Kidney Transplant Boosts CV Functional Reserve

Patients with end-stage renal disease can expect to see improvements in cardiovascular functional reserve measured using cardiopulmonary exercise testing (CPET) within a year of undergoing a kidney transplant, the prospective CAPER study shows.

Maximum oxygen consumption (VO₂max) increased in patients who received a new organ, whereas those with advanced chronic kidney disease (CKD) who were wait-listed experienced a decline. There were no concomitant changes, however, in LV mass.

“Our study found that partial restoration of kidney function by transplant was significantly associated with improved cardiovascular functional reserve as assessed by CPET, without major change in ventricular structural morphologic features,” according to lead author Kenneth Lim, MD, PhD (Massachusetts General Hospital, Boston), and colleagues. “The CPET-derived indexes were also sensitive enough to detect a decrease in cardiovascular functional reserve in wait-listed patients with CKD who did not receive transplants.”

The study, published online February 5, 2020, ahead of print in JAMA Cardiology, “appears to provide insight on cardiovascular structural-functional dynamics and the association of kidney function restoration with cardiovascular physiologic findings,” the authors continue. “The data presented indicate that VO₂max may be a sensitive index for assessing cardiovascular function and stratifying risk in patients with renal impairment.”

Mechanisms Unknown

Lim noted to TCTMD that CVD remains the leading cause of death in patients with CKD. The only real treatment for advanced CKD, he said, is kidney transplantation, which has been shown to have beneficial effects on cardiovascular morbidity, quality of life, and survival. Trials looking at ways to improve CV outcomes in patients with CKD have largely been neutral, and part of the problem is the lack of intermediate endpoints that can be used to assess efficacy, Lim said.

In the single-center, prospective CAPER study, he and his colleagues employed CPET, which is commonly used in cardiology but has not been extensively used in the nephrology field, to evaluate cardiovascular functional reserve before and after kidney transplantation. The investigators also used transthoracic echocardiography (TTE) to study morphological changes.

The study included 253 patients (mean age 48 years; 55.7% men) who were divided into three groups:

• 81 patients with stage 5 CKD who received a kidney transplant
• 85 patients with stage 5 CKD who did not receive a kidney transplant
• 87 patients with hypertension and preserved kidney function

At baseline, VO₂max and oxygen consumption at the point of anaerobic threshold (VO₂AT) were significantly lower in the two CKD groups compared with the hypertensive patients. CKD was also associated with lower maximal workload, endurance time, and maximum heart rate. TTE showed that mean cardiac LV mass index was higher in the patients with CKD, whereas mean LVEF was lower.

After kidney transplantation, there were improvements at 1 year in VO₂max (from 20.7 to 22.5 mL/min-1/kg-1) and VO₂AT (from 11.8 to 13.4 mL/min^-1/kg^-1). Maximum oxygen consumption in the transplant group did not reach the level seen in the hypertensive patients, however. Among the CKD patients who did not receive a new organ, VO₂max declined over the 12 months of follow-up (from 18.9 to 17.7 mL/min^-1/kg^-1).

Transplantation also was associated with an uptick in LVEF, from 60.0% at baseline to 63.2% at 1 year (P = 0.02), and improvements in maximal workload and endurance time. There was no significant change in LV mass index.

“Taken together, the marked changes in measures of functional cardiovascular reserve and the subtle difference in LVEF in the absence of other significant structural echocardiographic changes reported here suggest that the reduction in cardiovascular mortality associated with kidney transplant may be explained by improved cardiovascular functional reserve,” the authors write.

Lim said the physiology underlying the improvements in cardiovascular function seen after kidney transplantation is still not fully understood, but the fact that gains are seen in the absence of structural changes in the heart indicates that other factors are involved. He pointed to improvements in musculoskeletal function, declines in inflammatory markers, and reversal or uremia after transplantation as potential contributors.

‘Exciting’ Findings, With Caveats

In an accompanying editorial, George Bakris, MD, and Michelle Josephson, MD (both from University of Chicago Medicine, IL), call the findings exciting, but say they should be interpreted with caution due to a number of issues.

“First, these individuals overwhelmingly received living donor kidneys; thus, it is unclear whether these outcomes would be similar if deceased donor kidneys were implanted. Second, approximately one-third preemptively underwent transplant, and the remainder had relatively short dialysis duration (ie, mean of < 3 years). This scenario is not typical for transplant in the United States,” they write. And third, they say, more than 80% of the transplant group was white and “it is unclear whether these findings would be translatable to a more typical transplant cohort.”

Like Lim, they point out that the mechanisms underlying the cardiovascular benefits of kidney transplantation are not clear.

“The data from the current study demonstrate improvement of cardiovascular functional reserve after transplant despite the absence of left ventricular mass reduction,” Bakris and Josephson write. “Many factors likely contribute to this benefit. Reduced inflammation and anemia burden are likely pivotal elements associated with this benefit.”

Lim called CAPER a proof-of-concept study that “shows us that there is a significant role for CPET technology in the nephrology field. It is a very good way of assessing improvement or decline in cardiovascular health in kidney patients. . . . VO₂max, which is the outcome for CPET testing, could in fact be a potential new endpoint both for risk stratification of kidney patients as well as for clinical trials.”

Future studies, he said, should look at how CV function changes in early-stage CKD and also at whether there is a relationship between VO₂max declines and CV events.