AJKD Core Curriculum “Evaluation of Kidney Donors: Core Curriculum 2018”

Abstract

Nearly 100,000 patients are waiting for a kidney transplant, yet each year only 11,000 are transplanted with a deceased donor kidney. Annual death rates among waitlist registrants range from 5–15%; many die before receiving a transplant. Not surprisingly registrants turn to family and friends to become living kidney donors on their behalf. Living kidney donor selection practices aim to quantify lifetime risk for kidney failure based on a candidate’s pre-donation demographic and health characteristics. It has been established that estimated lifetime risk for kidney failure varies considerably based on pre-donation comorbidities, and as such, it is of paramount importance that potential living donor candidates undergo proper medical, surgical, and psychosocial screening prior to donation. This “Core Curriculum” will provide you with the tools necessary for proper evaluation of living kidney donor candidates.

Case

A 27 year-old African American (AA) woman comes forward to be considered as a living kidney donor for her sister who recently started dialysis. What evaluation is necessary to determine her suitability as a living kidney donor?

Epidemiology of living kidney donors in the United States

Kidney transplantation is recognized as the optimal therapy for end-stage renal disease and living donors are accepted as the ideal donor source. Despite a kidney transplant waiting list that has continued to grow yearly, with nearly 98,000 people waiting for a kidney transplant as of May 2017, the number of living kidney donors has remained ~5600 per year after several years of steady decline. The demographics of living kidney donors have changed over time. While women still represent the majority of donors (63.5%), there have been increases in the number of older donors (those aged 50–64 years) as well as donors with a body mass index (BMI) ≥ 30 kg/m², and a decline in the percentage of African American (AA) donors. The reasons underpinning these trends in donation are complex and have been variously attributed to changes in the allocation system (such as Share-35, which gave priority to pediatric patients on the deceased donor waiting list), population-based health trends (rise in obesity and diabetes) as well as financial disincentives to donation.

Despite these obstacles public opinion overwhelmingly supports living donation, with more than 73% of people surveyed nationally indicating they would be willing to donate a kidney, especially if the recipient was a family member. The question remains how best to engage with potential living donors. Work has been done to better educate potential recipients about the importance of transplant and living donation through educational series such as “Explore Transplant.” Others have explored using social media and mobile applications to solicit donors; use of a Facebook-based app was associated with a 6-fold increase in living donor inquiries compared to controls in one pilot study. The idea of a “living donor champion” program has also been tested as a means to increase living donation rates; participants go through a structured program that teaches them about living donation and coaches them on how to approach potential donors. Some transplant centers have expanded this idea and borrowed from general internal medicine practices to create a “living donor navigator” who serves as an educator, advocate and facilitator for the living donor evaluation process. Bringing the process to the patient and his or her community has also been trialed; Rodrigue and colleagues tested the idea of doing home visits for living donors and found that this intervention also increased the rate of living donor inquiries, especially in populations with historically low living donor rates. Each transplant center needs to critically evaluate the patient population it serves in order to decide which intervention will best facilitate living donation for their transplant candidates.

Key Reference(s):

• Kumar K, King EA, Muzaale AD. A Smartphone App for Increasing Live Organ Donation. 2016;16(12):3548–3553.

• Rodrigue JR, Paek MJ, Egbuna O, et al. Making house calls increases living donor inquiries and evaluations for blacks on the kidney transplant waiting list. Transplantation. 2014;98(9):979–986.

Case, continued:

She is blood group B, the same as her sister. She is afebrile, with a blood pressure of 120/85 mmHg, pulse of 76 and a body mass index of 32; her physical exam is otherwise normal. Past medical and surgical history is notable for arthroscopic knee surgery 5 years ago. She had a normal pregnancy 2 years ago with a baby boy delivered at term. She smoked cigarettes for 5 years but quit when pregnant; she drinks alcohol socially. She works as a school guidance counselor. Laboratory data reveals a serum creatinine of 0.6mg/dL, and urinalysis is negative for blood or protein. Oral glucose tolerance test is normal.

Medical evaluation of the living kidney donor

Once a donor has contacted a transplant center to start the living donor evaluation process, the purpose of the medical evaluation of the live kidney donor is to identify any conditions that might put the donor at increased risk for the development of chronic kidney disease (CKD) or end-stage kidney disease (ESRD) or places them at unacceptably high operative or psychosocial risk. Table 1 includes a comprehensive list of essential live kidney donor medical testing.

Table 1.

Living donor evaluation testing.

