The rate of end-stage renal disease (ESRD) in Australian Aboriginal and Torres Strait Islanders has increased markedly over the last three decades. The relative rate, overall, is four to five times that of nonindigenous Australians (1), and up to 20 to 30 times among remote communities (2). Much of this increase can be attributed to better medical attention and identification of ESRD and may only be starting to reflect the true population incidence.
The Northern Territory of Australia has a population of approximately 200,000 scattered over 1.4 million square kilometers. Most aboriginal people live in small remote communities, forcing them to travel to larger centers for treatment of end-stage kidney failure. The two major centers, Alice Springs and Darwin, are 1,500 km apart and a similar distance from the transplant surgical unit in Adelaide. Although all treatment options are offered, the ability of Indigenous Australians to access kidney transplantation is severely restricted (3). Relocation to a town with a dialysis unit is frequently associated with problems of social dislocation and socioeconomic disadvantage that consequently impact on health outcomes. A successful kidney transplant may offer the best option for returning home.
In general, renal transplantation provides mortality benefit, improved quality of life and a cost advantage for most population groups when compared to dialysis treatments (4). Whether transplantation offers a survival advantage for indigenous Australians is less certain (5), with a much higher rate of renal allograft loss in indigenous recipients (6). However, transplantation may provide other, less tangible benefits such as improved quality of life and the ability to return to their communities, without the time and dietary constraints coupled with dialysis.
Therefore we have sought to identify some of the factors potentially contributing to the inferior outcome of kidney transplantation among indigenous Australians within the Northern Territory.
We performed a retrospective review of all renal transplant recipients from the Northern Territory who had received an allograft between July 1, 1984 and June 30, 2004. These recipients were identified from records at both Royal Darwin and Alice Springs Hospitals, the only providers of renal services in the Northern Territory during this time period. These records were then confirmed with information available at the Queen Elizabeth Hospital in South Australia (where most of the surgery was performed) and the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry. A systematic review of all local medical records was undertaken.
Data retrieved included recipient demographic information, patient comorbidities, and transplant-specific information including immunosuppressive doses and outcomes.
An “infection” was recorded if diagnosed by a clinician; a microbiological diagnosis was not considered mandatory. “Hospitalization” excluded admission to hospital for procedures. “Rejection” was recorded according to histopathological findings: “biopsy proven rejection” was an acute deterioration in allograft function associated with histological changes on biopsy (at least Type 1A from Banff 1997 criteria ), while “presumed rejection” was defined as an episode of graft dysfunction clinically attributed to rejection but not histologically proven. The cumulative exposure to immunosuppressive medication was calculated according to averaged daily dose, except for cyclosporin and tacrolimus (2 hr postdose and trough levels respectively were used to reflect the area under the curve and overall drug exposure).
Data was analyzed using Intercooled STATA (version 8.0; Stata Corporation, College Station, TX). Values are expressed as mean±SD. Differences between indigenous and non-indigenous groups were compared using Student’s t test or Mann-Whitney U test. A two-tailed P value <0.05 was considered to be statistically significant. Multivariate analyses of graft survival data used Cox proportional hazards models to adjust for covariates. Kaplan-Meier survival curves were stratified by race, donor origin, and time of transplantation.
In the 20-year study period there were 134 active grafts, 77 indigenous, and 53 nonindigenous recipients of renal allografts (2 indigenous and 2 nonindigenous patients received 2 grafts each).
The characteristics of renal transplant recipients at the time of transplantation are shown in Table 1. Compared to nonindigenous recipients, differences specific to indigenous recipients include a longer waiting time, greater level of sensitization (as measured by peak panel of reactive antibodies [PRA]), and a greater number of human leukocyte antigen (HLA) mismatches when allocated cadaveric kidneys. The number of indigenous recipients having PRA peak >50% is twice that of a nonindigenous recipient (25% vs. 13%, P<0.001). In addition, 71% of indigenous recipients compared with 30% of nonindigenous recipients of cadaveric grafts had 5 or 6 HLA mismatches (P<0.001).
Patient and renal allograft survival in the non- indigenous group was excellent irrespective of whether they received a living or cadaveric donor kidney (Figs. 1 and 2). None of these recipients died during the follow-up period and only nine out of 53 grafts failed, most due to chronic allograft nephropathy (Table 2). Indigenous patients who received a living related allograft showed comparable survival to nonindigenous recipients. However, premature allograft failure was more likely among indigenous recipients of deceased donor grafts (HR 4.13, 95% CI 2.0–8.5, P<0.0001), with recipient death being the major contributor (Table 2).
By univariate analysis, a failed renal transplant was associated with: ≥5 HLA mismatches (OR 3.1, 95% CI 1.9– 4.9, P<0.0001), indigenous race (OR 1.8, 95% CI 1.3– 2.4, P<0.0001), cadaveric graft source (OR 1.8, 95% CI 1.3–2.6, P<0.001), waiting time >4 years (OR 2.5, 95% CI 1.6–4.0, P<0.001), and age >60 years (OR 2.5, 95% CI 1.1–5.3, P<0.05). PRA peak level and gender were not associated with graft failure. Biopsy proven rejection was also associated with poor graft outcome (OR 1.6, 95% CI 1.1–2.4, P<0.05). On multivariate analysis, ≥5 HLA mismatches was the only factor to significantly influence graft outcome (OR 2.3, 95% CI 1.2–4.2, P<0.01).
