BK‐Virus and the Impact of Pre‐Emptive Immunosuppression Reduction: 5‐Year Results

A 1‐year, single‐center, randomized trial demonstrated that the calcineurin inhibitor or adjuvant immunosuppression, independently, does not affect BK‐viruria or viremia and that monitoring and pre‐emptive withdrawal of immunosuppression was associated with resolution of BK‐viremia and absence of clinical BK‐nephropathy without acute rejection or graft loss. A retrospective 5‐year review of this trial was conducted. In cases of BK viremia, the antimetabolite was withdrawn and for sustained viremia, the calcineurin inhibitor was minimized. Five‐year follow‐up was available on 97% of patients. Overall 5‐year patient survival was 91% and graft survival was 84%. There were no differences in patient‐survival by immunosuppressive regimen or presence of BK‐viremia. Immunosuppression and viremia did not influence graft survival. Acute rejection occurred in 12% by 5‐years after transplant, was less common with tacrolimus versus cyclosporine (9% vs. 18%; p = 0.082), and was lowest with the tacrolimus‐azathioprine regimen (5%, p = 0.127). Tacrolimus was associated with better renal function at 5‐years (eGFR 63 FK vs. 52 CsA mL/min, p = 0.001). Minimization of immunosuppression upon detection of BK‐viremia was associated with excellent graft survival at 5‐years, low rejection rates and excellent renal function. It is a safe, short and long‐term strategy that resulted in freedom from clinically evident BK‐virus nephropathy.     

Prospective study of polyomavirus BK replication and nephropathy in renal transplant recipients in China: a single‐center analysis of incidence,reduction in immunosuppression and clinical course

Huang G, Chen L‐Z, Qiu J, Wang C‐X, Fei J‐G, Deng S‐X, Li J, Chen G‐D, Zhang L, Fu Q, Zeng W‐T, Zhao D‐Q. Prospective study of polyomavirus BK replication and nephropathy in renal transplant recipients in China: a single‐center analysis of incidence, reduction in immunosuppression and clinical course.
Clin Transplant 2009 DOI: 10.1111/j.1399‐0012.2009.01141.x
© 2009 John Wiley & Sons A/S. Abstract: Background: BK virus (BKV)‐associated nephropathy (BKVAN) in renal transplant recipients is an important cause of renal transplant dysfunction. Our aim was to determine the kinetics of BKV load within one yr after kidney transplantation under the impact of intensive monitoring and reduction in maintenance immunosuppression, the incidence of BKVAN, and the outcome of BKVAN treatment. Methods: Urine and peripheral blood (PB) were taken from 90 renal transplant recipients for BKV cytological testing and real‐time PCR for BKV DNA at one, three, six, nine, and 12 months after transplantation and treatment. Graft biopsies and urinary sediments of recipients with BKVAN were taken to monitor viral particles by conventional transmission electron microscopy (TEM). Results: By one post‐transplant year, urinary decoy cells (median, 8/10 HPF), BKV viruria (median, 2.60 × 10⁵ copies/mL), viremia (median, 9.65 × 10³ copies/mL ) , and BKVAN occurred in 42.2%, 45.6%, 22.2%, and 5.6% of patients, respectively. The incidence of BK infection was lower in patients who received cyclosporine A (CsA) (28.9%) compared to tacrolimus (FK506) (57.7%) (p = 0.007). An increased hazard of BK infection was associated with the use of FK506 (HR 2.6, p = 0.009) relative to CsA. After reduction in immunosuppression, viremia resolved in 95%, without increased acute rejection, allograft dysfunction, or graft loss. BKVAN was diagnosed in five patients (5.6%). The treatment of immunosuppression reduction was effective (i.e., decreased the viral load and number of decoy cells, and improved graft function) in our five patients with BKVAN. Quantitative count of decoy cells (e.g., >10 per 10 HPF) as a marker of viremia and BKVAN had increased positive predictive values of 85.7% and 57.1%, respectively. Conclusions: Choice of FK506 as immunosuppressive agent is an independent risk factor affecting BKV infection. Monitoring and pre‐emptive of immunosuppression reduction were associated with resolution of viremia and showed effective in BKVAN recipients at the early stage without acute rejection or graft loss. Quantitative count of urine cytology is a very convenient, useful, and sensitive method for evaluating BKV infection in renal transplant recipients.     

