Abstract
Purpose of review:
To review an international guideline on the evaluation and care of living kidney donors and provide a commentary on the applicability of the recommendations to the Canadian donor population.
Sources of information:
We reviewed the 2017 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors and compared this guideline to the Canadian 2014 Kidney Paired Donation (KPD) Protocol for Participating Donors.
Methods:
A working group was formed consisting of members from the Canadian Society of Transplantation and the Canadian Society of Nephrology. Members were selected to have representation from across Canada and in various subspecialties related to living kidney donation, including nephrology, surgery, transplantation, pediatrics, and ethics.
Key findings:
Many of the KDIGO Guideline recommendations align with the KPD Protocol recommendations. Canadian researchers have contributed to much of the evidence on donor evaluation and outcomes used to support the KDIGO Guideline recommendations.
Limitations:
Certain outcomes and risk assessment tools have yet to be validated in the Canadian donor population.
Implications:
Living kidney donors should be counseled on the risks of postdonation outcomes given recent evidence, understanding the limitations of the literature with respect to its generalizability to the Canadian donor population.
What was known before
The Canadian 2014 Kidney Paired Donation Protocol for Participating Donors was developed to harmonize assessment and acceptance criteria between the various transplant programs across Canada involved in the Kidney Paired Donation program. Despite this, there is still variability between transplant centers across the country with respect to donor acceptance criteria.
What this adds
The international 2017 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors provided recommendations based on systematic reviews of relevant studies, including those published after 2014. Many of the recommendations are ungraded and based on expert opinion. This review highlights the recommendations from the guideline and interprets them within the Canadian context.
Introduction
In 2006, the Canadian Council for Donation and Transplantation (CCDT) held its sixth forum with the goal to enhance living donation in Canada. 1 Recognizing the variability across transplant programs in the nation, the 2014 Kidney Paired Donation (KPD) Protocol harmonized assessment and acceptance criteria for participating donors. 2 In 2017, the Kidney Disease: Improving Global Outcomes (KDIGO) published the Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors. 3 This international collaboration included Canadian experts on the guideline committee and the recommendations were based on critically appraised studies evaluated by the Evidence Review Team (ERT). 3 Where applicable, recommendations were graded based on the quality of the evidence (Table 1). For topics where there was no or insufficient evidence in the literature, the KDIGO working group relied on expert opinion and the recommendations were not graded.
KDIGO Nomenclature and Description for Grading Recommendations and Final Grade for Overall Quality of Evidence.
Note. Reproduced from Lentine et al 3 KDIGO Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors. KDIGO = Kidney Disease: Improving Global Outcomes.
The additional category ‘Not Graded’ is used, typically, to provide guidance based on common sense or where the topic does not allow adequate application of evidence. The most common examples include recommendations regarding the monitoring intervals, counseling, and referral to other clinical specialists. Ungraded recommendations are generally written as simple declarative statements, but are not meant to be interpreted as being stronger recommendations than Level 1 or 2 recommendations.
This Canadian commentary represents another national collaboration around living kidney donation, in conjunction with the Canadian Society of Transplantation (CST) and the Canadian Society of Nephrology (CSN). The goal of this working group was to review the 2017 KDIGO Living Kidney Donor Guideline, evaluate its relevance and applicability to Canadian donors, compare the recommendations to the 2014 KPD Protocol, and highlight the impactful research led by Canadian investigators within this area. We considered many Canadian aspects, including our ethnic diversity, universal healthcare system, and our vast and variable geography and landscape. This review is intended to be used with the comprehensive KDIGO Living Kidney Donor Guideline to support shared decision-making in the evaluation of living kidney donor candidates and the care of past and future living kidney donors in Canada.
Review Process
A working group was formed consisting of members from the CST and/or CSN. Members were selected to have representation from across Canada and in various subspecialties related to living kidney donation, including nephrology, surgery, transplantation, pediatrics, and ethics. Two co-chairs were selected to oversee the Canadian commentary on the 2017 KDIGO Living Kidney Donor Guideline. Each section was designated to one or more members of the working group based on their clinical expertise and interest in that area. Overall consensus was reached among all members. The commentary was reviewed by the CST and CSN executive, prior to peer review and final approval.
