Donors with kidney stones
Incidental kidney stones are found in between 4 and 15% of potential kidney donors [
36,
37] and it is important to understand the risk that this confers on both donor and recipient. Mayo Clinic reported one of the largest series in which, among 1957 kidney donors, 53 (2.7%) reported previous symptomatic kidney stones and 210 (11%) had computed tomography (CT) evidence of current kidney stones [
38]. Interestingly, in this cohort, the presence of asymptomatic stones was not associated with common risk factors seen in patients with symptomatic stone disease, such as metabolic syndrome, obesity, hypertension and male gender.
In a retrospective analysis of 377 CT angiograms of potential kidney donors between October 2004 and May 2007, Olsburgh et al. found asymptomatic kidney stones in 55 (5%) patients, of whom 20 donated their kidney, and 17 underwent ex vivo ureteroscopy (stone size 2–12 mm, non-obstructing). After a mean follow-up of 10 months, there was no stone-related complication in the recipient and no stone recurrence in the donors [
39]. A similar US study of 325 potential kidney donors between 2000 and 2005 found incidental non-obstructing kidney stones in 24 (7.4%) [
40]. The median stone size was 2 mm (range 1–9 mm). Sixteen patients proceeded to donation, 11 donating the stone-containing kidney and 5 the stone-free kidney. Only one recipient developed symptomatic kidney stone disease and was found to have hyperoxaluria. No other recipient and no donor had any complications related to kidney stones after a year of follow-up. It is important to note that in both of the above studies, the donors had no evidence of a metabolic stone-forming tendency.
To investigate whether kidney donors have a higher incidence of kidney stone formation, or require more frequent surgical intervention if they do develop a stone, Thomas et al. assessed a cohort of 2019 Canadian patients who had donated a kidney between 1992 and 2009 and compared them with a control group of 20,190 healthy non-donors [
41]. Reassuringly, after a median follow-up of 8.4 years, they saw no significant difference in the rate of kidney stones requiring surgical intervention or hospital attendance for kidney stones between the two groups.
Clinical practice guidelines from the British Transplantation Society and the American Transplant Society suggest that kidney donors with small asymptomatic stones and without metabolic disease may be considered for kidney donation [
42,
43]. Appropriate donor and recipient counselling and availability of follow-up are important considerations.
Obese donors
Worldwide, the proportion of adults with a BMI of ≥ 25 kg/m
2 rose between 1980 and 2013 from 29 to 37% in men and from 30 to 38% in women [
44]. This increased rate of obesity in the general population is inevitably mirrored in the kidney donor population. The risk of hypertension, diabetes, metabolic syndrome, ESKD, morbidity and mortality are all increased in overweight and obese individuals [
45‐
47]. Currently, there is significant centre variation in the BMI cut-off for living kidney donation. It is therefore important to know whether obesity adversely affects kidney donors.
From the surgical perspective, there have been concerns about increased complications in overweight and obese donors. Heimbach et al. reported on 553 kidney donors who underwent laparoscopic donor nephrectomy between 1999 and 2003 [
48]. A total of 114 had a BMI between 30 and 34.9 kg/m
2 and 58 had a BMI ≥ 35 kg/m
2. They found no significant difference in the rate of conversion from laparoscopic to open nephrectomy between the two groups. Operating time was slightly longer in the high BMI group. Wound complications such as infections and seromas were more common in obese (9–10%) compared with non-obese donors (2–4%). Overall peri-operative risk was not significantly higher in the obese group compared with non-obese donors.
Unger et al. reported short-term outcomes following donor nephrectomy in obese versus non-obese donors [
49]. In a retrospective analysis of 289 Austrian kidney donors who underwent nephrectomy between 2006 and 2015, 126 donors had a BMI ≤ 25 kg/m
2, 120 had a BMI between 25 and 30 kg/m
2 and 43 had a BMI ≥ 30 kg/m
2. They observed no significant difference between the groups in the conversion rate from laparoscopic to open surgery or in the rate of post-operative complications, such as wound or systemic infection. They noted, however, that both male sex and higher BMI were associated with a statistically significant short-term decline in eGFR during the first post-operative week. The longer-term significance of this observation remains unclear.
