The purpose of evaluating glomerular filtration rate (GFR) in kidney donor candidates is to detect kidney disease and to project long-term outcomes for the candidate and their recipient should they go on to donation. Recommended methods for evaluating GFR in donor candidates are based on the 2012 KDIGO Chronic Kidney Disease (CKD) guideline. ^, Considering practicality, test availability, and costs, the 2017 KDIGO living donor guideline recommends initial estimated GFR (eGFR) based on serum creatinine (eGFRcr) and confirmation using one or more of the following measurements according to their availability: measured GFR (mGFR) from clearance of exogenous radiolabeled filtration markers, measured creatinine clearance (mCrCl) based on collecting a timed (24-hour) urine specimen, eGFR based on serum creatinine and cystatin (eGFRcr-cys), or repeated eGFRcr; the latter being the least preferred approach. ^{, ,}

The implication of inclusion of a race coefficient in commonly used equations to estimate GFR is a controversial topic due to concerns related to inaccuracy leading to health care disparities. A National Kidney Foundation (NKF)/American Society of Nephrology (ASN) Task Force assessed the continued use of race in GFR calculation and recommended implementation of the CKD-EPI (CKD Epidemiology Collaboration) 2021 equation without the race variable. At the higher eGFR thresholds recommended by KDIGO for donor candidacy, more Black adults may be declined early based on initial eGFR screening if the CKD-EPI equation without the race variable is used. In one study, if the eGFR was calculated using the CKD-EPI equation without the race variable, the proportion of kidney donor candidates that may be declined on the basis of acceptable eGFR thresholds would change from 38.5% to 40.6%, newly disqualifying 2.1% of Black adults from kidney donation. Thus confirmatory testing with mGFR or mCrCl is required in the United States, and implications of using race-neutral eGFR for donor screening should be carefully considered.

One strategy to optimize efficiency may include obtaining eGFRcr and eGFRcr-cys before a donor candidate’s visit to the center to determine the posttest probability that mGFR is <60mL/min/1.73 m ² . Donor candidates with a high posttest probability of mGFR <60mL/min/1.73 m ² could be excluded rather than undergo a complete evaluation( Fig. 70.3 ). ^, If there is a high probability that the mGFR is greater than a threshold needed for donation, and if urine albumin-to-creatinine ratio (ACR) is low, then these tests could be repeated for confirmation without mGFR, mCrCl, or timed albumin excretion rate (AER). Alternatively, donor candidates with either a high probability of mGFR <60 mL/min/1.73 m ² or high urine ACR could be reliably excluded from donation, with any additional testing conducted as indicated for the purposes of supporting the candidate’s long-term health. Donor candidates with eGFR or urine ACR in intermediate ranges would require confirmatory tests with mGFR, mCrCl, and/or urine AER.

Assessment of glomerular filtration rate. Initial test. eGFRcr is the initial test for most candidates. eGFRcys may be the preferred initial test for candidates with variations in non-GFR determinants of serum creatinine (e.g., variation in muscle mass or diet). Interpretation of eGFR should include consideration of the probability that mGFR is above or below threshold for decision making. High likelihood that eGFR <60 mL/min/1.73 m ² is justification for a decision to decline without further consideration. Confirmatory tests . mGFR or mCrCl are required in the United States. Elsewhere, eGFRcr-cys can be acceptable if mGFR or mCrCl is not available and eGFRcys was not used as the initial test. Repeat eGFRcr can be acceptable if none of the other confirmatory tests are available but are not preferred. Inconsistent test results suggest inaccuracy of one or more tests, which should be discarded or repeated. Very high likelihood that mGFR <60 mL/min/1.73 m ² is justification for a decision to decline without further consideration. Using GFR to estimate long-term ESKF risk . Long-term estimated risk of ESKF is compared with the transplant center threshold for acceptable risk. Long-term risk in the absence of donation can be computed from demographic and clinical characteristics including GFR ( http://www.transplantmodels.com/esrdrisk/ ). Additional risk attributable to donation is likely to be 3 to 5 times higher than risk in the absence of donation, but there is substantial uncertainty, especially in younger donor candidates, and we suggest caution in decision making. Postdonation risk above the threshold is justification for a decision to decline. Candidates with risk below the threshold are acceptable to make their own decision whether to donate. Colors are blended together to signify threshold for decision making is imprecise. eGFR, Estimated glomerular filtration rate; eGFRcr, estimated glomerular filtration rate based on serum creatinine; eGFRcr-cys, estimated glomerular filtration rate based on serum creatinine and cystatin; eGFRcys, estimated glomerular filtration rate based on cystatin; ESKF, end-stage kidney failure; GFR, glomerular filtration rate; mCrCl, measured creatinine clearance; mGFR, measured glomerular filtration rate.