Condition	Test	Exclusion
Compatibility	ABO verification	ABO incompatible*
	HLA antibody screening	HLA incompatible*
Renal function	24hr urine collection	GFR<80ml/m
	Iothalamate GFR	GFR<80ml/m
	Urinalysis	Proteinuria Hematuria
	Urine microalbumin to creatinine ratio	>30mg
	Imaging – CT or MRI	Solitary kidney
Blood pressure	2 clinic readings	≥140/90
	24hr ambulatory monitoring	Sustained readings ≥140/90
Diabetes	Fasting glucose	≥126
	Oral glucose tolerance testing	2hr ≥200
	HgA1C	≥6.5
Hyperlipidemia	Fasting lipid panel	Metabolic syndrome*
Transmissible infection	RPR	Positive result without treatment
	HIV antibody	HIV antibody positive*
	HCV NAT	HCV viral load positive*
	HBV NAT	HBV DNA positive
Cancer	Age/history driven screening	Active malignancy

^*relative exclusions to donation

Many centers begin the living donor evaluation process with a blood type determination and human leukocyte antigen (HLA) cross-match testing. Per the Organ Procurement and Transplantation Network (OPTN), donors must have blood type determined on 2 separate occasions prior to transplantation. ABO blood group incompatibility or HLA reactivity with the intended recipient no longer necessitates the end of the donor evaluation as paired kidney exchange and desensitization programs help to facilitate living donor transplants for incompatible donor-recipient pairs.

The medical evaluation of the donor includes a comprehensive general medical history and physical exam with a particular focus on renal disease history and risk factors. Donors should be queried for genetic or familial renal diseases, a history of acute or chronic renal injury, proteinuria, hematuria, recurrent urinary tract infections, congenital genito-urinary anomalies, or episodes of stone disease. Potential donors should be asked about hypertension (HTN) and diabetes, including gestational diabetes or gestational HTN. Both prescription and over the counter medications should be reviewed, with particular attention to non-steroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs) and any herbal medications or supplements. Social history taking should include assessment of adequate supports for post-operative recovery, substance use (e.g. alcohol, tobacco and illicit drugs), psychiatric disease history, travel history and behaviors meeting Public Health Service (PHS) high risk criteria (e.g. injection drug use, commercial sex work, history of jail time, etc). Assessment of the adequacy of health insurance for mandated post-donation follow up is also important, as donors lacking such resources are at increased risk of not completing post-donation visits and laboratory testing. Family history should review diabetes and HTN in first-degree relatives in addition to familial renal disease. A comprehensive physical exam is required, with particular attention to blood pressure and BMI. Many centers routinely use ambulatory blood pressure (BP) monitoring to screen for occult HTN.

Mandated laboratory testing for living donor candidates includes assessment of renal function via serum creatinine and GFR; most commonly this is achieved through a 24hr urine collection. Urinalysis and urine microalbumin to creatinine ratio are performed to screen for proteinuria and hematuria. Routine preoperative laboratory testing such as a complete blood count, full chemistry panel and coagulation studies are also performed. Premenopausal women should be screened for pregnancy with a beta HCG. Many centers will perform oral glucose tolerance testing (OGTT) for donors at increased risk for diabetes. Required donor infectious disease testing includes human immunodeficiency virus (HIV), hepatitis C (HCV) and hepatitis B (HBV) nucleic acid testing (NAT) within 28 days of the planned surgery; many centers will additionally screen for cytomegalovirus, syphilis or tuberculosis. Donors should have age-appropriate cancer screenings, including but not limited to pap smear, mammograms and colonoscopies.

Imaging studies vary by evaluating center but always include some assessment of kidney size and anatomy, usually by MRI or CT angiography. Chest Xrays are included as part of the evaluation as well.

Relative contraindications to living donation vary by transplant center. HTN is controversial; some centers will accept donors with well-controlled hypertension without evidence of end organ damage (e.g. left ventricular hypertrophy) while others exclude any donors on anti-hypertensive medications; centers may also have different thresholds for hypertension on the basis of donor race and be more reluctant to approve those who are both hypertensive and African American. BMI cutoffs for donation also vary by center protocol but generally donors must have a BMI<35 and at many centers <30 due to the risks of developing metabolic syndrome at higher BMIs. Living donors have to be adults; at some centers the minimum age for donation is 21 years while others will accept candidates as young as 18 years of age. There is no upper limit for donors in terms of age, but many candidates of advanced age have medical issues that preclude donation. Diabetes is always a contraindication to living donation; other absolute contraindications include active cancer, uncontrolled psychiatric disease as well as abuse of alcohol or drugs. Living donor candidates with abnormal renal function (glomerular filtration rate (GFR) <80ml/m) or suspicion for glomerular disease (hematuria or proteinuria) are not permitted to donate. Payment of donors or attempts to coerce donors is not permitted.

A key member of the living donor team is the independent living donor advocate (ILDA), who is charged with “the protection of living donors and prospective donors”. The ILDA evaluates all prospective living donors and assesses the donor’s ability to make an informed choice to donate. He serves as an advocate for donor autonomy in the process, and as such, functions independently of the medical evaluation team.

Key Reference(s):

• Kidney Disease Improving Global Outcomes. KDIGO Clinical Practice Guideline on the Evaluation and Follow-up Care of Living Kidney Donors. 2015.

Case, continued:

Her father is deceased and was on dialysis for several years before he died; his cause of ESRD is unknown. Her mother is alive and has well-controlled hypertension. She wants to help her sister but expresses concerns about her own risk of developing kidney disease in the future. She asks if there is any “extra” testing she can do that will help us decide. What do you tell her about her risk of ESRD should she choose to donate?