In a single centre study of 3752 living kidney donors who underwent nephrectomy between 1975 and 2014, 656 (17.5%) were obese with a BMI ≥ 30 kg/m
2 [
50]. Obese donors were more likely to be older, to be black and to have a higher eGFR at donation. There was no significant difference in intra- or post-operative complications between the obese and non-obese donors, but operating time and length of hospital stay were longer in the obese group. Reassuringly, there was no significant difference in eGFR and risk of ESKD between the two groups after 20 years (
p = 0.71). Diabetes and hypertension were more common (for diabetes: aHR 3.14;
p < 0.001 and for hypertension: aHR 1.75;
p < 0.001) and occurred earlier in obese donors (diabetes mellitus: 12 vs. 18 years post nephrectomy; hypertension: 11 vs. 15 years).
Bellini et al., in a single centre UK study, reported the mean eGFR at 6 months and up to 60 months in 889 living kidney donors between 2000 and 2017. Twenty-six percent of the donors had a BMI ≥ 30 kg/m
2 pre-donation. The authors found no significant difference in eGFR pre- or post-donation between obese and non-obese donors [
51]. This is similar to the findings of Rees et al. who studied 5304 donors, of whom 2108 (40%) were overweight (BMI 25–30 kg/m
2), 944 (17.8%) were obese (BMI 30–35 kg/m
2) and 250 (4.7%) were very obese (BMI ≥ 35 kg/m
2). There was no difference in re-admission or reoperation rate across the BMI groups and no significant difference between BMI groups with respect to decline in eGFR at 6 months [
52]. Although the donors with higher BMI had higher blood pressure pre-donation and at 6 months post-donation, the change in blood pressure in each BMI group was similar. Holscher et al. have studied the risk of developing hypertension or diabetes after kidney donation in 41,260 donors who underwent nephrectomy between 2008 and 2014 [
53]. A total of 74, 162 and 310 cases per 10,000 developed hypertension at 6 months, 1 and 2 years, respectively. The incidence of hypertension was higher in donors with a higher BMI (relative risk 1.29 per 5 units, 95%CI, 1.17–1.43). Very few donors developed diabetes including 2, 6 and 15 cases per 10,000 donors after 6, 12 and 24 months. The risk of developing diabetes was higher in donors with higher BMI (adjusted incidence rate ratio 1.52 per 5 units; 95%CI, 1.04–2.21). The low incidence of diabetes is most likely related to the short follow-up time. These results again highlight the importance of long-term follow-up for kidney donors.
In a very large study of 119,769 living kidney donors in the US with a maximum of 20-year follow-up, Locke et al. studied the association between BMI and development of ESKD [
54]. After adjustment for age, sex, ethnicity, blood pressure and baseline GFR, they found the incidence of ESKD to be 1.9 times higher in obese donors (BMI ≥ 30) compared with non-obese donors (BMI ≤ 30). At 20 years post-donation, the estimated incidence of ESKD was 93.9 per 10,000 in the obese group and 39.7 per 10,000 in the non-obese kidney donors. Obese donors were more likely to be male, black and to have higher blood pressure. Interestingly, they noted a 7% increase in the risk of ESKD for each unit increase in BMI above 27 kg/m
2, although below this threshold, there was no significant increase in risk.
More recently, the same group has reported the risk of mortality in the same kidney donor population [
55]. They found the estimated risk of mortality in obese donors to be 304 per 10,000 and 209 per 10,000 in non-obese living kidney donors. After adjustment for variables such as age, sex, race, eGFR, blood pressure and smoking, the obese kidney donors had a 30% increased risk of long-term mortality compared with the non-obese group (aHR 1.32, 95% CI: 1.09–1.60,
p = 0.006). It is likely that this increased risk of ESKD and mortality is related to obesity rather than to kidney donation per se.
Most transplant guidelines support kidney donation in otherwise healthy donors with a BMI below 30 kg/m2. Donors with a BMI between 30 and 35 kg/m2 must be counselled regarding their long-term risk of cardiovascular and kidney disease and should be encouraged to lose weight. As long-term safety data is not available for donors with a BMI greater than 35 kg/m2, donation in this population is discouraged.
Donors of African ancestry
Although donors of African descent represent a minority in most studies of kidney donation, this subgroup frequently demonstrates a higher risk of adverse outcomes, both peri-operatively [
56] and in the longer term.
