Donor medicine: An emerging field in nephrology

Abstract

Donor medicine is an emerging field in nephrology. Medical specialties develop from how organ systems organize, new technologies, or groups of diseases. Donor medicine stands at the intersection of medicine, surgery, public health, and the humanities, but unlike recipient medicine does not involve immunology. Living kidney donors (LKDs) start from a position of excellent health and normal predicted lifespan. Nephrologists have a special obligation to follow altruistic LKDs over the long-term, even though the safety of donation has been generally well established. This paper summarizes the physiological changes associated with LKD surgery, resulting from reduced nephron mass, glomerular hyperfiltration, and blood pressure elevation, to the health risks associated with LKD surgery including chronic kidney disease, proteinuria, hypertension, preeclampsia, adverse psychology, and financial burden. Successful kidney transplantation does not simply mean performing a large number of transplants or even achieving a high long-term recipient graft or patient survival rate. Successful kidney transplantation means that the LKD also performs well in a situation that nature never intended for them. Placing long-term donor health into better perspective will help to provide a framework for establishing donor medicine as a distinct medical specialty, which will in turn encourage LKD and increase organ donation rates.

Key Words: Kidney donation; Health risk; Glomerular filtration rate; Chronic kidney disease; Nephrectomy

Core Tip: Even though living kidney donation has existed for over 60 years, there has been limited systematic collection of information related to the long-term health of donors. Establishing a distinct medical specialty called donor medicine is a moral obligation that will also encourage more living kidney donation. Donor medicine will also provide a framework for donor-centered care and rigorous long-term follow up.

INTRODUCTION

Chronic kidney disease (CKD) and its mortality burden is increasing worldwide[1-3]. Once a CKD patient reaches end-stage kidney disease (ESKD), living kidney donor (LKD) transplantation becomes the treatment of choice[4], offering improved survival, quality of life, and lower costs to healthcare systems[5]. However, LKD surgery violates donor non-maleficence in favor of recipient beneficence. About a third or more of kidney transplants worldwide originate from LKD[6]. Ethical concerns relate to maladaptive physiological changes in the LKD after nephrectomy and its effects on the LKD’s short and long-term outcome. This paper is a narrative review to argue that donor medicine deserves its own designation as a medical specialty so that concerns about donor outcomes can be properly addressed.

This paper describes physiological changes in the LKD, risks to the LKD surgery, and then a framework for donor medicine. In this narrative review, we searched public databases (MEDLINE, EMBASE, PubMed 1965-present) for English-language articles using terms such as “living kidney donor”, “kidney donation”, “donor outcomes”, “donor ethics”, and “donor complications”.

PHYSIOLOGIC CHANGES AFTER LIVING KIDNEY DONATION

Reduced nephron mass and glomerular hyperfiltration

Unilateral donor nephrectomy is associated with an immediate 50% nephron loss. Adaptation via glomerular hypertrophy and hyperfiltration in the remaining kidney augments the estimated glomerular filtration rate (eGFR), ultimately leading to a 30%-40% net eGFR loss[7,8]. Kidney function stabilizes by an improved filtration coefficient without glomerular hypertension[9]. Due to the compensatory adaptive response over time, the eGFR either slowly rises or drops more slowly than in non-donors, ultimately stabilizing in the 30-60 mL/minute/1.73 m² range[10]. Predicting which trajectory an individual donor will follow remains a central challenge for donor medicine. In both these cases, the remaining kidney likely retains the capacity to increase eGFR during periods of physiologic stress despite a reduced overall renal reserve in the LKD[11].

Proteinuria

Subtle change in glomerular permeability manifests as a mildly increased urine albumin excretion. This increase can be noticed in the immediate post donation period and is generally mild[12]. The urine albumin-to-creatinine ratio returns to its baseline by 6-12 months post-nephrectomy without affecting kidney function otherwise in the absence of comorbid conditions[13]. Proteinuria in the LKD likely represents glomerular hyperfiltration in the absence of demonstrable structural renal pathology.

Blood pressure

The systemic blood pressure (BP) trajectory alters slightly over time. A systolic BP elevation of 5 mmHg can be expected 5-10 years after nephrectomy[14], although the incidence of true hypertension is equivalent to that of non-donors after accounting for baseline characteristics[10]. A more frequent diagnosis of post-donation hypertension may reflect surveillance bias[15,16].