Specific risks of living kidney donation

Donors must be counseled about the risks, both short term and long term, associated with living kidney donation, including risks related to the surgery itself as well as long-term health risks due to having reduced renal mass. Currently, living kidney donation is mostly performed using a laparoscopic approach, and as such the upfront surgical mortality associated with the procedure is low. The most common causes of early surgical mortality include bleeding and blood clots. Longer term data on donor mortality from the United States and Canada suggests that donor longevity is similar to the general population. However, at least one study from Norway demonstrated an increased risk of death among donors followed for more than 2 decades.

Progression to ESRD among living kidney donors is of great concern to patients and clinicians alike; while prior living donors are given priority access to deceased donor kidneys should they progress to ESRD themselves, modern selection practices aim to avoid this occurrence. Available data suggests that while well-selected living kidney donors are at increased risk for ESRD, the absolute magnitude of this risk is small. Data from the OPTN, which tracks all transplants performed in the United States, was linked to data the Centers for Medicare and Medicaid Services (CMS) to ascertain development of ESRD among former living kidney donors and then compared to ESRD rates among a segment of the general population enrolled in the National Health and Nutrition Examination Survey (NHANES); over a median follow up time of 7.6 years, only 99 former living donors developed ESRD. A more recent study encompassing all living kidney donors from 1987–2015 identified additional donors who had progressed to ESRD (n=331) but the projected rate of ESRD by 20 years of follow-up was only 34 per 10,000. As in previous analyses, males, AAs and biologically related donors were at greatest risk for development of ESRD.

Indeed the risk of ESRD for living kidney donors is not uniform among all candidates. Not surprisingly, the risk is greater in younger donors as they have more life-years ahead of them in which to develop ESRD or other complications of donation. While younger donors are often the easiest to clear from a medical perspective, they can be the most challenging to counsel about long-term risk. Using data from the Coronary Artery Risk Development in Young Adults Study (CARDIA), our group developed a risk calculator to model risk for the development of CKD in young donors. For example, among 30 year old European American (EA) potential donors without any comorbidities or family history of first-degree relative with diabetes or HTN, the 25 year risk of CKD was 0.62–1.08%, whereas among 30 year old AAs the baseline rate was higher (1.08–1.86%); addition of known risk factors such obesity or smoking increased that rate, but the greatest driver of risk was presence of genetic variants in Apoplipoprotein L1 (APOL1) (see section below for further discussion of genetic risk).

The majority of live donor nephrectomies in the US are performed laparoscopically, and with increasing experience, few are converted to open procedures. The 90-day all-cause mortality is estimated to be 1 in 3,000 (0.03%). The reported complication rate ranges from 4.2–10.6%, and includes pain, infection (e.g. urinary tract, pneumonia, surgical site), damage to the donated kidney or surrounding structures, blood clots (e.g. deep venous thrombosis, pulmonary embolism), allergic reaction to anesthesia, and lymphocele. A meta-analysis by Yuan et al. estimated operative times to be 51 minutes longer for laparoscopic compared to open nephrectomy, and in contrast, perioperative blood loss was significantly greater for open compared to laparoscopic approach. Differences in reoperation rates based on surgical approach are conflicting. On average laparoscopic nephrectomy has been associated with shorter length of stay compared to the open technique. Moreover, laparoscopic nephrectomy has been associated with reduction in time to return to work, improved functional status, and lower pain scores compared to open nephrectomy.

As historically the majority of living kidney donors have been women, and many are of childbearing age, there has been concern regarding the effect of kidney donation on future pregnancy outcomes. A national study of living donors from Norway demonstrated a small but increased risk in preeclampsia among pregnancies occurring after living donation (5.7% vs. 2.6%, p=0.026) but the absolute number of events in the cohort (n=22) was small. A single center study from the United States comparing pre- and post-donation pregnancy outcomes demonstrated a significant increase in adverse events (e.g. preterm delivery, gestational diabetes, gestational HTN and preeclampsia) in post-donation pregnancies, but this rate was not higher than that observed in the general population. A Canadian study matched donors with non-donors and demonstrated an increased odds of both gestational HTN and preeclampsia (OR 2.4, 95% CI 1.2–5.0) among women living kidney donors. Taken collectively, these data indicate that there is likely a real increase in risk for adverse pregnancy outcomes for prior living kidney donors, but importantly, the magnitude of this increased risk is small; however these data should be incorporated into decision making for women who wish to be evaluated as donors but have not yet completed their families.

An important, but often overlooked complication of living donation, are the emotional and financial consequences of donation. Data from a multi-center living donor cohort study demonstrated that while most donors (95%) rated the experience of donation positively, some had negative experiences. Donors who experienced medical complications from donation, had psychological difficulties pre-donation, or whose donated kidneys failed were more likely to have had a negative experience with donation. Importantly, 20% of donors reported some degree of financial difficulty surrounding donation, which has led to calls for greater financial neutrality for donors.

Key Reference(s)

• Segev DL, Muzaale AD, Caffo BS, et al. Perioperative mortality and long-term survival following live kidney donation. Jama. 2010;303(10):959–966.

