Alfredo Mota

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transplantation were randomly assigned at 3 months to remain on triple therapy (SRL‐CsA‐ST, n = 215) or to have CsA withdrawn and SRL trough concentrations increased (SRL‐ST, n = 215).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= 430) receiving SRL‐CsA‐ST were randomized at 3 months after transplantation to remain on SRL‐CsA‐ST, or to have CsA withdrawn (SRL‐ST group).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 improvement in renal function with sirolimus after early cyclosporine withdrawal in renal transplant recipients: 2-year results of the Rapamune Maintenance Regimen Study.

Introduction. The purpose of this study was to evaluate early cyclosporine (CsA) withdrawal from a sirolimus (SRL)-CsA-steroid (ST) regimen. Methods. Within 48 hr after transplantation, 525 primary (90%) or secondary (10%) renal allograft recipients with cadaveric (89%) or living (11%) donors received 2 mg of SRL (troughs >5 ng/mL; immunoassay), CsA, and ST. Those eligible (430) were randomly assigned (1:1) at 3 months ± 2 weeks to remain on triple-drug therapy (SRL-CsA-ST group) or to have CsA withdrawn and SRL trough concentrations targeted to 20 to 30 ng/mL (SRL-ST group) until month 12, and 15 to 25 ng/mL thereafter. Results. At 24 months, there were no statistically significant differences in patient survival (94.0% vs. 95.3%), graft survival (91.2% vs. 93.5%), acute rejection after randomization (5.1% vs. 9.8%) or discontinuations (34% vs. 33%) for SRL-CsA-ST versus SRL-ST, respectively. Serum creatinine level was significantly better in patients who had CsA withdrawn (167 vs. 128 &mgr;mol/L, P <0.001), as was the slope of 1/creatinine. Similarly, systolic blood pressure was lower in patients who had CsA withdrawn (141 vs. 134 mm Hg, P <0.001). High-density lipoprotein cholesterol was significantly higher in the SRL-ST group, whereas total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels were not significantly different. Hypertension, creatinine increase, abnormal kidney function, toxic nephropathy, edema, hyperuricemia, cataracts, Herpes zoster, and malignancy were reported significantly more often in patients continuing CsA. Thrombocytopenia, hypokalemia, abnormal liver function tests, abnormal wound healing, ileus, and pneumonia were reported significantly more frequently with SRL-ST. Conclusion. Data at 2 years confirm that early CsA withdrawal followed by an SRL-ST maintenance regimen results in long-term improvement in both renal function and blood pressure, without increased risk of graft loss or late acute rejection.

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 ml/min (quartile 1, n=104), >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 ≤45 ml/min.

Incidence of anemia in sirolimus-treated renal transplant recipients: the importance of preserving renal function

Sirolimus (SRL) has a concentration‐related effect on hematopoiesis. In this study, 430 renal transplant recipients were randomized (1:1) 3 months post‐transplantation to continue SRL‐cyclosporine (CsA)‐steroids (ST) or to have CsA withdrawn (SRL‐ST). Over 5 years, on therapy calculated glomerular filtration rate (GFR), hematological indices, erythropoietin (EPO) use, and rates of mild, moderate, and severe anemia were determined. Longitudinal analyses using linear mixed models examined covariates predicting hemoglobin (Hgb) levels. Mean Hgb was significantly lower with SRL‐ST at 6 months; but subsequently became significantly higher (at 2 years, 129 vs. 135 g/l, SRL‐CsA‐ST vs. SRL‐ST, P < 0.001). Mean corpuscular volume was low with both therapies, and significantly lower with SRL‐ST. EPO use was similar in the two groups, approximately 30% during the first year and 10% thereafter. The incidence of anemia was significantly higher with SRL‐CsA‐ST ≥2 years. At year 5, only 39.1% of SRL–CsA–ST patients had normal Hgb vs. 68.5% of SRL–ST patients. GFR and recipient age as well as the interaction term × treatment time were significant covariates predicting Hgb. CsA withdrawal followed by SRL immunotherapy resulted in significantly less anemia than SRL–CsA–ST, despite twofold higher SRL exposure. This suggests that the improvement in GFR accompanying CsA withdrawal may mitigate the effect of SRL on hematopoiesis.