影响肾移植受者BK病毒感染的危险因素分析

目的 探讨影响肾移植受者BK病毒(BKV)感染的危险因素.方法 选取2006年3月至2007年3月间进行肾移植术的90例受者为研究对象,分别于肾移植术后第1、3、6、9、12个月收集血、尿标本,进行尿沉渣Decoy细胞计数与BK病毒DNA含量的检测,对部分肾移植受者进行移植肾活检.根据尿液BKV DNA是否阳性分成BKV感染组与非感染组.比较2组受者在年龄、性别、术前有无糖尿病、是否为活体肾移植、是否使用抗白细胞介素-2受体单克隆抗体进行诱导、围手术期是否使用多克隆抗体及抗CD3单克隆抗体、术后免疫抑制剂方案、术后是否发生急性排斥反应、移植肾功能恢复延迟及肺部感染等临床指标的差异,应用Logistic回归法分析筛选BKV感染的危险因素.结果 90例肾移植受者尿液Decoy细胞、尿BKV DNA及血BKVA DNA的阳性率分别为42.2%(38/90)、45.6%(41/90)和22.2%(20/90).BKV感染组应用他克莫司(FK506)加霉酚酸酯(MMF)方案的比例为68.3%(28/41),明显高于BKV非感染组40.8%(20/49,P＜0.01).FKS06加MMF的免疫抑制方案是影响肾移植受者BKV感染的独立危险因素(X2=6.579,P=0.01,OR=3.123).确诊BKV相关性肾病(BKVAN)5例.结论 FK506加MMF的组合免疫抑制方案易发生BKV活化及BKVAN,术后受者需进行密切观察并进行相关检测.     

Conversion from cyclosporin to FK 506 after liver transplantation

Thirty-seven liver-grafted patients with steroid-resistant acute or chronic graft rejection or with cyclosporin-related complications were converted from CyA to FK 506. The clinical outcome of the patients primarily depended on the degree of liver dysfunction present at initiation of FK 506 treatment. In patients switched to FK 506 for treatment of acute or early chronic graft rejection, CyA nephrotoxicity, or CyA malabsorption, the FK 506 therapy was associated with a clear improvement in the clinical course. In contrast, in patients with advanced chronic graft rejection, a lower response rate to the conversion in immunosuppression was observed. The lower response rate was associated with a higher patient mortality. These studies demonstrate that FK 506 represents a valuable alternative immunosuppressant for liver-grafted patients. The conversion from CyA to FK 506 should take place before serious — and potentially irreversible — disturbances in liver function are observed.     

Does reduction in immunosuppression in viremic patients prevent BK virus nephropathy in de novo renal transplant recipients? A prospective study

BACKGROUND: BK virus nephropathy (BKVN) is a severe complication of renal transplantation, resulting in graft loss in >50% of cases. Because patients with BKV viremia are at high risk for developing BKVN, the aim of our study was to analyze whether early reduction of immunosuppression (IS) could prevent BKVN in viremic patients. METHODS: BKV viruria was prospectively screened every 3 months by real-time polymerase chain reaction during the first year after transplantation in 123 consecutive renal transplant recipients. Plasma viral load was measured by polymerase chain reaction whenever viruria was positive; in viremic patients a graft biopsy was systematically performed and IS was reduced. RESULTS: Viruria, viremia, and BKVN occurred in 48.8%, 10.5%, and 2.4% of patients, respectively. In the 13 patients with positive viremia, initial graft biopsy showed BKVN in two. After reduction of IS in patients without BKVN, viremia disappeared in 8 of 11, decreased in 2 of 11, and increased in one patient who eventually developed BKVN. In contrast, viremia remained positive in one patient with BKVN and disappeared in the second but renal function deteriorated in both of them. Initial viral load was higher in patients who developed BKVN. CONCLUSION: Reduction of IS is probably an effective therapeutic option to clear viremia and prevent BKVN in viremic renal transplant patients.     

Rescue therapy with tacrolimus (FK 506) in renal transplant recipients -a Scandinavian multicenter analysis

Abstract All renal allograft recipients ( n = 32) in Sweden and Norway who were converted from cy-closporin(CyA)-based immunosuppression to FK 506 (tacrolimus) between October 1992 and June 1995 were analyzed retrospectively. The reasons for conversion were acute refractory rejection ( n = 21), chronic rejection ( n = 4), and suspected CyA toxicity ( n = 6); one patient was converted for psychological reasons. The mean time from transplantation to conversion was 29 (range 1–243) weeks and there was a mean follow-up of 46 (2–143) weeks. Overall graft survival was 59 %, with graft survival 52 % in patients converted because of acute rejection, 50 % in patients converted because of chronic rejection, and 83 % in patients converted because of CyA toxicity. There was no significant correlation between preconversion serum creatinine and outcome. Seventy-two percent of the patients had significant side effects during FK 506 treatment, the most frequent ones being neurological and gastrointestinal symptoms. These improved after dose reduction. Two patients became overimmunosup-pressed and developed lymphoma. One patient died of the primary kidney disease, hemolytic uraemic syndrome. We conclude that FK 506 therapy is able to salvage kidneys with acute refractory rejection and that it is an alternative in patients with CyA toxicity. However, the risk of overimmunosuppression must be considered.     