• Ibrahim HN, Foley R, Tan L, et al. Long-term consequences of kidney donation. N Engl J Med. 2009;360(5):459–469

• Mjoen G, Hallan S, Hartmann A, et al. Long-term risks for kidney donors. Kidney Int. 2014;86(1):162–167.

• Muzaale AD, Massie AB, Wang MC, et al. Risk of end-stage renal disease following live kidney donation. Jama. 2014;311(6):579–586.

Special Considerations

Selection practices aim to quantify lifetime risk for kidney failure based on a candidate’s pre-donation demographic and health characteristics. It has been established that estimated lifetime risk for kidney failure varies considerably based on pre-donation comorbidities. The Kidney Disease Improving Global Outcomes (KDIGO) guidelines for assessing living donor risk recommend that: 1) transplant centers develop and communicate a quantitative threshold of “acceptable risk” for post-donation kidney failure risk; 2) when a donor candidate’s estimated risk is below the acceptable risk threshold, the transplant center should accept the candidate, and it should be the candidate’s decision whether to proceed with donation or not after being informed of the risks; and 3) when a candidate’s estimated risk is above this threshold, the transplant center is justified in declining the candidate and can ground their decision in a quantitative evidence-based framework (Figure 1). Establishing an “acceptable risk” threshold requires working knowledge of baseline pre-donation risk, as well as, post-donation risk of ESRD.

Figure 1.

Defining an “acceptable risk” threshold (adapted from the Kidney Disease Improving Global Outcomes (KDIGO) 2015 guidelines for assessing living donor risk).

Medically complex living kidney donors

Historically, living kidney donors were healthy and free of isolated medical abnormalities (IMA) at the time of donation. More recently, and in parallel with the general US population, donor demographics have changed, and transplant centers have relaxed selection criteria to include donors with IMAs such as pre-hypertension (pre-HTN), HTN, obesity, gestational diabetes, metabolic syndrome (MS), and the aged. At a general population level, individuals with IMAs are more likely to develop comorbid diseases such as diabetes, HTN, CKD, and ESRD. It remains unclear what impact, if any, living donation will have on the development of these comorbidities, and as such, understanding risk among potential living kidney donors with pre-donation IMAs remains an area of ongoing research.

1. Pre-HTN has been defined by the 8^th Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC8) as intermediate systolic pressures between 120–139mmHg and diastolic pressures between 80–89mmHg. Approximately 30% of the general US population is defined as having pre-HTN. Recent data from the Reasons for Geographic And Racial Differences in Stroke (REGARDS) study demonstrated that 62.9% of AA in the study population met criteria for pre-HTN compared to only 54.1% among EA, and that among pre-HTN participants microalbuminuria was more common in AA. Prehypertension has been established as a risk factor for cardiovascular disease and end-stage renal disease.

   Key Reference(s):

   • Glasser SP, Judd S, Basile J, et al. Prehypertension, racial prevalence and its association with risk factors: Analysis of the REasons for Geographic And Racial Differences in Stroke (REGARDS) study. Am J Hypertens. 2011;24(2):194–199.

2. Hypertension (HTN) is defined as clinic systolic blood pressure (SBP) ≥140 mmHg or diastolic blood pressure (DBP) ≥90 mmHg, out-of-clinic daytime mean ambulatory blood pressure of SBP ≥135 mmHg or DBP ≥ 85 mmHg, or the need for anti-hypertensive medication. Loss of kidney function (reduction in GFR) may accelerate the progression of HTN over time secondary to physiologic alterations in the setting of uni-nephrectomy, including hyperfiltration in the remaining kidney, changes in vascular tone and renin-angiotensin-aldosterone regulation. Importantly, HTN is a known cause of CKD and ESRD in the general population. A recent meta-analysis of 7 general US population cohorts found that for every 20mmHg increase in SBP there was an associated 42% increase risk of ESRD (adjusted hazard ratio [aHR]: 1.42, 95%CI: 1.27–1.58), and use of anti-hypertensives was associated with 35% increase risk of ESRD (aHR: 1.35, 95%CI: 1.01–1.82). Post-donation HTN has been shown to be more common among AAs (aHR 1.52, 95% CI: 1.23–1.88), Hispanics (adjusted HR 1.36, 95%CI: 1.04–1.78), and older donors (aHR 1.06, 95%CI 1.06–1.07 ); and those having pre-donation hypertension had a significant increase in their need for antihypertensive agents after donation (aHR 20.9, 95% CI: 8.8–49.3).

   With regard to living kidney donors, Segev et al. linked Scientific Registry of Transplant Recipients (SRTR) data to national death records and found higher perioperative mortality among donors with versus without pre-donation HTN (36.7 vs. 1.3 per 10,000). A smaller single center Norwegian study with 25-years of follow-up, comparing living donors with matched controls, demonstrated each 1 mmHg increase in SBP was associated with increased risk for ESRD. However, other studies have demonstrated no associated increased risk for ESRD among carefully selected living donors (Caucasian, ≥55 years of age, well-controlled on single anti-hypertensive). While their remains heterogeneity in available outcomes data, most centers consider uncontrolled HTN or HTN with end-organ damage (e.g. proteinuria, microalbuminuria, left ventricular hypertrophy, hypertensive retinopathy) as absolute contraindications to living donation.

