Among patients with chronic kidney disease (CKD), the leading cause of death is cardiovascular disease. In patients receiving maintenance dialysis, left ventricular hypertrophy and systolic and diastolic dysfunction are predictors of worse cardiovascular outcomes. In patients with advanced CKD, the myocardium is exposed to complex metabolic stressors resulting from uremia-related inflammation, oxidative stress, renin-angiotensin-aldosterone system activation, calcitriol and klotho deficiency, increased fibroblast growth factor 23 (FGF 23), and changes in mineral metabolism. This leads to myocyte hypertrophy, reduced myocardial capillarization, and nonvascularized interstitial fibrosis, and arteriosclerosis and arterial stiffening. Combined, the changes reduce pump efficiency and increase cardiac energy expenditure and consumption of myocardial oxygen.
The optimal treatment for end-stage renal disease (ESRD) is kidney transplant; restitution of kidney function is associated with reduced cardiovascular morbidity and improved quality of life and survival. Previous studies of the mechanisms involved with improved cardiovascular survival have relied in most part on static measures from echocardiography or cardiac magnetic resonance imaging; to date, results from those studies have been conflicting.
Kenneth Lim, MD, PhD, and colleagues conducted a prospective, nonrandomized, single-center, three-arm, controlled cohort study to examine cardiovascular functional reserve in patients with ESRD prior to and following kidney transplant. The researchers also sought to examine the functional and morphologic alterations of structural-functional dynamics in that patient population. Results were reported online in JAMA Cardiology [doi:10.1001/jamacardio.2019.5738].
The cohort included patients with ESRD who underwent kidney transplant (KTR group), patients with ESRD on the transplant wait-list who did not undergo kidney transplant (NTWC group), and a control group of patients with hypertension but without CKD, cardiovascular disease (heart failure, ischemic heart disease, or cerebrovascular disease), or diabetes (HTC group). Baseline data were gathered from April 2, 2010, to January 1, 2103. Patients were followed up longitudinally for up to 1 year. Patients were assessed at baseline, 2 months, and 1 year.
The total study cohort included 253 participants; mean age was 48.5 years, 55.7% (n=141) were men, 81 were in the KTR group, 85 were in the NTWC group, and 87 were in the HTC group. Of the patients in the KTR group, 91.4% (n=74) received a living donor kidney transplant. Following transplant, the patients received a maintenance immunosuppression regimen consisting of combination treatment with corticosteroids (97.5%, n=79), tacrolimus (93.6%, n=96), or cyclosporine (1.2%, n=1), and azathioprine (50.6%, n=41) or mycophenolate mofetil (44.4%, n=36).
Seventy-three patients (90.1%) in the KTR group completed assessments at two-months post baseline, compared with 81 (95.3%) of those in the NTWC group. Assessments at 12 months were completed by 68 patients (84.0%) in the TKR group, 61 patients (71.8%) in the NTWC group, and 71 patients (81.6%) in the HTC group. None of the 81 patients in the KTR group had serious infectious complications that would have required exclusion from the study. During the 12-month study period, 27 in the KTR group required treatment for acute graft rejection episodes, but were not excluded from the study. Mean estimated glomerular filtration rate (eGFR) of all patients in the KTR group was 55.3 mL/min/1.73 m2 at 2 months and 59.1 mL/min/1.73 m2 at 12 months.
Mean age of the patients in the KTR group was 43.1 years, compared with 49.7 years in the NTWC group (P=.002) and 53.6 years in the HTC group (P<.001). Patients in the KTR group had significantly lower mean body mass index compared with the other two groups. There were no significant differences in sex, race/ethnicity, prevalence of hypertension, duration of antihypertensive use, and tobacco smoking status among the three groups. In the two CKD groups (KTR and NTWC), there were no significant differences in the antihypertensives used, prevalence of diabetes or cardiovascular disease, dialysis vintage, or levels of hemoglobin, highly sensitive C-reactive protein, serum calcium, or albumin.
At baseline, mean maximum oxygen consumption (VO2max) was significantly lower in the two CKD groups (KTR group, 20.7 mL · min-1 · kg-1; NTWC group, 18.9 mL · min-1 · kg-1; P=.03) compared with the HTC group (24.9 mL · min-1 · kg-1) (P<.001). Mean cardiac left ventricular mass index was higher in patients with CKD (KTR group, 104.9 g/m2; NTWC group, 113.8 g/m2) compared with the HTC group (878. g/m2) (P<.001). Mean left ventricular ejection fraction was significantly lower in patients with CKD (KTR group, 60.1%; NTWC group, 61.4%) compared with the HTC group (66.1%) (P<.001).
At 12 months, there was a significant improvement in VO2max in the kidney transplant group (22.5 mL · min-1 · kg-1; P<.001); the value did not reach the VO2max in the HTC group (26.0 mL · min-1 · kg-1). Compared with baseline, at 12 months VO2max decreased in the NTWC group (17.7 mL · min-1 · kg-1; P<.001).
Compared with the KTR group (63.2%, P=.02) or the NTWEC group (59.3%, P=.003) at baseline, there was a significant association between transplant and improved left ventricular ejection fraction at 12 months. There was no association between transplant and improved left ventricular mass index.
The researchers cited some limitations to the study, including lack of randomization and significant baseline differences in known variables associated with cardiovascular risk; the use of echocardiography to assess structural cardiac changes rather than cardiac magnetic resonance imaging; and the lack of assessment of noninvasive measures of cardiac output.
In conclusion, the researchers said, “Our study found that partial restoration of kidney function by transplant was significantly associated with improved cardiovascular functional reserve as assessed by CPET [cardiopulmonary exercise testing], without major change in ventricular structural morphologic features. 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 appears to provide insight on cardiovascular structural-functional dynamics and the association of kidney function restoration with cardiovascular physiologic findings. The data presented indicate that VO2max may be a sensitive index for assessing cardiovascular function and stratifying risk in patients with renal impairment.”
- Researchers conducted a prospective, nonrandomized, single-center, three-arm, controlled cohort study to examine cardiovascular functional reserve in patients with end-stage renal disease prior to and after kidney transplantation.
- At 12 months post-transplantation, there was an association between kidney transplant and improved cardiovascular functional reserve.
- There was no association between kidney transplant and left ventricular mass index.