Steroid withdrawal 3 months after liver transplantation - does FK 506 confer any advantage over cyclosporin?

Abstract Eighty-one liver recipients were randomised to FK 506 Or cyclosporin (CyA) and azathioprine (AzA), both in combination with steroids. Twenty-even FK 506 and 29 CyA/AzA patients continued in the trial 3 months after transplantation. Steroids were ceased in 23 (85%) FK 506 patients and in 27 (93%) CyA patients. After steroid withdrawal, 2 FK 506 and 4 CyA patients were excluded from the study, all for reasons other than rejection. The median follow-up was 16 months for the FK 506, and 19 months for CyA group. There were no acute rejection episodes or graft losses in the FK 506 group. None of the CyA patients lost their graft but three (13%) had episodes of acute rejection requiring steroids to be recommenced in two cases. There was no evidence of chronic rejection in any of the annual review biopsies in either group. Our results suggested no advantage of FK 506 over CyA in its steroid-paring effect.     

Renal Function Impairment in Kidney Transplantation: Importance of Early BK Virus Detection

Background

BK virus allograft nephropathy is a major complication of kidney transplantation that markedly reduces graft survival (50% graft failure 24 months after being diagnosed). BK virus replication can occur at any time posttransplantation. Viruria detection is a signal of virus reactivation and precedes viremia. Only viremia has been related to BK nephropathy. Early detection appears to be important in the prevention of BK nephropathy.

Prospective, Pilot, Open-Label, Short-Term Study of Conversion to Leflunomide Reverses Chronic Renal Allograft Dysfunction

Leflunomide (LEF) is a synthetic isoxazole derivative with anti-inflammatory and antiviral properties, which has been reported to prevent acute rejection and delay progression of chronic allograft nephropathy (CAN) in animal models. We performed a pilot, crossover trial in 22 renal transplant recipients who were converted from azathioprine (AZA) or mycophenolate mofetil (MMF) to LEF in an effort to slow progression of renal dysfunction [deteriorating renal function (n = 5), cyclosporine (CyA) nephrotoxicity (n = 4) or biopsy-proven CAN (n = 13)]. Baseline maintenance immunosuppression consisted of CyA, AZA or MMF and prednisone. Six-month postconversion patient and graft survival was 100% and 91%, respectively. Mean serum creatinine 6months preconversion was 2.2 +/- 0.6mg/dL, at initiation was 3.0 +/- 1.1 mg/dL, and 6 months postconversion was 2.8 +/- 1.3 mg/dL. The rate of change in serum creatinine was 35 +/- 39%/6 months preconversion and -5 +/- 21%/6 months postconversion to LEF (p = 0.003). Two patients discontinued LEF for diarrhea and myalgia. No readmissions, increase in liver function tests, infections or acute rejection episodes occurred. Mean CyA levels did not change, 146 +/- 72 ng/ mL pre-LEF vs. 132 +/- 51 ng/mL post-LEF, p = NS. Conversion to LEF reversed progression of chronic renal allograft dysfunction with minimal toxicity.     

Long-term survival of an extremity composite tissue allograft with FK506-mycophenolate mofetil therapy.

BACKGROUND: High-dose tacrolimus (FK506) monotherapy has significantly prolonged rat hindlimb allograft survival. With an eye toward direct clinical application, we used a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination FK506-mycophenolate mofetil (MMF) treatment. METHODS: Radial forelimb osteomyocutaneous flap transplants were performed between size-matched outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression and 9 animals received a once-daily oral FK506-MMF-prednisone regimen. Rejection was assessed by visual inspection of flap skin and was correlated with serial histopathologic examination of skin biopsy specimens. RESULTS: In all control pigs the flap was completely rejected on day 7. Of the 9 pigs receiving treatment, 3 died from pneumonia on days 29, 30, and 83 without signs of rejection and another died from gastric rupture on day 42 with persistent mild rejection. The remaining 5 animals were free of rejection at the end of the 90-day follow-up period (P < 0.005 vs controls). Overall, 5 pigs had pneumonia, 4 septic arthritis, 3 toe abscesses, and 5 diarrhea and decreased weight gain. CONCLUSIONS: Combination oral FK506-MMF treatment provided a superior antirejection effect but more produced more toxicity than that previously demonstrated with cyclosporin A-MMF therapy in our model. Our results suggest that reduction of FK506 or MMF doses might decrease both infectious and drug-specific side effects while still providing adequate prophylaxis against rejection.     

