Phase 3 trial Design of the Hepatocyte Growth Factor Mimetic ANG-3777 in Renal Transplant Recipients With Delayed Graft Function.

INTRODUCTION: One-third of kidney transplantation patients experience acute kidney injury (AKI) resulting in delayed graft function (DGF), associated with increased risk of graft failure and mortality. Preclinical and phase 2 data indicate that treatment with ANG-3777 (formerly BB3), a hepatocyte growth factor (HGF) mimetic, may improve long-term kidney function and reduce health care resource use and cost, but these data require validation in a phase 3 randomized controlled trial. METHODS: The Graft Improvement Following Transplant (GIFT) trial is a multicenter, double-blind randomized controlled trial, designed to determine the efficacy and safety of ANG-3777 in renal transplantation patients showing signs of DGF. Subjects are randomized 1:1 to ANG-3777 (2 mg/kg) administered intravenously once daily for 3 consecutive days starting within 30 hours after transplantation, or to placebo. RESULTS: The primary endpoint is estimated glomerular filtration rate (eGFR) at 12 months. Secondary endpoints include proportion of subjects with eGFR >30 at days 30, 90, 180, and 360; proportion of subjects whose graft function is slow, delayed, or primary nonfunction; length of hospitalization; and duration of dialysis through day 30. Adverse events are assessed throughout the study. CONCLUSION: GIFT will generate data that are important to advancing treatment of DGF in this medically complex population.

Hepatocyte Growth Factor Mimetic ANG-3777 for Cardiac Surgery-Associated Acute Kidney Injury.

INTRODUCTION: Nearly one-third of patients undergoing cardiac surgery involving cardiopulmonary bypass (CPB) experience cardiac surgery-associated (CSA) acute kidney injury (AKI); 5% require renal replacement therapy. ANG-3777 is a hepatocyte growth factor mimetic. In vitro, ANG-3777 reduces apoptosis and increases cell proliferation, migration, morphogenesis, and angiogenesis in injured kidneys. In animal models, ANG-3777 mitigates the effects of renal damage secondary to ischemia reperfusion injury and nephrotoxic chemicals. Phase 2 data in AKI of renal transplantation have shown improved renal function and comparable safety relative to placebo. The Guard Against Renal Damage (GUARD) study is a phase 2 proof of concept trial of ANG-3777 in CSA-AKI. METHODS: GUARD is a 240-patient, multicenter, double-blind, randomized placebo-controlled trial to assess the efficacy and safety of ANG-3777 in patients at elevated pre-surgery risk for AKI undergoing coronary artery bypass graft (CABG) or heart valve repair/replacement requiring CPB. Subjects are randomized 1:1 to receive ANG-3777 (2 mg/kg) or placebo. Study drug is dosed via 4 daily intravenous 30-minute infusions. The first dose is administered less than 4 hours after completing CPB, second at 24 ± 2 hours post-CPB, with two subsequent doses at 24 ± 2 hours after the previous dose. RESULTS: The primary efficacy endpoint is percent change from baseline serum creatinine to mean area under the curve from days 2 through 6. Secondary endpoints include change in estimated glomerular filtration rate from baseline to day 30, the proportion of patients diagnosed with AKI by stage through day 5, and the length of CSA-AKI hospitalization. Safety will include adverse events and laboratory measures. CONCLUSION: This phase 2 study of ANG-3777 provides data to develop a phase 3 registrational study in this medically complex condition.

Effect of ferric citrate on serum phosphate and fibroblast growth factor 23 among patients with nondialysis-dependent chronic kidney disease: path analyses.