Unilateral nephrectomy affects circadian rhythm but not absolute BP values[17]. Sustained BP elevation risks cardiovascular disease. However, large population-based studies do not demonstrate increased cardiovascular events or mortality compared to health-matched non-donors[18].

Endocrine adaptation

The renin angiotensin system maintains fluid balance and vascular tone. Nephrectomy alters the renal response to circulating angiotensin II by increasing glomerular pressure without significantly increasing the systemic BP, although it is unclear if these changes are caused by systemic or intra-renal renin angiotensin system activation[19]. Serum erythropoietin concentrations rise during the first three months post-nephrectomy but then normalize[20].

Bone and mineral metabolism

Subtle changes in bone and mineral metabolism include increased fibroblast growth factor (FGF) and parathyroid hormone (PTH) concentrations. Vitamin D activation via 1-α hydroxylation reduces[21], although calcium and phosphate concentrations remain within a normal range without evidence for long-term bone disease[22].

Pregnancy

Pregnancy imposes physiologic stress. Pregnancy in female LKDs due to increased angiotensin II concentrations may further increase an already established increased single nephron glomerular filtration rate and may thus potentially unmask hypertension or proteinuria, although clear evidence for such a hypothesis is lacking[23]. Preeclampsia may increase[24] although the overall risk of pregnancy-related complications remains minimal[25].

RISKS ASSOCIATED WITH LIVING KIDNEY DONATION

It would be naïve to assume that LKD surgery is risk-free. Risks relate to overall kidney health, psychosocial and financial outcomes of the donor[26] (Figure 1). Documenting these risks has proven difficult. In developing countries where LKD prevails, close post-donation follow-up remains challenging. A delay in diagnosing potentially treatable conditions is an ongoing concern. Evolving population characteristics over time adds to the complexity in assessing risk. Understanding risk potential helps provide better pre-donation evaluation and selection procedures, as well as construct post donation follow-up strategies[27].

Figure 1 Potential risks after kidney donation. CKD: Chronic kidney disease; ESKD: End-stage kidney disease.

Perioperative risk

Perioperative donor mortality is rare. The documented risk is as low as 0.02%-0.04%[28]. Based on the data from Organ Procurement and Transplantation Network from 2000-2012, about 0.4% donor nephrectomies necessitated blood transfusion, 0.3% had vascular complications and 0.5% required re-exploration for bleeding.

There is an approximately 20% risk of developing immediate complications including hemorrhage, wound infection, pneumonia or urinary retention. About 10% patients may develop late complications including incisional hernia and chronic post-surgical pain[29]. An integrated United States transplant registry analysis (2008-2012) found that 16.8% LKDs experienced perioperative complications, including gastrointestinal complications (4.4%), bleeding (3.0%), respiratory illness (2.5%) and directly surgery-related (2.4%)[30]. Complications relate to the donor’s demographics, underlying comorbid conditions, and surgical technique, but remain rare due to the LKD’s presumed excellent pre-donation health. Accurately capturing data regarding perioperative risk remains comparatively simpler than for long-term health, but can be further improved.

CKD

Based on United States registry data from 2008-2014, about 35000 donors had post donation eGFR of 66.7 ± 15.6 mL/minute/1.73 m²[31]. Elderly male donors, black race and increased body mass index (BMI) were associated with a greater decline in kidney function including proteinuria[32].

A drop in eGFR to below 60 mL/minute/1.73 m² typically defines CKD, but its clinical impact even in non-donation situations remains uncertain. On the one hand, unilateral nephrectomy constitutes a structural change that justifies categorizing LKDs as having CKD based on eGFR criteria alone. On the other hand, LKDs do not experience further decline in kidney function except a physiological age-related change[33]. There is no evidence for an ongoing insult to the renal system[31], with the contralateral kidney being perfectly functional and anatomically normal. Nonetheless, despite reassuring findings that LKDs are not the same as other hyperfiltrating populations, eGFR requires ongoing follow-up[33]. Aberrant physiological adaptation and response to future insults cannot be predicted with sufficient accuracy from currently available pre-transplant evaluation.