Health-related quality-of-life outcomes of sirolimus-treated kidney transplant patients after elimination of cyclosporine A: results of a 2-year randomized clinical trial.

Background. This study compared 2-year health-related quality-of-life (HRQL) outcomes of sirolimus (SRL)-treated kidney transplant patients after elimination of cyclosporine A (CsA) to patients continuing on a combined CsA and SRL regimen. Methods. A randomized, open-label, clinical trial was performed in Europe, Australia, and Canada. Four hundred thirty kidney transplant patients were randomly assigned to sirolimus plus steroids (ST) (n=215) or SRL and CsA+ST (n=215) therapy after 3 months of combined SRL+CsA+ST treatment. HRQL was measured using the Kidney Transplant Questionnaire (KTQ) and the SF-36 Health Survey at month 3 (time of randomization) and months 12 and 24 after transplantation. Repeated-measures analysis of covariance was used to evaluate treatment differences in HRQL scores over the 2-year period. Results. HRQL scores were available for 361 (86%) eligible study patients. Statistically significant treatment-by-assessment time interactions, favoring SRL+ST, were found on KTQ Fatigue (P =0.0158) and Appearance scores (P =0.0007). No treatment differences were observed in KTQ Physical Symptom, Uncertainty-Fear, and Emotion scores. Statistically significant treatment-by-assessment time interactions were observed for SF-36 Vitality scores (P =0.0203) but not other SF-36 scores (P >0.05). For Vitality scores, the SRL+ST group remained stable (mean, 0.4-point change) from month 3 to month 24 compared with decreases in the SRL+CsA+ST group (mean, −6.5-point change). Conclusions. SRL-based therapy with early elimination of CsA results in fewer appearance-related problems, less fatigue, and better vitality compared with continuous treatment with SRL, CsA, and ST.

Delayed Renal Graft Function: Risk Factors and Impact on the Outcome of Transplantation

OBJECTIVES The objectives of this study were to determine whether delayed graft function (DGF) implied a higher incidence of poor prognostic markers and to determine its impact on renal transplantation outcomes, particularly graft and patient survivals. METHODS This retrospective study included 997 cadaveric kidney transplantations between January 1, 1996 and December 31, 2007. Two groups were created: immediate diuresis (ID; n = 803; 80.5%) and DGF (n = 194; 19.5%). RESULTS These donor related variables showed significant differences (P < .05): age (ID, 35.20 ± 15.681; DGF, 42.49 ± 16.316), weight (ID, 70.54 ± 12.896; DGF, 74.86 ± 14.402), death cause (stroke: ID, 24.9%; DGF, 42.6%), hourly urinary output (ID, 225.55 ± 168.107; DGF, 187.29 ± 125.623), and creatinine (ID, 1.004 ± 0.3737; DGF, 1.075 ± 0. 4148). The significant recipient-related age (ID, 42.95 ± 13.095; DGF, 45.57 ± 13.138), dialysis time ID, 39.41 ± 38.172; DGF, factors were as follows 56.14 ± 44.243), dialysis type, and comorbidities. The significant transplant-related variables were follows: cold ischemia time (ID, 19.489 ± 4.841; DGF, 21.469 ± 5.297) and surgery duration (ID, 2.549 ± 1.105; DGF, 3.028 ± 1.738). Acute rejection and chronic allograft nephropathy (CAN) were greater among the DGF group (ID, 27.3% and 15.0% and DGF, 55.2% and 34.0%, respectively). Average graft (ID, 127.8 months; DGF, 93.9 months) and patient survival (ID, 143.2 months; DGF, 125.6 months) were higher in patients with ID. Multivariate analysis identified these independent risk factors for graft loss: CAN (hazard ratio [HR], 3.30) and DGF (HR, 2.30) but neither had an influence on patient survival. CONCLUSIONS DGF was associated with multiple risk factors and contributed to worse graft outcomes. It is an independent risk factor for graft loss and an important marker of other factors that affect decisively the outcome of renal transplantation.