   Key Reference(s):

   • Ibrahim HN, Foley R, Tan L, et al. Long-term consequences of kidney donation. N Engl J Med. 2009;360(5):459–469.

   • Segev DL, Muzaale AD, Caffo BS, et al. Perioperative mortality and long-term survival following live kidney donation. Jama. 2010;303(10):959–966.

   • Mjoen G, Hallan S, Hartmann A, et al. Long-term risks for kidney donors. Kidney Int. 2014;86(1):162–167.

3. Obesity (BMI >30kg/m²) is strongly correlated with increased risk for CKD, as data from a population-based case control study conducted in Sweden and US studies (Framingham Offspring cohort and Hypertension Detection and Follow-up Program) have shown higher weight for height was associated with increased risk for CKD. Beyond CKD, obesity has been linked with ESRD with reported risks among obese persons 1.16–3.57-fold higher than persons considered normal weight. Moreover, obesity has been associated with proteinuria, micoalbuminuria, and glomerulopathy. In fact, high waist-to-hip ration has an associated 1.29–2.74-fold increased odds of CKD and rapid decline in kidney function; central fat distribution associated with 1.7-fold increased risk of microalbuminuria, 2-fold higher odds of CKD, and rapid decline in estimated glomerular filtration rate (eGFR); and liver adiposity (higher fat content) associated with 1.8–6.14-fold increased odds of CKD.

   In parallel with the general population, the mean BMI of living donors has increased over time, from 24.3 in the 1970’s to 27.3 in the 2000’s. Currently, more than 25% of all living kidney donors are obese compared to fewer than 8% in the 1970’s. Determining candidacy for living kidney donation among obese individuals remains challenging as the appropriate BMI cutoff above which donation is no longer safe is unknown. Most centers have implemented a “one size fits all” approach to setting BMI limits (e.g. individuals with BMI ≥ 35kg/m² are excluded from donation) rather than a personalized approach that accounts for individual baseline differences. Recent data have emerged linking pre-donation obesity with post-donation ESRD risk. Specifically, Ibrahim et al reported results from a single center study of 3,956 donors and found that higher BMI was associated with 10% increased risk of proteinuria (aHR: 1.10; 95%CI: 1.06–1.13) and 3% risk of reduced GFR (<60ml/min) (aHR: 1.03; 95%CI: 1.01–1.04). Donors with a higher BMI were also more likely to experience a composite endpoint of GFR<30ml/min or ESRD (aHR: 1.08, 95%CI: 1.04–1.07). The study, however, was limited by lack of generalizability as no AAs were included and fewer than 100 obese donors were studied. Most recently, our group linked SRTR data to CMS claims and identified 119,769 living kidney donors. Risk of ESRD 20-years post-donation was 93.9 per 10,000 for obese vs. 39.7 for non-obese living kidney donors. It is important to note however that both studies were limited by lack of appropriate non-donor controls to assess ESRD risk directly attributable to the donation itself.

   Key Reference(s):

   • Locke JE, Reed RD, Massie A, et al. Obesity increases the risk of end-stage renal disease among living kidney donors. Kidney Int. 2017;91(3):699–703.

4. Impaired fasting glucose (IFG) in the setting of a normal 2-hour oral glucose tolerance test (OGTT) is not an absolute contraindication to living kidney donation. In contrast, most US centers do not accept donors with diabetes or impaired glucose tolerance (IGT). The physiology of IFG and IGT differ; specifically, isolated IFG is the result of hepatic insulin resistance with normal peripheral insulin sensitivity whereas isolated IGT results from increased peripheral insulin resistance. The presence of either IFG or IGT increases risk for diabetes by 5–10% per year depending on ethnicity and family history). Despite the correlation between pre-diabetes and subsequent development of diabetes, over the last 20-years there has been a trend among US centers toward accepting more living donors with glucose problems. This is significant given the fact that hyperfiltration, which occurs in the setting of uni-nephrectomy, is known to play an important role in progression of diabetic nephropathy. Animal studies have demonstrated progression of renal disease among diabetic animals after nephrectomy; and among humans, the Framingham study demonstrated increased risk for CKD among patients with IFG and IGT. Moreover, the development of gestational diabetes has an associated 37-fold increased risk for the subsequent development of type 2 diabetes mellitus, and as such, all female potential donors with a history of gestational diabetes should undergo a 2-hour OGTT.

   Key Reference(s):

   • Fox CS, Larson MG, Leip EP, et al. Glycemic status and development of kidney disease: the Framingham Heart Study. Diabetes Care. 2005;28(10):2436–2440.