Nephrectomy in a healthy donor (removal of 50% of the nephron mass) is associated with an adaptive increase of the remaining kidney’s GFR such that postdonation GFR is stable at approximately 60% to 70% of the predonation value over the first-decade postdonation ( Fig. 70.4 ), although the degree of adaption can vary (e.g., may be lower in donors who are older, obese, and hypertensive). This information is relevant in considering an acceptable baseline predonation GFR. The 2017 KDIGO living kidney donor guideline recommends a GFR ≥90 mL/min/1.73 m ² as an acceptable level of kidney function for donation, while donor candidates with GFR <60 mL/min/1.73 m ² should not donate. The decision to approve donor candidates with GFR 60 to 89 mL/min/1.73 m ² should be individualized on the basis of demographic and health profiles. It is important to note that some other guidelines on the assessment of living kidney donor candidates incorporate an age-specific criteria for donor selection based on GFR. There are concerns that more candidates may be considered potentially ineligible when an absolute GFR threshold of 90 mL/min/1.73 m ² is used compared with age-adapted GFR thresholds, and this may be more pronounced with eGFR measurements compared with mGFR measurements. Whether an absolute threshold or an age-adapted GFR threshold is used, transplant centers should consider an overall personalized risk estimate to determine donor eligibility.

Mean estimated glomerular filtration rate (eGFR) over time in living kidney donors (solid line) and matched healthy nondonor controls (dotted line).

Reproduced with permission.

Elevated protein in the urine (proteinuria) may suggest the presence or risk of developing kidney disease due to increased permeability of the glomeruli to protein and/or an inability of the renal tubules to reabsorb protein. Until acceptable standardization methods are available for quantifying deficiencies in tubular reabsorption, urine albumin remains the most reliable indicator of kidney disease, standardized to urinary creatinine as the ACR. The 2017 KDIGO living kidney donor guideline recommends initial evaluation using urine ACR in a random urine specimen with confirmation by AER (from a timed urine specimen) or otherwise a second random urine ACR. Donor candidates with an AER >100 mg/day should not donate. Such candidates have moderately increased albuminuria and are at an elevated risk of developing CKD in their lifetime. Candidates with an AER <30 mg/day may be acceptable for donation, while the decision to approve donor candidates with AER 30 to 100 mg/day should be individualized on the basis of demographic and health profiles in relation to the transplant program’s acceptable risk threshold.

The persistent presence of blood in the urine (hematuria) is another indicator for the presence or risk of developing kidney disease. Presence of hematuria is established by visualizing two to five red blood cells per high-powered field on microscopic evaluation. “Persistence” is established if hematuria is observed in more than 50% of urine samples obtained from two to three separate occasions. When hematuria is persistent, further investigation is warranted, which may include urine culture for bacterial or fungal infection (this may be treated without affecting candidacy); 24-hour urine stone panel; cystoscopy; imaging to rule out a urinary tract malignancy or asymptomatic stone (imaging, such as a computed tomography angiogram, is often done as part of the donor evaluation regardless of the presence of hematuria); genetic testing donor candidates with a family history of kidney disease (see next section on Genetic Kidney Diseases); and a kidney biopsy to rule out underlying kidney disease (thin basement membrane may not be a contraindication to donation).

