Risk For Subsequent Hypertension And Cardiovascular Disease After Living Kidney Donation: Is It Clinically Relevant? Part 2

URAEMIC CARDIOMYOPATHY

The term uraemic cardiomyopathy was coined in the 1980s with reports of frequent abnormalities in cardiac function and structure in patients with CKD/ESKD: namely increased left ventricular (LV) mass and left ventricular hypertrophy (LVH); diastolic and systolic dysfunction; together with, often extreme myocardial fibrosis on histology [107–114]. However, LV hypertrophy had been noted in conjunction with kidney disease as early as 1827 by Richard Bright at Guys Hospital in London [115]. The etiology of uraemic cardiomyopathy is likely to be multifactorial and includes pressure and volume overload, anemia, increased oxidative stress, and activation of the renin–angiotensin–aldosterone system, as well as elevated concentrations of cardiotonic steroids, uric acid, parathyroid hormone, fibroblast growth factor-23 (FGF-23) and other uraemic toxins [112, 113, 116, 117]. Many of these factors including uric acid, parathyroid hormone, and FGF-23 increase post-kidney donation [36, 37, 40, 118]. The severity of uremic cardiomyopathy as measured by LV mass is a powerful predictor of cardiovascular mortality [119–131]. Uraemic cardiomyopathy is probably not only present in almost all patients with ESKD on dialysis but also appears to present to a lesser degree in patients with milder forms of CKD [109–111]. Studies of subjects with stage 2 and 3 CKD have reported a high frequency of cardiac abnormalities consistent with uraemic cardiomyopathy [43, 111, 116]. 

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As uraemic cardiomyopathy appears to begin early in patients with CKD, it might be expected that some features might be present in kidney donors, particularly those with lower post-donation renal function. Until recently, data were restricted to a few small, cross-sectional, or uncontrolled studies that reported conflicting results after kidney donation. A small cross-sectional echocardiographic and cardiac magnetic resonance imaging (CMR) study of 15 Italian donors compared with age and sex-matched healthy controls from the USA at a median of 8.4 years (minimum of 5 years) from donation found that most measures of LV geometry and function were not different in donors and controls, but donors did exhibit abnormalities of LV apical rotation and torsion [132]. In an uncontrolled study of 23 kidney donors using CMR, LV mass increased at 12 months without a change in office blood pressure [133]. By contrast, a two-dimensional speckle tracking echocardiographic study of 30 kidney donors at baseline and 12 months after donation found no significant differences in left or right ventricular function [134].

A UK prospective, controlled study of myocardial structure and function in kidney donors has provided 1- and 5-year data. In 68 donors and 56 equally healthy controls (many of whom were worked up for donation but did not donate), with a blinded endpoint analysis at 12 months, there was an increase in LV mass measured by CMR in donors but not controls [36]. The global circumferential strain was also decreased, indicating early changes in systolic dysfunction. There was no change in blood pressure measured by 24-h ambulatory monitoring and no association between change in LV mass and changes in blood pressure. However, at 5 years post-donation, 50 donors and 45 controls from the original cohort were restudied using CMR imaging [37]. In this subgroup, the increase in LV mass at 1- year post-donation was still observed. However, the change in LV mass in kidney donors at 5 years was not different from healthy controls [0.40 (95% CI 4.68–5.49 g)]. There were no significant differences in the changes in LV or left atrial volumes, LV geometry, global longitudinal strain, or global circumferential strain at 5 years [37]. Furthermore, at 5 years, there were no differences between donors and controls in surrogate CMR markers of LV fibrosis (T1 mapping and late gadolinium enhancement) [37]. There was an increase in high-sensitivity C-reactive protein, high-sensitivity troponin T and vitamin D over time in both donors and controls. At 12 months, the prevalence of detectable troponin T was greater in donors than in controls; at 5 years, the prevalence had increased in both groups, reducing the between-group difference [37].

There are several potential explanations for the different findings at 1 year and 5 years in kidney donors compared with controls. Effects due to random chance given the relatively low number of participants are certainly one possibility. Another possibility is the narrowing in the difference in renal function between donors and controls 1–5 years post-donation. Whereas in donors the mean GFR increased by 2 mL/min/1.73 m2 over this period, the GFR in controls declined by 1 mL/min/1.73 m2 per year. Given the strong association between GFR and LV mass in observational studies [125, 131, 135], a reduced difference in GFR between donors and controls would be expected to be associated with a reduced difference in LV mass. Furthermore, other factors associated with increased LV mass such as anemia, increased erythropoietin, and C-reactive protein levels are seldom present after 12 months in donors [136]. 

Coronary microvascular dysfunction, as measured by coronary flow reserve velocity, is highly prevalent in patients with CKD and is associated with an adverse prognosis [137]. It is also thought to be a contributor to the development of uraemic cardiomyopathy [137]. In a small cross-sectional study of 23 donors with a median of 30 months post-donation and 25 closely matched controls, donors were found to have significantly lower coronary flow reserve velocity than controls [138]. These findings need to be replicated in larger, prospective, longitudinal studies.

In summary, there are few studies investigating cardiac structural and functional change after kidney donation. The studies that do exist have small sample sizes and have provided conflicting results. Current evidence suggests that although kidney donation may result in small changes in cardiac structure and function within 1 year, these do not appear to be sustained in the longer term. Well-controlled and much longer follow-up studies with serial cardiac investigations are required.

CONCLUSION

Ronald never had any regrets about donating a kidney to his brother. Then, as now, live donor kidney donation offers patients with ESKD the best chance of long-term, dialysis-free survival [58, 139]. Donors get no direct reward for their efforts. However, well before donation, potential donors need and indeed deserve, to have good quality information on the future risks to their overall health, quality of life, and potential impact on life expectancy. Given the close relationship between cardiovascular disease and CKD, information on future risks of cardiovascular disease and hypertension is particularly relevant. This is especially true given the ongoing relaxation of selection criteria, as a direct consequence of the increasing demand for kidney transplants, including donors with metabolic syndrome, diabetes, and hypertension [140–143]. As this review highlights, the evidence required is still sadly lacking. It is therefore perhaps not surprising that there is a large variation in how often (from always to never) different long-term risks are discussed with potential donors [144].

Long-term (at the very least 20 years) prospective studies and registries, with appropriate healthy control groups, with adequate representation of different racial groups and comorbidities, are required so that donation-attributable risks can be calculated as required [140]. It is perhaps a comforting thought that there is increasing evidence that altruism and volunteering are associated with longer life expectancy and reduced healthcare use [145–147]. However, given that their actions benefit not only the recipient but also the much wider society as a whole, live donors deserve much more than just wishful thinking. Considering the current uncertainty over the risks involved with kidney donation, transplanting centers should develop a long-term relationship with donors allowing close follow-up of all factors related to cardiovascular risk. For the moment, it seems reasonable to provide counseling, monitoring, and treatment of modifiable cardiovascular risk factors, and reassurance that although the evidence base is imperfect, no study has provided robust evidence of increased risk of cardiovascular death or disease.

CONFLICT OF INTEREST STATEMENT

None declared.

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