5. Metabolic syndrome (MS), as defined by the National Cholesterol Education Program’s Adult Treatment Panel, requires evidence of at least three of the following five measures: (1) BMI ≥25 kg/m²; (2) systolic blood pressure ≥130mmHg or diastolic blood pressure ≥85mmHg; (3) triglyceride levels ≥150mg/dL; (4) high density lipoprotein (HDL) cholesterol levels <40mg/dL in males or <50mg/dL in females; and (5) fasting blood glucose ≥100mg/dL. According to data from NHANES the prevalence of MS in the general US population is 34%. It has been established that both MS and each of its components are independently associated with an increased risk of cardiovascular disease and incident CKD. Emerging data from the Renal and Lung Living Donors Evaluation (RELIVE) consortium demonstrate that AA donors were more likely to be obese and have hyperglycemia at the time of donation, suggesting that a higher rate of MS may exist among AA kidney donors. Further, a recent study examined the association between MS and kidney function in 410 living kidney donors. The study determined that donors with MS were more likely to have chronic histologic changes on implant biopsies, and this finding was associated with impaired kidney function recovery among recipients. The study was limited by lack of donor follow-up and absence of non-donor controls to assess attributable risk, and as such it is unclear what role MS may play in development of post-donation comorbidities in the living kidney donor.

   Key Reference(s):

   • Taler SJ, Messersmith EE, Leichtman AB, et al. Demographic, metabolic, and blood pressure characteristics of living kidney donors spanning five decades. Am J Transplant. 2013;13(2):390–398.

6. Aged Donor. Compensatory hyperfiltration in the remaining kidney is normal after nephrectomy, however, the aging process may impair compensation and reduce post-donation GFR. It is therefore, critical, to accurately assess pre-donation GFR in the aged donor, and as such, isothalamate GFR may complement 24-hour urine collection.

   Key Reference(s):

   • Reese PP, Bloom RD, Feldman HI, et al. Mortality and cardiovascular disease among older live kidney donors. Am J Transplant. 2014;14(8):1853–1861.

7. Hematuria is not normal and should be evaluated when found in a potential living kidney donor candidate. The evaluation aims to determine whether the hematuria is secondary to correctable causes (e.g. urinary tract infection, recent intercourse, menses), malignancy, or a glomerular disease (e.g. IgA nephropathy, thin basement membrane disease). Microscopic hematuria is typically defined as microscopic evidence of >2–5 red blood cells per high-power field of urinary sediment on 2–3 separate occasions unrelated to exercise, trauma, sexual activity, or menstruation. No consensus exists on hematuria work-up for the living donor candidate, but a recent Canadian protocol recommends: 1) urine culture and cytology, 24-hour urine calcium, and metabolic stone profile; and 2) if cause remains unknown after completing (1), then perform cystoscopy and native biopsy. Consensus based recommendations from the “Expert Guidelines for the Management of Alport Syndrome and Thin Basement Membrane Nephropathy (TBMN)” suggest that individuals with TBMN are safe to donate in the setting of normal BP and renal function and no evidence of proteinuria.

   Key Reference(s):

   • Savige J, Gregory M, Gross O, et al. Expert guidelines for the management of Alport syndrome and thin basement membrane nephropathy. J Am Soc Nephrol. 2013;24(3):364–375.

8. Kidney stones are common with an estimated 10–15% of the general population at risk for developing kidney stones in their lifetime. The risk of developing a kidney stone after living kidney donation does not differ between living donors without a pre-donation stone history and selected non-donors. One or more episodes of kidney stones has been associated with a 2-fold higher risk of ESRD. However, there are no data comparing rates of recurrent stones or long-term kidney function in donors with and without pre-donation kidney stones. Living donor candidates with a history of kidney stones should have comprehensive evaluation to elucidate the cause, including a 24hr urine collection to assess urine pH, calcium, oxalate, uric acid, citrate and sodium levels, review of available imaging studies to quantify stone burden, measurement of intact parathyroid hormone level, examination of urine sediment, and a detailed dietary history. Additionally, potential living donors should be screened for conditions which predispose to recurrent nephrolithiasis including primary hyperparathyroidism, medullary sponge kidney, type I renal tubular acidosis, chronic urinary tract infections or conditions predisposing to chronic diarrhea such as irritable bowel disease, gastric bypass and short gut syndrome.

Apopolipoprotein L1 (APOL1) renal-risk variants and living kidney donation

AAs have been shown to be at increased risk for CKD and ESRD both within the general population and among previous living kidney donors; the reasons for this observation are multiple and include genetic differences such as variants in APOL1. Individuals with two APOL1 risk alleles carry a 15% lifetime risk of renal disease, but having APOL1 genetic variants alone is insufficient to guarantee development of CKD, and it is thought that a second insult is required. There is concern that living donor nephrectomy may serve as a possible “second hit” for these individuals. Screening of AA living donor candidates is neither mandated nor universally accepted, and the practice varies on a center-level basis. There is concern that incorporating genetic testing for APOL1 into the living donor evaluation may worsen already disparate access to living donor kidney transplants among AAs, and that restricting patient’s ability to donate on the basis of genetic testing alone may be unfounded as not all individuals with APOL1 genetic variants develop renal disease. However, there have been at least 2 reports of living kidney donors with APOL1 risk alleles who subsequently developed ESRD themselves. We believe that APOL1 genetic data is valuable and can enhance current CKD/ESRD risk prediction algorithms (Figure 2); however APOL1 testing in renal transplantation remains controversial. Given the equipoise that surrounds the testing of AA living donor candidates for APOL1 risk variants, the National Institutes of Health is embarking on a multi-center, prospective trial (APOL1 Long-term Kidney Transplantation Outcomes Network) to screen AA kidney donors and recipients for APOL1 and assess the impact on renal outcomes for donors and recipients.

