Contribution of VKORC1 and CYP2C9 polymorphisms in the interethnic variability of warfarin dose in Malaysian populations.

Within the Asian populations, Indian patients had been reported to require higher warfarin dose compared with the Chinese and Malay patients, and this could not entirely be explained by cytochrome P450 (CYP)2C9 gene variants. Genetic variants of vitamin K epoxide oxidase reductase complex subunit 1 (VKORC1) has been well established as one of key determinants in the different responses of warfarin amongst patients. Adult patients who attended an anticoagulation clinic with stable INR were recruited. VKORC1 and CYP2C9 genotype were sequenced, and clinical characteristics were assessed. A total of 91 Malays, 96 Chinese, and 46 Indian patients were recruited. The mean age was 55 years and 51.5% were males. The mean dose of warfarin for all patients was 3.7 mg, and the mean daily dose of warfarin was significantly higher in Indians compared with the Chinese and Malay patients, 4.9 versus 3.5 and 3.3 mg, respectively (p < 0.001). VKORC1 GG genotype was more commonly seen in Indian patients. The mean warfarin dose in patients with GG genotype required a significant higher warfarin dose compared with those with AG and AA genotype (4.9 vs. 3.7 vs. 3.1 mg, respectively; p < 0.001). CYP2C9*2 and *3 is associated with a lower maintenance dose, 2.9 versus 3.7 mg in CYP2C9*1; p < 0.01. In multivariate analysis, age, ethnic groups, and genotypes had a significant influence on the required warfarin dose. In conclusion, VKORC1 and CYP2C9 polymorphism contribute to the difference dose requirement amongst the patients but other additional possible factors may play a role in the Indian race.

Post-kidney transplant weight change as marker of poor survival outcomes.

BACKGROUND: There are few studies on the associations of postkidney transplant weight change on survival. Weight change in different posttransplant periods may have different causes and implications. We used the Australian and New Zealand Dialysis and Transplant Registry data to examine these issues. METHODS: All adult white primary kidney transplant recipients from April 1991 to December 2004 were included. The associations of first (year 1, n=3899) and second (year 2, n=3419) year weight change with subsequent graft and patient survival were analyzed using multivariable Cox regression. RESULTS: Weight gain 10% to 19.9% in year 1 and stable weight (0%-4.9% gain) in year 2 were associated with the best outcomes. Weight loss more than 5% was associated with subsequent death (year 1 adjusted hazard ratio [aHR]=1.64 [1.08-2.48], P=0.019; year 2 aHR=2.09 [1.44-3.02], P=0.013) but not death-censored graft loss. Weight gain more than or equal to 20% in year 1 and more than or equal to 10% weight gain in year 2 were also associated with subsequent death (year 1 aHR=1.78 [1.13-2.81], P=0.013; year 2 aHR=1.67 [1.01-2.76], P=0.047). These associations were minimally changed by excluding outcomes within 1 year of the weight change. Deaths were from cardiovascular disease (35%), cancer (35%), infections (15%), and "other" causes (15%). Weight gain more than or equal to 20% in year 1 was associated with infection or "other" deaths, and weight loss more than 5% or weight gain more than or equal to 10% in year 2 with cardiovascular deaths. CONCLUSIONS: Significant posttransplant weight gain or loss was associated with poorer transplant outcomes. Reasons underlying these associations may differ between year 1 and year 2 weight changes.

Trends in adult post-kidney transplant immunosuppressive use in Australia, 1991-2005.

