Bioavailability of once-daily tacrolimus formulations used in clinical practice in the management of De Novo kidney transplant recipients: the better study.

Multicenter, prospective, observational study to compare the relative bioavailability of once-daily tacrolimus formulations in de novo kidney transplant recipients. De novo kidney transplant recipients who started a tacrolimus-based regimen were included 14 days post-transplant and followed up for 6 months. Data from 218 participants were evaluated: 129 in the LCPT group (Envarsus) and 89 in the PR-Tac (Advagraf) group. Patients in the LCPT group exhibited higher relative bioavailability (Cmin /total daily dose [TDD]) vs. PR-Tac (61% increase; P < .001) with similar Cmin and 30% lower TDD levels (P < .0001). The incidence of treatment failure was 3.9% in the LCPT group and 9.0% in the PR-Tac group (P = .117). Study discontinuation rates were 6.2% in the LCPT group and 12.4% in the PR-Tac group (P = .113). Adverse events, renal function and other complications were comparable between groups. The median accumulated dose of tacrolimus in the LCPT group from day 14 to month 6 was 889 mg. Compared to PR-Tac, LCPT showed higher relative bioavailability, similar effectiveness at preventing allograft rejection, comparable effect on renal function, safety, adherence, treatment failure and premature discontinuation rates.

Uncontrolled donation after circulatory death: A cohort study of data from a long-standing deceased-donor kidney transplantation program.

Despite good long-term outcomes of kidney transplants from controlled donation after circulatory death (DCD) donors, there are few uncontrolled DCD (uDCD) programs. This longitudinal study compares outcomes for all uDCD (N = 774) and all donation after brain death (DBD) (N = 613) kidney transplants performed from 1996 to 2015 at our center. DBD transplants were divided into those from standard-criteria (SCD) (N = 366) and expanded-criteria (N = 247) brain-dead donors (ECD). One-, 5-, and 10-year graft survival rates were 91.7%, 85.7%, and 80.6% for SCD; 86.0%, 75.8%, and 61.4% for ECD; and 85.1%, 78.1%, and 72.2% for uDCD, respectively. Graft survival was worse in recipients of uDCD kidneys than of SCD (P = .004) but better than in transplants from ECD (P = .021). The main cause of graft loss in the uDCD transplants was primary nonfunction. Through logistic regression, donor death due to pulmonary embolism (OR 4.31, 95% CI 1.65-11.23), extrahospital CPR time ≥75 minutes (OR1.94, 95%CI 1.18-3.22), and in-hospital CPR time ≥50 minutes (OR 1.79, 95% CI 1.09-2.93) emerged as predictive factors of primary nonunction. According to the outcomes of our long-standing kidney transplantation program, uDCD could help expand the kidney donor pool.

The impact of darbepoetin alfa in early post-transplant anaemia management: retrospective exploratory study.

BACKGROUND AND OBJECTIVES: The use of darbepoetin alfa in the first week of post-renal transplant (RT). METHODS: Retrospective observational study carried out in four hospitals, which included all adult patients that underwent RT for 9 months with haemoglobin data during the first 6 months of post-transplant (n=129). Darbepoetin alfa was administered in accordance with the clinical practice. RESULTS: Darbepoetin alfa was administered in the first week to 60 individuals (46.5%), who had a mean baseline Hb (± standard deviation) of 12.7 g/dl ± 1.6g/dl. Anaemia incidence (Hb<11 g/dl) during the first month was higher in patients who did not receive darbepoetin alfa (40.6% vs. 25.0% in patients treated with darbepoetin alfa, P=.045). No anaemia incidence differences were observed during months +2 to +6. There was a tendency towards transfusion decrease in patients who received darbepoetin alfa (13.3% vs. 20.3%, P=.295). Renal recovery time was similar but in the subgroup which received grafts from donors with asystole there was a tendency towards a faster recovery with darbepoetin alfa (15.1 ± 7.7 vs. 20.1 ± 8.8 days, P=.157). The creatinine clearance rate at 3 and 6 months was similar. Fourteen patients (10.9%) suffered from cardiovascular events with no relation to darbepoetin alfa (P=.772). CONCLUSIONS: Administering darbepoetin alfa in the first week following renal transplant reduces anaemia incidence during the first month without increase cardiovascular events.