Figure 2.

Algorithm for selection of the young potential living kidney donor candidate.

*APOL1 genetic testing is recommended but not required.

Key Reference(s):

• Locke JE, Sawinski D, Reed RD, et al. Apolipoprotein L1 and Chronic Kidney Disease Risk in Young Potential Living Kidney Donors. Ann Surg. 2017.

Altruistic living kidney donors

Altruistic donors are characterized by donation to a stranger or someone with whom the donor has no previous relationship and for which they receive no direct benefit. The transplant community has traditionally been skeptical of these donors’ motivation to donate and their psychological well-being, but this non-traditional living donor source has become more accepted, increasing 8-fold from 20 transplants in 2000 to 163 transplants in 2015 and accounting for just over 3% of all living donors in 2014. While the concept of altruistic donation has become widely accepted in the United States, it is important to note that altruistic donors lack a pre-donation connection to the recipient and are less likely to report having had personal experiences with transplantation or medicine prior to contacting the transplant center than their traditional counterparts. They are also are less likely to report having received support for their decision to donate when compared to traditional donors, with some even reporting resistance from spouses or other family members. Although medical risks may not differ between traditional and altruistic or non-directed living kidney donors, these findings highlight the need for more in-depth psychosocial evaluation of altruistic or non-directed living kidney donors. In fact, a national consensus conference held to discuss practice guidelines for approval and care of these donors concluded that initial screening of non-directed or altruistic donors should accomplish three objectives: medical history, knowledge of non-directed donation, and donor-related issues; and emphasized that many potential altruistic donors have only a limited understanding of these issues and upon learning more about living donation withdraw from the process. A study at the University of Minnesota demonstrated that among individuals who expressed an initial interest in non-directed donation, 60% made no further contact with the transplant center after receipt of additional education or discussion about non-directed donation. Encouragingly, however, recent data suggest that altruistic donors are more likely to complete post-donation follow-up screening compared to their traditional counterparts, suggesting that current pre-donation screening practices may be adequate.

Key Reference(s):

• Maple H, Chilcot J, Burnapp L, et al. Motivations, outcomes, and characteristics of unspecified (nondirected altruistic) kidney donors in the United Kingdom. Transplantation. 2014;98(11):1182–1189.

• Adams PL, Cohen DJ, Danovitch GM, et al. The nondirected live-kidney donor: ethical considerations and practice guidelines: A National Conference Report. Transplantation. 2002;74(4):582–589.

• Reed RD, Shelton BA, MacLennan PA, Sawinski D, Locke JE. Living kidney donor phenotype and likelihood of postdonation follow-up. Transplantation. 2017; [Epub ahead of print].

Hepatitis C (HCV) antibody positive (Ab+), nucleic acid test negative (NAT-) living kidney donors

Chronic HCV infection is a recognized risk factor for the development of CKD and has been linked with a multitude of glomerular diseases including focal sclerosing glomerulosclereosis (FSGS), membranoproliferative glomerulonephritis (MPGN) and cryoglobulinemia, in addition to being an established risk factor for systemic diseases such as diabetes which is an important contributor to renal disease burden worldwide. HCV infection also accelerates the progression to ESRD. Historically HCV infection has been a contraindication for living donation given concerns surrounding disease transmission to the recipient and risk of subsequent renal disease in the donor. Since the approval of highly effective direct acting antivirals (DAAs) for the treatment of HCV in 2013, there has been renewed interest in the prospect of permitting candidates who have either cleared the infection spontaneously (HCV Ab+, NAT-) or those who have been successfully treated to serve as living kidney donors. In fact, the most recent version of the KDIGO 2017 guidelines submitted for public comment listed this as a potentially acceptable practice on the basis of “expert opinion”; they propose that living donors with HCV should have an evaluation of liver fibrosis after DAA therapy and achievement of a sustained viral response (SVR) measured at 12 and 24 weeks after therapy. There are now several case reports in the literature of using HCV Ab+ NAT- living donors, but the practice has not been widely adopted and concerns regarding potential for disease transmission and donor safety remain.

Key Reference(s):

• Cruzado JM, Gil-Vernet S, Castellote J, et al. Successful treatment of chronic HCV infection should not preclude kidney donation to an HCV negative recipient. Am J Transplant. 2013;13(10):2773–2774.

Human Immunodeficiency Virus positive (HIV+) living kidney donors

Passage of the HIV Organ Policy Equity Act in 2013 created the opportunity for HIV+ individuals to serve as living kidney donors, and the United States Department of Health and Human Services established the safeguards and research criteria for use of HIV+ organs in 2015. Under these provisions, HIV+ living donors must first meet all center-specific HIV-independent criteria for living donation, and in addition have a CD4 count ≥500 cells/uL, undetectable viral load, no history of invasive opportunistic infections and undergo a native kidney biopsy. There is reasonable concern in the transplant and nephrology community regarding the safety of living donation for HIV+ individuals. HIV infection is a risk factor for development of CKD and HIV+ individuals remain at increased risk of ESRD compared to the general population despite the widespread adoption of antiretroviral therapy. To date, no living HIV+ person has been a kidney donor and attempts have been made to model the risk of ESRD they may face. One simulation projected an ESRD risk ranging from 1.8–25.5 per 10,000 persons at risk; this risk varied greatly based upon metrics of viral control, presence of other comorbidities, age and race. AAs had the highest risk of ESRD among all potential donor cohorts. This wide range in risk highlights the fact that HIV+ persons are not a homogeneous group and that other factors, including APOL1 renal-risk variants or other genetic variants, may play an important role in their long-term risk for ESRD.