AIM: Kidney transplant outcomes have improved over the past 15 years, partly due to improvements in immunosuppression. We used data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry to examine trends in immunosuppressive use post transplant. METHODS: All adult (recipient age 16+ years) kidney-only transplants performed in Australia from April 1991 to December 2005 were followed to graft loss or December 2005. Immunosuppressive use at induction, 1, 3 and 5 years post transplant were analysed by transplant cohort. RESULTS: Calcineurin-inhibitors (CNI) were used in most recipients for induction and maintenance immunosuppression, with increasing tacrolimus use. Induction cyclosporin dose increased since 2001 (from 5.8 to 7.9 mg/kg per day), but maintenance cyclosporin and tacrolimus dose decreased (from 3.8 to 3.0 mg/kg per day cyclosporin at 1 year post transplant). CNI-free induction increased since 2002 (from 1.4% to 8.4%), while CNI-free maintenance increased throughout the study period. Mycophenolates were the predominant antimetabolite used. Steroid-free maintenance decreased (from 22.7% to 8.7% at 1 year post transplant), as did median prednisolone doses (from 0.12 to 0.09 mg/kg per day at 1 year post transplant). Sirolimus or everolimus are increasingly used for CNI-sparing rather than as antimetabolites substitutes. OKT3 or antithymocyte globulin induction decreased, while anti-CD25 antibody usage increased from 9.5% to 57.1% since 2000. CONCLUSION: There is a trend to more potent induction immunosuppression with tacrolimus, mycophenolates and anti-CD-25 antibodies, but with CNI avoidance or minimization during maintenance phase. While steroid avoidance/cessation decreased, maintenance steroid dose has also decreased. Anti-CD25 antibodies are now used in >50% of recipients.

Parental donors in live-donor kidney transplantation associated with increased rejection rates and reduced glomerular filtration rates.

BACKGROUND: Living unrelated and related kidney transplantation has been shown to have similar allograft survival. However, the effect of donor-recipient relatedness in living-related and unrelated kidney transplantation on graft and patient survival remains uncertain. METHODS: Using Australia and New Zealand Dialysis and Transplant Registry, primary living renal transplant recipients in Australia between 1995 and 2004 were studied (n=1989). Donors were categorized according to their relationship with recipients: parent (n=606), child (n=103), spouse (n=358), sibling (n=656), other living-related donors (n=81), and other living-unrelated donors (n=185). Outcomes analyzed included the presence of rejection at 6 months, estimated glomerular filtration rate (eGFR) at 1 and 3 years, graft survival, and patient survival. RESULTS: A greater proportion of renal transplant recipients from parental and spousal donors were transplanted preemptively. Donor groups had no relationship with graft or patient survival. Parental donors were associated with an increased relative odds of acute rejection (odds ratio 1.69, 95% confidence interval 1.13-2.53, P=0.009) and a lower eGFR at both 1 and 3 years (coefficient -2.99 and -5.68, respectively; P<0.0001) compared to other donor groups (reference sibling donor group). CONCLUSIONS: This study has established that donor-recipient relatedness in both related and unrelated living kidney transplantation had no significant effect on graft and patient survival. Parental donors were associated with a higher relative risk of rejection and lower eGFR in the transplant recipients, although these findings did not translate to a worse graft outcome.

Effects of body mass index at transplant on outcomes of kidney transplantation.

BACKGROUND: While obesity increases postoperative complications and cardiovascular risks, its effects on long-term kidney transplant outcomes are less clear. METHODS: We used data from the Australian and New Zealand Dialysis and Transplant (ANZDATA) Registry to examine the relationships between body mass index (BMI, classified according to World Health Organization criteria) at transplant and transplant outcome. Patients starting renal replacement therapy from April 1991 and who received a single-organ, primary kidney transplant (when aged > or =16 years) from April 1991 to December 2004 were included, and followed up to death or December 2005. Survival outcomes adjusted for important covariates were analyzed using Cox models, and cause-specific failures by competing risks analysis. Analysis using BMI at various times posttransplant was also performed. Intermediate outcomes were delayed graft function (DGF) and any acute rejection at 6 months. RESULTS: In all, 5684 patients were included. Obese patients had worse graft and patient survival only in univariate analyses, not in multivariate analyses (adjusted hazard ratio [HR] for graft loss: 1.10 [0.94-1.259], P=0.25; for patient death: 1.02 [0.83-1.25], P=0.87). Underweight patients had greater late (> or =5 years) death-censored graft loss (adjusted HR: 1.70 [1.10-2.64], P=0.02), mainly due to chronic allograft nephropathy. Obesity was associated with greater odds for DGF (adjusted OR: 1.56 [1.23-1.97], P<0.001) and 6-month risk of acute rejection (adjusted OR: 1.25 [1.01-1.54], P=0.04). CONCLUSIONS: Obesity per se was not associated with poorer kidney transplant outcomes, although it was associated with factors that led to poorer graft and patient survival. Underweight was associated with late graft failure, mainly due to chronic allograft nephropathy.

Trends in kidney transplantation in Australia and New Zealand, 1993-2004.

