Early Posttransplantation Hyperglycemia in Kidney Transplant Recipients Is Associated With Overall Long-term Graft Losses
Background: The association of early-onset posttransplantation hyperglycemia with long-term renal allograft survival is unknown. Methods: Seventy-one (SD 9) days after transplantation, 1410 first-time kidney transplant recipients without diabetes underwent an oral glucose tolerance test and were observed until primary outcome (graft loss) or December 31, 2008 (median [range], 6.0 years [0.3–13.8 years]). We used multivariable Cox regression analysis adjusted for age, gender, body mass index, creatinine level, donor age, preemptive transplantation, deceased donor, early rejection, and early cytomegalovirus infection to estimate hazard ratios for overall and death-censored allograft survival. Results: A total of 392 (28%) recipients experienced graft failure, and 235 (60%) were induced by death. Each 1 mmol/L increase in 2-hr plasma glucose (2hPG) was associated with 7% and 3% increased risk of unadjusted and adjusted overall graft failure (hazard ratio [95% confidence interval], 1.07 [1.04–1.10] and 1.03 [1.00–1.07]). Fasting plasma glucose was associated with unadjusted but not adjusted overall graft failure (1.09 [1.01–1.18] and 1.07 [0.98–1.17]). Neither 2hPG nor fasting plasma glucose was associated with death-censored graft loss (P=0.578 and P=0.896). Compared with recipients with normal glucose tolerance, recipients with posttransplantation diabetes mellitus showed a tendency toward increased overall multiadjusted graft failure (1.30 [0.98–1.73]). This was not observed in patients with impaired fasting glucose or impaired glucose tolerance. Conclusions: In this study, 2hPG was associated with overall graft failure but not death-censored graft failure. The link between 2hPG and graft failure may be explained by the association with mortality.
Thursday, November 8, 2012
Polyomavirus BK Replication in De Novo Kidney Transplant Patients Receiving Tacrolimus or Cyclosporine: A Prospective, Randomized, Multicenter Study
Polyomavirus BK Replication in De Novo Kidney Transplant Patients Receiving Tacrolimus or Cyclosporine: A Prospective, Randomized, Multicenter Study
Polyomavirus BK (BKV)-associated nephropathy causes premature kidney transplant (KT) failure. BKV viruria and viremia are biomarkers of disease progression, but associated risk factors are controversial. A total of 682 KT patients receiving basiliximab, mycophenolic acid (MPA), corticosteroids were randomized 1:1 to cyclosporine (CsA) or tacrolimus (Tac). Risk factors were analyzed in 629 (92.2%) patients having at least 2 BKV measurements until month 12 posttransplant. Univariate analysis associated CsA-MPA with lower rates of viremia than Tac-MPA at month 6 (10.6% vs. 16.3%, p = 0.048) and 12 (4.8% vs. 12.1%, p = 0.004) and lower plasma BKV loads at month 12 (3.9 vs. 5.1 log10copies/mL; p = 0.028). In multivariate models, CsA-MPA remained associated with less viremia than Tac-MPA at month 6 (OR 0.60; 95% CI 0.36–0.99) and month 12 (OR 0.33; 95% CI 0.16–0.68). Viremia at month 6 was also independently associated with higher steroid exposure until month 3 (OR 1.19 per 1 g), and with male gender (OR 2.49) and recipient age (OR 1.14 per 10 years) at month 12. The data suggest a dynamic risk factor evolution of BKV viremia consisting of higher corticosteroids until month 3, Tac-MPA compared to CsA-MPA at month 6 and Tac-MPA, older age, male gender at month 12 posttransplant.
Polyomavirus BK (BKV)-associated nephropathy causes premature kidney transplant (KT) failure. BKV viruria and viremia are biomarkers of disease progression, but associated risk factors are controversial. A total of 682 KT patients receiving basiliximab, mycophenolic acid (MPA), corticosteroids were randomized 1:1 to cyclosporine (CsA) or tacrolimus (Tac). Risk factors were analyzed in 629 (92.2%) patients having at least 2 BKV measurements until month 12 posttransplant. Univariate analysis associated CsA-MPA with lower rates of viremia than Tac-MPA at month 6 (10.6% vs. 16.3%, p = 0.048) and 12 (4.8% vs. 12.1%, p = 0.004) and lower plasma BKV loads at month 12 (3.9 vs. 5.1 log10copies/mL; p = 0.028). In multivariate models, CsA-MPA remained associated with less viremia than Tac-MPA at month 6 (OR 0.60; 95% CI 0.36–0.99) and month 12 (OR 0.33; 95% CI 0.16–0.68). Viremia at month 6 was also independently associated with higher steroid exposure until month 3 (OR 1.19 per 1 g), and with male gender (OR 2.49) and recipient age (OR 1.14 per 10 years) at month 12. The data suggest a dynamic risk factor evolution of BKV viremia consisting of higher corticosteroids until month 3, Tac-MPA compared to CsA-MPA at month 6 and Tac-MPA, older age, male gender at month 12 posttransplant.