Commentary on Chapter 1: Goals of Evaluation, Framework for Decision-Making and Roles and Responsibilities
The recommendations in Chapter 1 are based on expert opinion and are “Not Graded.” In general, they align with the KPD Protocol’s ethical principles. Both the 2017 KDIGO Guideline and 2014 KPD Protocol emphasize the importance of respecting donor autonomy, the duty to protect the living donor candidate from anticipated harm from donation, and to proceed with nephrectomy only after informed and freely given consent.2,3 The Chapter 1 recommendations are clear, reasonable, ethically based, and noncontentious. The KPD Protocol does not detail donor follow-up and the KDIGO recommendation to formulate a donor follow-up plan is an important addition (see Chapter 19). Currently, there is no national standard for living kidney donor follow-up, in part, due to the lack of existing evidence.
A central component of the KDIGO Chapter 1 recommendations is establishing postdonation risk for each donor. 3 Providing living kidney donor candidates with a numeric assessment of their individual long-term risk is ideal but in practice is limited by the lack of validated risk assessment tools. To assist with this, the KDIGO working group developed a tool to estimate the 15-year and lifetime incidence of end-stage renal disease (ESRD) in the absence of donation based on various demographic and health characteristics (http://www.transplantmodels.com/esrdrisk/). 4 There are limitations and considerations with this risk assessment tool. First, the tool was developed using population-level incidence rates of ESRD and mortality from the United States and has not been adapted to the Canadian population. The tool is also limited in its ability to confidently predict long-term risk (ie, beyond 15 years postdonation) for younger donors and ethnically diverse donors, including Indigenous populations. Lastly, the model does not take into account the donor candidate’s genetic relationship with the recipient, which is a key factor for long-term risk. 5
The KDIGO Chapter 1 recommendations also include having each transplant center set a quantitative threshold of “acceptable risk.” 3 In practice, this also poses difficulty when the absolute individual risk assessment has wide confidence intervals (CI). Instead of relative risk, absolute contraindications modified by age and donor-recipient genetic relationship may be preferable. In addition to this, if transplant centers establish a uniform acceptance threshold for all donor candidates, they lose the flexibility to account for potential psychosocial benefits and harms that could occur to some candidates if they are beyond the threshold. For example, a nondirected donor would be considered equally as a directed donor to their spouse or child. There are reasonable ethical arguments on each side of this principle. Nonetheless, we agree that each center should have a transparent threshold for donor risk estimated using the best tools available beyond which they would not accept donation.
Commentary on Chapter 2: Informed Consent
The recommendations in Chapter 2 are based on expert opinion and are “Not Graded.” The recommendations pertaining to informed consent are clear and reasonable. They are in alignment with the KPD Protocol’s ethical principles of proceeding with a living donor nephrectomy with the living donor candidate’s informed and freely given consent, to respect the autonomy of the living donor candidate, and to be transparent with respect to the knowledge of health risks associated with living donation. 2 The KDIGO Guideline places more emphasis than the KPD Protocol on obtaining informed consent for the evaluation process, not just the donor nephrectomy. The evaluation process includes risks of discovery such as health conditions or misattributed biological relationships. For example, misattributed paternity is estimated to occur in up to 0.5% of Canadian living kidney donor evaluations and transplant centers should have established protocols on how this information is handled (Table 2). 8 As well, while both the KDIGO Guideline and KPD Protocol discuss having separate evaluation teams for the living donor candidate and the intended recipient, the KPD Protocol does not explicitly discuss that informed consent should be obtained in the absence of individuals who could influence the decision, such as the intended recipient. Lastly, the KPD Protocol does not address substitute decision makers, whereas the KDIGO Guideline recommends against their use except under extraordinary circumstances. 3 We recommend that the KPD Protocol consider these issues in their recommendations.
Summary of Studies Involving Canadian Living Kidney Donors.