Using data linkage between the Organ Procurement and Transplantation Network (OTPN) between 1987 and 2007 and billing claims from a private health insurer between 2000 and 2007, Lentine et al. [
57] investigated the rates of hypertension and kidney disease in 4650 living kidney donors, of whom 13.1% were African American. In comparison with white donors, black donors had an increased risk of hypertension (aHR 1.52; 95%CI, 1.23–1.88) and chronic kidney disease (aHR 2.32; 95% CI, 1.48–3.62). Using data from the same study [
56], Lentine et al. also noted that 7 years after donation and after adjustment for age and gender, the African American donors had a higher incidence of kidney-related conditions, including CKD (12.6% vs. 5.6%; aHR 2.32, 95% CI 1.48–3.62), proteinuria (5.7% vs. 2.6%; aHR 2.27, 95% CI 1.32–3.89), nephrotic syndrome (1.3% vs. 0.1%; aHR 15.7, 95% CI 2.97–83.0) and any renal diagnosis (14.9% vs. 9%; aHR 1.71, 95% CI 1.23–2.41).
In the previously mentioned study [
13], Muzaale compared the incidence of ESKD in 96,217 donors with 20,024 matched healthy non-donor controls and noted that after an average follow-up of 7.6 years, African American donors had a higher risk of ESKD in comparison with white and Hispanic donors, and also with black healthy controls. At 15 years after donation, the absolute risk of ESKD in black donors was 74.7 per 10,000 versus 23.9 per 10,000 in black non-donors (
p < 0.001). The absolute risk increase was 50.8 per 10,000 in African-Americans, 25.9 per 10,000 in Hispanics and 22.7 per 10,000 in white donors.
Although some of this increased risk may be attributable to the increased prevalence of hypertension as well as to socioeconomic factors, there is increasing evidence that variants in the gene encoding apolipoprotein L1 (APOL1) might play a contributory role.
Two common protein-changing alleles in the
APOL1 gene are associated with the observed increased risk of ESKD in African Americans [
57]. Given that the majority of donors donate to family members [
58], it has been proposed that the presence of these genetic variants may alter the course of post-donation kidney function in black donors. To address this, Doshi et al. [
59] examined the effect of
APOL1 risk alleles on outcomes in black living kidney donors. Among 136 black donors, 19 (14%) carried two risk alleles (high-risk group) and the remaining 117 carried one or zero risk alleles (low-risk group). The high-risk group had lower pre-donation and post-donation eGFR and at a median of 12-year follow-up showed a more rapid decline in kidney function. Two donors in the high-risk group developed ESKD. They also matched 115 black donors with 115 black non-donor controls; interestingly, the rate of decline in eGFR was similar in both groups irrespective of
APOL1 genotype. Thus, live kidney donation per se does not amplify the risk associated with
APOL1-related kidney disease. There was no difference in the prevalence of hypertension between donors on the basis of the
APOL1 genotype, although the donors were more likely to develop hypertension than non-donors, even after matching for family history of ESKD and
APOL1 genotype.
Currently, there is insufficient evidence to recommend screening all black donors for the presence of the high-risk
APOL1 genotype. However, the NIH-funded APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) [
60], which prospectively assesses the effects of
APOL1 variants on kidney outcomes for black living donors and the recipients of their kidneys, could potentially determine the risk of kidney donation in individuals carrying the high-risk gene.
Future pregnancy
Over half of living kidney donors are female and a significant proportion are of child-bearing age. Given that kidney donation and pregnancy both lead to kidney hyperfiltration, there have been concerns that kidney donation may lead to hypertension during pregnancy with or without pre-eclampsia. A large Norwegian study [
61] analysed registry data regarding kidney donors between 1967 and 2002 and identified 726 pregnancies in 326 donors. Of these, 106 pregnancies in 69 donors occurred after donation. The incidence of gestational hypertension and pre-eclampsia was compared between this group and a random sample of 21,000 pregnancies from the medical birth registry. In adjusted analysis, the risk of pre-eclampsia was higher in pregnancies post-donation than in pregnancies pre-donation (5.7% vs. 2.6%,
p = 0.026). There was no difference between the groups in foetal outcomes such as low birth weight or preterm delivery. A different study by Ibrahim et al. [
62] analysed data from 3213 pregnancies in 1085 US donors and compared the incidence of pre-eclampsia pre- and post-donation. They noted an increased risk of gestational hypertension (5.7% vs. 0.6%,
p < 0.0001), proteinuria (4.3% vs. 1.1%,
p < 0.0001) and pre-eclampsia (5.5% vs. 0.8%,
p < 0.0001) in pregnancies after donation. They also found a lower likelihood of full-term delivery in post-donation pregnancies (73.7% vs. 84.6%,
p = 0.0004) and a higher likelihood of foetal loss (19.2% vs. 11.3%,
p < 0.0001). However, foetal and maternal outcomes after donation remained comparable to the general population.
