Stephen P. McDonald

Vascular Access and All-Cause Mortality: A Propensity Score Analysis

The native arteriovenous fistula (AVF) is the preferred vascular access because of its longevity and its lower rates of infection and intervention. Recent studies suggest that the AVF may offer a survival advantage. Because these data were derived from observational studies, they are prone to potential bias. The use of propensity scores offers an additional method to reduce bias resulting from nonrandomized treatment assignment. Adult (age 18 yr or more) patients who commenced hemodialysis in Australia and New Zealand on April 1, 1999, until March 31, 2002, were studied by using the Australian and New Zealand Dialysis and Transplant Association (ANZDATA) Registry. Cox regression was used to determine the effect of access type on total mortality. Propensity scores were calculated and used both as a controlling variable in the multivariable model and to construct matched cohorts. The catheter analysis was stratified by dialysis duration at entry to ANZDATA to satisfy the proportional-hazard assumption. There were 612 deaths in 3749 patients (median follow-up, 1.07 yr). After adjustment for confounding factors and propensity scores, catheter use was predictive of mortality. Patients with arteriovenous grafts (AVG) also had a significantly increased risk of death. Effect estimates were also consistent in the smaller propensity score-matched cohorts. Both AVG and catheter use in incident hemodialysis patients are associated with significant excess of total mortality. Reducing catheter use and increasing the proportion of patients commencing hemodialysis with a mature AVF remain important clinical objectives.

Relationship between Dialysis Modality and Mortality

Mortality differences between peritoneal dialysis (PD) and hemodialysis (HD) are widely debated. In this study, mortality was compared between patients treated with PD and HD (including home HD) using data from 27,015 patients in the Australia and New Zealand Dialysis and Transplant Registry, 25,287 of whom were still receiving PD or HD 90 d after entry into the registry. Overall mortality rates were significantly lower during the 90- to 365-d period among those being treated with PD at day 90 (adjusted hazard ratio [HR] 0.89; 95% confidence interval [CI] 0.81 to 0.99]; P < 0.001). This effect, however, varied in direction and size with the presence of comorbidities: Younger patients without comorbidities had a mortality advantage with PD treatment, but other groups did not. After 12 mo, the use of PD at day 90 was associated with significantly increased mortality (adjusted HR 1.33; 95% CI 1.24 to 1.42; P < 0.001). In a supplementary as-treated analysis, PD treatment was associated with lower mortality during the first 90 d (adjusted HR 0.67; 95% CI 0.56 to 0.81; P < 0.001). These data suggest that the effect of dialysis modality on survival for an individual depends on time, age, and presence of comorbidities. Treatment with PD may be advantageous initially but may be associated with higher mortality after 12 mo.

Obesity Is Associated with Worse Peritoneal Dialysis Outcomes in the Australia and New Zealand Patient Populations

Although obesity is associated with increased risks of morbidity and death in the general population, a number of studies of patients undergoing hemodialysis have demonstrated that increasing body mass index (BMI) is correlated with decreased mortality risk. Whether this association holds true among patients treated with peritoneal dialysis (PD) has been less well studied. The aim of this investigation was to examine the association between BMI and outcomes among new PD patients in a large cohort, with long-term follow-up monitoring. Using data from the Australia and New Zealand Dialysis and Transplant Registry, an analysis of all new adult patients (n = 9679) who underwent an episode of PD treatment in Australia or New Zealand between April 1, 1991, and March 31, 2002, was performed. Patients were classified as obese (BMI of >/=30 kg/m(2)), overweight (BMI of 25.0 to 29.9 kg/m(2)), normal weight (BMI of 20 to 24.9 kg/m(2)), or underweight (BMI of <20 kg/m(2)). In multivariate analyses, obesity was independently associated with death during PD treatment (hazard ratio, 1.36; 95% confidence interval, 1.14 to 1.54; P < 0.05) and technique failure (hazard ratio, 1.17; 95% confidence interval, 1.07 to 1.26; P < 0.01), except among patients of New Zealand Maori/Pacific Islander origin, for whom there was no significant relationship between BMI and death during PD treatment. A supplementary fractional polynomial analysis modeled BMI as a continuous predictor and indicated a J-shaped relationship between BMI and patient mortality rates and a steady increase in death-censored technique failure rates up to a BMI of 40 kg/m(2); the mortality risk was lowest for BMI values of approximately 20 kg/m(2). In conclusion, obesity at the commencement of renal replacement therapy is a significant risk factor for death and technique failure. Such patients should be closely monitored during PD and should be considered for early transfer to an alternative renal replacement therapy if difficulties are experienced.