Note. Data are presented as mean (SD) or median [IQR]. LKD = living kidney donors; IQR = interquartile range; OR = odds ratio; CORR = Canadian Organ Replacement Registry; CI = confidence interval; IRD = incidence rate difference; KPD = Kidney Paired Donation; CT = computed tomography; MRA = magnetic resonance angiography; QALY = quality-adjusted life year; ICER = incremental cost-effectiveness ratio; eGFR = estimated glomerular filtration rate; MDRD = Modifications of Diet in Renal Disease; N/A = not applicable/available; RR = rate ratio; SD = standard deviation; HR = hazard ratio.
Commentary on Chapter 3: Compatibility Testing, Incompatible Transplantation, and Paired Donation
The recommendations in Chapter 3 are based on expert opinion and are “Not Graded.” The recommendations for evaluation and counseling on issues relating to compatibility and options for incompatible pairs are clear and consistent with program norms in Canada, although the specifics of this have not been addressed by the Canadian KPD Protocol.
Since Canada has a national KPD program, counseling should highlight the benefits of enrolment in the national KPD program versus provincial or local exchanges, yet also highlight the increased requirement for travel for donors across Canada in the national program. In addition, donor candidates should be counseled on the anticipated expenses associated with KPD and the availability of provincial programs that offer partial re-imbursement for travel expenses incurred by the donor and a travel companion. Future considerations for enrolment of compatible pairs in KPD algorithms should also be considered and may also be offered to selected donors, particularly if there is an anticipated advantage to the recipient.
Commentary on Chapter 4: Preoperative Evaluation and Management
The recommendations in Chapter 4 are based on expert opinion and are “Not Graded.” The first recommendation addressing preoperative risk assessment uses sound clinical practice, including a history and physical examination, and applies general population guidelines for preoperative evaluation to minimize surgical risks to the donor. 3 We agree with this recommendation and it aligns with the KPD Protocol, despite variable practices in Canada in preoperative donor evaluations. 2 Given the altruistic nature of the surgery, some programs advocate additional testing (eg, nuclear stress testing) that would usually not be considered for a similar patient undergoing another operation. Given the lack of direct evidence in the donor population, there will always be some degree of practice variation in preoperative assessment but adhering to appropriate guidelines (eg, American Heart Association, Canadian Heart and Stroke Foundation) seems appropriate. 51
The second recommendation suggests that donor candidates should quit smoking at least 4 weeks before donation and continue smoking abstinence lifelong. 3 We agree with this recommendation, and it is consistent with the KPD Protocol. 2 While the KDIGO recommendation provides a timeline, the KPD Protocol advises donors to stop smoking before the donation surgery, without a specified timeline. The optimal time predonation to quit smoking is not known, but it seems reasonable to quit as early as possible before surgery to maximize the perioperative benefits.
Commentary on Chapter 5: Predonation Kidney Function
Most of the recommendations in Chapter 5 are based on expert opinion and are “Not Graded,” except for recommendation 5.10 which is graded as 2C. Having sufficient kidney function is the sine qua non for being a living kidney donor. Unfortunately, estimates of glomerular filtration rate (eGFR) are numerous and imperfect. Even with standardized laboratory methods, measurements of serum creatinine are subject to variation (analytical and intra-patient day-to-day) and so a single measurement is insufficient. Multiple measurements for the initial screen should be considered prior to further full evaluation. 52 The KDIGO Guideline recommends eGFR assessment using the 2009 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation to screen for kidney function adequacy.3,53 The KPD Protocol recommends 2 eGFR measurements using either the CKD-EPI or Cockcroft-Gault. 2 For most Canadians, including those of diverse ethnic backgrounds, eGFR by the CKD-EPI equation is practical and accurate.