In a more recent study [
63], Garg et al. retrospectively assessed the incidence of gestational hypertension and pre-eclampsia in Canadian kidney donors between 1992 and 2009. Over a mean follow-up period of 11 years (maximum 20 years), 131 pregnancies in 85 donors were compared with 788 pregnancies in 510 healthy non-donors. After matching for several criteria, they noted that gestational hypertension and pre-eclampsia were more common in kidney donors than in non-donors (11% vs. 5%; odds ratio 2.4;
p = 0.01). Reassuringly, the incidence of low birth weight and preterm birth was the same in both groups.
It is important to note that in the above studies, donors were slim (BMI < 30) and normotensive. With increasing acceptance of donors with higher BMI and treated hypertension, together with increasing maternal age, it is important to continue surveillance of pregnancy outcomes in past donors. Although the absolute risk of pre-eclampsia remains low, young female donors must be informed of the increased risk.
Older and younger donors
The increasing need for kidney transplantation coupled with growing confidence regarding the superior outcomes from living kidney transplantation has resulted in increasing uptake in kidney donation from older living donors. Hence, the safety and efficacy of such donations has come under scrutiny. There is no agreed threshold for what constitutes an older donor and different studies have used different thresholds to define older living kidney donors.
To assess the risk of cardiovascular disease and mortality in older donors, Reese et al. [
64] matched 3368 individuals older than 55 years who had donated a kidney between 1996 and 2006 with the same number of healthy non-donors selected from a health and retirement study database. The mean age in both groups was 59 years. After a median follow-up of 7.8 years, they noted no significant difference in mortality (4.9 vs. 5.6 deaths per 1000 person-years, HR 0.90, 95%CI 0.71–1.15,
p = 0.21) or in a composite cardiovascular outcome including ischaemic heart disease, congestive heart failure, stroke, peripheral vascular disease or death (HR 1.02, 95%CI 0.87–1.20,
p = 0.7).
Another study of 219 healthy US adult kidney donors older than 70 years [
65] showed that mortality in this group was lower than in healthy matched controls from the National Health and Nutrition Examination Survey (HR 0.37, 95%CI 0.21–0.65,
p < 0.001). This was perhaps due to stringent donor selection criteria in this age group. However, graft loss from older donors was noted to be higher than that from younger living donors aged between 50 and 59 (subhazard ratio (SHR) 1.62, 95%CI 1.16–2.28,
p = 0.005) and closer to outcomes for kidney transplants from matched 50–59-year-old deceased donors (SHR 1.19, 95%CI 0.87–1.63,
p = 0.3).
Given that older living donors have a lower pre-donation GFR, the inevitable reduction in GFR post-donation is another important concern. Dols et al. [
66] have assessed long-term kidney function in 539 living kidney donors who donated between 1994 and 2006. A total of 422 of this group were less than 60 years of age and 117 were more than 60 years old. The older group had a lower pre-donation GFR (80 vs. 96 ml/min,
p < 0.001). After a median of 5.5 years of follow-up, the rate of GFR decline was similar in both groups (38 ± 9%). At 5 years after donation, more of the older donors had a GFR below 60 ml/min (80% vs. 31%,
p < 0.001) but no donor had a GFR below 30 ml/min. Interestingly, in this study, recipient outcome did not differ between older and younger donors. Given the shorter life expectancy of older donors, it may be reasonable to accept a lower post-donation eGFR in this group. This is reflected in the GFR thresholds for living kidney donation in the British Transplantation Society Clinical Practice Guidelines [
42].
In the previously cited US registry study by Muzaale et al. [
13], although the cumulative incidence of ESKD per 10,000 was low among living kidney donors overall, there was significant variation with donor age, being 29.4 in donors aged between 18 and 39, 17.4 in donors aged between 40 and 49, 54.6 in those aged between 50 to 59 and 70.2 in those older than 60 years.
There is also heightened concern about accepting very young individuals as kidney donors [
16]. Younger people have a long length of life ahead of them, and, as life expectancy increases and lifestyles change, it is increasingly difficult to make accurate predictions about the degree and nature of risk that a young person may encounter during their lifetime. Long-term prospective studies will improve our understanding about these risks, but in the meantime, it is important to communicate this lack of certainty to younger potential donors.