Impacto de darbepoetina alfa en el manejo de la anemia precoz postrasplante renal: estudio retrospectivo exploratorio / The impact of darbepoietin alfa in early post-transplant anaemia management: retrospective exploratory study

Antecedentes y objetivos: Se ha evaluado el uso de darbepoetina alfa en la primera semana postrasplante renal (TR). Métodos: Estudio observacional, retrospectivo, realizado en cuatro hospitales, que incluyó todos los pacientes adultos que fueron sometidos a TR durante un período de 9 meses con los datos de hemoglobina (Hb) durante los primeros 6 meses postrasplante (n = 129). Darbepoetina alfa fue administrada de acuerdo con la práctica clínica. Resultados: Se administró darbepoetina alfa en la primera semana a 60 individuos (46,5 %), los cuales presentaban una Hb media (± desviación estándar) basal de 12,7 ± 1,6 g/dl. La incidencia de anemia (Hb < 11 g/dl) durante el primer mes fue superior en los pacientes que no recibieron darbepoetina alfa (40,6 % vs. 25,0 % en los pacientes tratados, p = 0,045). No se observaron diferencias en la incidencia de la anemia entre los meses +2 a +6. Hubo una tendencia hacia la disminución de transfusiones en los pacientes que recibieron darbepoetina alfa (13,3 % vs. 20,3 %, p = 0,295). El tiempo de recuperación renal fue similar, pero, en el subgrupo que recibió injertos procedentes de donantes en asistolia, hubo una tendencia hacia una recuperación más rápida con darbepoetina alfa (15,1 ± 7,7 vs. 20,1 ± 8,8 días, p = 0,157). El aclaramiento de creatinina a los 3 y 6 meses fue similar. Catorce pacientes (10,9 %) sufrieron un evento cardiovascular, sin relación con darbepoetina alfa (p = 0,772). Conclusiones: La administración de la darbepoetina alfa en la primera semana tras el trasplante renal reduce la incidencia de anemia durante el primer mes, sin aumentar los eventos cardiovasculare (AU)

Background and objectives: The use of darbepoetin alfa in the first week of post-renal transplant (RT). Methods: Retrospective observational study carried out in four hospitals, which included all adult patients that underwent RT for 9 months with haemoglobin data during the first 6 months of post-transplant (n=129). Darbepoetin alfa was administered in accordance with the clinical practice. Results: Darbepoetin alfa was administered in the first week to 60 individuals (46.5%), who had a mean baseline Hb (±standard deviation) of 12.7g/dl±1.6g/dl. Anaemia incidence (Hb<11g/dl) during the first month was higher in patients who did not receive darbepoetin alfa (40.6% vs. 25.0% in patients treated with darbepoetin alfa, P=.045). No anaemia incidence differences were observed during months +2 to +6. There was a tendency towards transfusion decrease in patients who received darbepoetin alfa (13.3% vs. 20.3%, P=.295). Renal recovery time was similar but in the subgroup which received grafts from donors with asystole there was a tendency towards a faster recovery with darbepoetin alfa (15.1±7.7 vs. 20.1±8.8 days, P=.157). The creatinine clearance rate at 3 and 6 months was similar. Fourteen patients (10.9%) suffered from cardiovascular events with no relation to darbepoetin alfa (P=.772). Conclusions: Administering darbepoetin alfa in the first week following renal transplant reduces anaemia incidence during the first month without increase cardiovascular events (AU)

Serum level of fibroblast growth factor 23 in maintenance renal transplant patients.

