“It’s important to have immunosuppression to protect people from rejection, but we wanted to be able to say, ‘What are the other causes of kidney failure that we might be able to identify that help improve longer-term outcomes’,” coauthor Andrew Bentall, MBChB, MD, a Mayo Clinic nephrologist, told this news organization.
“And I think the main thing we found is that we need to differentiate people into two groups,” he said, including younger, nondiabetic patients who develop graft failure due to alloimmunity and older often diabetic patients “who are less likely to have a rejection episode but who are still at high risk for death from a malignancy or infection so maybe we can modify their immunosuppression, for example, and reduce their mortality risk which could be very helpful.”
The study was published online Jan. 17 in Transplantation Direct.
Cohort study
The cohort was made up of 5,752 consecutive kidney transplant recipients treated at one of three Mayo Clinic sites. The mean age of recipients was 53.8 years and one-quarter were 65 years of age or older. “At the time of transplantation, 69.8% were on dialysis, and 10.3% had received a prior kidney,” of which half were from a deceased donor, the authors note.
Almost all patients received tacrolimus as part of their maintenance immunosuppressive regimen. At a median follow-up of 3.5 years, overall graft failure occurred in 21.6% of patients, including death with a functioning graft (DWFG) in 12% and graft failure in 9.6% of patients. The most common causes of DWFG included malignancy at 20.0%, followed closely by infection at 19.7%, investigators note.
Cardiac disease was the cause of DWFG in 12.6% of patients, and the cause was unknown in 37%. Of those patients who died with a functioning graft, 12.3% died within the first year of transplantation. Roughly 45% died between 1 and 5 years later, and 42% died more than 5 years after transplantation.
On multivariable analysis, independent predictors of DWFG included:
- Older age at transplantation (hazard ratio, 1.75; P < .001)
- Male sex (HR, 1.34; P < .001)
- Dialysis prior to transplant (HR, 1.49; P < .001)
- Diabetes as a cause of end-stage renal disease (ESRD) (HR, 1.88; P < .001)
- Prednisone use as maintenance therapy (HR, 1.34; P = .008)
Graft failure
Of patients who had graft failure, almost one-quarter occurred within the first year of transplantation, about 42% occurred 1 to 5 years later, and a third occurred more than 5 years later.
Most patients (39%) who went on to graft failure did so as a result of “alloimmunity”, a term investigators used to cover all types of rejection, with a smaller number of graft failures being caused by glomerular diseases, at 18.6%, and renal tubular injury, at 13.9%.
“In the first year after transplantation, surgical complications and primary nonfunction of the allograft caused 60.3% ... of graft losses,” the authors point out. Beyond the first year, alloimmunity accounted for approximately half of the cases of graft failure, investigators note.
In the multivariable analysis for overall graft failure, risk factors included:
- Young recipient age (HR, 0.80; P < .001)
- History of a previous kidney transplant (HR, 1.33; P = .042)
- Dialysis at time of transplantation (HR, 1.54; P < .001)
- Black recipient race (HR, 1.40; P = .006)
- Black donor race (HR, 1.35; P = .038)
- Diabetes as a cause of ESRD (HR, 1.40; P = .002)
- HLA mismatch (HR, 1.27; P < .001)
- Delayed graft function (HR, 2.20; P < .001)
“Over time, DWFG was more common than graft failure,” the authors note.
Modifiable risk factors
As Dr. Bentall acknowledged, not all risk factors contributing to DWFG or graft failure are modifiable. However, diabetes – which stood out as a risk factor for both DWFG and graft failure – is potentially modifiable before patients reach ESRD, as he suggested. Diabetes is currently a cause for up to 40% of all ESRD cases in the United States.
“We can’t necessarily always reverse the diabetes, but there are significant new medications that can be used along with weight loss strategies to improve diabetes control,” he noted.
Similarly, it’s well established that patients who come into transplantation with a body mass index in excess of 30 kg/m2 have more scarring and damage to the kidney 5- and 10-years post-transplantation than healthy weight patients, as Dr. Bentall observed. “Again, this is a key modifiable component, and it fits into diabetes intervention strategies as well,” he emphasized. The use of prednisone as maintenance immunosuppressive therapy similarly emerged as a risk factor for DWFG.
Transplant recipients who receive prednisone may well be a higher risk population to begin with, “but we are also using prednisone in our older patients because we try to use less induction immunosuppression at the time of transplantation. So if we can try and get people off prednisone, that may lessen their risk of infection and subsequent mortality,” Dr. Bentall noted.
A version of this article first appeared on Medscape.com.