BACKGROUND: We hypothesize that transplant outcome in Australia and New Zealand has improved despite more unfavorable transplant characteristics. Data from the Australia and New Zealand Dialysis and Transplant registry was used to examine this hypothesis. METHODS: All adult kidney-only transplants from January 1993 to December 2004 in Australia or New Zealand were followed-up until death or December 2005. Outcomes were adjusted for covariates in multivariate models, with transplant year modeled as a continuous variable. RESULTS: Altogether 6764 patients were included. There were proportionately more live donor and primary transplants, older donors and recipients, and higher recipient body mass index, waiting time, and human leukocyte antigen mismatch in recent cohorts. Death-censored graft loss decreased (adjusted hazard ratio: 0.92 [0.90-0.95] per year, P<0.001). This trend was seen at both 0-1 and 1-5 years posttransplant, and was mainly for immune-mediated graft losses. Patient survival improved only in New Zealand, and only for the first posttransplant year (adjusted odds ratio: 0.88 [0.82-0.95] per year, P=0.001). Cardiovascular deaths decreased while infection or cancer deaths were unchanged. Adjusted delayed graft function rates were unchanged. The acute rejection incidence at 6 months decreased (adjusted odds ratio: 0.88 [0.85-0.90] per year, P<0.001). One and 3-year graft function significantly improved, even after adjusting for rejection. All outcomes did not vary by expanded donor criteria status. CONCLUSIONS: Graft survival and function have improved in recent years, but long-term patient survival remains unchanged. With longer follow-up, the improvement in rejection rates and graft function may lead to further improvements in long-term graft survival and potentially better patient survival.

Trends in hemodialysis vascular access from the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) 2000 to 2005.

BACKGROUND: Australia historically has been recognized for its high fistula use. STUDY DESIGN: Observational study using registry data. SETTING & PARTICIPANTS: Adult patients registered in the Australia and New Zealand Dialysis and Transplant Association Registry on hemodialysis in Australia. PREDICTOR: Cohort year. OUTCOMES & MEASUREMENT: Hemodialysis access trends were examined from 2000 to 2005 for incident patients (within 60 days of hemodialysis therapy start), patients on hemodialysis therapy for 6 to 8 months, and prevalent hemodialysis patients. Multivariate analyses were performed to examine the relationship between access type and cohort year for each group, with adjustment for age, sex, race, body mass index, late referral, smoking status, cause of end-stage renal disease, comorbidities, and dialysis vintage. RESULTS: During 2000 to 2005, catheter use increased from 39% to 53% in incident patients, 10% to 22% in the 6- to 8-month groups, and 6% to 13% in prevalent patients. Fistula use decreased from 56% to 43% in incident patients and 78% to 67% in the 6- to 8-month group and remained at 73% to 75% in prevalent patients. Graft use decreased in all groups. Adjustment for factors associated with access type did not significantly change these results. LIMITATIONS: The registry collects only the access in use at the end of the survey period; thus, it was not possible to determine whether another access had failed or was present, but not in use. The small number of incident numbers prevented separate analysis of arteriovenous fistulas and arteriovenous grafts. CONCLUSION: Incident use of fistulas and grafts decreased, with an unexpected increase in both incident and prevalent catheters between 2000 and 2005. Adjustment for factors associated with access type did not significantly alter the trends. Changes in unidentified practice patterns, attitudes, or preferences are contributing to these trends. Ongoing evaluation of data and investigation into processes of care are required to increase functioning fistulas, together with reevaluation of the role of grafts in patients without a fistula.

Donor human leukocyte antigen specific antibodies predict development and define prognosis in transplant glomerulopathy.

