New perspectives on CV risk assessment of prospective kidney recipients, donors
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CVD leads to approximately 40% to 50% of deaths in patients with advanced chronic kidney disease or end-stage renal disease, so CV risk assessment of recipients and donors is an important part of the kidney transplantation process.
Chronic kidney disease (CKD) is associated with a persistent proinflammatory state that damages the vasculature and can create increased cardiac strain. Thus, patients with advanced CKD are at high risk for CV events and undergo routine cardiac screening during transplant evaluation. This screening step represents an important opportunity to examine new data and update routine practices. Furthermore, “healthy” live kidney donors undergo pre-donation CV screening, which is another chance to modernize cardiac evaluation practices.
Current practices
There are extensive discrepancies in current preoperative recommendations. It is standard of care that patients who present with ACS should undergo PCI or CABG in conjunction with guideline-directed medical therapy; however, the lines begin to blur soon after. The 2014 American College of Cardiology/American Heart Association guidelines state that preoperative cardiac testing should be reserved for patients with unknown or poor functional status regardless of CV risk. Poor functional status is defined as a score of less than 4 metabolic equivalents of task (METs); for reference, a score of 4 is like walking up two flights of stairs.
In contrast, the American Society of Transplantation (AST) and National Kidney Foundation (NKF) recommend more aggressive screening strategies, including echocardiogram and routine stress testing. These guidelines were greatly influenced by a randomized controlled trial from 1992, which compared outcomes in candidates for kidney transplantation assigned initial invasive strategy or medical therapy. Notably, this study had a sample size of only 26 and the medical therapies used in the control group are largely outdated and are now known to be suboptimal.
The Kidney Disease: Improving Global Outcomes (KDIGO) 2020 guidelines recommend cardiac screening via noninvasive methodologies for high-risk asymptomatic patients but also specify that coronary revascularization should not be done if only to reduce the risk for events. These guidelines are summarized in the Table. The inconsistency in recommendations has led to great variability in practice patterns. In a study published in JAMA Internal Medicine in 2019, researchers identified a wide range (11% to 96%) in the percentage of transplant patients undergoing cardiac stress testing across 217 sites.
Reality of transplant medicine
When making screening and practice recommendations for CVD, it is crucial to consider the realities of transplant medicine. There is a high demand for transplants and the recent HHS goal is to double the number of kidney transplants in the next decade. Transplant centers are under close scrutiny by the federal government and organizations such as the United Network for Organ Sharing (UNOS) to have excellent outcomes in both allograft and patient survival.
High demand and close examination place considerable pressure on transplant physicians and centers performing pre-transplant CV screening, which has led to more defensive and risk-averse medical practices. With regard to CVD, this means increased screening and intervention for donors and recipients with the hopes of severely minimizing cardiac risk. Unfortunately, this also can lead to increased risk for use of dual antiplatelet therapy as well as prolonged wait times and health care costs for individuals undergoing evaluation for CVD.
Emerging data
ISCHEMIA-CKD compared the efficacy of initial invasive coronary angiography with revascularization followed by optimal medical therapy compared with initial conservative management with optimal medical therapy for individuals with moderate to severe CAD and CKD. A recent post hoc analysis of these data specifically examined 194 patients listed for kidney transplant.
These patients met the following inclusion criteria: end-stage renal disease on dialysis or an estimated glomerular filtration rate less than 30 mL/min/1.73 m2 and chronic coronary syndrome, either well controlled or no angina, and at least moderate to severe myocardial ischemia. Exclusion criteria included left main disease, late-stage HF, recent ACS or persistent angina despite medical therapy. Clinical outcomes were assessed at 3 years.
Ultimately, half of the patients initially randomly assigned to the invasive strategy received coronary revascularization and 22% of those randomly assigned to initial medical therapy underwent coronary revascularization. Figure 1 shows the 30% of the optimal medical therapy group had primary outcome events (all-cause death or nonfatal MI) compared with 29% in the initial invasive strategy group (adjusted HR = 0.91; 95% CI, 0.54-1.54).
