PRESENTED BY
CHARLES  FERRO

Presentation Summary

Written by Milica Maksimovic
Reviewed by Charles Ferro

The first successful human organ transplant took place in 1954, when 23-year-old Ronald Herrick donated a kidney to his identical twin brother. Ronald eventually developed end-stage renal disease (ESRD) requiring haemodialysis and died at age 79 of cardiovascular disease [1]. The critical questions whether donating a kidney causes or contributes to ESRD, cardiovascular disease or other complications known to be associated with chronic kidney disease (CKD) remain unanswered still today. A study of 430 Swedish donors followed up from 15 to 31 years reported no evidence of increased mortality due to renal diseases or of a decreased overall survival as compared to mortality data for Swedish general population [2]. Similarly and even more reassuring, survival and the risk of ESRD in carefully screened 3698 kidney donors matched with NHANES controls on the basis of age, sex, race or ethnic group, and body-mass index, appeared to be comparable to those in the general population [3]. Relying on these data Mark Paulson donated a kidney to a non-related member at the age of 18 [4]. He went on to become a doctor and did a research project into the effects of kidney donation on mortality and renal survival. He was a bit horrified when he found a 2014 study showing a greater long-term risk of developing ESRD in kidney donors [5]. Whereas in the previous studies the risk of ESRD in kidney donors has been compared with the risk faced by the general population, this study included a comparison to similarly screened healthy non-donors which presumably would be a better control group for comparison. Another study that same year raised the possibility that kidney donors may face a heightened risk of dying of cardiovascular disease and all-cause mortality as well, compared with a control group of non-donors who would have been eligible for donation [6].

Informed consent policy has changed since then, and it is nowadays a legal requirement in the US, at least, to inform potential donors that although the risk to develop ESRD does not exceed that of the general population with the same demographic profile, it can, however, exceed that of healthy non-donors with medical characteristics similar to living kidney donors. KDIGO Guidelines for the evaluation of living kidney donors include similar recommendations. Despite that the estimated absolute risk of developing ESRD is only 0.3% at 15 years, the relative risk to develop ESRD of living donors is 3.5 to 5.3 fold higher than of healthy persons in the absence of donation.

Association of living kidney donation with increased cardiovascular mortality

The mechanisms by which CKD exerts adverse effects on cardiovascular structure and function are diverse. Potential mediators include increased arterial stiffness, hypertension, increased left ventricular (LV) mass and abnormal bone mineral metabolism, which may increase vascular calcification.

The expanding practice of live kidney donation provides a unique opportunity to study the cardiovascular effects of an isolated reduction in GFR without the multiple confounding factors associated with renal disease. The ALTOLD [7], the CRIB-Donor [8] and the EARNEST [9] studies are prospective, longitudinal studies comparing living kidney donors with similarly healthy control on structural and functional cardiovascular effects.

The CRIB-Donor study showed that in donors as compared to controls, there were significant increases in LV mass, which had a graded independent association with the reduction in GFR after adjustment for demographic and hemodynamic factors [8]. The data suggest that reduced GFR is an independent risk factor for adverse LV remodelling, independent of blood pressure. All the studies unequivocally show that kidney donation causes increases in weight, PTH, FGF23, uric acid, and tubular excretion of phosphate. With respect to the effects of kidney donation on peripheral blood pressure, the data are inconclusive. Uninephrectomy may be regarded as an “acute kidney injury,” with an immediate 50% reduction in GFR followed by a compensatory hypertrophy in the remaining kidney, possibly increasing the albuminuria.

Figure 1: Risk factors for ESRD in living kidney donors (slide 24, [10]).

Despite no evidence, it is an opinion of Prof Ferro that hypertension in these patients shall be treated, setting lower targets for blood pressure. Moreover, he would recommend using renin-angiotensin-aldosterone inhibitors should patients develop albuminuria, and possibly in the future, SGLT2 inhibitors with the ability to lower hyperfiltration especially if they gain weight. There exists evidence of improving kidney outcomes in adults with CKD by using uric acid-lowering therapy. However, extending this conclusion to living kidney donors is currently not scientifically justified. Despite yet unknown implications of kidney donation on mineral and bone disorders biomarkers, it is rational to ensure vitamin D supplementation if deficient. Donors are at increased risk to develop features of the metabolic syndrome that perfectly illustrates the necessity of their longitudinal follow-up, allowing for the detection of important risks [11]. Although genetic screening of potential donors for the genes and SNPs associated with ESRD seems far ahead, its greater role is envisioned in the future.

References

1. Kasiske BL, Asrani SK, Dew MA, et al. . The Living Donor Collective: A Scientific Registry for Living Donors. . Am J Transplant. 2017;17(12):3040-3048. DOI: 10.1111/ajt.14365.

2. Fehrman-Ekholm I, Elinder CG, Stenbeck M, Tyden G, Groth CG.. Kidney donors live longer. . Transplantation. 1997;64(7):976-978.. DOI: 10.1097/00007890-199710150-00007

3. Ibrahim HN, Foley R, Tan L, et al. . Long-term consequences of kidney donation. . N Engl J Med. 2009;360(5):459-469. DOI: 10.1056/NEJMoa0804883

4. Poulson M. . At 18 years old, he donated a kidney. Now, he regrets it. . Washington Post. 2016. DOI: /

5. Muzaale AD, Massie AB, Wang MC, et al. . Risk of end-stage renal disease following live kidney donation. . JAMA. 2014;311(6):579-586. DOI: 10.1001/jama.2013.285141

6. Mjoen G, Hallan S, Hartmann A, et al. . Long-term risks for kidney donors. . Kidney Int. 2014;86(1):162-167. DOI: 10.1038/ki.2013.460

7. Kasiske BL, Anderson-Haag T, Ibrahim HN, et al. . A prospective controlled study of kidney donors: baseline and 6-month follow-up. . Am J Kidney Dis. 2013;62(3):577-586.. DOI: 10.1053/j.ajkd.2013.01.027

8. Moody WE, Ferro CJ, Edwards NC, et al. . Cardiovascular Effects of Unilateral Nephrectomy in Living Kidney Donors. . Hypertension. 2016;67(2):368-377. DOI: 10.1161/hypertensionaha.115.06608

9. Moody WE, Tomlinson LA, Ferro CJ, et al. . Effect of A Reduction in glomerular filtration rate after NEphrectomy on arterial STiffness and central hemodynamics: rationale and design of the EARNEST study. . Am Heart J. 2014;167(2):141-149. DOI: e142.10.1016/j.ahj.2013.10.024

10. Ferro C. . Kidney protection in living donors. . Oral presentation at 56th ERA-EDTA Congress; June 15, 2019; Budapest, Hungary. . DOI: /

11. Grupper A, Angel Y, Baruch A, et al.. Long term metabolic and renal outcomes of kidney donors compared to controls with excellent kidney function.. BMC Nephrol. 2019;20(1):30. DOI: 10.1186/s12882-019-1214-4

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