BACKGROUND: The discovery of fibroblast growth factor 23 (FGF23) provides a new conceptual framework that improves our understanding of the pathogenesis of post-transplant bone disease. Excess FGF23 is produced in the early post-transplant period; levels return to normal in the months following transplant. However, few manuscripts discuss FGF23 levels in stable long-term renal transplant recipients. METHODS: We performed a cross-sectional observational study of 279 maintenance kidney recipients with chronic kidney disease (CKD) Stages 1-4 and stable allograft function who had received their transplant at least 12 months previously. We calculated the estimated GFR (eGFR) using the MDRD4 equation. RESULTS: FGF23, parathyroid hormone (PTH) and phosphorus values were higher in more advanced stages, while the serum calcitriol levels and the phosphate reabsorption rate were lower. A significant inverse correlation was found between eGFR and FGF23 (r = -0.487; P < 0.001), PTH (r = -0.444; P < 0.001), serum phosphate levels (r = -0.315; P < 0.001) and fractional excretion of magnesium (r = -0.503; P < 0.001). Multivariable analysis showed that increased time on corticosteroids (P < 0.001), PTH (P < 0.001), serum phosphate (P = 0.003), decreased serum calcitriol (P = 0.049) and estimated glomerular filtration (P = 0.003) rate were associated with high FGF23 levels. In contrast with pre-transplant patients and first year post-transplant patients, higher FGF23 values were not correlated with increased phosphate excretion. An elevated phosphate reabsorption rate was associated with decreased PTH (P < 0.001) and calciuria (P = 0.028) and increased serum calcitriol (P = 0.009), plasma bicarbonate (P = 0.024) and estimated glomerular filtration (P = 0.003). CONCLUSIONS: Serum FGF23 concentrations remain increased in long-term kidney graft recipients, even in the early stages of CKD. It remains to be seen whether measures aimed at reducing serum levels of PTH and phosphate and/or corticosteroid doses might help to lower serum FGF23 and whether this will improve kidney recipient outcomes.

Limited-sampling strategy for mycophenolic acid in renal transplant recipients reciving enteric-coated mycophenolate sodium and tacrolimus.

BACKGROUND: Substantial research has been conducted to develop limited-sampling strategies (LSS) to estimate the area under the curve (AUC(0-12h)) in patients treated with mycophenolate mofetil. However, no LSS has been validated for enteric-coated mycophenolate sodium (EC-MPS). Our aim was to develop an LSS to measure the AUC(0-12h) of mycophenolic acid in kidney recipients treated with tacrolimus and EC-MPS. STUDY DESIGN: Thirteen serial blood samples were collected over 12 hours from 71 patients treated with tacrolimus and EC-MPS. Mycophenolic acid was measured in plasma using the enzyme-multiplied immunoassay. LSSs were developed and validated by multiple regression analysis using a 2-group method (test, n = 47; validation, n = 24). RESULTS: The best LSS obtained in the test group were for 3 and 4 time points AUC(0-12h) (mg·h(-1)·L(-1)) = 15.99 + 0.87C1 h + 0.68C2 h + 7.85C4 h and AUC(0-12h) (mg·h(-1)·L(-1)) =11.15 + 0.68C1 h + 0.45C1.5 h + 0.57C2 h + 8.16C4 h, respectively. When these LSS were tested in the validation group, the results were acceptable (adjusted r(2) = 0.71, bias =-0.214 [95% confidence interval (CI): -7.91 to 7.48], precision = 7.48 (95% CI: 3.69-19.39) for 3 time points and adjusted r(2) = 0.76, bias = -1.48 (95% CI: -8.23 to 5.27), precision = 7.68 (95% CI: 4.23-13.50) for 4 time points). CONCLUSIONS: : An LSS using time points at C(1h)-C(2h)-C(4h) or C(1h)-C(1.5h)-C(2h)-C(4h) provides the most reliable and accurate estimation of the AUC(0-12h) of mycophenolic acid in stable renal transplant recipients treated with EC-MPS and tacrolimus.

Everolimus as primary immunosuppression in kidney transplantation: experience in conversion from calcineurin inhibitors.

BACKGROUND: We analyzed our clinical experience with everolimus (EVL) and identified prognostic factors for a successful conversion. METHODS: Retrospective study of 220 kidney recipients consecutively converted to EVL with calcineurin inhibitor elimination. We studied risk factors for proteinuria at 1 year after conversion, decline in renal function, and graft survival. RESULTS: Baseline creatinine clearance was 52.4±17.8 mL/min vs. 53.4±20.1 mL/min 1 year after conversion (P=0.150). Median proteinuria increased from 304 mg/day (interquartile range 160-507) to 458 mg/day (interquartile range 238-892; P<0.001). Risk factors for development of proteinuria ≥900 mg/day (P75) at 1-year postconversion were creatinine clearance less than 60 mL/min (odds ratio [OR] 3.37; 95% confidence interval [CI]: 1.15-9.89), serum triglycerides ≥150 mg/day (OR 4.35; 95% CI: 1.70-11.17), no treatment with prednisone (OR 3.04; 95% CI: 1.22-7.59), baseline proteinuria ≥550 mg/day (OR 10.37; 95% CI: 3.99-26.99), and conversion ≥3 years after transplant (OR 5.77; 95% CI: 1.89-17.59). An interaction was observed between baseline proteinuria and time to conversion: in patients with baseline proteinuria ≥550 mg/day, the risk of developing proteinuria ≥900 mg/day was 77.1% if they were converted after ≥3 years posttransplant. However, this risk was 29.8% in the subgroup converted before (P=0.02). Actuarial graft survival at 1 and 4 years postconversion was 98.2% and 86.5%, respectively. Baseline proteinuria ≥550 mg/day was a risk factor for graft loss in patients converted after the third year but not in patients converted before this time. EVL discontinuation rate was 24% in the first year postconversion. CONCLUSIONS: Conversion to EVL and elimination of calcineurin inhibitors is safe. Success depends on not making late conversions and not converting patients with high baseline proteinuria.