In 1996, liberalisation of the patient selection criteria occurred with the arrival of a full-time nephrologist in the major center of Darwin. Prior to 1996, 39 renal transplants were performed (18 non-indigenous and 21 indigenous recipients). Surprisingly, survival was significantly better in those patients transplanted prior to 1996 (Fig. 2), such that the HR for graft failure (for a renal transplant performed after 1996) is 2.3 (95% CI 1.17–4.56, P=0.016). The poorer survival rate seen is accounted for by the increased mortality rate in indigenous patients transplanted after 1996. The time waiting on dialysis prior to transplantation was longer after 1996, but not significantly so. Selection of patients for transplantation is likely to be the major contributor for these results, yet there were no differences between the two groups in terms of immunological or demographic markers (data not shown). The causes of death were similar in both time periods.
In addition, patients originating from central Australia (Alice Springs) had poorer graft survival compared with those from the Darwin area (HR for graft failure in Darwin 0.39, 95% CI 0.22–0.68, P<0.001), but no specific differences were identified between the two groups in terms of recipient baseline data.
Indigenous patients were more likely to have an infection during the observation period (RR 4.1, 95% CI 3.5–4.7, P<0.0001). The majority of infections were bacterial in origin; no microbiological diagnosis was made in 26% of indigenous and 43% of nonindigenous patients. Skin was the most common site of infection in indigenous renal transplant recipients, and urinary tract for non-indigenous recipients. The relative risk of infection in indigenous patients was increased at all major organ sites and for all infecting organisms except viruses (Fig. 3). Indigenous patients also developed their first infection earlier (191 vs. 598 days postoperatively, P<0.01).
The major cause of death in indigenous recipients was infection (Table 3) and most patients presented with or developed sepsis. There was no apparent delay in diagnosis or treatment, with prompt transfer to tertiary medical centers as appropriate. On multivariate analysis, increased infection rate was associated with female gender (OR 2.1, 95% CI 1.84–2.4, P<0.0001), poor diabetic control with Hba1c >8.0% (OR 1.3, 95% CI 1.11–1.44, P<0.001), averaged prednisolone dose >10 mg/day (OR 1.2, 95% CI 1.05–1.38, P=0.006) and >2 boluses of methylprednisolone (OR 1.5, 95% CI 1.33–1.73, P<0.0001).
Hospitalization was more frequent among indigenous recipients (RR 3.9, 95% CI 3.2–4.9, P<0.0001); 76% and 55% of hospital admissions were due to infection in indigenous and nonindigenous groups respectively. This excessive hospitalization rate was associated with female gender (OR 1.2, 95% CI 1.02–1.4, P<0.05), serum albumin <35 g/L (OR 2.5, 95% CI 2.1–2.9), and age >60 years (OR 2.8, 95% CI 1.6–4.9, P<0.0001) on multivariate analysis. Length of stay in hospital was also prolonged (average stay 10.3 vs. 3.0 days per admission, P<0.001), possibly reflecting the severity of illnesses experienced by this group.
Indigenous patients were more likely to be biopsied than nonindigenous transplant recipients (2.7 vs. 2.0 biopsies per patient, P<0.01). Rates of rejection were higher in indigenous patients (all rejection episodes: RR 2.5, 95% CI 1.8–3.5, P<0.001; biopsy proven rejection: RR 1.5, 95% CI 1.02– 2.5, P<0.05; presumed rejection: RR 7.4, 95% CI 3.5–15.3, P<0.0001). Biopsy proven rejection was associated with ≥5 HLA mismatches (OR 9.4, 95% CI 3.8–23.1, P<0.0001) and a cadaveric source of transplant (OR 3.5, 95% CI 2.0–6.3, P<0.0001), but not an increased level of sensitization (defined as PRA peak >50%) on multivariate analysis.
More than 90% of all rejection episodes were adequately treated with a bolus dose (3×1 g dose) of methylprednisolone (MTP), with a higher number of bolus doses in the indigenous group (2.0 vs. 1.2 boluses per patient, P<0.01). This is accounted for by the higher rates of both biopsy proven and presumed rejection; 30% of indigenous and only 12% of nonindigenous patients received >2 bolus doses of MTP. Twelve indigenous and 4 nonindigenous patients received monoclonal antibody for rejection (RR 2.1, 95% CI 1.8–2.5, P<0.0001). The average daily prednisolone dose was not significantly higher in indigenous patients. Comparison of other immunosuppressive agents failed to reveal any significant difference in drug exposure (data not shown).
Impressive improvements in early renal allograft survival in the last two decades in the Caucasian population have not been replicated in other minority groups around the world (8–10). Systemic differences exist in social, economic, immunologic and other medical conditions, producing outcomes that are difficult to modify by altering apparently simple, correctable factors (11–14). This same disparity exists between indigenous and nonindigenous Australian renal transplant recipients.