If the donor candidate is biologically related to the intended recipient, the cause of the recipients’ kidney disease should be well understood before accepting the candidate. Candidates with a genetic kidney disease are not eligible, generally, to become donors. If a candidate has a family history of a genetic kidney disease, the candidate may be eligible to donate if the risk of developing kidney disease after donation is acceptably low and the risks are discussed with the candidate. Genetic diseases that may be assessed during the donor candidate evaluation include autosomal dominant polycystic kidney disease, atypical hemolytic uremic syndrome, Alport syndrome, Fabry disease, familial focal segmental glomerulosclerosis, and autosomal dominant tubulointerstitial kidney disease. Genetic testing may be offered to asymptomatic donor candidates with a family history of genetic disease after appropriate counseling that includes the challenges, limitations, and uncertainties inherent in the process and results. One approach to genetic testing of donor candidates with a family history of genetic disease involves sequential testing of the affected family member first (often this is the intended recipient candidate) to determine the genetic basis of the disease (and to see if it can be identified with modern testing) and then do targeted testing of the donor candidate ( Fig. 70.5 ).

Approach to genetic testing of living donor candidates.

LD, living donor; VUS, variant of uncertain significance.

Reproduced with permission.

For donor candidates of sub-Saharan African ancestry, testing for apolipoprotein L1 (APOL1) -related kidney disease risk alleles may be offered. The presence of two APOL1 risk alleles increases the lifetime chance of developing kidney failure, yet the effect of kidney donation on this risk is unknown but is a topic of active research. One study from the United States compared 136 Black living kidney donors, of whom 19 were considered APOL1 high-risk genotype (two risk alleles) and 117 were considered APOL1 low-risk genotype (zero or one allele). Donors who were APOL1 high-risk genotype had a lower predonation eGFR compared with donors who were APOL1 low-risk genotype (98 vs. 108 mL/min/1.73 m ² , P = 0.03) and lower postdonation eGFR (57 vs. 67 mL/min/1.73 m ² , P = 0.02) after a median of 12 years postdonation and after adjusting for predonation eGFR. The rate of decline was also faster in donors who were APOL1 high-risk genotype (1.1 vs. 0.4 mL/min/1.73 m ² per year, P = 0.02), although this was not significantly different from matched nondonor controls. Some studies have suggested the potential importance of genotyping for a modifying genetic variant in the APOL1 gene encoding an amino acid change N264K, which confers protection when coinherited with high-risk genotypes. This modifying N264K variant is uncommon and may be inherited with G2 but is mutually exclusive with G1 renal risk variants. Future research should assess whether this variant increases the safety for kidney donation in such potential donors.

A renal calculus in the donor’s remaining kidney may affect kidney function if it results in ureteral obstruction. Reassuringly, living kidney donors without a history of predonation kidney stones do not appear to have an increased risk of postdonation kidney stones requiring treatment with surgical intervention compared with healthy, matched nondonor controls (median follow-up of 8 years). Evaluation of kidney stones in living kidney donor candidates includes a history from the candidate, laboratory investigations including urine samples for evaluation of persistent microscopic hematuria, and renal imaging such as computed tomography. If suspected, further investigations may be performed, including parathyroid hormone measurements and 24-hour urine collections for metabolic testing. A history of previous kidney stone disease does not necessarily rule out donation, particularly small, unilateral, nonrecurrent stones. There is also the option to remove small kidney stones at the time of procurement before transplantation.