Wednesday, October 31, 2012
A Randomized Pharmacokinetic Study of Generic Tacrolimus Versus Reference Tacrolimus in Kidney Transplant Recipients
A Randomized Pharmacokinetic Study of Generic Tacrolimus Versus Reference Tacrolimus in Kidney Transplant Recipients
Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open-label, randomized, two-period (14 days per period), two-sequence, crossover and steady-state pharmacokinetic study was undertaken to compare twice-daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC0-12h and peak concentration (Cmax) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97-108%, p = 0.486) for AUC0-12h and 1.09 (90% CI 101-118%, p = 0.057) for Cmax. Mean (SD) C0 was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines.
Pharmacokinetic analyses comparing generic tacrolimus preparations versus the reference drug in kidney transplant patients are lacking. A prospective, multicenter, open-label, randomized, two-period (14 days per period), two-sequence, crossover and steady-state pharmacokinetic study was undertaken to compare twice-daily generic tacrolimus (Sandoz) versus reference tacrolimus (Prograf®) in stable renal transplant patients. AUC0-12h and peak concentration (Cmax) were calculated from 12 h pharmacokinetic profiles at the end of each period (days 14 and 28). Of 71 patients enrolled, 68 provided evaluable pharmacokinetic data. The ratios of geometric means were 1.02 (90% CI 97-108%, p = 0.486) for AUC0-12h and 1.09 (90% CI 101-118%, p = 0.057) for Cmax. Mean (SD) C0 was 7.3(1.8) ng/mL for generic tacrolimus versus 7.0(2.1) ng/mL for reference tacrolimus based on data from days 14 and 28. Correlations between 12 h trough levels and AUC were r = 0.917 for generic tacrolimus and r = 0.887 for reference drug at day 28. These data indicate that generic tacrolimus (Sandoz) has a similar pharmacokinetic profile to the reference drug and is bioequivalent in kidney transplant recipients according to US Food and Drug Administration and European Medicines Agency guidelines.
Pulsatile Pump Decreases Risk of Delayed Graft Function in Kidneys Donated After Cardiac Death
Pulsatile Pump Decreases Risk of Delayed Graft Function in Kidneys Donated After Cardiac Death
Organ storage techniques have been under scrutiny to determine the best preservation method, particularly in donation after cardiac death (DCD) kidneys. Conflicting literature on the benefit of pulsatile perfusion (PP) over cold storage (CS) warrants further investigation. We analyzed the risk of developing delayed graft function (DGF) in recipients of DCD and donation after brain death (DBD) kidneys undergoing PP or CS. We stratified on basis of cold ischemic time (CIT) to determine the interaction of preservation techniques, CIT and DCD kidneys on developing DGF. Of 54 136 recipients, 4923 received DCD kidneys of which 3330 (67%) underwent PP. Of 49 213 DBD recipients, 7531 (15%) underwent PP. DCD had a higher risk of DGF versus DBD (adjusted odds ratio, AOR 3.2; 3.0-3.5). PP kidneys had less DGF (AOR 0.59; 0.56-0.63) compared to CS. Interaction models of method by donor type referenced to PP/DBD revealed CS/DBD kidneys had higher DGF (AOR 1.8; 1.7-1.9), whereas CS/DCD kidneys had the highest risk of DGF (AOR 5.01; 4.43-5.67). Even though suggestive for a benefit of PP on DGF, this retrospective analysis cannot address whether this is an intrinsic effect of PP or is associated with the logistics of PP such as discard of DCD kidneys based on pump parameters.
Organ storage techniques have been under scrutiny to determine the best preservation method, particularly in donation after cardiac death (DCD) kidneys. Conflicting literature on the benefit of pulsatile perfusion (PP) over cold storage (CS) warrants further investigation. We analyzed the risk of developing delayed graft function (DGF) in recipients of DCD and donation after brain death (DBD) kidneys undergoing PP or CS. We stratified on basis of cold ischemic time (CIT) to determine the interaction of preservation techniques, CIT and DCD kidneys on developing DGF. Of 54 136 recipients, 4923 received DCD kidneys of which 3330 (67%) underwent PP. Of 49 213 DBD recipients, 7531 (15%) underwent PP. DCD had a higher risk of DGF versus DBD (adjusted odds ratio, AOR 3.2; 3.0-3.5). PP kidneys had less DGF (AOR 0.59; 0.56-0.63) compared to CS. Interaction models of method by donor type referenced to PP/DBD revealed CS/DBD kidneys had higher DGF (AOR 1.8; 1.7-1.9), whereas CS/DCD kidneys had the highest risk of DGF (AOR 5.01; 4.43-5.67). Even though suggestive for a benefit of PP on DGF, this retrospective analysis cannot address whether this is an intrinsic effect of PP or is associated with the logistics of PP such as discard of DCD kidneys based on pump parameters.