Given the need for highly accurate GFR assessment for donor candidate evaluation, confirmatory testing is necessary. 54 The confirmatory measure is also controversial as not all measurements in recommendation 5.4 are considered equivalent. If being conservative (avoiding overestimation), then creatinine clearances, plasma clearances of exogenous markers, and radioactive tracer scintillation counting by nuclear medicine techniques may not be the best confirmatory tests. 55 Few centers use the gold standard of urinary clearance of exogenous markers due to its limitations, including time, expense, and day-to-day variation. Moreover, there is no evidence that using exogenous urinary clearance methods improves decision-making. The KPD Protocol requires two 24-hour urine studies measure creatinine clearance and/or 1 measured GFR to confirm adequate function. 2
The KDIGO Guideline recommends an eligibility criterion of a GFR ≥90 mL/min/1.73 m2, which is conservative given that the CKD-EPI equation underestimates kidney function. Likewise, a GFR <60 mL/min/1.73 m2 is a reasonable cut point to deny donation, although historically some centers have done so inadvertently. 56 As shown by the KDIGO ESRD risk assessment tool, younger individuals have a higher lifetime cumulative risk of ESRD compared to older individuals. 4 For example, a 20-year-old individual with an eGFR of 90 mL/min/1.73 m2 has a higher lifetime risk of ESRD, in the absence of donation, than a 60-year-old individual with an eGFR of 60 mL/min/1.73 m2. Personalized estimates of postdonation ESRD risk have been developed for the U.S. population (http://www.transplantmodels.com/donesrd/), but have not been studied and validated in the Canadian donor population. 57 In contrast, the KPD Protocol recommends age-dependent eGFR cut-offs for donor acceptability, but the KDIGO Guideline did not endorse this either because there is a lack of evidence or need to do so with their ESRD risk assessment tool.2-4
In focus groups involving 56 living kidney donors from a single center in British Columbia, donors identified their own postdonation kidney function and kidney failure among their top 5 most important outcomes (Table 2). 50 With respect to counseling, living kidney donor candidates should be informed of their risk of ESRD, in the absence and presence of donation. While this risk may be comparatively higher following donation, the absolute risk for most donors is small (<0.5% over 15 years). 58 Nonetheless, the lifetime risk of ESRD may be elevated, particularly for younger donors, justifying the need for increased surveillance postdonation (see Chapter 19).
Commentary on Chapter 6: Predonation Albuminuria
The recommendations in Chapter 6 are based on expert opinion and are “Not Graded.” The KDIGO Guideline recommends that predonation albuminuria should be evaluated using a 2-stage testing approach, with urine albumin-to-creatinine ratio (ACR) as the initial test and albumin excretion rate (AER) or repeat ACR as the confirmatory test. 3 These recommendations are reflective of a strong body of evidence from general population studies demonstrating an association between albuminuria and an increased risk of ESRD, cardiovascular disease, and death.4,59,60 The KPD Protocol recommends that predonation proteinuria be evaluated using a 24-hour urine collection for total protein and ACR. 2 We agree with the KDIGO recommendations that the assessment of albuminuria, rather than proteinuria, is the preferred approach in living kidney donors. Albuminuria is a more sensitive marker of kidney damage than proteinuria and is one of the earliest markers of glomerular disease, often occurring prior to the decline in kidney function. As such, the KPD Protocol has been revised to recommend a two-stage testing approach for albuminuria in living kidney donors similar to the KDIGO Guideline.
The KDIGO Guideline acceptance criteria for albuminuria in living kidney donors align with the KDIGO Chronic Kidney Disease (CKD) Guideline definition and classification.3,61 Donors with an AER of <30 mg/day, which is considered normal or mildly increased, are acceptable for donation. The risk to living kidney donors with predonation albuminuria of >30 mg/day is unclear. Therefore, the KDIGO Guideline recommends that living kidney donors with albuminuria of 30 to 100 mg/day be accepted on a case-by-case basis, based on the individual risk profile of the donor candidate. The KDIGO Guideline recommends that individuals with >100 mg/day of albuminuria should not donate. Accounting for the different methods for assessment of albuminuria and proteinuria, the albuminuria thresholds for donor acceptance in the KDIGO Guideline are similar to the proteinuria thresholds in the KPD Protocol. However, the KPD Protocol has also been modified to align with the albuminuria acceptance thresholds in the KDIGO Guideline. In light of donor safety, we agree with the KDIGO Guideline predonation albuminuria recommendations for donor selection. It is important to note that the recommendations are largely based on data from general population studies. The association between predonation albuminuria and postdonation outcomes needs further study to better define acceptance thresholds for living kidney donors.