BACKGROUND: Among patients with nondialysis-dependent chronic kidney disease (NDD-CKD) and iron-deficiency anemia (IDA), ferric citrate increases hemoglobin and iron parameters and reduces serum phosphate and fibroblast growth factor 23 (FGF23), a key phosphate-regulating hormone. We conducted post hoc analyses of a phase 3 trial to explore associations between iron replacement, serum phosphate changes and FGF23 regulation. METHODS: We employed multivariable regression and longitudinal mixed-effects models to identify and confirm, respectively, whether baseline demographic and laboratory variables were associated with ferric citrate-induced changes in serum phosphate or FGF23 concentrations. We employed path analyses to determine whether changes in FGF23 concentrations were mediated via changes in serum phosphate and/or transferrin saturation (TSAT). RESULTS: We analyzed a total of 117 and 115 ferric citrate-treated and placebo-treated patients, respectively. At 16 weeks, ferric citrate significantly reduced serum phosphate versus placebo (P = 0.006) only among patients with elevated baseline serum phosphate (≥4.5 mg/dL) and did not reduce serum phosphate among patients with baseline serum phosphate within the population reference range. Ferric citrate reduced intact FGF23 and C-terminal FGF23 partially via changes in TSAT (for C-terminal FGF23) and serum phosphate (for intact FGF23) and partially via unknown/unmeasured mechanisms. CONCLUSIONS: Ferric citrate reduced serum FGF23 concentrations (partially via effects on serum phosphate and iron balance) and did not reduce serum phosphate among patients with baseline serum phosphate concentrations within the population reference range.

Usefulness of Oral Ferric Citrate in Patients With Iron-Deficiency Anemia and Chronic Kidney Disease With or Without Heart Failure.

Patients with chronic inflammatory conditions including chronic kidney disease (CKD) and heart failure (HF) are undertreated with iron-deficiency anemia (IDA). Progressive inflammation and reduced iron transport associated with CKD and HF may reduce the efficacy of oral iron therapy. Oral ferric citrate improves anemia markers in CKD, but its effects in patients with CKD and concomitant HF have not been described. Patients with CKD not on dialysis and IDA from a phase 2 and 3 trial were treated with ferric citrate (n = 190) or placebo (n = 188); patients with HF were identified from medical histories. Hemoglobin response was defined as a ≥10.0-g/L increase in hemoglobin. Changes in hemoglobin, transferrin saturation, ferritin, and serum phosphate from baseline to week 12 and the incidence of adverse events potentially related to HF were evaluated. HF was reported in 22% (n = 81) of patients. The proportion of patients with hemoglobin response to ferric citrate treatment did not significantly differ in patients with and without HF (43% vs 49%, respectively; p = 0.47); changes from baseline in hemoglobin, iron parameters, and serum phosphate were similar. Adverse events potentially related to HF were noted more frequently in patients with HF (ferric citrate, 23%; placebo, 17%) versus those without HF (ferric citrate, 12%; placebo, 11%). In conclusion, these results indicate a potential role for ferric citrate in the treatment of IDA in patients with CKD not on dialysis and concomitant HF.

Safety and efficacy of ferric citrate in patients with nondialysis-dependent chronic kidney disease.

Two randomized, placebo-controlled trials conducted in patients with nondialysis-dependent (NDD) chronic kidney disease (CKD), iron deficiency anemia, and normal or elevated serum phosphorus demonstrated that ferric citrate (FC) significantly increased hemoglobin and decreased serum phosphate concentrations. Pooling these trial results could provide a more robust evaluation of the safety and efficacy of FC in this population. We pooled results of a phase 2 (n = 149) and 3 trial (n = 233) of patients randomized and treated for up to 12 and 16 weeks, respectively. The starting dose in both trials was three 1-g (elemental iron 210 mg) tablets/day with food, up to 12 tablets/day. Doses were titrated in the phase 2 and 3 trials to lower serum phosphate concentrations to a target range (0.97-1.13 mmol/L) and to achieve a ≥10-g/L hemoglobin increase, respectively. Safety was assessed in all patients who received ≥1 dose of FC (n = 190) and placebo (n = 188). Treatment-emergent adverse events (AEs) were reported in 143 of 190 (75.3%) FC-treated and 116 of 188 (61.7%) placebo-treated patients; gastrointestinal AEs were the most frequent (94 [49.5%] vs. 52 [27.7%], respectively). Specific events reported in >5% of patients (FC vs. placebo, respectively) included discolored feces (41 [21.6%] vs. 0 [0.0%]), diarrhea (39 [20.5%] vs. 23 [12.2%]), constipation (35 [18.4%] vs. 19 [10.1%]), and nausea (18 [9.5%] vs. 8 [4.3%]). Twenty FC-treated (10.5%) and 21 placebo-treated patients (11.2%) experienced a serious AE. Two patients (1.1%) died in each group. A pooled efficacy assessment demonstrated a consistent hemoglobin rise and modest serum phosphate decline, with few excursions below the normal range. When used for treatment of patients with NDD-CKD, FC contributes to gastrointestinal AEs at higher rates than placebo, while simultaneously correcting two of the principal metabolic manifestations of CKD (iron deficiency anemia and relative hyperphosphatemia).

Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial.

BACKGROUND: Long-term immunosuppression imposes increased malignancy risk in renal allograft recipients, significantly contributing to overall morbidity and mortality. This study examined malignancy rates in renal allograft recipients at 2 years after conversion to a sirolimus (SRL)-based, calcineurin inhibitor (CNI)-free regimen. METHODS: This open-label, randomized, multicenter study (the CONVERT Trial) randomly assigned 830 patients to SRL conversion (n=555) or CNI continuation (n=275). Patients with history of posttransplant lymphoproliferative disease or known/suspected malignancy within 5 years before screening were excluded. As part of standard safety measurements, subjects were monitored for any malignancy occurrence; both skin and nonskin malignancies were reported, even if the patient discontinued from the therapy. Malignancy rates were analyzed based on exposure time to study drugs (i.e., number of events per 100 person-years of follow-up). RESULTS: At 2 years postconversion, the total number of malignancies per 100 person-years of exposure was significantly lower among SRL conversion patients compared with CNI continuation (2.1 vs. 6.0, P<0.001). Patients undergoing SRL-based, CNI-free therapy had significantly lower rates of the subset of nonmelanoma skin carcinomas through 2 years postconversion (1.2 vs. 4.3, P<0.001). This difference persisted after excluding patients with a history of malignancy before randomization. The rate of all other malignancies was not significantly different between treatment groups (P=0.058). CONCLUSION: In renal allograft recipients, SRL-based immunosuppression was associated with a lower rate of malignancy at 2 years postconversion compared with continuation of CNI-based immunosuppression. This reduction was driven by a significant reduction in nonmelanoma skin carcinoma rates; the rate of all other malignancies was numerically lower but did not achieve statistical significance.

Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial.

BACKGROUND: The efficacy and safety of converting maintenance renal transplant recipients from calcineurin inhibitors (CNIs) to sirolimus (SRL) was evaluated. METHODS: Eight hundred thirty renal allograft recipients, 6 to 120 months posttransplant and receiving cyclosporine or tacrolimus, were randomly assigned to continue CNI (n=275) or convert from CNI to SRL (n=555). Primary endpoints were calculated Nankivell glomerular filtration rate (GFR; stratified at baseline: 20-40 vs. >40 mL/min) and the cumulative rates of biopsy-confirmed acute rejection (BCAR), graft loss, or death at 12 months. Enrollment in the 20 to 40 mL/min stratum was halted prematurely because of a higher incidence of safety endpoints in the SRL conversion arm. RESULTS: Intent-to-treat analyses at 12 and 24 months showed no significant treatment difference in GFR in the baseline GFR more than 40 mL/min stratum. On-therapy analysis of this cohort showed significantly higher GFR at 12 and 24 months after SRL conversion. Rates of BCAR, graft survival, and patient survival were similar between groups. Median urinary protein-to-creatinine ratios (UPr/Cr) were similar at baseline but increased significantly after SRL conversion. Malignancy rates were significantly lower at 12 and 24 months after SRL conversion. Post hoc analyses identified a subgroup with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11, whose risk-benefit profile was more favorable after conversion than that for the overall SRL conversion cohort. CONCLUSIONS: At 2 years, SRL conversion among patients with baseline GFR more than 40 mL/min was associated with excellent patient and graft survival, no difference in BCAR, increased urinary protein excretion, and a lower incidence of malignancy compared with CNI continuation. Superior renal function was observed among patients who remained on SRL through 12 to 24 months, particularly in the subgroup of patients with baseline GFR more than 40 mL/min and UPr/Cr less than or equal to 0.11.

