Living donors have gradually become a vital source of transplanted kidneys in the past two decades. With the expansion of the living donor pool, a closer look at the short- and long-term effects of uninephrectomy was warranted. Several concerns regarding the outcome of uninephrectomized patients have been raised considering the risk of hyperfiltration injury reported in other debatably similar models. In rats, a significant reduction in nephron mass was associated with subsequent proteinuria and hypertension with a gradual decline in renal function [45, 46]. Physiologically, renal adaptation to nephron loss is through augmented filtration per single nephron. With hyperfiltration, glomerular hypertension and glomerulosclerosis ensue and eventually compromise renal function. Clinically, the observed effect of donor uninephrectomy does not seem to parallel that seen in other models of nephron loss. The exact underlying physiology is yet unknown, although it appears that the excision of half of the functional nephrons does not seem to bring about a maladaptive hyperfiltration, essentially due to the lack of a significant upsurge in glomerular capillary pressure. In other words, the required increase in single nephron glomerular filtration (SNGFR) brought on by uninephrectomy is fairly tolerated by the remaining nephrons due to an increase in glomerular plasma flow rather than an increase in pressure [47].

In kidney donors, initial cross-sectional studies made little to advance our understanding of the long-term outcomes following kidney donation particularly considering the variable methods and definitions used, conflicting results, significant losses to follow-up, and modest follow-up periods. Nevertheless, no significant risks were reported following kidney donation. In 2009, Ibrahim et al. presented a follow-up of 3,698 donors with time since donation ranging from 3 to 45 years. The authors found no significant long-term consequences compared to the general population. When donors were compared to their age-, sex-, and gender-matched controls, no significant increase in mortality was noted. Furthermore, the risk of developing hypertension, proteinuria, and ESRD was comparable to the general population [48].

Criticism concerning the choice of controls in prior studies led to newer investigations targeting healthy matched controls that would have been eligible for donation themselves. Two such studies conducted by Mjøen et al. in 2013 and Muzaale et al. in 2014 found a significant increase in long-term adverse outcomes in donors following donation [49, 50]. Mjøen et al. showed that comparing donors to matched non-donors eligible for donation yielded a higher hazard ratio for the development of ESRD (11.38) in donors over a median follow-up period of 15.1 years [49]. Overall, the study showed that ESRD, cardiovascular, and all-cause mortality is significantly increased in donors compared to non-donors who meet the criteria for donation. Similarly to previous studies, all-cause mortality was not increased in donors in the first 5–10 years, but it significantly increased thereafter [49, 51–53]. Unfortunately, Mjøen et al. did not evaluate for the presence of comorbidities and risk factors that may contribute to the increased cardiovascular risk in the donor population. Since ESRD in kidney donors was mostly due to a primary renal disease and most donors are first-degree relatives of patients with ESRD, the authors eventually raised the concern whether genetic familial factors, rather than uninephrectomy, may have guided their novel findings [49].

In another study, Muzaale et al. also reported a slightly elevated risk of ESRD with similarly profiled controls. The estimated lifetime risk of ESRD was 90 per 10,000 donors, compared to 14 per 10,000 in healthy matched controls. The investigators also pointed out the problematic comparisons previously made to the general population. When compared to unscreened controls (comparable to the general population), the risk of ESRD was threefold lower in donors given the increased prevalence of comorbidities in the unscreened cohort. At 15 years, donors who were 50 years of age and older, those of black ethnicity, and male donors had significantly higher cumulative incidence of ESRD than younger donors, donors of white ethnicity, and female donors [50]. Similarly to Mjøen et al., the authors did not incorporate other comorbidities in assessing the etiology of the increased risk of ESRD in the donor group [49, 50].