Secondary outcomes included death, nonfatal MI, stroke or hospitalization for unstable angina, HF or resuscitated cardiac arrest. Those event rates were 34% in the initial optimal medical therapy group and 33% in the initial invasive therapy group (aHR = 0.89; 95% CI, 0.55-1.46). This analysis also compared event rates between patients listed for transplant with those not listed for transplant, with no significant interaction for primary (P = .68) or secondary events (P = .35).
These results are in line with previous data that also suggested no survival benefit of revascularization compared with optimal medical therapy for patients on the transplant list. Similarly, another study suggested that cardiac stress testing in the 18 months prior to transplant was not associated with reduction in death or MI. These data are limited in overall primary outcome events and cannot be generalized for severely symptomatic patients.
For patients with no symptoms and well-controlled coronary disease, these data suggest that an early invasive procedure does not lead to improvement in survival. This lends itself to the next question: How much and what type of preoperative cardiac testing should we be doing for kidney transplant candidates? The CARSK trial is seeking to answer this question.
The other half
Often overlooked in these discussions is the live kidney donor. Approximately one-third of kidney transplants come from living donors who are also at risk for CVD. Similar to patients awaiting transplant, guidelines for living donors vary greatly from site to site. The most recent guidelines for living donors by KDIGO in 2017 recommend counseling patients on lifestyle modifications, including diet, exercise, smoking cessation and weight loss as indicated prior to undergoing surgery.
This report specifically highlights that cardiac testing to assess for CAD such as stress testing is not indicated per the ACC/AHA guidelines for asymptomatic patients with a MET score of at least 4 undergoing noncardiac surgery. As such, there are little data available examining the prevalence of CVD in potential live kidney donors. Post-donation studies are similarly limited; however, one study evaluating living donors compared with controls at 15 years after transplant demonstrated an increase in risk for CVD and death and end-stage renal disease.
As demand for donors continues to grow, so has use of “extended criteria” donors, which is broadly defined as individuals who are older and/or have existing comorbidities, including treated hypertension and diabetes. A study published in the Clinical Journal of the American Society of Nephrology in 2019 examining these extended criteria donors showed no increase in mortality at 15 years after donation; however, there is a higher risk for developing CKD than age-matched nonhypertensive donors. CV morbidity and mortality outcomes were not examined in this study.
Although it is crucial to minimize extraneous and unnecessary testing, the paucity of data on living donors documents a knowledge gap that could be addressed. Individuals may have low risk entering the procedure, but particularly as living donors now include older individuals with more comorbidities, it becomes more prudent to closely screen and monitor their CVD risk, both pre-and posttransplant, as potential risks for CVD and CKD begin to compound.
Reevaluating current practices
Current standards of care and guidelines for CVD risk assessment of patients awaiting kidney transplants are variable and result in expensive cardiac testing and intervention for many patients. Emerging data from a post hoc analysis of ISCHEMIA-CKD in conjunction with previous trials indicate that current practices do not necessarily result in increased survival benefit for patients awaiting kidney transplant. Similarly, lack of data regarding CVD risk of living donors provides an opportunity for new research. Now is the time to reevaluate current practices and update guidelines with a stronger emphasis on mitigating risk factors through comprehensive medical and lifestyle management.
References:
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- National Kidney Foundation. www.kidney.org/news/newsroom/factsheets/Organ-Donation-and-Transplantation-Stats. Accessed Dec. 28, 2021.
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For more information:
Roger S. Blumenthal, MD, is director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease and professor of medicine at Johns Hopkins University School of Medicine. He is also the editor of the Prevention section of the Cardiology Today Editorial Board. Twitter: @rblument1.
Hamid Rabb, MD, is professor of medicine at Johns Hopkins University School of Medicine and medical director of the Johns Hopkins Kidney Transplant Program.
Aarti Thakkar, MD, MPH, is an internal medicine resident at Johns Hopkins Hospital. Twitter: @aarti693.
Maitreya Thakkar, MBBS, is assistant professor of medicine at Duke University School of Medicine. Twitter: @maitreyathakkar.
The authors can be reached at Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Division of Cardiology, Johns Hopkins University School of Medicine, 600 N. Wolfe St., Halsted 560, Baltimore, MD 21827.
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