Stroke-Related Deaths among Kidney Transplant Recipients

The most effective treatment option for kidney failure is kidney transplantation, which is associated with improved long-term outcomes in appropriately selected patients. While patients with end-stage kidney disease are at increased risk for stroke and stroke-related mortality, recipients of kidney transplantation have a lower risk of cardiovascular disease compared with patients on dialysis. The lower cardiovascular risk is due, in part, to improved kidney function and selection bias related to extensive cardiovascular risk screening in potential kidney transplant recipients.

In the past 10 years in Australia and New Zealand, preventive treatment and improved risk factor control have halved the stroke mortality rates in the general population. However, according to Nicole L. De La Mata, PhD, and colleagues, it is unclear whether kidney transplant recipients have benefited from stroke prevention and management at levels similar to those in the general population over the past 20 years.

The researchers conducted a population-based retrospective cohort study designed to compare stroke mortality among kidney transplant recipients to that of the general population and define the risk factors associated with stroke-related mortality in kidney transplant recipients in Australia and New Zealand. The study also sought to examine whether the rate of stroke-related mortality and the risk factors for stroke death differed in kidney transplant recipients with polycystic kidney disease. Results of the study were reported in Transplantation [2020;104(10);2129-2138].

The cohort included all adult and pediatric kidney transplant recipients in Australia (January 1, 1980, to December 31, 2013) and New Zealand (January 1, 1988, to December 31, 2012). Both countries have similar demographics, including life expectancies and racial background, as well as universal healthcare systems, where free medical care is provided in public health systems. The study used data linkage between kidney transplant recipients in the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) and the national death registries in both countries. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification codes were used to determine the primary cause of death.

The analysis included data on 17,628 kidney transplant recipients. Over 175,084.3 person-years with a median 8.3-year follow-up posttransplant, there were 158 stroke deaths and 5126 other deaths. The remaining 12,344 recipients (70%) were in active follow-up. Of the total study population, 15,579 recipients underwent their first kidney transplant, 1798 underwent their second kidney transplant, and 251 underwent their third or more kidney transplant.

Graft failure occurred in 3733 recipients, 518 experienced two graft failures, and 79 experienced three or more graft failures. The agreement for fact of death between ANZDATA and the death register was nearly perfect in Australia (Kappa statistic, 0.89; 95% confidence interval [CI], 0.88-0.90) and New Zealand (Kappa statistic, 0.93; 95% CI, 0.91-0.95).

More than half (60%) of the study population were <50 years of age at time of transplantation (median, 45 years of age). Most of the transplants were conducted in Australia (88%) and during 2000 or later (56%). Sixty-one percent were male, 36% had normal weight body mass index (BMI), and 25% were overweight. BMI was not collected for 17% of the cohort. The main cause of kidney failure was glomerulonephritis/IgA nephropathy (44%), followed by other causes (28%) and polycystic kidney disease (12%).

Of the 158 stroke deaths, 36% (n=57) were intracerebral hemorrhages, 7% (n=11) were intracranial hemorrhages, 13% (n=20) were ischemic strokes, 12% (n=19) were subarachnoid hemorrhages, and 32% (n=51) were unspecified strokes. An additional 76 stroke deaths were listed in the secondary causes of death where kidney disease was the primary cause. The leading underlying causes of death in the remaining 5126 deaths were coronary heart disease (n=787), diabetes (n=440), and kidney failure (n=427).

Among patients with preexisting cerebrovascular disease, the cumulative incidence for stroke morality was higher than among those without preexisting cerebrovascular disease (P<.001). At 2 years, the incidence was 0.14% for those with and 0.04% for those without cerebrovascular disease. At 5-years posttransplant, the incidence was 0.49% for patients with and 0.15% for patients without cerebrovascular disease.

The overall mortality rate for stroke was 90.2 per 100,000 person-years (95% CI, 77.2-105.5). Subgroup mortality rates were: intracerebral hemorrhage, 32.6 per 100,000 person-years (95% CI, 25.1-42.2) and 11.4 per 100,000 person years (95% CI, 7.4-17.7) for ischemic stroke. During the first year posttransplant, there was no discernible pattern in stroke mortality rates over time, unlike rates for other deaths which were highest in the first 3 months following transplant. After the first 3 months, there was a steady increase in stroke mortality rates from 47.7 per 100,000 person years (95% CI, 23.9-95.5) in the first year to 140.0 per 100,000 person years (95% CI, 77.5-252.8) in the 10th year after transplant. For other deaths, rates declined after the first year posttransplant and steadily increased thereafter.

In the multivariate model, risk factors for stroke mortality included older age at transplant, having ever had a kidney transplant fail, earlier era of transplant, preexisting cerebrovascular disease, and not previously having had cancer. There was no association between previous duration of dialysis and risk of stroke death.

Among the 2196 transplant recipients with polycystic kidney disease who were followed over 19,491.2 person-years, there were 28 stroke deaths and 608 other deaths. The overall stroke mortality rate in that subgroup was 143.7 per 100,000 person-years (95% CI, 99.2-208.1), and the overall stroke standardized mortality ratio was 4.2 (95% CI, 2.9-6.0).

Limitations to the study cited by the researchers included the inability to include data on concurrent medications or other relevant stroke risk factors in the analyses, using the underlying cause of death from the national death registries to determine stroke deaths, and using the general population as the reference population for this estimates.

In conclusion, the researchers said, “Kidney transplant recipients have a high excess of stroke death, particularly young recipients, and risk factors for stroke death include preexisting cerebrovascular disease and graft failure. While there were improvements over time, it is unclear whether kidney transplant recipients have access to stroke prevention or are receiving effective stroke prevention. Preexisting cerebrovascular disease being a risk factor presents an opportunity for secondary prevention. Further studies are needed to assess the benefits and harms of current stroke management in kidney transplant recipients or determine whether specialized strike prevention and intervention need to be developed through novel clinical trials.”

Takeaway Points

  1. There are few data available on the risk of stroke among kidney transplant recipients; researchers reported results of a population-based retrospective cohort study.
  2. The cohort included 17,628 kidney transplant recipients in Australia and New Zealand. There were 158 stroke deaths and 5126 nonstroke deaths in 175,084 person-years.
  3. Risk factors for stroke included older age at transplant, ever graft failure, earlier era of transplant, preexisting cerebrovascular disease, and no previous malignancy.