Prospective Monitoring of Polyomavirus BK Replication and Impact of Pre-Emptive Intervention in Pediatric Kidney Recipients

Polyoma BK virus (BKV)-associated nephropathy (PVAN) is a relevant cause of poor renal allograft survival. In a prospective analysis, we monitored BKV DNA in blood and urine samples from 62 consecutive pediatric kidney recipients. In patients with BKV replication, we analyzed the impact of reduction of maintenance immunosuppression on viral load kinetics and PVAN in patients with BKV replication. BKV-specific immunity was concomitantly evaluated on blood samples of viremic patients, by measuring the frequency of BKV-specific interferon-gamma-producing and cytotoxic T cells, and BKV IgG antibody levels. At a median follow-up of 24 months, BK viruria was observed in 39 of 62 patients, while BK viremia developed in 13 patients (21%). In all viremic patients, immunosuppression reduction resulted in the clearance of viremia, and prevented development of PVAN, without increasing the rate of acute rejection or causing graft dysfunction. As a consequence of immunosuppression adjustment, an expansion of BKV-specific cellular immunity was observed that coincided with viral clearance. We conclude that treating pediatric kidney transplant patients pre-emptively with immunosuppression reduction guided by BKV DNA in blood is safe and effective to prevent onset of PVAN. BKV-specific cellular immunity may be useful to guide this intervention.     

Polyomavirus BK versus JC replication and nephropathy in renal transplant recipients: a prospective evaluation

BACKGROUND: JC virus (JCV) viruria is more common than BK virus (BKV) viruria in healthy individuals but in kidney transplants (KT), polyomavirus nephropathy (PVAN) is primarily caused by BKV. Few cases of PVAN have been attributed to JCV. Systematic studies on JCV replication in KT are lacking. METHODS: Out of a cohort of KT patients screened with urine cytology, patients shedding decoy cells were studied (n=103). Molecular studies demonstrated BKV, JCV, or BKV+JCV shedding in 58 (56.3%), 28 (27.2%), and 17 (16.5%), respectively. Biopsy was performed when decoy cells persisted 2 months or serum creatinine increased >20%. RESULTS: BKV viruria was strongly associated with BKV viremia (93%), PVAN (48%, P=0.01) and graft loss (P=0.03). Higher BKV viremia correlated with graft dysfunction (P=0.01), more advanced histological pattern of PVAN (P<0.0001), and more infected cells in biopsy (P=0.0001). BKV viremia of > or =10,000 copies/mL was significantly associated with histologically confirmed PVAN (P=0.0001). Reduction of immunosuppression lead to disappearance of decoy cells in patients shedding BK (>93%). JCV viruria, was more often asymptomatic (P=0.002) and affected older patients (P=0.02). JCV PVAN was less common (21.4%) and was characterized by sparse cytopathic changes but significant inflammation and fibrosis. JCV viremia was rare (14.2%), transient, and low (mean 2.0E+03/mL). After reduction of immunosuppression decoy cells persisted in >50% of patients with JCV (P=0.0001), but no graft loss occurred. During the period of the current study, the incidence of BKV-PVAN was 5.5% and the incidence of JCV-PVAN was 0.9%. CONCLUSIONS: The data point to significant differences of BKV and JCV biology regarding replication and disease in KT patients, with important implications for screening and management.     