Key Reference(s):

• Muzaale AD, Althoff KN, Sperati CJ, et al. Risk of End-Stage Renal Disease in HIV-Positive Potential Live Kidney Donors. Am J Transplant. 2017.

Case, continued:

The patient was offered the option to undergo screening for APOL1 allelic variants, which she decided to have done. She was found to be heterozygous for the G1 allele. Using our risk calculator we estimated that her 25 year risk of developing CKD was 4.1% (95%CI: 2.72–5.46%). We discussed this risk projection with her, in the context of her risk factors for developing renal disease and which ones were modifiable. She indicated she was still interested in serving as a living donor and was therefore asked to lose weight in order to have a BMI<30 kg/m². She returned to donor evaluation clinic 6 months later having lost 30 lbs and now with a BP of 112/76. She elected to proceed with donation and was approved by the selection committee.

Post donation care and follow up

The transplant center is mandated to follow all living kidney donors for at least 2 years after donation; however life-long medical care with an established primary care physician is the ideal. Living donors should have their blood pressure checked at least once yearly, along with determination of renal function as measured by serum creatinine and screening for proteinuria by urinalysis or microalbumin to creatinine ratio. Younger age, AA race, lack of insurance, living far away from a transplant center or having donated at a high volume center have all been established as risk factors for lack of living donor follow up. As current health care legislation prohibits denying coverage to patients on the basis of preexisting conditions, such as living donation, living donors should not have increased difficulty obtaining health insurance, but this could change, and transplant centers need to remain vigilant in order to ensure that their donors have access to appropriate medical care and follow up after donation.

Key Reference(s):

• Kidney Disease Improving Global Outcomes. KDIGO Clinical Practice Guideline on the Evaluation and Follow-up Care of Living Kidney Donors. 2015.

Living Donor Core Curriculum Questions & Answers

Question 1.

A 42 year old man would like to be evaluated as a living kidney donor to his 10 year old daughter with FSGS. He is normotensive but his BMI is 35 kg/m² and his evaluation laboratory testing is notable for a fasting glucose of 115mg/dL. His wife has been previously evaluated and declined because she has lupus; there are no other available family members. Would you permit him to donate and how would you describe his risk of ESRD?

1. Not permit him to donate. His risk of ESRD is prohibitively high. His daughter will have to wait for a deceased donor transplant which she should get quickly through Share-35.

2. Ask him to do an OGTT; if it is normal then he is at low risk for diabetes and can proceed to donation without further testing.

3. Ask him to lose weight to a BMI<30kg/m² and check an OGTT at that time. Counsel him that he is at increased risk for ESRD after donation but that risk is acceptable to your transplant center.

Answer:

While we have focused on the medical considerations around living kidney donation, it is important to respect and understand the potential donor’s perspective and autonomy in decision making. Being declined as a donor candidate can have a negative psychological impact and depending on whom the intended recipient is, larger ramifications for the donor’s overall wellbeing. In this particular instance of a parent donating to a child, we would favor answer “c”; using this approach we are counseling him about his increased health risks associated with donation while providing guidance on how to mitigate those risks to the best of his ability.

Question 2.

Your 30 year old patient has had several family members come forward to be evaluated as donors. She is not yet on dialysis and anxious to be transplanted pre-emptively. Both her brother and her sister have contacted the donor team, but she is concerned about her brother’s suitability. He was in jail over night after a DUI 6 months ago and may be using other, illegal substances. What do you advise her?

1. Not to worry about catching an infectious disease from her brother if he ends up being her donor – PHS increased risk designation only applies to deceased donors and no one has ever contracted HIV or HCV from a living donor transplant.

2. Inform her that all living donors are screened not only for transmissible infections at the time of evaluation but again no more than 28 days prior to the planned surgery.

3. Inform her that all living donors are screened by a health care professional with appropriate mental health training and that this will be thoroughly investigated before he can be approved as a donor.

4. Tell her not to worry, her brother will definitely not be approved as a donor.

Answer:

In this case both “b” and “c” are correct. The PHS-increased risk donor designation applies to both living and deceased donors and is made by review of social factors that increase a donor’s risk of disease transmission in the window period. While the majority of reported transmissions involve HCV and the source is predominantly deceased donors, there has been at least 1 documented case of a living donor transmitting HIV. Evaluation of living donors includes screening for behaviors that would designate that person as “PHS-increased risk”. Furthermore the evaluation of donors includes a comprehensive assessment by a trained mental health professional with particular attention to substance use and abuse behaviors.