Endothelial progenitor cells: novel biomarker and promising cell therapy for cardiovascular disease.

Bone-marrow-derived EPCs (endothelial progenitor cells) play an integral role in the regulation and protection of the endothelium, as well as new vessel formation. Peripheral circulating EPC number and function are robust biomarkers of vascular risk for a multitude of diseases, particularly CVD (cardiovascular disease). Importantly, using EPCs as a biomarker is independent of both traditional and non-traditional risk factors (e.g. hypertension, hypercholesterolaemia and C-reactive protein), with infused ex vivo-expanded EPCs showing potential for improved endothelial function and either reducing the risk of events or enhancing recovery from ischaemia. However, as the number of existing cardiovascular risk factors is variable between patients, simple EPC counts do not adequately describe vascular disease risk in all clinical conditions and, as such, the risk of CVD remains. It is likely that this limitation is attributable to variation in the definition of EPCs, as well as a difference in the interaction between EPCs and other cells involved in vascular control such as pericytes, smooth muscle cells and macrophages. For EPCs to be used regularly in clinical practice, agreement on definitions of EPC subtypes is needed, and recognition that function of EPCs (rather than number) may be a better marker of vascular risk in certain CVD risk states. The present review focuses on the identification of measures to improve individual risk stratification and, further, to potentially individualize patient care to address specific EPC functional abnormalities. Herein, we describe that future therapeutic use of EPCs will probably rely on a combination of strategies, including optimization of the function of adjunct cell types to prime tissues for the effect of EPCs.

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

Backgound. 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 ≥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 (≥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.

Higher Peritoneal Transport Status Is Associated with Higher Mortality and Technique Failure in the Australian and New Zealand Peritoneal Dialysis Patient Populations

Although early studies observed that peritoneal membrane transport characteristics were determinants of morbidity and mortality in peritoneal dialysis (PD) patients, more recent investigations, such as the Ademex trial, have refuted these findings. The aim of this study was to determine whether baseline peritoneal transport status predicted subsequent survival in Australian and New Zealand PD patients. The study included all adult patients in Australia and New Zealand who commenced PD between April 1, 1999, and March 31, 2004, and had a peritoneal equilibration test (PET) performed within 6 mo of PD commencement. Times to death and death-censored technique failure were examined by Kaplan-Meier analyses and multivariate Cox proportional hazards models. PET measurements were available in 3702 (72%) of the 5170 individuals who began PD treatment in Australia or New Zealand during the study period. In these patients, high transporter status was found to be a significant, independent predictor of death-censored technique failure (adjusted hazard ratio [AHR] 1.23; 95% confidence interval [CI] 1.02 to 1.49; P = 0.03) and mortality (AHR 1.34; 95% CI 1.05 to 1.79, P = 0.02) compared with low-average transport status. High-average transport class was also associated with mortality (AHR 1.21; 95% CI 1.00 to 1.48; P = 0.047) but not death-censored technique failure (AHR 1.04; 95% CI 0.90 to 1.21) compared with low-average transport status. When transport status was alternatively analyzed as a continuous variable, dialysate:plasma creatinine ratio at 4 h was independently predictive of both death-censored technique failure (AHR 1.07; 95% CI 1.01 to 1.295; P = 0.031) and death (AHR 1.09; 95% CI 1.01 to 1.373; P = 0.036 per 0.1 change in dialysate:plasma creatinine). Peritoneal transport rate is a highly significant risk factor for both mortality and death-censored technique failure in the Australian and New Zealand incident PD patient populations.

