Is the Risk of Cardiovascular Disease Increased in Living Kidney Donors?

A Danish Population-Based Cohort Study

Philip Munch; Christian Fynbo Christiansen; Henrik Birn; Christian Erikstrup; Mette Nørgaard

Disclosures

American Journal of Transplantation. 2021;21(5):1857-1865. 

In This Article

Discussion

In this nationwide population-based cohort study, we identified a higher risk of initiating treatment for hypertension after living kidney donation when compared with blood donors. While this finding may suggest a higher risk of hypertension after kidney donation, there are potential sources of bias that should be considered. However, we did not identify higher risks of AF, ischemic stroke, ischemic heart disease, or death after living kidney donation neither when comparing with the general population nor in the comparison with healthy blood donors.

Kidney donors are highly selected through a thorough medical evaluation to ensure that only healthy persons are allowed to donate their kidney. Despite the inclusion criteria for the general population cohort, the comparisons from the general population cohort had more comorbidities and were prescribed more lipid lowering and antidepressant medication before index date than the kidney donors. This may at least partly explain the observed lower risks of CVD and death among kidney donors. If this is the case, then the fact that kidney donors and comparisons from the general population had virtually similar risk of initiating treatment for hypertension could actually indicate a potentially increased risk of hypertension in kidney donors. Although the pre-donation medical workup for blood donors is less extensive than for kidney donors, the health requirements are similar with respect to hypertension, CVD, chronic disease, etc. (Table S2).[24,25] This suggests that blood donors are at least as healthy as kidney donors as also indicated by the fact that they had fewer comorbidities and were prescribed less medication. Interestingly, despite this difference the risk of CVD did not substantially differ between kidney donors compared with blood donors, except for the risk of initiating treatment for hypertension.

To our knowledge, no previous studies have specifically investigated the association between living kidney donation and AF and our finding of no increased risk of atrial fibrillation or flutter thus adds to the existing literature. In line with our findings a previous study based on regional health care databases found a reduced risk of major cardiovascular events and death (HR, 0.66; 95% CI, 0.48–0.90) in living kidney donors compared with a general population cohort[8] which the authors also attributed to confounding by a better health among kidney donors. In contrast, our study could not confirm the 40% increased risk of CVD Mjøen et al. found when comparing kidney donors with self-proclaimed healthy individuals during a median follow-up of 15 years. Multiple studies have investigated the risk of hypertension after kidney donation. Similar to our study, two recently published studies by Holscher et al. and Haugen et al. found increased risks of hypertension among kidney donors (HR, 1.19; 95% CI, 1.01–1.41 and odds ratio, 1.25; 95% CI, 1.12–1.39, respectively),[17,18] while a meta-analysis identified an association between living kidney donation and increased diastolic blood pressure but no clear association with hypertension.[3] Several biological mechanisms may explain a potential increased risk of hypertension in living kidney donors. The reduced renal function observed after donor nephrectomy may lead to elevated sympathetic and renin-angiotensin-aldosterone system activity as well as hypervolemia, salt retention, and endothelial dysfunction which are linked to increased risk of hypertension.[26–28] While hypertension is a well-known risk factor for CVD, there are a number of potential explanations for not observing an increased risk of CVD in the kidney donor cohort. Firstly, it is possible that the follow-up time was too short to identify this effect. Secondly, Danish kidney donors are offered regular nephrology follow-up after donation which may lead to a greater likelihood of initiating on antihypertensive treatment or being more aggressively treated, even if having only mild hypertension, in particular given their previous nephrectomy and reduced kidney function. Compared with the general population they may therefore have milder hypertension as well as receiving an earlier and/or more aggressive antihypertensive treatment which may reduce the risk of adverse CVD outcomes.

This study takes advantage of the Danish population-based nationwide databases with long and virtually complete follow-up. Still, several limitations should be considered when interpreting our results. First, although we have included virtually all living kidney donors in Denmark during a 23-year period, the total number of kidney donors was limited. This affected the precision of our estimates, due to the limited numbers of events, especially for the CVD outcomes and death, and may have masked small adverse effects of kidney donation. Second, the exclusion of kidney donors with significant comorbidities implies that our results are not necessarily valid for all potential kidney donors. Third, Mjøen et al.[14] showed an increase in all-cause mortality to become evident 15 years after kidney donation. Thus, our follow-up time with a median of 8 years may be insufficient to detect such adverse effects of kidney donation. Fourth, we lacked pre-index baseline information on some additional and potentially significant confounders including actual blood pressure levels, GFR, and body mass index, therefore, unmeasured confounding cannot be ruled out. Fifth, hypertension and diabetes are known to be considerably underdiagnosed and undertreated in the Danish population;[29,30] and thus, despite excluding patients with antihypertensive drugs and diabetes/antidiabetic drugs before index data, the included comparisons from the general population and blood donors may still have suffered from unreported hypertension and diabetes. This may have led to residual confounding making us underestimate the relative risks of the outcomes among kidney donors. Sixth, kidney donors had more comorbidities and were prescribed more medication than blood donors. This may have led to a greater likelihood that kidney donors would start treatment with antihypertensive drugs making us overestimate the relative risk of hypertension among kidney donors. Seventh, the study was conducted in a homogenous population mainly constituted of Caucasians, while this enhances the internal validity, the lack of diversity implies that the results may not be generalized to all ethnicities. Finally, emergency room diagnoses were included in the last 4 years of follow-up when comparing with blood donors and these diagnoses may have lower validity than in- and outpatient diagnoses. However, our sensitivity analyses suggested that the effect of this was negligible. Previous studies have shown that inpatient and outpatient diagnoses of AF, angina pectoris, MI, and ischemic stroke are recorded accurately in DNPR.[31–33] Likewise, the definition of hypertension as the redemption of minimum 2 antihypertensive drugs has been shown to have high specificity.[34] Thus, we believe that potential misclassification of these outcomes was limited.

In conclusion, this study identified a slightly increased risk of initiating treatment for hypertension. Whether this reflects a greater risk of hypertension or represent surveillance bias, confounding and/or differences in the threshold for treatment remains to be clarified. In contrast, we did not identify increased risks of CVD or death after living kidney donation. The potential increased risk of hypertension emphasizes the importance of regular follow-up care for kidney donors. The lack of associations between living kidney donation and CVD as well as death; however, supports the safety of living kidney donation based on current principles involving rigorous medical examination and strict requirements for living kidney donation.

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