Sustained elevated blood pressure is a common cause of kidney disease, and conversely, kidney disease may accelerate the development of high blood pressure. Candidates with hypertension are eligible for donation only if their blood pressure can be well controlled with a simple regimen (commonly defined as one or two antihypertensive medications), and they are without end-organ damage related to their hypertension. The characteristics used to disqualify a candidate from donation, such as the level of systolic and/or diastolic blood pressure, nature of the antihypertensive medications used (e.g., number of agents, class of drugs, and dosage used), and other candidate characteristics (e.g., hypertension onset at a young age) may vary across programs. Trained personnel should perform blood pressure measurements on at least two separate occasions. An ambulatory (e.g., 24-hour) blood pressure monitor may be used if hypertension is suspected. In a single-center study of 578 prospective donors in the United States, lower thresholds of <123/82 mm Hg and <120/78 mm Hg for office and automated blood pressure used to prompt 24-hour ambulatory blood pressure monitor recording improved the sensitivity (from 79% to 87%) of diagnosing hypertension (based on a threshold of <135/85 mm Hg by daytime ambulatory blood pressure monitoring) and reduced the prevalence of missed (masked) hypertension by 2%. Thus using lower screening thresholds may identify donor candidates who would most benefit from ambulatory blood pressure monitoring to diagnose hypertension.

Obesity is a strong risk factor for diabetes, cardiovascular disease, and kidney disease. Living donor nephrectomy is more difficult for patients with excess visceral fat, increasing the risk of perioperative complications including infection, blood loss, and delayed wound healing. Various body mass index (BMI) cut-points have been reported in the literature as absolute or relative contraindications to donation. Elevated serum glucose or glucose intolerance are also strong risk factors for diabetes mellitus. Apart from personal and family history assessments of diabetes mellitus (childhood, adult-onset, gestational), glycosylated hemoglobin and serum and urinary glucose are typically measured early in the assessment of all candidates. Fasting glucose and oral glucose tolerance tests are recommended for high-risk candidates (e.g., high random glucose, positive family history). According to the 2017 KDIGO living kidney donor guideline, donor candidates with type 1 diabetes mellitus should not donate. The decision to approve donor candidates with prediabetes or type 2 diabetes mellitus should be individualized on the basis of demographic and health profile in relation to the transplant program’s acceptance threshold. Donor candidates with prediabetes and type 2 diabetes mellitus should be counseled that their condition may progress over time and may lead to end-organ complications, regardless of whether or not they donate. Less evidence is available to comment on the influence of predonation lipid levels (e.g., cholesterol, triglycerides, and high-density and low-density lipoproteins) and predonation active smoking on donor candidacy, although notably, smoking was a strong risk factor for ESKF in healthy persons. While candidates should be educated and encouraged to modify their dietary and smoking habits, eligibility based on these factors may vary across programs.

To reduce the risk of viral transmission from the donor to the recipient, the evaluation should include assessment of prior history of infections, recent travel history, and virology screens early in the evaluation and again within the 2 to 4 weeks of donation to minimize the window of infection. The 2017 KDIGO living kidney donor guideline recommends screening for human immunodeficiency virus (HIV), hepatitis B and C, Epstein-Barr virus, cytomegalovirus, syphilis, urinary tract infection, and other potential infections based on geography and environmental exposures. If a donor candidate is found to have a potentially transmissible infection, then the donor candidate, the intended recipient, and transplant team should weigh the risks and benefits of proceeding with donation and develop a management plan if the decision is to proceed with donation. One case series in the United States reported three successful LDKT from donors with HIV to transplant recipients with HIV and showed promising results after 2 to 4 years of follow-up, although the long-term postdonation risk remains unknown. In South Africa, ∼20% of people aged 15 to 64 years are living with HIV in South Africa; therefore facilitating safe organ donation and transplantation from HIV-positive donors could increase donation and transplantation rates. A clinical practice guideline has been developed for HIV-positive organ donors and recipients, which considers eligibility, risk of transmission, and ethical considerations.