ESKD

The estimated lifetime risk of developing ESKD remains very low. It is important to understand that an unscreened general population is not a true comparator to LKDs. One study documented almost 100 cases of ESKD out of 10000 LKDs with a cumulative incidence of about 30/10000 after 15 years[34]. This incidence compares adversely to age-matched healthy non-donors (14/10000) but still remains substantially less than that of the general population (326/10000)[34]. Another study reported that the late-onset ESKD in kidney donors with diabetes was mostly due to diabetic nephropathy[35].

There is about a threefold more risk of ESKD in LKDs who are black[35]. Genetic testing for APOL1 has therefore been proposed as part of the LKD selection process among African Americans[36]. The APOL1 gene has been associated with low post donation eGFR in black LKDs[37]. Genetic testing for kidney diseases in selective high-risk populations was proposed in 2023[38] but currently remains optional in most programs. A structured donor medicine program may enable more genetic testing in LKDs.

Hypertension

Glomerular hyperfiltration does not associate directly with the changes leading to hypertension[14]. Data regarding increased hypertension risk is inconsistent due to the limited inclusion of hypertensive donors and small sample sizes[39]. In 2006, a systematic review of 5145 LKDs showed a systolic BP elevation of 6 mmHg and diastolic BP elevation of 4 mmHg[16]. Another prospective study by the Swiss Organ Living Donor Health Registry followed 1201 LKDs for 32 months. After one year, hypertension risk increased by 3.6%, and was accompanied by microalbuminuria[40]. Among those who remained normotensive, the risk of developing hypertension after 1 year was similar to the healthy population.

Contrary to these findings, another cohort study that included 3700 kidney donors showed a hypertension prevalence of 4% at 5 years post donation[41]. Several other studies compared donors to matched non-donors for as long as 10 years but could not detect BP elevations[42-44].

Cardiovascular disease

Available data does not show any association of LKD surgery with new onset coronary artery disease or peripheral vascular disease[45]. There is no established association of increased cardiovascular risk with donation for at least the first 10 post-donation years. Moreover, the risk of mortality was also not different in LKDs compared with matched non-donors[18]. Nonetheless, cardiovascular events may be higher in donors with pre-existing hypertension[46]. Hypertensive donors also had increased cardiovascular mortality[46]. However, it should be emphasized that data about hypertension incidence and cardiovascular morbidity and mortality outcome is primarily derived from mostly retrospective observational studies with short follow-up and is therefore subject to all their limitations. Prospective evaluation of hypertension onset and cardiovascular events is extremely challenging even in the general population, which is the closest available comparator group, despite more numerical events occurring.

Diabetes and obesity

LKDs are not at an exceptionally high metabolic risk[47]. Insulin resistance does not differ from the general population. A study of over 41000 LKDs from the United States Scientific Registry of Transplant Recipients demonstrated a post-donation diabetes incidence rate of 2/10000, 6/10000, and 15/10000 at 6 months, 1 year, and 2 years respectively. A high BMI may be a risk factor[48].

Extrahepatic gluconeogenesis and insulin metabolism occur in the kidney, so in principle, LKD surgery may result in insulin resistance[49]. A pilot observational study showed that fasting insulin concentrations and insulin resistance were significantly higher in LKDs[50]. However, due to a small sample size and short follow-up, this correlation remains poorly understood and hypothetical. According to 2017 KDIGO guidelines, while type-I diabetes mellitus absolutely contraindicates kidney donation, those with prediabetes or type-II diabetes may proceed as LKDs provided risks for prediabetes progression and diabetic kidney involvement are carefully discussed[27].

It is not clear whether kidney donation can lead to obesity. However, there is a well-documented risk of hypertension and diabetes in donors with an elevated preoperative BMI[51]. Another meta-analysis has found a significant increase in 15-year post-donation ESKD risk with pre-operative BMI > 30 kg/m² especially in African Americans[52]. ESKD risk in donors with BMI of > 30 kg/m² may approach 16%. Each unit increase in BMI beyond 27 kg/m² increases ESKD risk by 7%[53], most likely due to a further increase in already increased glomerular filtration[54].