AZA/Tacrolimus Is Associated with Similar Outcomes as MMF/Tacrolimus among Renal Transplant Recipients

There have been several retrospective studies indicating benefits associated with mycophenalate mofetil (MMF) compared to azathioprine (AZA) for renal transplant recipients. However, these analyses evaluated outcomes prior to changes in utilization patterns of concomitant immunosuppression. Recent prospective trials have indicated similar outcomes among patients treated with MMF and AZA. The aim of this study was to evaluate outcomes in a broad group of patients in the more recent era. We evaluated adult solitary renal transplant recipients from 1998 to 2006 with the national SRTR database. Primary outcomes were time to patient death and graft loss, complications and renal function. Models were adjusted for potential confounding factors, propensity scores and stratified between higher/lower risk transplants and concomitant immunosuppression. Adjusted models indicated a modest risk among AZA patients for graft loss (AHR = 1.14, 95% CI 1.07–1.20); however, this was not apparent among AZA patients also treated with tacrolimus (AHR = 0.97, 95% CI 0.85–1.11]. One-year acute rejection rates were reduced for patients on MMF versus AZA (10 vs. 13%, p < 0.01); there were no statistically significant differences of malignancies, renal function or BK virus at 1 year. The primary findings suggest the association of MMF with improved outcomes may not be apparent in patients also receiving tacrolimus.     

Campath-1H诱导在小肠移植免疫抑制中的作用

目的探讨Campath-1H诱导在小肠移植免疫抑制中的作用。方法回顾性总结1例小肠移植患者的临床资料。结果术中采用Campath-1H静脉注射诱导,术后予以FK506加MMF加激素三联免疫抑制方案。Campath-1H诱导后淋巴细胞及白细胞数目明显减少．经提升白细胞治疗和调整免疫抑制剂用量后逐渐恢复正常。术后早期,患者未发生急性排斥反应及移植物抗宿主病（GVHD）,无严重感染症状,患者顺利渡过围手术期,康复出院。结论Campath-1H术中诱导．术后小剂量FK506加MMF加激素三联免疫抑制方案．可有效控制小肠移植术后早期排斥反应和GVHD的发生。     

The status of BK polyomavirus replication in adult renal transplant recipients in northeastern Poland

Purpose

BK polyomavirus (BKV) infection and BKV-associated nephropathy (BKVAN) are among the most important problems in renal transplantation. We aimed to determine the incidence of BK viruria, viremia, and BKVAN in renal transplant recipients in the northeastern part of Poland.

Methods

Urine and blood samples from 126 cadaveric renal transplant recipients were analyzed for BK viruria and viremia using quantitative real-time polymerase chain reaction and the patients were followed prospectively. The diagnosis of BKVAN was established on the allograft biopsy.

Results

Based on the BKV DNA analysis, the patients were divided into three groups: group 1 (n = 89; 70.6%) without viruria or viremia, group 2 (n = 24; 19.1%) with isolated viruria, and group 3 (n = 13; 10.3%) with both viruria and viremia. The presence of BK viremia negatively correlated with time after the transplantation. BK viruria was associated with mycophenolate mofetil daily dose. In group 3 there were four patients (3.2%) with high viremia (>10⁴ genome equivalents [gEq]/mL) and viruria (>10⁷ gEq/mL) loads. Only one patient from this group developed clinical symptoms and had BKVAN in allograft biopsy. In all four cases, the maintenance immunosuppression therapy was based on tacrolimus and steroids.

Conclusion

Prevalence of BKV infection in renal transplant recipients in the northeastern part of Poland is similar to that reported by studies from other countries. We confirm that BK viremia could be predicted by the presence of intense viruria. Time after transplantation and the type of immunosuppression strategy are the most important predictors of BK viremia and viruria in patients after renal transplantation.     

Liver transplantation for primary biliary cirrhosis: influence of primary immunosuppression on survival

INTRODUCTION: Liver transplantation is the only established curative therapy for end-stage primary biliary cirrhosis (PBC). However, the influence of primary immunosuppression on long-term patient and graft survival is still controversial. PATIENTS AND METHODS: Among 1372 patients who underwent liver transplantation from April 1989 to January 2001, 95 (6.9%) suffered from PBC. The primary immunosuppression consisted of cyclosporine (CyA; n = 56) and tacrolimus (FK; n = 39). RESULTS: The median survival of all PBC patients at 5 years was 92% and at 10 years, 90%. There was no difference between the two primary immunosuppression agents. Seven patients died, including five in the cyclosporine group (median = 25 months) and two in the tacrolimus cohort (median = 37 months). One CyA patient group died due to PBC recurrence. Seven patients underwent retransplantation without any difference in primary immunosuppression (CyA 7%; FK 10%). Fifty patients developed an acute rejection episode (CyA 57%; FK 46%); 2 patients, chronic rejection (CyA 2%; FK 4%). Fifty-five patients developed AMA titers after liver transplantation (CyA 66%; FK 46%). Patients presented cyclosporine-based regimens showed significantly (P = .001) more side effects. CONCLUSION: Long-term follow-up after liver transplantation for PBC shows excellent organ and patient survival. The choice of the primary immunsuppressant had no significant influence on patient survival, PBC-related graft loss, or development of acute or chronic rejection episodes.     