Renal transplantation with expanded criteria donors: the experience of one portuguese center

BACKGROUND The shortage of kidneys available for transplantation has led to enlarged criteria donors (ECD): namely, donors older than 60 years or aged between 50 and 59 years with 2 of the following characteristics-hypertension, predonation serum creatinine level higher than 1.5 mg/dL or cerebrovascular disease as the cause of death. The aim of this study was to analyze renal transplants using ECD compared with standard criteria donors (SCD) concerning the incidences of delayed graft function (DGF), acute rejection episodes (ARE), and patient and graft survivals. MATERIALS AND METHODS This retrospective study of 409 cadaveric renal transplants over the last 4 years identified ECD in contrast with SCD. RESULTS Of the transplants, 24.4% used ECD. The baseline characteristics of recipients of ECD versus SCD kidneys were similar, except for age and cold ischemia time. Comparing ECD and SCD, we observed an higher incidence of DGF (35% vs 18%), occurrence of ARE (34.4% vs 16.6%), average serum creatinine levels at 6 (1.87 vs 1.4 mg/dL), and 12 months (1.88 vs 1.43 mg/dL) as well as lower graft survival at 1 (82% vs 91%) and 3 years (75% vs 84%) after transplantation. Recipient survival at 1 year was not different. Multivariate analysis identified recipient age, cold ischemia time, ARE, and DGF as risk factors for graft failure. CONCLUSIONS Renal transplantation with grafts from ECD shows significantly worse outcomes with higher rates of DGF and ARE, worse graft function, and lower graft survival.

Interfacial properties of hypoxanthine adsorbed at the mercuryelectrolyte interface

The adsorption of hypoxanthine on a mercury electrode from sulfate solutions 0.2 and 0.5 M at pH 2.0 and 5.0 is studied. Differential capacity, zero charge potential and maximum surface tension measurements are used to establish the characteristics of the dilute layer. Condensed film formation is reported for first time, detected from differential capacity data at high hypoxanthine concentrations in solutions at pH 5.0. The data for the dilute layer conform to a Frumkin isotherm, contrary to previous findings about a Langmuir isotherm. The data are also analysed following the Nikitas approach and a value for the size ratio parameter close to one is obtained. The discussion in terms of Esin-Markov effect and electrosorption valency in comparison with other aromatic compounds allows some conclusions to be drawn about the orientation of the molecule, the role played by electrostatic and π-electron interactions and the effect of intermolecular interactions.

The Prognostic Value of Pre-implantation Graft Biopsy on the Outcomes of Renal Transplantations

INTRODUCTION The pre-implantation graft biopsy is an important tool for the selection of donors, providing objective information about graft function outcomes. The degree of histological lesions is related to the incidence of delayed graft function (DGF) and long-term survival of the graft. MATERIALS AND METHODS We analyzed 30 graft biopsy specimens by a semi-quantitative evaluation of chronic lesions. We evaluated the clinical characteristics of recipients, the presence of DGF, and the renal function in the immediate posttransplantation period, as well as month 3 and month 6 after transplantation. RESULTS Histological evaluation showed glomerulosclerosis score 0 in 77% versus score of 1 in 23%; fibrosis score 0 in 46.5% versus score 1 in 46.5% and score 2 in 7%; tubular atrophy score 0 in 53.5% versus score 1 in 36.5% and score 2 in 10%; vascular score 0 in 17% versus score 1 in 50% and score 2 in 33%. Approximately 33% of patients displayed DGF and 13% acute rejection episodes. There was a positive correlation between the presence of interstitial fibrosis and serum creatinine values at 3 (P = .01) and 6 months (P = .02). No correlation was observed between graft function and the presence of tubular atrophy, glomerulosclerosis, and vascular changes. CONCLUSION We observed that a large number of graft biopsy specimens (83%) displayed vascular changes related to the age of the donor. Only a minor degree of interstitial fibrosis, was related to better graft function. The presence of tubular atrophy, vascular changes, and glomerulosclerosis showed no impact on short-term graft function.