Early statin use is an independent predictor of long-term graft survival.

Background. Statin use in renal transplantation has been associated with a lower risk of patient death but not with an improvement of graft functional survival. The aim of this study is to evaluate the effect of statin use in graft survival, death-censored graft survival and patient survival using the data recorded on the Spanish Late Allograft Dysfunction Study Group.Patients and methods. Patients receiving a renal allograft in Spain in 1990, 1994, 1998 and 2002 were considered. Since the mean follow-up in the 2002 cohort was 3 years, statin use was analysed considering its introduction during the first year or during the initial 2 years after transplantation. Univariate and multivariate Cox regression analyses with a propensity score for statin use were employed to analyse graft survival, death-censored graft survival and patient survival.Results. In the 4682 evaluated patients, the early statin use after transplantation significantly increased from 1990 to 2002 (12.7%, 27.9%, 47.7% and 53.0%, P < 0.001). Statin use during the first year was not associated with graft or patient survival. Statin use during the initial 2 years was associated with a lower risk of graft failure (relative risk [RR] = 0.741 and 95% confidence interval [CI] = 0.635-0.866, P < 0.001) and patient death (RR = 0.806 and 95% CI = 0.656-0.989, P = 0.039). Death-censored graft survival was not associated with statin use during the initial 2 years.Conclusion. The early introduction of statin treatment after transplantation is associated with a significant decrease in late graft failure due to a risk reduction in patient death.

Relationship between residual renal function, inflammation, and anemia in peritoneal dialysis.

In peritoneal dialysis (PD) patients, we analyzed the relationship between residual renal function (RRF) and well-known predictors of mortality such as anemia, inflammation, and nutrition. We also investigated possible associations between the foregoing parameters and cardiovascular comorbidity, peritoneal transport rate, statin and antihypertensive treatments, and ultrafiltration volume. Our study enrolled 24 patients (17 men, 7 women; mean age: 56 +/- 12 years) who had started PD at our hospital between 1998 and 2004. Patients who had been hospitalized or had had peritonitis before the study were excluded. Nutrition status, inflammation, anemia, RRF and dialysis adequacy were assessed after 1-2 months. We found that RRF was positively correlated with normalized protein equivalent of nitrogen appearance (nPNA: r = 0. 52, p = 0. 03) and negatively correlated with C-reactive protein (CRP: r = -0.47, p < 0.01) and peritoneal ultrafiltration (r = -0.42, p < 0.05). Only the nPNA and CRP correlations remained statistically significant on multivariate logistic regression analysis (CRP: r = 0.8, p = 0.011; nPNA: p = 0.013). Moreover, as compared with patients without inflammation, patients with inflammation had significantly lower hemoglobin (Hgb) levels (11.8 +/- 1.1 g/dL vs. 13.2 +/- 1.2 g/dL, p < 0.02), serum prealbumin levels (27.3 +/- 8 mg/dL vs. 36.6 +/- 9 mg/dL, p < 0.05), and serum transferrin levels (168 +/- 34 mg/dL vs. 202 +/- 31 mg/dL, p < 0.05), and a higher erythropoietin resistance index (ERI: 10 +/- 4 vs. 6 +/- 3.5, p < 0. 02). We observed no differences in RRF or nutrition status between the patients with high and with low peritoneal transport. Regarding comorbidity, patients with pre-existing cardiovascular disease had higher CRP levels (0.8 +/- 0.4 mg/dL vs. 0.4 +/- 0.4 mg/dL, p < 0.05) and lower mean Hgb levels (13.3 +/- 1 g/dL vs. 14.4 +/- 1 g/dL, p < 0.05) than did patients without such pre-existing disease. A strong, predictable association exists between RRF and inflammation and nutrition status in incident patients on PD. Serum CRP is a good indicator of inflammation, which correlates well with nutrition status, anemia, and responsiveness to erythropoietin therapy.