The coronavirus disease 2019 (COVID-19) pandemic had a global impact on organ donation and transplantation activity, especially LDKTs. From 2010 to 2019, the global rate of LDKT was stable at 4.6 pmp and then dramatically decreased to 3.3 pmp in 2020. In the early waves of the pandemic, many transplant programs decreased or suspended living donor candidate evaluations and LDKT surgeries for a variety of reasons. ^, This included safety concerns for the donor, recipient, and health care staff; strains on the health care system with many intensive care units converted to COVID-19 units; and hospital and government restrictions. By 2022, the global LDKT activity had improved to 6.7 pmp with many centers screening donor and recipient pairs for COVID-19 infection, mostly using the polymerase chain reaction testing from nasopharyngeal swab samples. One retrospective cohort study from India reported on 64 LDKTs in which both the donor and the recipient had previously recovered from COVID-19 infections. After a median follow-up of 227 days (interquartile range, IQR, 109–309 days), the outcomes were reassuring for both the donor and the recipient with no reported deaths, graft loss, reactivation/reinfection, or complications related to the surgery or COVID-19. This suggests that it is safe to proceed with donor candidates who have cleared the infection without residual lung, kidney, or systemic sequalae. There is considerable variability in the practice patterns for accepting living kidney donors with a history of COVID-19 infections, suggesting that further research is needed to better guide optimal practices to ensure the safety of living donation and LDKT as COVID-19 transitions from a pandemic to an endemic infection.

All candidates should be up to date with local cancer screening guidelines according to age, sex, and family history. Donors with active cancer are generally not eligible to donate. Donors with a prior history of successfully treated cancer with a high risk of recurrence may be excluded from donation because antineoplastic agents may be nephrotoxic and transmission of cancer from the donor to the recipient can have serious consequences for the immunocompromised recipient. Candidates with a prior history of cancer with a minimal or low risk of recurrence (<1%, e.g., nonmelanoma skin cancers, and solitary papillary thyroid carcinomas) may be considered on a case-by-case basis. In some cases, candidates with small renal tumors (high-grade Bosniak renal cysts [III or higher] or small [T1a] renal cell carcinoma curable by nephrectomy) may be acceptable for donation, and the donor and recipient must provide consent for the cancer to be resected at the time of donor nephrectomy. ^,

During the evaluation process, female donor candidates should be asked about any prior history of pregnancy complications, including gestational diabetes, gestational hypertension, and preeclampsia, as well as any future childbearing plans. Women of childbearing age should not be excluded from donation solely because they wish to have children after donation, but they should be counseled on the potential increased risk of pregnancy complications postdonation (see Risks and Outcomes of Living Kidney Donation). Women with a prior history of pregnancy complications should be informed of their potential increased risk of long-term complications, with or without donation, and any uncertainty in the donor-attributable risks. One single-center study from the United States included 1862 female living kidney donors (1963–2020) with predonation pregnancies. The median time from first pregnancy to donation was 18.5 years, and the median postdonation follow-up was 18.0 years. Of these donors, 43 had a history of predonation gestational diabetes mellitus, 49 had gestational hypertension, and 48 had preeclampsia/eclampsia. Compared with matched donor controls, donors with predonation gestational diabetes mellitus had a 3-fold increased risk of developing postdonation diabetes mellitus (hazard ratio [HR] 3.04, 95% confidence interval [CI] 1.33–6.99, P ≤ 0.01). Those with predonation gestational diabetes mellitus had a 17% chance of developing diabetes mellitus within 20 years after donation compared with an 8% chance for matched controls. Donors with predonation gestational hypertension had a 2-fold increased risk of developing postdonation hypertension (HR 1.89, 95% CI 1.26–2.83, P ≤ 0.01). Those with predonation gestational hypertension had a 53% chance of developing hypertension within 20 years after donation compared with a 32% chance for controls. Lastly, donors with predonation preeclampsia/eclampsia had a twofold increased risk of developing postdonation cardiovascular disease, although this did not reach statistical significance. While the 2017 KDIGO guideline states that women with a predonation history of pregnancy complications could still potentially donate, other guidelines consider this to be a relative/absolute contraindication to donation. ^,