Commentary on Chapter 7: Predonation Hematuria
The recommendations in Chapter 7 are based on expert opinion and are “Not Graded.” Overall, the KDIGO Guideline and KPD Protocol are similar in their recommendations on the assessment and selection of donor candidates with predonation microscopic hematuria. The KPD Protocol recommends kidney biopsy following a negative cystoscopy in the assessment of persistent hematuria in donor candidates. 2 For younger donors, cystoscopy is controversial given the low risk of malignancy in this population. 62
The KDIGO Guideline recommends that donor candidates with hematuria from a reversible cause that resolves (eg, treated infection) may be eligible for donation. 3 The KPD Protocol is more specific in its eligibility criteria, including potential donors with thin basement membrane disease when all other testing is normal and those with hematuria who have no abnormality on imaging, cystoscopy, and kidney biopsy. 2 In addition to IgA nephropathy, the KPD Protocol also recommends exclusion of donor candidates with Alport syndrome.2,63
Commentary on Chapter 8: Kidney Stones
The recommendations in Chapter 8 are based on expert opinion and are “Not Graded.” We concur with these recommendations. The Canadian Urological Association (CUA) guidelines strongly advocate for performing two 24-hour urine collections as part of the metabolic evaluation, noting that a second collection will change management for a significant number of patients.64,65 In addition to this, the CUA guidelines recommend measuring vitamin D levels in those with elevated parathyroid hormone levels and/or low normal serum calcium. 64
The KPD Protocol does not specify the number of 24-hour urine collections needed but does recommend that all donor candidates with stones should be assessed by an urologist. 2 In Canada, many centers have kidney transplant surgeons who are also urologists. This may not be necessary for the majority of donor candidates who have asymptomatic, unilateral, small (<15 mm) stones found incidentally on imaging as these patients likely have a low risk of recurrence, particularly if the metabolic workup is negative. 3 Donor candidates with a history of predonation kidney stones should be counseled on modifiable risks, which may affect the candidate’s ability to donate. One study from Ontario compared 2019 living kidney donors with 20,190 matched, healthy nondonors without a history of kidney stones (Table 2). 45 Reassuringly, after a follow-up of 8 years, there was no significant difference between the 2 groups with respect to the rate of hospitalizations for kidney stones or the rate of kidney stones treated with surgical intervention. 45
Commentary on Chapter 9: Hyperuricemia, Gout, and Mineral and Bone Disease
The recommendations in Chapter 9 are based on expert opinion and are “Not Graded.” The decrement in GFR associated with living donor nephrectomy is associated with a rise in serum uric acid levels,66,67 which may in turn increase the incidence of gout. Whether this occurs is unclear. In a retrospective study of 1988 living kidney donors and 19,880 matched, healthy nondonors from Ontario, the incidence rate of gout and incidence of medications used to treat gout were higher in donors than nondonors (Table 2). 48 The KPD Protocol does not make any recommendations regarding the assessment or counseling of hyperuricemia or gout. We recommend that donor candidates be asked about prior episodes of gout. The most compelling reason to do so in donor candidates may be the potential for associated nonsteroidal anti-inflammatory drug (NSAID) use postdonation. Given the uncertainty surrounding the role of donation in future episodes of gout, transplant programs may elect to defer lifestyle and dietary counseling to reduce the risk of hyperuricemia and gout to the primary care physician.