The pathogenesis of transplant glomerulopathy (TG) remains unclear, with evidence of human leukocyte antigen (HLA) antibodies as important contributors to the disease. We studied the risk factors and the associations of HLA antibodies in the development of TG. Sixty-one cases with morphologic features of TG were identified and compared with contemporaneous matched patients (without TG) from a 17-year period, all undergoing renal biopsy in a single center. Univariate risk factors for TG were previous glomerulitis [odds ratio (OR) 3.3, 95% confidence interval (95% CI) [1.2-9.4], p = 0.025), delayed graft function (OR 2.3 [1.0-5.1], p = 0.042), HLA class I presensitization defined by Luminex solid-phase immunoassays (OR 5.0 [2.3-11.0]. p < 0.001), and de novo posttransplant development of donor HLA specific antibody (DSA) (OR 4.7 [1.7-13.2], p = 0.002). Only DSA remained significantly associated with TG after adjustment (OR 3.8 [1.1-12.9], p = 0.032). DSA was detected in >50% of TG patients, suggesting HLA antibodies play a critical role in TG pathogenesis. TG patients with DSA had increased risk of graft loss (median graft survival 4.4-5.2 years), whereas patients with morphologic features of TG without DSA had similar graft survival compared with the non-TG group (median graft survival 15 years). Thus, DSA is a useful predictor for graft failure in TG patients.

Outcomes of transplantation using kidneys from donors meeting expanded criteria in Australia and New Zealand, 1991 to 2005.

BACKGROUND: Kidneys from expanded criteria donors (ECD) are reported to have inferior transplant outcomes. METHODS: Using the Australia and New Zealand Dialysis and Transplant Registry, we reviewed deceased donor kidneys transplanted from 1991 to 2005 in Australia and New Zealand, followed until December 2006. ECD was defined using United Network for Organ Sharing criteria. Graft and patient outcomes, estimated glomerular filtration rates (eGFR), acute rejection, and delayed graft function were analyzed by donor-age and ECD status, with adjustment for important covariates. RESULTS: There were 3248 recipients of non-ECD kidneys and 781 recipients of ECD kidneys. Compared with donors aged less than 50 years, adjusted hazard ratios for graft failure (GF) at 0 to 1 and 1 to 5 years for ECD kidneys from donors aged 60 years or above were 1.92 (1.48-2.49; P<0.001) and 2.52 (1.97-3.23; P<0.001). The hazard ratios for GF were 1.87 (1.31-2.70; P<0.05) for ECD kidneys from donors aged 50 to 59 years in the first year but were not increased subsequently. Mean eGFR at 1 year decreased with increasing donor age and ECD status (56.4 [53.8-58.9] mL/min for kidneys from donors aged <50, 46.6 [45.0-48.3] and 43.5 [41.1-45.9] for non-ECD and ECD donors aged 50 to 59 years, respectively, and 38.6 [36.9-40.4] for donors > or =60; P<0.001) but subsequent eGFR loss was similar except for donors aged 60 years or above (P=0.021). Acute rejection and delayed graft function were more frequent in ECD kidney recipients, but the associations between GF and donor age/ECD status were independent of these factors. CONCLUSIONS: For recipients of ECD kidneys, donor age 60 years or above is the most significant determinant of poor outcome; donor age 50 to 59 years represents a category of intermediate risk.

Interleukin-2 receptor antibody reduces rejection rates and graft loss in live-donor kidney transplant recipients.

BACKGROUND: The use of interleukin-2 receptor antibody (IL-2Ra) induction has been associated with reduced rejection rates in both live and deceased donor kidney transplantation. However, the longer term effect of IL-2Ra induction on estimated glomerular filtration rates and graft and patient survival remains unclear. METHODS: Using Australia and New Zealand Dialysis and Transplant Registry, live donor renal transplant recipients in Australia between 2001 and 2005 were studied (n=1106). Multiple organ graft recipients and those receiving T-cell depletive induction therapy or steroid- or calcineurin-free inhibitor regimens were excluded. Outcomes analyzed included the presence of rejection at 6 months, estimated glomerular filtration rate at 1 and 3 years, 5 years graft and patient survival. RESULTS: A total of 41.7% of live donor renal transplant recipients received IL-2Ra induction. Recipients of IL-2Ra experienced a 51% reduction in the incidence of acute rejection (odds ratio 0.49, 95%CI 0.36-0.67; P<0.001). In addition, the use of IL-2Ra was associated with reduced overall graft loss (hazard ratio 0.58, 95%CI 0.35-0.96; P=0.03) and higher mean estimated glomerular filtration rate at 1 year but not 3 years. There was no association between IL-2Ra induction and death-censored graft loss or death with functioning graft. CONCLUSION: This registry analysis demonstrates that IL-2Ra induction in live donor kidney transplantation is associated with substantial clinical benefits of reduced risk of acute rejection, improved short-term graft function, and reduced graft loss.