After nephrectomy, the number of nephrons is reduced by half. Serum creatinine rises, and the estimated glomerular filtration rate (eGFR) immediately drops after around 50% reduction in kidney mass [8]. Unlike unilateral nephrectomy in individuals with comorbidities, the LD remaining kidney has adequate kidney functional reserve capacity, which enables compensatory, adaptive hyperfiltration, typically increasing its function in the months post donation. About a year after nephrectomy, kidney function stabilizes at approximately 60%–65% of the initial pre-operative function. Similarly, eGFR decreases after surgery regardless of baseline levels, age, and gender, remaining stable long-term, as in healthy non-donors [9]. The annual eGFR decline was 0.35 mL/min/1.75 m² in donors compared to 0.85 mL/min/1.75 m² in healthy controls in a retrospective matched cohort study of 604 Canadian donors from 2002 to 2016, a difference attributed to donor glomerular hyperfiltration in the first five years post donation. A Dutch registry-based analysis confirmed these findings, although it was noted that in approximately 13% of donors, the expected increase in eGFR post-nephrectomy was not observed [10]. These findings suggest that in some individuals the kidney functional reserve capacity is decreased, perhaps due to factors such as low nephron mass and low birth weight, preventing enhanced function in the remaining kidney, The risk of progressing to ESKD after kidney donation is minimal, occurring in less than 1:200 donors (0.5%) [11]. This risk is significantly lower than in the general (unscreened) population. Muzaale reported on the long-term follow-up of 96,217 kidney donors in the United States, comparing the outcomes to a control population of 20,024 participants from the NHANES III study [12]. Ninety-nine of 96,217 donors (0.1%) developed ESKD on average 8.6 years after donation compared to 36 of 96,217 (0.04%) matched healthy non-donors. Based on this, the estimated risk of ESKD 15 years after donation was 30.8 per 10,000 donors and 3.9 per 10,000 controls. On further analysis of the same registry data, 10 per 10,000 donors developed ESKD within 10 years post donation, primarily due to glomerulonephritis. Twenty-five years post-donation, 85 out of 10,000 donors had developed ESKD, mainly due to diabetes and hypertension [13].

Mjøen reported on the long-term kidney function of 1,901 Norwegian donors, comparing transplant registry data to 32,621 individuals who could have but did not donate a kidney [14]. The average follow-up was 15.1 years for donors and 24.9 years for non-donors. The risk of ESKD was 11.38 times higher in kidney donors. Notably, this elevated risk is based on only nine donors requiring kidney replacement therapy 18.7 years after donation, with seven of these recipients being first-degree relatives of the donors. Similarly, in the U.S. study [12], the authors found that 67% of donors who developed ESKD were biologically related to their recipients. In contrast, most controls had no family history of kidney disease.

Assessing the genetic predisposition to kidney disease is advisable in selected cases when donor and recipient are first-degree relatives [13]. When the recipient’s kidney disease is known, specific cases in which genetic testing might be considered include Alport’s, aHUS, hereditary focal and segmental glomerulosclerosis, Fabry’s, and autosomal dominant polycystic kidney disease. However, this approach remains a matter of debate and there is wide variation in clinical practice [15]. There is concern in the transplant community about the lack of prospective data evaluating the risk of ESKD in donors of African ancestry with a high-risk APOL 1 genotype. A retrospective study found that donors with high-risk APOL1 genotypes had significantly lower pre-donation and post-donation eGFR. However, the rate of eGFR decline was comparable to APOL1-matched non-donor controls [16].

Several adaptive compensatory mechanisms develop post-nephrectomy; kidney plasma volume increases, resulting in glomerular growth and accentuated hyperfiltration. However, hyperfiltration does not cause high glomerular pressure or damage in kidney donors, although albuminuria may occur [17]. A key question is whether nephrectomy affects the prevalence of hypertension. Studies indicate that the prevalence of hypertension increases after kidney donation, with risk varying from zero to a threefold increase. Meta-analyses suggest donor blood pressure rises by 5 mmHg compared to healthy controls [18]. Despite extensive research, varying methodologies challenge the possibility of drawing definite conclusions, as outlined in Table 1.

Hypertension raises the risk of progressing to ESKD and cardiovascular events; these are reduced if blood pressure is maintained below 130/80 mm Hg after donation [19] because mean blood pressure over 140/80 increases the risk of progressing to ESKD fourfold [12]. The risk of hypertension increases when risk factors such as obesity, smoking, genetic predisposition, older age, and low eGFR accumulate [20]. Weight gain increases the risk of hypertension more in kidney donors than in controls. However, both obese donors and non-donors had a similar hypertension incidence [21].