Commentary on Chapter 10: Predonation Blood Pressure
Most of the recommendations in Chapter 10 are based on expert opinion and are “Not Graded,” except for recommendation 10.6 which is graded as 2D. The KDIGO Guideline makes 6 recommendations regarding blood pressure in the living kidney donor candidate. The first 2 recommendations deal with the evaluation and measurement of blood pressure. At the time the KDIGO Guideline was published, the recommendations were very similar to the KPD Protocol. Recently, Hypertension Canada (previously known as Canadian Hypertension Education Program, CHEP) revised its guideline for the evaluation and diagnosis of hypertension. 68 Rather than office readings using auscultation, Hypertension Canada recommends measuring blood pressure using a validated digital oscillometric device (eg, BpTRU, OMRON HEM 907XL, MicroLife WatchBP Office, or PRO BP2400) as the preferred method. 68 These devices take an automated series of measurements while the patient is alone in a quiet room (usually 3-6 measurements spaced 1 minute apart over 4-7 minutes) with averaging of the results. This technique has repeatedly been demonstrated to correlate more closely with daytime ambulatory blood pressure measurement (ABPM) compared to manual office measurements and is already widely used in Canada.69,70 If blood pressure is normal (systolic blood pressure <135 mmHg and diastolic blood pressure <85 mmHg) using an office-based automated device, then hypertension can safely be excluded. 68 Values above this will need confirmation using ABPM or a series of home-based readings. 68 We recommend that the new Hypertension Canada guidelines be followed for the evaluation of living donor candidates. This will allow hypertension to be excluded in many patients with just 1 office visit. In addition, it will align with guidelines being used by Canadian primary care practitioners. If donor nephrectomy is delayed, we suggest that the blood pressure be re-checked at annual intervals using an office-based automated device.
The KDIGO Guideline and KPD Protocol differ in the criteria for selection of hypertensive donors. The KDIGO Guideline states that donors with controlled hypertension on 1 or 2 agents may be suitable for donation, regardless of age. 3 The decision to proceed should be based on the donor candidate’s predicted lifetime incidence of ESRD in relation to the program’s acceptance risk threshold. In contrast, the KPD Protocol requires that hypertensive donors be ≥50 years of age and well controlled on just 1 agent. 2 While we understand the need to minimize variability between programs for KPD to function properly, the data supporting the age cutoff are weak. The medical risks postdonation are unlikely to be different for a 48-year-old donor compared to a 51-year-old donor. The assessment of overall risk seems like a more logical approach. To operationalize this in a Canadian context, programs will need to agree on the same methods for determining risk postdonation (eg, use of an ESRD risk assessment tool that is validated in a Canadian population). 4
In a retrospective cohort study from Ontario matching 1278 living kidney donors to 6359 healthy nondonors, donors were more frequently diagnosed with hypertension than controls after a mean follow-up of 6 years (Table 2). 36 However, the authors concluded that while the observed increase in hypertension diagnoses may have been associated with the nephrectomy, it could also have been noted due to the increased surveillance for hypertension among living donors by their primary care physicians. The KDIGO Guideline has 2 specific recommendations regarding counseling that are not addressed in the KPD Protocol. First, the KDIGO Guideline recommends that hypertensive donors be counseled on lifestyle interventions to reduce their blood pressure and cardiovascular risk (eg, healthy body weight, regular exercise, smoking cessation). 3 Second, they suggest that donor candidates be informed that nephrectomy may accelerate the rise in blood pressure that accompanies aging, necessitating earlier treatment for hypertension than might be expected based on age. 3 We agree with both of these recommendations. Implementation would not be onerous and may already be occurring in many Canadian programs, given the first recommendation applies to all members of the general population, including living kidney donors.
Commentary on Chapter 11: Predonation Metabolic and Lifestyle Risk Factors
The recommendations in Chapter 11 are based on expert opinion and are “Not Graded.” Overall, we agree with the recommendations in this chapter and they align with the recommendations in the KPD Protocol, with a few exceptions. First, in the KPD Protocol, donor candidates with type 2 diabetes mellitus and those with a body mass index (BMI) >35 kg/m2 would be excluded from donation. 2 One retrospective study from Japan followed 225 living kidney donors, 14 had predonation diabetes mellitus, and 211 did not, over a median follow-up of 4.3 and 4.6 years, respectively. 71 At the end of follow-up, the eGFR was not significantly different between the 2 groups (51.7 vs. 52.1 mL/min/1.73 m2; P = .9). Similar results were found in a larger cohort of living kidney donors from the United States who developed postdonation diabetes mellitus. 72 In this study, donors who developed diabetes had a significantly higher risk of hypertension and proteinuria compared to donors who did not develop diabetes mellitus.