Comparison of sirolimus plus tacrolimus versus sirolimus plus cyclosporine in high-risk renal allograft recipients: results from an open-label, randomized trial.

BACKGROUND: The efficacy and safety of sirolimus (SRL) plus tacrolimus (TAC) versus SRL plus cyclosporine (CsA) were compared in high-risk renal allograft recipients. METHODS: Evaluable patients (448) were randomly assigned (1:1) before transplant to receive SRL+TAC or SRL+CsA with corticosteroids. Eligible patients were black and/or repeat transplant recipients, and/or those with high titer of panel-reactive antibodies. RESULTS: Demographics were similar between groups. Both treatments demonstrated equivalent efficacy of the composite endpoint at 12 months with efficacy failure rates of 21.9% vs. 23.2% (SRL+TAC vs. SRL+CsA, respectively, 95% CI -10.0 to 7.1, P=0.737). Biopsy-confirmed acute rejection rate (13.8% vs. 17.4%) and graft survival rate (89.7% vs. 90.2%) were similar (SRL+TAC vs. SRL+CsA, respectively). In evaluable patients (received at least 1 dose of study drug), renal function (calculated Nankivell glomerular filtration rate) was not superior in SRL+TAC versus SRL+CsA (54.5 vs. 52.6 mL/min, P=0.466); however, in on-therapy patients, glomerular filtration rate was significantly higher in SRL+TAC at most time points. At 12 months, there were no significant differences in rates of death, discontinuation because of adverse events, hypercholesterolemia, hyperlipemia, or proteinuria. Diarrhea and herpes simplex infections occurred significantly more often in SRL+TAC patients. Hypertension, cardiomegaly, increased creatinine, overdose (primarily calcineurin inhibitor toxicity), acne, urinary tract disorders, lymphocele, and ovarian cysts occurred significantly more often in SRL+CsA patients. CONCLUSIONS: This study demonstrated that SRL-based therapy was efficacious in high-risk renal allograft recipients in the first year after transplant, providing equivalent efficacy with CsA or TAC, similar graft survival, low biopsy-confirmed acute rejection rates, excellent renal function, and an acceptable safety profile.

Accuracy and variability of equations to estimate glomerular filtration rates in renal transplant patients receiving sirolimus and/or calcineurin inhibitor immunosuppression.

Measured glomerular filtration rates (mGFRs) were obtained by (99)mTc-DPTA, (125)I-iothalamate, iohexol, (51)Cr-EDTA, non-radiolabeled iothalamate, or inulin clearance from centers agreeing to perform mGFR in six completed and one ongoing Wyeth Research multicenter trials evaluating sirolimus (SRL) in regimens with or without a calcineurin inhibitor (CNI). Estimated GFRs (eGFRs) were calculated by the Cockcroft-Gault (eGFR(CG)), Nankivell (eGFR(NK)), and simplified Modification of Diet in Renal Disease (eGFR(MDRD)) equations. Bias, precision, and accuracy for each of these equations were estimated by tertiles and by regimen. For the Rapamune Maintenance Regimen (RMR) trial, eGFR outcomes were also compared between treatments {[SRL-cyclosporine (CsA) versus SRL]} using the three eGFR formulas. In the lowest mGFR tertile (6-40 ml/min), eGFR(MDRD) gave the best accuracy with the least bias whereas eGFR(NK) and eGFR(CG) performed better in the highest mGFR tertile (58-139 ml/min). At 24 months in the RMR study, mean differences in eGFR between treatments were 13.6, 14.2, and 13.5 ml/min/1.73 m(2) for eGFR(CG), eGFR(NK), and eGFR(MDRD), respectively, favoring CsA withdrawal (P-values for all <0.001). The accuracy of the three eGFR equations was affected by mGFR range but not by immunosuppressive regimens utilizing SRL, SRL-CNI or CNI-based therapy.

