of increased levels, the dosage is reduced in order to prevent CsA-induced nephrotoxicity. There is a paucity of data, however, on the kinetics of CsA in association with dysfunction of the transplanted kidney. This study documents dramatic rises in serum cyclosporine trough levels at the time of rejection crises, as well as following periods of nonimmunological allograft oliguria. Decreases in CsA dosage in such patients failed to result in a significant lowering in trough levels. Therapeutic CsA trough levels were generally at the 70-140 ng/ml level; at the time of rejection, the same doses of CsA resulted in a rise of trough levels to 300-500 ng/ml. As the rejection crises resolved and kidney function improved, the CsA serum trough levels returned to their lower levels. These results suggest that the urinary elimination of CsA and its metabolites may be a key determinant of CsA trough levels, and that the status of renal function at the time of testing must be considered in the interpretation of the data. In support of this observation, the CsA concentrations in 4-6 hr post-CsA-administration urine samples ranged from 400 ng/ml to 4500 ng/ml, as measured by high pressure liquid chromatography. The data suggest that rising CsA trough levels in a previously stable recipient may serve as a valuable early warning index of impending allograft dysfunction (rejection, infection, and obstruction). This appears particularly true during the first 30 days after renal transplantation, when the incidence of rejection is the greatest in this patient population.     

Cyclosporin A toxicity of the renal allograft--a late complication and potentially reversible

Cyclosporin A (CsA) has improved patient and organ graft survival, but the dichotomy of benefit and toxicity is still an issue. In a retrospective analysis of 392 renal transplant recipients we documented CsA nephrotoxicity (striped fibrosis, arteriolar wall hyalinosis) in 28 (7.1%) patients (23 male/5 female) in a follow-up of more than one year post transplantation. Median age at renal transplantation was 41 years (13-60) and the period between transplantation and graft biopsy was 42 months (12-122). Median CsA trough levels (ng/ml) at 12 months post transplantation, at time of graft biopsy and at last follow-up were: 114 (71-265), 130 (78-285), 66 (24-115). The following parameters were assessed at 12 months post transplantation, at time of biopsy and at last follow-up: s-creatinine (micromol/l), Doppler resistive index, systolic and diastolic blood pressure (mm Hg) and the number of antihypertensives. Median s-creatinine at 12 months post transplantation was 150.3 (94.6-247.5), at biopsy 225.4 (121.1-353.6) and at last follow-up 160.0 (106.1-247.5) (p < 0.001 for biopsy vs. last follow-up). Resistive index decreased from 0.70 (0.64-0.88) to 0.68 (0.51-0.84) (p < 0.005), systolic blood pressure from 137 (100-168) to 130 (105-144) (p < 0.05) and the number of patients with more than 4 antihypertensives from 10 to 6 between biopsy and last follow-up, with no acute rejection episodes after modification of immunosuppressive therapy (50% of previous CsA trough level and addition of azathioprine or mycophenolate mofetil). Conclusion: CsA nephrotoxicity occurs late after renal transplantation with increased systolic blood pressure and Doppler resistive index. Reduction of CsA improves renal function, reduces graft resistive index and systolic blood pressure.