A BMI >30 doubles the relative risk of ESKD compared to BMI <30 at 15-year follow-up. However, the incidence of ESKD in these groups remain very low (40 cases in BMI >30 vs. 20 cases if BMI <30 out of 10,000 donors) [11].

A recent meta-analysis of over 900 studies found a perioperative mortality rate of 0.01% with low incidence of intraoperative complications (2.3%). With the current laparoscopic nephrectomy technique, the rate of infections, bleeding, and reoperations are quite low. Among these complications, infections are most common and easily treatable [22]. A recent analysis of 164,593 kidney donations reported a death rate 90 days post-surgery less than 1 event per 10,000 donations. Perioperative mortality after living donation declined substantially in the past decade. The risk was higher for male donors and donors with a history of hypertension [23].

Studies in Sweden [24] and the United States [25] have shown that survival is better for live donors compared to the general population. However, when the comparison group consists of healthy individuals from the general population, it is less clear if kidney donation has a detrimental effect on long-term cardiovascular mortality. The previously mentioned U.S. [12] and Norwegian [14] studies present conflicting findings. In Mjøen’s study, the mortality risk ratio was 1.3 for LD compared to controls, and the cardiovascular mortality risk ratio was 1.4. Muzaale reported no increase in long-term mortality risk for donors compared to controls. Both studies face several methodological challenges; for example, in the Norwegian study, the control group consisted of younger individuals, living in rural areas who smoked less and had no family history of kidney disease.

Particular attention should be given to how cardiovascular risk factors change after kidney donation. A small number of studies examined the changes in metabolic factors post-donation [26]. In an Israeli study, LD had higher increases in BMI, triglycerides, type 2 diabetes, and incidence of metabolic syndrome, compared to controls over a five-year follow-up period. Blood pressure was similar between LD and healthy individuals, but paradoxically, cardiovascular events were more common in healthy individuals. A U.S. study also reported similar levels of blood pressure, HbA1c, albuminuria, and lipoproteins in LD and healthy controls after 9 years of follow-up. Noteworthy, LD had higher levels of parathyroid hormone and uric acid, probably because of decreased kidney mass [27].

A recent systematic review compiled the results of 16 studies over a 35-year period, including 1,399 post-donation pregnancies [28]. These studies employed different methodologies, and only six of them included a control group. Based on the available evidence, eight clinical practice guidelines, three consensus statements, and four expert-opinion papers were published between 2010 and 2020. The general conclusion is that the occurrence of hypertension during pregnancy increased from 1% to 9% pre-donation or matched controls to 4%–12% post-donation. Pre-eclampsia also increased from 1% to 3% pre-donation or in non-donors to 4%–10% post-donation. The recommendations universally state that women should be counseled about the increased risk of gestational hypertension or pre-eclampsia. Additionally, it should be stressed that, according to the literature, most women had uncomplicated pregnancies post-donation, and the aspiration to have a child should not be seen as a contraindication for donation. In most studies, fetal and neonatal outcomes after kidney donation are like those in non-donor pregnancies.

Live kidney donors may find recovery is hindered by post procedure tiredness, although the majority recover within several months. While 14% of US kidney donors experienced persistent fatigue 1 year after donation, this rate was comparable to healthy controls [29]. Donors with a history of affective disorders, anxiety or lower levels of physical activity were identified as highest risk for persistent fatigue.

Type of surgery does not seem important, with both open and laparoscopic nephrectomy donors experiencing equal mental fatigue and reduced motivation. Although these symptoms had resolved by 3 months, the physical fatigue could persist for up to 12 months [30]. A Dutch study on health-related quality of life (HRQoL), also found that there was no difference in physical scores between pre- and 12 months post-donation [2] but mental scores varied significantly, declining from pre- to 6 months post-donation and then improving from 6 to 12 months. Predictors of greater fatigue included higher baseline fatigue, poorer baseline physical functioning, younger age, longer hospital stays, and greater influence of the recipient’s condition.

Female donors are more affected. A German HRQoL study found similar QoL outcomes across genders, except for the mental component in SF-36, when 51–60-year-old females scored lower than both age-matched males and general female population [31]. This was corroborated by a Norwegian long-term study (217 donors) although fatigue levels were generally low. Here, higher QoL was associated with donors who received recognition whereas donors with regret reported generally elevated fatigue [32]. A Dutch 10-year study reported significant declines in physical function, pain, and general health (SF-36) at follow-up but unfortunately, the lack of a comparator makes it difficult to distinguish the impact of donation from general aging but reinforces the need for psychosocial support [33].