The health status of indigenous Australians is worse than nonindigenous Australians with a reduced life expectancy and an excess of chronic diseases including kidney disease (15). While the incidence of end-stage kidney disease continues to rise, mortality rates from renal replacement therapies remain at least 70% higher than in non-indigenous people (16). This is reflected in the renal transplant outcomes seen in this paper.
The Northern Territory has developed a specific expertise in the health care of indigenous Australians, particularly in renal disease (17, 18). Despite this, indigenous recipient survival remains poor. The results for kidney transplantation in nonindigenous people within the Northern Territory, however are excellent by international standards demonstrating the standard of health care that is available in these major centers. This paper is a first step to understand some of the reasons for these poor outcomes in an attempt to begin to improve what is still most likely the best treatment option for indigenous people with end-stage renal failure.
The likelihood of an indigenous Australian receiving a graft is approximately 30% that of their nonindigenous counterparts (3, 5). Despite living donor outcomes in our study being excellent, the majority of indigenous patients will receive an allograft from a cadaveric source. Few indigenous potential living donors are assessed as medically suitable due to the high incidence of diabetes, hypertension, and kidney disease. Therefore, if indigenous patients do receive a graft from the waiting list, they have spent longer on dialysis, are more sensitized, and have a greater number of HLA mismatches due to genetic differences between the donor and recipient genetic pool. All of these factors are associated with poorer long-term outcome (19); hence indigenous renal transplant recipients are disadvantaged from the outset.
The predominant cause of graft loss in Australia is chronic allograft nephropathy or recipient death due to a cardiac or malignant cause (20). However, among Indigenous recipients in this study, death due to septicemia is the most common cause of graft loss. In addition, there were a greater number of infective episodes, with more frequent and prolonged admissions to hospital for treatment of infections. Local recognition of this has altered local protocols and the use of prophylactic antibiotics has been commonplace for several years in an attempt to reduce this occurrence (21).
The combination of higher PRA, more HLA mismatches, and higher rates of acute rejection suggests a higher immunological risk transplant, requiring more immune modulation. In general indigenous transplant recipients are treated with similar immune suppressant protocols as nonindigenous recipients, yet we currently lack pharmacokinetic, pharmacogenetic and immunological data to support this. In the present study, indigenous recipients were more frequently treated for rejection, particularly with an increased use of methylprednisolone. This was accounted for predominantly by a vastly increased rate of presumed rather than biopsy proven rejection for which there are at least two reasons. Firstly, the remote locations of most indigenous patients who return home and cannot readily access transport to the main city and secondly, lack of an on-site renal pathologist and drug assays, resulting in a 24–48 hr delay in processing and interpreting biopsy samples and drug concentrations. Hence fluctuations in graft function rely on clinical judgement and many patients are treated empirically. We believe this is also affected by health professional perception of non-compliance among indigenous patients, and an assumption that any fluctuation in serum creatinine is thus related. Improvement in remote transport and access to a rapid pathological and pharmacological diagnosis are areas that may reduce the use of bolus steroids with subsequent clinical benefits.
Although some increased infection risk can be accounted for by augmented prednisolone exposure, other factors including poorer diabetic control, inferior nutrition (reflected in lower average serum albumin levels), substandard housing and inadequate infrastructure for sanitation also contribute (22). All of these factors are beyond the immediate control of the transplant unit and are by no means unique to people on renal replacement therapy.
We initially expected that the lower survival rates among indigenous renal transplant recipients would be explained by the lack of medical services at major centers responsible for postoperative care. This was not borne out by our analysis, which showed inferior survival after 1996 when an increase in local medical expertise occurred. A selection bias is the most likely reason for this observation, with only the best patients being selected pre-1996 and as services expanded the selection criteria broadened (demonstrated by a 300% increase in the number of people transplanted post-1996) (23). The smaller proportion of living donor transplants and the trend towards longer waiting times for those transplanted after 1996 may also contribute to this disparity.
The retrospective nature and a small number of subjects in this study limits the clinical applicability of the findings, but certainly raises many issues that warrant further research to improve transplantation outcomes within remote Australia. In addition, the outcomes measured do not include functional or quality of life outcomes, absent due to lack of validity in the indigenous Australian population, but as important as the outcomes reported.
Improvements in transplant outcome may be made by provision of increased services locally, particularly in the areas of education, language and cultural understanding, but also in such basic issues as living conditions. Provision of health-care resources including local pathology, drug assays, and easily accessed remote transport is no doubt of value implementing, even before considering individual biological differences.
In summary, we have shown that the Northern Territory produces excellent outcomes for most recipients of kidney transplants. However, indigenous recipients of cadaveric kidney transplants have poor outcomes, mostly due to increased mortality and morbidity from infective causes.
Data collection was facilitated by generous funding from Janssen-Cilag Pty Ltd. Many thanks to Dr Stephen McDonald for statistical help.
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