Renal osteodystrophy and fractures

A diminution in eGFR post-nephrectomy increases PTH and FGF23, and reduces activated vitamin D concentrations[21]. However, the effects of these changes remain relatively unexplored in LKDs. Calcium and phosphate remain in the normal range[22]. A small comparative study of 203 LKDs compared to 201 paired normal controls showed a positive association of abnormal bone markers with reduced bone health. Out of 203 donors, 182 were found to have elevated PTH and FGF23 concentrations with a lower concentration of 1,25 vitamin D3. Bone resorption markers including osteocalcin, procollagen type-I N-terminal peptide, and carboxyterminal cross-linking telopeptide of bone collagen were higher[55]. A large-scale Canadian trial failed to demonstrate an increase fracture risk in LKDs[56]. A review of 10-year follow-up records of LKDs found a significantly lower overall fracture risk[57], although recall bias was a concern.

Nephrolithiasis

Due to a risk of stone formation in the remaining kidney, the majority of transplant centers decline individuals with a history of nephrolithiasis as LKDs. However, a survey of United States transplant practices indicates that some centers accept as donors those with kidney stones after evaluating other parameters such as the metabolic profile[58]. There is no reason to indicate that LKD surgery per se increases the risk for nephrolithiasis with or without a prior history of kidney stones. A review of 14 studies that included 432 LKDs with a history of kidney stones showed a primary outcome of a stone-related event in 138 donors[59]. Longer-term follow up was lacking in most studies. Overall, the risk of stone formation and stone recurrence remains low and favorably compared to non-donors[60,61].

Pregnancy

Females of child-bearing age contribute significantly to the LKD population[62]. There do not seem to be any concerns related to fetal outcome[25]. However, maternal heath is of prime importance especially if the LKD meets CKD criteria by eGFR. The risks for gestational hypertension and preeclampsia may be significant[63,64]. While some studies point to an increased risk of hypertensive disorders[23,24], many other studies do not reveal significant outcome differences compared to non-donor females[65,66]. Overall, the available literature indicates maternal and fetal outcomes in female LKDs to be comparable to non-donor females.

Psychological outcomes

LKDs undergo major anatomical and physiological changes to their body, raising psychosocial, ethical and moral issues[67]. The majority of the donors continue to enjoy an excellent quality of life with a high satisfaction level[68]. They have improved self-esteem and improved relationships with their recipients. However, a subset of LKDs undergo emotional stress and feel guilt due to unresolved inner conflicts[69]. Some donors also experience significant depression after LKD surgery if the recipient loses their graft[70].

A recent cross-sectional analysis demonstrated a very low incidence of significant mental health issues related with LKD surgery. About 9% of LKDs experienced psychological changes including an inability to work and insomnia. Some LKDs experienced these changes because their recipients had passed away or lost their graft[71]. Mild mood disturbances were seen in only 4% of donors although none experienced extreme depression.

Another long-term outcome study including 2455 LKDs showed that only 1% donors sustained a negative mental health impact[72]. A recent thematic analysis highlighted the association of post-donation psychological outcome with impaired pre-donation mental health[73]. Thorough understanding is required to better address donor selection processes and manage those experiencing post-donation psychological symptoms[74,75].

Finances

Some LKDs face financial burdens associated with insurance difficulties, cost of travel, and unpaid leave from work[76]. LKDs performing manual labor may need more time off work compared to other donors yet are also more economically vulnerable[77]. One cohort study documented an increased risk of employment loss for up to 5 years post-donation[78]. As of 2019, the average cost burden to the donor ranges from USD $900 to $19900. Most donors remain under-compensated[79]. In Canada, LKDs are paid for out-of-pocket expenses from CAD $5000 to $5700 to cover travel, accommodation, meals, and childcare[80]. Some states in the United States offer $700 to $6000 to eligible donors. Some employers offer additional protection through paid leaves and insurance. Despite these efforts, there remains a need of revisiting reimbursement policies that protect the financial health of LKDs and their families.

Vulnerable racial and ethnic groups

LKD surgery outcomes unfortunately differ among racial groups. Even access to kidney transplantation differs among racial groups. According to the United States Renal Data System report in 2021, the incidence of ESKD in blacks is three times higher than in the non-Hispanic White population. Black ESKD patients are less likely to receive an LKD transplant despite increased donation in the white population[81]. Black patients bear 35% of the ESKD burden, exaggerating the racial disparity of kidney transplantation. Policymakers, nephrologists, and surgeons carry a moral burden to ensure equal access to this vital treatment modality[82].