Factors influencing glomerular filtration rate in renal transplantation after cyclosporine withdrawal using sirolimus-based therapy: a multivariate analysis of results at five years.

Changes in calculated glomerular filtration rate (GFR) from baseline to five yr were analyzed in relation to risk factors among renal transplant recipients. At three months after transplantation (baseline), 430 eligible patients receiving sirolimus (SRL), cyclosporine (CsA), and steroids (ST) were randomly assigned (1:1) to continue SRL-CsA-ST or have CsA withdrawn and SRL trough levels increased (SRL-ST group). For each risk factor, changes from baseline were compared within each treatment using a t-test and between treatments using ANCOVA. Univariate then multivariate robust linear regression analyses were also performed. In the SRL-ST group, changes from baseline were not significantly different for any risk factor. With the exception of cold ischemia time >24 h, GFR values declined significantly for all risk factors in SRL-CsA-ST patients. For all risk factors, except second transplant or cold ischemia time >24 h, renal function was significantly different between groups. By order of significance in the multivariate analysis, treatment (p < 0.001), donor age (p < 0.001), proteinuria (p < 0.001), and biopsy-confirmed rejection (p = 0.010) were significant predictors of GFR change from baseline. In conclusion, patients with risk factors for reduced renal function benefit from SRL maintenance therapy without CsA vs. those remaining on CsA.

Sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation.

Sirolimus (SRL) is a mammalian target of rapamycin inhibitor that, in contrast to cyclosporine (CsA), has been shown to inhibit rather than promote cancers in experimental models. At 3 mo +/- 2 wk after renal transplantation, 430 of 525 enrolled patients were randomly assigned to remain on SRL-CsA-steroids (ST) or to have CsA withdrawn and SRL troughs increased two-fold (SRL-ST). Median times to first skin and nonskin malignancies were compared between treatments using a survival analysis. Mean annualized rates of skin malignancy were calculated, and the relative risk was determined using a Poisson model. Malignancy-free survival rates for nonskin malignancies were compared using Kaplan-Meier estimates and the log-rank test. At 5 yr, the median time to a first skin carcinoma was delayed (491 versus 1126 d; log-rank test, P = 0.007), and the risk for an event was significantly lower with SRL-ST therapy (relative risk SRL-ST to SRL-CsA-ST 0.346; 95% confidence interval 0.227 to 0.526; P < 0.001, intention-to-treat analysis). The relative risks for both basal and squamous cell carcinomas were significantly reduced. Kaplan-Meier estimates of nonskin cancer were 9.6 versus 4.0% (SRL-CsA-ST versus SRL-ST; P = 0.032, intention-to-treat analysis). Nonskin cancers included those of the lung, larynx, oropharynx, kidney, gastrointestinal tract, prostate, breast, thyroid, and cervix as well as glioma, liposarcoma, astrocytoma, leukemia, lymphoma, and Kaposi's sarcoma. Patients who received SRL-based, calcineurin inhibitor-free therapy after CsA withdrawal at month 3 had a reduced incidence of both skin and nonskin malignancies at 5 yr after renal transplantation compared with those who received SRL therapy combined with CsA. Longer follow-up and additional trials are needed to confirm these promising results.

Superior outcomes in renal transplantation after early cyclosporine withdrawal and sirolimus maintenance therapy, regardless of baseline renal function.