Improved Renal Function After Early Conversion From a Calcineurin Inhibitor to Everolimus: a Randomized Trial in Kidney Transplantation
Improved Renal Function After Early Conversion From a Calcineurin Inhibitor to Everolimus: a Randomized Trial in Kidney Transplantation
In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric-coated mycophenolate sodium and corticosteroids. The primary endpoint, change in measured GFR (mGFR) from week 7 to month 12, was significantly greater with everolimus than controls: 4.9 (11.8) mL/min versus 0.0 (12.9) mL/min (p = 0.012; analysis of covariance [ANCOVA]). Per protocol analysis demonstrated a more marked difference: an increase of 8.7 (11.2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p < 0.001; ANCOVA). There were no differences in graft or patient survival. The 12-month incidence of biopsy-proven acute rejection (BPAR) was 27.5% (n = 28) with everolimus and 11.0% (n = 11) in controls (p = 0.004). All but two episodes of BPAR in each group were mild. Adverse events occurred in 95.1% of everolimus patients and 90.0% controls (p = 0.19), with serious adverse events in 53.9% and 38.0%, respectively (p = 0.025). Discontinuation because of adverse events was more frequent with everolimus (25.5%) than controls (3.0%; p = 0.030). In conclusion, conversion from CsA to everolimus at week 7 after kidney transplantation was associated with a greater improvement in mGFR at month 12 versus CNI-treated controls but discontinuations and BPAR were more frequent.
In an open-label, multicenter trial, de novo kidney transplant recipients at low to medium immunological risk were randomized at week 7 posttransplant to remain on CsA (n = 100, controls) or convert to everolimus (n = 102), both with enteric-coated mycophenolate sodium and corticosteroids. The primary endpoint, change in measured GFR (mGFR) from week 7 to month 12, was significantly greater with everolimus than controls: 4.9 (11.8) mL/min versus 0.0 (12.9) mL/min (p = 0.012; analysis of covariance [ANCOVA]). Per protocol analysis demonstrated a more marked difference: an increase of 8.7 (11.2) mL/min with everolimus versus a decrease of 0.4 (12.0) mL/min in controls (p < 0.001; ANCOVA). There were no differences in graft or patient survival. The 12-month incidence of biopsy-proven acute rejection (BPAR) was 27.5% (n = 28) with everolimus and 11.0% (n = 11) in controls (p = 0.004). All but two episodes of BPAR in each group were mild. Adverse events occurred in 95.1% of everolimus patients and 90.0% controls (p = 0.19), with serious adverse events in 53.9% and 38.0%, respectively (p = 0.025). Discontinuation because of adverse events was more frequent with everolimus (25.5%) than controls (3.0%; p = 0.030). In conclusion, conversion from CsA to everolimus at week 7 after kidney transplantation was associated with a greater improvement in mGFR at month 12 versus CNI-treated controls but discontinuations and BPAR were more frequent.
Monday, October 15, 2012
Value of Routine Voiding Cystourethrography After Renal Transplantation.
Value of Routine Voiding Cystourethrography After Renal Transplantation.
The impact of vesicoureteral reflux (VUR) on renal allograft outcomes is debatable, with small cohort studies reporting controversial results. The objective of this retrospective study was to evaluate long-term clinical effects of early VUR in a large cohort of kidney transplant patients. Posttransplantation voiding cystourethrography was used to evaluate 646 consecutive kidney transplant recipients before discharge. The study endpoints included VUR grade, death-censored graft or patient survival, renal function, proteinuria and occurrence of urinary tract infections (UTIs). Of the 646 recipients, 263 (40.7%) were diagnosed with VUR. VUR grade II was most common (19.8%), followed by grades III (10.2%), I (7.9%) and IV (2.8%). VUR was less common in transplantations performed by experienced compared to inexperienced surgeons (36% vs. 48%; p = 0.004). VUR did not affect death-censored graft or patient survival and was not associated with proteinuria or occurrence of UTIs. Patients with VUR had a lower eGFR at 1 year after transplantation than did patients without VUR (60 vs. 52 mL/min/1.73 m(2) ; p = 0.02), although this difference was not observed at 3 and 5 years after transplantation. We conclude that early VUR, a common finding among renal transplant patients, may not have a meaningful impact on long-term transplant outcomes.
The impact of vesicoureteral reflux (VUR) on renal allograft outcomes is debatable, with small cohort studies reporting controversial results. The objective of this retrospective study was to evaluate long-term clinical effects of early VUR in a large cohort of kidney transplant patients. Posttransplantation voiding cystourethrography was used to evaluate 646 consecutive kidney transplant recipients before discharge. The study endpoints included VUR grade, death-censored graft or patient survival, renal function, proteinuria and occurrence of urinary tract infections (UTIs). Of the 646 recipients, 263 (40.7%) were diagnosed with VUR. VUR grade II was most common (19.8%), followed by grades III (10.2%), I (7.9%) and IV (2.8%). VUR was less common in transplantations performed by experienced compared to inexperienced surgeons (36% vs. 48%; p = 0.004). VUR did not affect death-censored graft or patient survival and was not associated with proteinuria or occurrence of UTIs. Patients with VUR had a lower eGFR at 1 year after transplantation than did patients without VUR (60 vs. 52 mL/min/1.73 m(2) ; p = 0.02), although this difference was not observed at 3 and 5 years after transplantation. We conclude that early VUR, a common finding among renal transplant patients, may not have a meaningful impact on long-term transplant outcomes.
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