Victims of cardiac arrest occurring outside the hospital: a source of transplantable kidneys.

BACKGROUND: The use of non-heart-beating donors could help shorten the list of patients who are waiting for a kidney transplant. Several reports describe acceptable results of transplantations from non-heart-beating donors who had in-hospital cardiac arrest, but few reports describe results of transplantations from non-heart-beating donors who had cardiac arrest that occurred outside of the hospital (Maastricht type I and type II donors). OBJECTIVE: To compare graft survival rates among patients receiving kidneys from heart-beating donors versus type I or type II non-heart-beating donors. DESIGN: Retrospective cohort study of transplantations performed from January 1989 to December 2004. SETTING: Kidney transplant program of a teaching hospital in Madrid, Spain. PATIENTS: 320 patients who received a kidney transplant from non-heart-beating donors (273 type I donors and 47 type II donors) and 584 patients who received a kidney transplant from heart-beating donors divided into 2 groups according to donor age (age <60 years [n = 458] and age > or =60 years [n = 126]). MEASUREMENTS: The primary outcome measure was graft survival. The median follow-up time was 68 months (range, 9 to 198 months). RESULTS: One- and 5-year graft survival rates were 90.7% and 85.5%, respectively, for transplants from heart-beating donors younger than 60 years of age; 79.8% and 73.3%, respectively, for transplants from heart-beating donors 60 years of age or older (P < 0.001); and 87.4% and 82.1%, respectively, for transplants from non-heart-beating donors (P = 0.22 [vs. those from heart-beating donors < 60 years of age] and P = 0.014 [vs. those from heart-beating donors >or = 60 years of age]). Graft survival did not differ between patients who received kidneys from heart-beating donors younger than 60 years of age and patients who received kidneys from non-heart-beating donors. LIMITATIONS: This single-site, observational study was retrospective, and immunosuppressive therapy regimens given to transplant recipients varied over time. CONCLUSIONS: Outcomes of transplants from non-heart-beating donors and younger heart-beating donors are similar, and results for transplants from non-heart-beating donors improved compared with those from older heart-beating donors. On the basis of these results, the authors encourage other transplant units to adopt the use of type I and type II non-heart-beating donors.

Effects of angiotensin II receptor blocker (irbesartan) on peritoneal membrane functions.

Angiotensin II receptor blockers (ARBs) are effective in controlling blood pressure and have been shown to reduce proteinuria with fewer adverse effects than angiotensin converting enzyme inhibitors. In the present prospective study, we evaluated the action of irbesartan, an ARB with a long half life, on proteinuria, peritoneal protein losses, and peritoneal transport in patients with chronic renal failure (CRF) undergoing peritoneal dialysis (PD). We enrolled 15 stable patients (11 with diuresis of more than 500 mL/day; 40% women; 40% with diabetes) into the study. Mean age of the patients was 65 +/- 15 years, and mean time on PD was 33 +/- 21 months. The study was performed in two stages. In stage I, patients received no irbesartan. In stage II, patients received 30 days of treatment with irbesartan (145 +/- 72 mg/day). After treatment with irbesartan, and no changes in blood pressure level as compared with baseline, we observed a reduction in proteinuria (r = 0.690, p < 0.05), decreased peritoneal protein losses at 4 hours' and 24 hours' dwell time (r = 0.910 and r = 0.930, p < 0.001), decreased peritoneal Kt/V(r = 0.586, p < 0.05), and increased peritoneal creatinine clearance (r = 0.943, p < 0.001). Levels of serum albumin (r = 0.630, p < 0.05), prealbumin (r = 0.810, p < 0.001), and transferrin (r = 0.551, p < 0.05) increased after treatment with irbesartan. We conclude that treatment with irbesartan in patients with CRF undergoing PD modifies peritoneal transport and reduces peritoneal and urinary protein loss. This effect probably has a positive impact on nutritional parameters. Further studies are required to elucidate the mechanisms involved.