THE CASE FOR DONOR MEDICINE

LKD is fundamentally anchored in the ethical concepts of beneficence and nonmaleficence. Donation-related substantial health benefits to recipients must be weighed against a low but not zero risk to the donors. As discussed extensively in the previous paragraphs, the LKD’s increased perioperative morbidity and mortality, reduced eGFR, pregnancy alterations, cardiovascular risk compromise and metabolic derangements, psychosocial and financial stress, and amplified racial disparities all serve to make a case for establishing a dedicated medical specialty devoted to studying and managing these altruistic individuals. Donor medicine stands at the intersection of medicine, surgery, public health, and the humanities. These four groups of specialists form the pillars of donor medicine.

A careful yet practical approach that weighs the benefits and risks to the individual potential LKD is warranted. Clear communication of the absolute and relative risks to donation is mandatory. No LKD should ever feel forgotten or abandoned by their transplant program. Recipients require and receive lifetime follow-up as part of their post-transplant care. If LKDs are considered to be equal as human beings to recipients, then they require the privilege of lifetime follow-up as well. The success of transplant programs depends on the success of its donors. There is a paucity of data about long-term donor outcomes. Most transplant centers provide only very short-term follow-up. The core reason for this anomaly is the unavailability of healthcare teams dedicated to donor health outcomes. Donor teams simply move on to the next donor, pushing to increase the total number of transplants performed. Prioritizing LKDs with ESKD for deceased donor kidney transplantation is a moral obligation if they do not have an LKD themselves.

Successful kidney transplantation does not simply mean a large number of transplants or even a high long-term recipient graft or patient survival rate. Success means that the LKD also performs well in a situation that nature never intended for them. Medical specialties are currently organized based on organ systems, medical technologies, or groups of diseases. There may not yet be enough real-world evidence to create a new medical specialty. One can look at how donor follow-up is already being handled in transplant programs and registries, analyze practical challenges like staffing, costs, resources, and what might get in the way of making it happen. However, LKD surgery has been around for more than sixty years. Nephrologists manage LKDs under their own networks as and when needed. It is indeed time to designate a distinct donor medicine specialty to attract the attention of governments and administrators and increase funding for the study and care of LKDs. Society actively encourages LKD surgery. Any effort less than this is morally indefensible.

Essential elements in a donor medicine program would need to include a demarcated curriculum to train physicians and allied healthcare professionals, and correspondingly include questions in their qualifying examinations. Protected time for nephrologists and other healthcare providers to ensure adequate compensation for donor care equal to that provided to them for recipient care, universal access to health insurance for LKDs and prioritized clinic appointments, access to psychosocial care, and reasonable financial support are all needed to ensure that donor medicine succeeds. Comprehensive donor registries funded by government support are required just like recipient registries currently are, so that every donor can contribute to furthering knowledge about donor outcomes beyond that reported by single-center or small multi-center reports. Every donor must contribute a data point to the medical knowledge corpus. Improved long-term care for LKDs might also promote a wider awareness of kidney donation and address ongoing organ shortages.

We could not include in this mini-review a detailed account of individual study methodologies or comparatively analyze them. Most studies included are North American, limiting generalizability especially to low- and middle-income countries. Studies from Europe, Australia, and New Zealand may also serve to enhance generalizability. The unavailability of data from developing countries is another limitation of this review. Many studies are also limited by short-term follow up, small sample size, selection bias, and under-representation of minority populations. Further inputs like model of care delivery, implementation strategies and cost effectiveness are needed. Almost all LKD studies show only associations, not cause-and-effect, and are subject to selection bias and surveillance biases. All these limitations however can only serve to enhance the moral need to create donor medicine.

CONCLUSION

LKDs have been around for more than sixty years. Long-term care for LKDs remains fragmented and sparse. Study of the moral, ethical, social, and financial implications of living kidney donation and not just the medical consequences of a unilateral nephrectomy is an urgent need in 21^st century healthcare. Creating a distinct medical specialty called donor medicine will go a long way towards achieving most if not all of these objectives.