Beyond renal function in donors, alterations in arterial structure and function have recently become a major point of interest given the link between reduced kidney function and cardiovascular disease. Evaluating a proposed arterial dysfunction brought on by reduced renal mass has been attempted by several investigators primarily by assessing the risk for higher blood pressure and hypertension in the donor population. Following donor nephrectomy, studies have inconsistently shown an increased risk for the development of hypertension. Furthermore, despite a documented increase in systolic and/or diastolic blood pressure values in certain donors, most were still below a hypertensive-range blood pressure. Albeit, with findings of increased cardiovascular mortality with elevated blood pressure readings even below the hypertensive threshold, additional investigations in the kidney donor population are needed [54]. A meta-analysis by Boudville et al. pooling 48 studies on blood pressure following kidney donation showed a 5 mmHg increase beyond the expected for normal aging over a 5–10-year follow-up period. A higher risk for developing hypertension was documented in patients with male sex, older age at donation, higher pre-donation blood pressure, and lower pre-donation GFR [55]. Still, the tendency toward a higher blood pressure in donors has been contested by other investigators that documented a similar prevalence of hypertension compared to matched controls [48].

A similar trend was observed in studies reporting the estimated cardiovascular risk in donors. Variable results have been reported even with well-matched controls. Garg et al. showed a lower risk of death or a major cardiovascular event in a cohort of 2,028 donors and 20,280 healthy matched non-donors with a median follow-up of 6.5 years [53]. Conversely, Mjøen et al. reported results for a similar-sized cohort with a longer median follow-up of 15.1 years. The study showed an elevated hazard ratio for all-cause and cardiovascular mortality in donors compared to matched controls fitting classical donor selection criteria [49].

Although not yet clearly outlined, uninephrectomy may have some effect on the arterial dysfunction implicated in cardiovascular outcome in donors. The identification of surrogate measures to identify arterial integrity and to recognize early subclinical cardiovascular disease is thus essential in this unique population. The utility of arterial stiffness, a well-established predictor of cardiovascular outcome in patients with ESRD and renal transplant recipients, has been scarcely utilized among kidney donors. Bahous et al. were the first to report increased arterial stiffness in a cohort of kidney donors compared to healthy matched controls by means of cfPWV and pulse pressure (PP). The investigators showed that donors had a significantly higher mean cfPWV (9.5 ± 2.5 m/s) compared to healthy matched controls (8.5 ± 1.5). In addition to the association between elevated cfPWV and older donor age, higher mean arterial pressure, higher fasting plasma glucose, and smoking, unique renal factors such as longer time since kidney donation were also implicated in arterial stiffness post nephrectomy. Interestingly, the study postulated that the involvement of these renal factors in arterial stiffness might ultimately suggest a role for uninephrectomy in the worsening of arterial stiffness. In their study, the authors questioned whether the gradual development of the abovementioned factors could be in fact partly attributed to the “age” of unilateral nephrectomy, speculating a temporal relation between uninephrectomy and increased cfPWV. These results were the first to usher the association between uninephrectomy and elevated aortic PWV independently of other classically reported risk factors. Additionally, the investigators also described an independent positive relationship between PP and macroalbuminuria and/or microalbuminuria in donors, further strengthening a link between renal function and large artery stiffness [34]. Nonetheless, the real link between uninephrectomy and arterial stiffness remains poorly defined due to paucity of available data. Studies with a larger population of donors and a longer follow-up period are required to verify the association between donor uninephrectomy and increased arterial stiffness.

In conclusion, renal transplantation remains the renal replacement modality of choice for patients with ESRD. It confers great advantage in the amelioration of cardiovascular disease risk and arterial stiffness compared to other renal replacement therapies. Nonetheless, it was shown that arterial stiffness might still be greater in renal transplant recipients compared to age- and gender-matched subjects from the general population. This significant increase may be attributable to recipient, transplant, and donor characteristics that cumulatively predispose these patients to an increased cardiovascular disease burden.

While earlier studies focused on arterial stiffness in transplant recipients, emerging data is scrutinizing into arterial stiffness in the donor pool as well. However, the literature to date is still conflicting, and more long-term research is indeed warranted to better outline the true relation between arterial stiffness and cardiovascular risk in both renal transplant recipients and donors. Needless to say, kidney donation is undeniably an altruistic unrivaled act that confers better outcome to recipients and does not carry a significant risk for the living donor. Support of this act should remain unequivocal.