The pattern of excess cancer in dialysis and transplantation

BACKGROUND After transplantation, cancer risk varies from no increase for several common cancers to a many-fold increase for a number of, chiefly virus-associated, cancers. The smaller excess of cancer in dialysis has been less well described, but two studies suggested that impaired immunity might be responsible. METHODS In a population-based cohort study of 28 855 patients who received renal replacement therapy (RRT), we categorized incident cancers as end-stage kidney disease (ESKD) related, immune deficiency related, not related to immune deficiency, or of uncertain status, according to whether they were, or were not, increased in published reports of cancer in ESKD prior to starting RRT, organ transplantation or human immunodeficiency virus infection. Standardized incidence ratios for, and excess burdens of, cancer were calculated for all persons normally resident in Australia starting treatment by dialysis or renal transplantation from 1982 to 2003. RESULTS The risk for ESKD-related cancers was increased 4-fold in dialysis and during transplant function. For immune deficiency-related cancers, the increase was 1.5 (95% CI 1.3-1.6) times in dialysis, and 5-fold after transplantation. ESKD- or immune deficiency-related cancers contributed to approximately 90% of the excess burden of cancer, 48% and 36%, respectively, in dialysis, and 10% and 78% after transplantation. The remaining excess malignancy was contributed by cancers whose relationship with ESKD and immune deficiency is not yet certain. CONCLUSIONS In RRT, the increase in cancer is restricted, largely if not wholly, to cancers with origins in ESKD or related to immune deficiency. For the former, the cancer risk is similar in dialysis and transplantation, but for immune deficiency-related cancers, the relative risk is much greater after transplantation.

Reduction in Cardiovascular Death After Kidney Transplantation

Background. Cardiovascular (CVS) disease is the commonest cause of death after kidney transplantation. In the general population, CVS mortality has reduced significantly over the last two decades; however, this trend has not been specifically examined in the kidney transplant population. Methods: We studied all patients in Australia and New Zealand with a functioning kidney transplant between 1980 and 2007 and examined trends in the cause and timing of all 2195 deaths recorded after kidney transplantation in the Australia and New Zealand Dialysis and Transplant registry. Poisson regression was used to compare death rates over the time periods. Results: CVS events were the commonest cause of death throughout all the time points examined; however, CVS death rates significantly decreased with an adjusted risk ratio of 0.61 (95% confidence interval, 0.38–0.96; P=0.034) for 2005 to 2007 era. In comparison, death rates due to malignancy have increased significantly over this period. Decreased CVS death rates have occurred despite increasing comorbidity at the time of transplantation. Factors associated with CVS death were older recipient age, preexisting CVS disease, and diabetes mellitus. There was a significantly lower CVS death rate in patients with a glomerular filtration rate >48 mL/min compared with those with poor renal function (risk ratio, 0.66; 95% confidence interval, 0.45–0.95; P=0.024). Conclusions: These trends suggest improvements in CVS risk management and outcomes in the kidney transplant population in Australia and New Zealand.

The cost effectiveness of increasing kidney transplantation and home based dialysis

Background:  Renal replacement therapy (RRT) consumes sizable proportions of health budgets internationally, but there is considerable variability in choice of RRT modality among and within countries with major implications for health outcomes and costs. We aimed to quantify these implications for increasing kidney transplantation and improving the rate of home‐based dialysis.

Encapsulating peritoneal sclerosis: incidence, predictors, and outcomes.

Encapsulating peritoneal sclerosis is a complication of peritoneal dialysis characterized by persistent, intermittent, or recurrent adhesive bowel obstruction. Here we examined the incidence, predictors, and outcomes of encapsulating peritoneal sclerosis (peritoneal fibrosis) by multivariate logistic regression in incident peritoneal dialysis patients in Australia and New Zealand. Matched case-control analysis compared the survival of patients with controls equivalent for age, gender, diabetes, and time on peritoneal dialysis. Of 7618 patients measured over a 13-year period, encapsulating peritoneal sclerosis was diagnosed in 33, giving an incidence rate of 1.8/1000 patient-years. The respective cumulative incidences of peritoneal sclerosis at 3, 5, and 8 years were 0.3, 0.8, and 3.9%. This condition was independently predicted by younger age and the duration of peritoneal dialysis, but not the rate of peritonitis. Twenty-six patients were diagnosed while still on peritoneal dialysis. Median survival following diagnosis was 4 years and not statistically different from that of 132 matched controls. Of the 18 patients who died, only 7 were attributed directly to peritoneal sclerosis. Our study shows that encapsulating peritoneal sclerosis is a rare condition, predicted by younger age and the duration of peritoneal dialysis. The risk of death is relatively low and not appreciably different from that of competing risks for mortality in matched dialysis control patients.