BACKGROUND: It has become increasingly important to refine therapeutic strategies according to individual patient characteristics. We evaluated the long-term impact of renal function at the time of withdrawing cyclosporine (CsA) in renal allograft recipients receiving sirolimus (SRL), CsA, and steroids (ST). METHODS: At 3 months+/-2 weeks, 430 of 525 patients were eligible to be randomized to remain on triple-therapy (SRL-CsA-ST, n=215) or to have CsA withdrawn (SRL-ST, n=215). Patients were divided into quartiles according to their baseline (last value before randomization) calculated GFR: 45 to 56 ml/min (quartile 2, n=105), >56 to 67 ml/min (quartile 3, n=112), and >67 ml/min (quartile 4, n=107). All data were included (ITT analysis). RESULTS: At 4 years, calculated GFR for SRL-CsA-ST vs. SRL-ST was 22.1 vs. 37.7 ml/min (P=0.017), 38.6 vs. 56.6 ml/min (P<0.001), 50.7 vs. 66.8 ml/min (P=0.006), and 62.7 vs. 71.4 ml/min (P=0.436), for quartiles 1 to 4, respectively. Death-censored graft loss ranged from 21.2% vs. 7.7% (SRL-CsA-ST vs. SRL-ST, P=0.092) in quartile 1 to 5.5% vs. 1.9% (P=0.618) in quartile 4. The incidence of death and biopsy-confirmed acute rejection also decreased with increasing baseline GFR, but was not significantly different between treatments. Overall, more patients remained on therapy in the SRL-ST group (46.3% vs. 57.9%, P=0.020). CONCLUSIONS: Early and complete withdrawal of CsA from a combination of SRL, CsA, and steroids was preferable to continuing on this regimen, regardless of baseline renal function. The benefit was most marked in patients with a baseline calculated GFR

Early cyclosporine withdrawal from a sirolimus-based regimen results in better renal allograft survival and renal function at 48 months after transplantation.

We report the 48-month results of a trial testing whether withdrawal of cyclosporine (CsA) from a sirolimus (SRL)-CsA-steroid (ST) regimen would impact renal allograft survival. Eligible patients receiving SRL-CsA-ST from transplantation were randomly assigned at 3 months to remain on triple therapy (SRL-CsA-ST, n = 215) or to have CsA withdrawn and SRL trough concentrations increased (SRL-ST, n = 215). SRL-ST therapy resulted in significantly better graft survival, either when including death with a functioning graft as an event (84.2% vs. 91.5%, P = 0.024) or when censoring it (90.6% vs. 96.1%, P = 0.026). Calculated glomerular filtration rate (43.8 vs. 58.3 ml/min, P < 0.001) and mean arterial blood pressure (101.3 vs. 97.1 mmHg, P = 0.047) were also improved with SRL-ST. Differences in the incidences of biopsy-proven acute rejection after randomization (6.5% vs. 10.2%, SRL-CsA-ST versus SRL-ST, respectively) and mortality (7.9% vs. 4.7%) were not significant. SRL-CsA-ST-treated patients had significantly higher incidences of adverse events generally associated with CsA, whereas those in the SRL-ST group experienced greater frequencies of events commonly related to higher trough levels of SRL. In conclusion, early withdrawal of CsA from a SRL-CsA-ST regimen rapidly improves renal function and ultimately results in better graft survival.

Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years.

Graft function and histology are predictive of renal transplant survival. The Rapamune Maintenance Regimen study demonstrated that early cyclosporine (CsA) withdrawal from a sirolimus (SRL)-CsA-steroid (ST) regimen improved renal function and blood pressure. We report the protocol-mandated biopsy findings from that study. Renal transplant patients (n = 430) receiving SRL-CsA-ST were randomized at 3 months after transplantation to remain on SRL-CsA-ST, or to have CsA withdrawn (SRL-ST group). Protocol-mandated biopsies were performed at engraftment and at 12 and 36 months. Two pathologists blindly evaluated 484 biopsies to obtain the Chronic Allograft Damage Index (CADI) scores. At 36 months among patients with serial biopsies (n = 63), the mean CADI score was significantly lower with SRL-ST(4.70 vs. 3.20, p = 0.003), as was the mean tubular atrophy score (0.77 vs. 0.32, p < 0.001). All six components of the CADI score were numerically lower in SRL-ST group; moreover, inflammation and the tubular atrophy scores decreased significantly in the SRL-ST group between 12 and 36 months. The calculated glomerular filtration rate at 36 months was significantly better in the CsA-withdrawal group (54.8 vs. 68.2 mL/min, p = 0.009). In conclusion, withdrawing CsA from the SRL-CsA-ST regimen resulted in improved renal histology and function.

Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal.

Graft function at 6 or 12 mo is positively correlated with renal transplant survival. The 36-mo results of a study that tested whether withdrawing cyclosporine (CsA) from a sirolimus (SRL)-CsA-steroid (ST) regimen would affect renal graft survival are reported. Eligible patients (n = 430) who were receiving SRL-CsA-ST were randomly assigned at 3 mo to remain on SRL-CsA-ST or to have CsA withdrawn (SRL-ST group). At 36 mo, the calculated GFR was significantly better with SRL-ST (47.3 versus 59.4 ml/min; P < 0.001) as was the slope of the GFR (-3.6 versus 0.8 ml/min; P < 0.001). This was accompanied by growing trend for improved graft survival in the SRL-ST group (85.1% versus 91.2%, P = 0.052 at 36 mo; 81.4% versus 91.2%, P = 0.015 in a cumulative data analysis up to 54 mo), despite numerically more biopsy-proven acute rejections after randomization (5.6% versus 10.2%; P = 0.107). Lipid parameters were similar between groups, whereas both systolic and diastolic BP were significantly lower in the SRL-ST group. Investigator-reported hypertension, abnormal kidney function, edema, hyperuricemia, hyperkalemia, gingival hyperplasia, and Herpes zoster occurred significantly more often in SRL-CsA-ST patients. Abnormal liver function test results, hypokalemia, thrombocytopenia, and abnormal healing were reported significantly more often with SRL-ST. The discontinuation rate was significantly higher for SRL-CsA-ST (48% versus 38%; P = 0.041). In conclusion, withdrawing CsA from a SRL-CsA-ST regimen at 3 mo after transplantation resulted in long-term benefits for renal transplant recipients.

The influence of Duffy blood group on renal allograft outcome in African Americans.

BACKGROUND: African American patients demonstrate higher rates of acute allograft rejection and lower kidney-graft survival compared with white patients. Duffy antigen receptor for chemokines (DARC) on red blood cells has been suggested to have an anti-inflammatory role by acting as a "chemokine sink." We investigated the relationship of Duffy blood group type to renal allograft outcome in African American patient population. METHODS: A total of 163 African American kidney-transplant recipients were studied for Duffy blood group status. Patient outcomes were assessed at 6 to 42 months after transplantation and monitored for acute rejection episodes, graft function, and graft survival. RESULTS: A total of 117 (71.8%) patients were Duffy (a-b-), 14 (8.6%) Duffy (a+b-), 21 (12.9%) Duffy (a-b+), and 11 (6.8%) Duffy (a+b+). No significant differences were observed among the groups with respect to median serum-creatinine values or the incidence of biopsy-confirmed acute-rejection episodes. Although only 15.4% of the patients had Duffy (a+) antigen, none lost their allograft during the study period, and Kaplan-Meier graft survival was not significantly different compared to Duffy (a-) group (log-rank test, P=0.12). Duffy (a-b-) patients demonstrated lower allograft survival compared with the other three groups, although statistical significance was not reached (log-rank test P=0.15). Delayed graft function (DGF) was strongly associated with graft failure for only Duffy (a-b-) patients (log-rank test P=0.003). CONCLUSIONS: Duffy (a-b-) patients have lower allograft survival in the presence of DGF. DARC may attenuate the inflammatory effects of DGF by acting as a "chemokine sink," and DARC-negative patients may be more vulnerable to DGF.