Mycophenolate mofetil vs azathioprine in a large population of elderly renal transplant patients.

BACKGROUND: Mycophenolate mofetil (MMF) has been shown to decrease acute rejection episodes after kidney transplantation, and has been associated with better graft and patient survival vs azathioprine (AZA). Previous studies reported a higher risk of death due to infection in elderly recipients treated with MMF-based immunosuppression. METHODS: We analysed 5069 elderly ( > 65 years of age) primary renal allograft recipients treated with either MMF or AZA reported to the Scientific Registry of Transplant Recipients between 1988 and 2000, and compared rates of acute rejection, late acute rejection, graft survival, death-censored graft survival, patient survival and death with a functioning graft. RESULTS: In Cox proportional hazard models, MMF was associated with lower rates of late acute rejection with 12 (RR = 0.72, P = 0.11) and 24 months (RR = 0.50, P = 0.028) of continuous therapy. In univariate analysis (Kaplan-Meier), MMF was associated with improved patient (P = 0.0003) and graft (P<0.0001) survival vs AZA, and trends toward improved patient and graft survival in multivariate analyses. CONCLUSIONS: These findings demonstrate the efficacy of MMF-based immunosuppression in elderly transplant recipients and do not suggest an increased risk of death compared to treatment with AZA.     

肾移植急性排斥后环孢素切换成他克莫司对移植肾的影响

目的 探讨肾移植术后急性排斥发生后环孢素（CsA）切换成他克莫司（FK506）抗排斥治疗对移植肾的影响。 方法 回顾性分析本中心肾移植患者发生病理证实的急性排斥86例,经过抗排斥治疗后有23例由CsA治疗切换成FK506为基础的免疫抑制治疗（FK506组）,63例继续应用CsA为基础的免疫抑制治疗（CsA组）。比较两组临床资料,包括性别、年龄、冷和热缺血时间、淋巴毒、术前群体反应性抗体（PRA）水平、人类白细胞抗原（HLA）错配、血脂、血清肌酐、血尿酸、再次排斥的发生率和移植肾存活等情况。 结果 抗排斥治疗后1年内再次病理证实的排斥率,FK506组显著低于CsA组[1/23（4.35%）比16/63（25.40%）,P = 0.033]。FK506组急性排斥发生后5年内的移植肾存活率为100%,高于CsA组的81.4%。FK506组急性排斥发生后24个月及36个月血尿酸分别为（265.5±147.9） μmol/L和（245.8±88.9） μmol/L,均显著低于CsA组的（428.5±119.3） μmol/L和（441.2±125.3） μmol/L（P < 0.01）。 结论 肾移植术后急性排斥发生后由CsA治疗切换成FK506治疗可降低再次排斥的发生率,而降低血尿酸水平有利移植肾的存活。     

C4d-positive acute humoral renal allograft rejection: rescue therapy by immunoadsorption in combination with tacrolimus and mycophenolate mofetil

OBJECTIVE: We investigated the efficacy of immunoadsorption (IA) in combination with tacrolimus (FK506) and mycophenolate mofetil (MMF) rescue therapy for C4d-positive acute humoral rejection (AHR) of renal transplants. METHODS: Six of 185 cadaveric renal allograft recipients developed AHR at a mean of 4.8 +/- 0.8 days after the operation. C4d deposits were observed in peritubular capillaries (PTC) with accumulation of granulocytes. IA with staphylococcal protein A and FK506-MMF combination therapy were administered. RESULTS: After treatment with IA for 6.3 +/- 1.03 sessions combined with FK506 (0.14 to 0.16 mg.kg(-1).d(-1)) and MMF (1.5 g/d) therapy, renal function recovered in all the patients. The mean duration of treatment to a serum creatinine decrease was 14 +/- 2.9 days. The pre-IA panel reactive antibody reactivity (PRA) peaked at 50.2% +/- 6.1%, and was significantly reduced to 8.3% +/- 2.9% after IA. In four of six patients repeat allograft biopsy revealed a remission of AHR. With a mean follow-up of 18.8 +/- 5.46 months, patient and allograft survival are 100% and renal function remains stable with a mean serum creatinine of 1.2 +/- 0.22 mg/dL. CONCLUSION: The optimal treatment for alloantibody-mediated AHR remains uncertain. Our findings suggest that a therapeutic approach combining IA and FK506-MMF rescue improves the outcome of AHR.