Given that many of the studies guiding these recommendations are based on Caucasian donors, Canadian transplant programs should be cautious in generalizing these results given the ethnic diversity of our population. Although the prevalence of living kidney donation and transplantation in the Canadian Indigenous population is low, 10 medical clearance must consider the unique pathophysiology in this group. Diabetes mellitus has a more aggressive course in Indigenous peoples and the incidence of associated ESRD and death is higher compared to non-Indigenous Canadians.73,74 Since the ESRD risk assessment tool for living kidney donor candidates does not take into account family history or race (beyond Caucasian or African-American), 4 it is limited in predicting ESRD risk in young Indigenous donor candidates with a family history of diabetes. Similar limitations exist for other high-risk ethnic minority populations, such as South Asian Canadians. These unique differences in Canadian living donor candidates support a more conservative approach in medical acceptance until more robust Canadian data on living donor outcomes in these populations are available.
Large cohort studies document an increased risk of postdonation ESRD with increasing BMI >30 kg/m2.4,57,75 As the prevalence of obesity in the Canadian population increases, it is likely that individuals with elevated BMI will proceed to kidney donation. Canadian transplant programs must be aware of these risks and ensure donor safety is not compromised. Further research is required to understand the impact of BMI on the development of ESRD following donation including the accuracy of BMI vs. waist-to-hip ratio and the effect of predonation weight loss or postdonation weight gain.
Commentary on Chapter 12: Preventing Infection Transmission
The recommendations in Chapter 12 are based on expert opinion and are “Not Graded.” Every Canadian transplant program is closely monitored to ensure the prevention of infectious transmission in the process of cell, tissue, and organ donation. All programs must comply with Health Canada’s regulations pertaining to the safety of human cells, tissues, and organs for the purpose of transplantation. 76 Within these regulations, Health Canada outlines which infectious diseases need to be monitored and the timing and method of testing. These align with the KDIGO Guideline; however, do not include the seasonal and geographic endemic infections. 3 Although these infections are rare in Canada, the ease of global travel and the increasing approval of out-of-country donors make testing for these pathogens prudent.
Currently, there are no reports of kidney transplants from living donors who are hepatitis C virus (HCV) or human immunodeficiency virus (HIV) infected, only deceased donor cases.77,78 Individuals infected with HCV have a high chance of cure following therapy with newer direct-acting antiviral therapy.79,80 Certain Canadian transplant centers with access to these newer therapies are already accepting kidneys from deceased donors who are HCV positive to be transplanted into recipients who are HCV negative. It is conceivable that living donor candidates with HCV may proceed to donation and research protocols will need to be developed to ensure the long-term safety of both the donor and recipient. With respect to HIV, 1 study from the United States reported that the 9-year cumulative incidence of ESRD in individuals with HIV is higher than in individuals without HIV, yet the absolute risk was low and varied by age, sex, and race. 81 Thus, we would advocate that the risks and benefits of living donation be thoroughly discussed with HIV-positive individuals who are motivated to donate.
Commentary on Chapter 13: Cancer Screening
The recommendations in Chapter 13 are based on expert opinion and are “Not Graded.” The KDIGO Guideline and the KPD Protocol both recommend cancer screening based on recommendations from local/national agencies, but the KPD Protocol specifically provides screening instructions for breast, cervical, prostate, and colon cancer.2,3
The KDIGO Guideline and the KPD Protocol have similar selection and exclusion criteria for kidney donation related to cancer. Both documents suggest excluding donors with active cancer. However, in the KDIGO Guideline, this position is nuanced by mentioning that donors with active cancer, but low risk of transmission to the recipient (for instance, cancers with low risk of progression in the donor), may be considered.
In both documents, a living kidney donor with a history of cancer associated with a low risk of recurrence or low risk of transmission is acceptable on a case-by-case basis. Patients with a history of melanoma are formally excluded from donation. In the KDIGO Guideline, this recommendation is not found in the summary, but rather in the rationale section. Lastly, the KDIGO Guideline formulates specific recommendations for the donor with renal cysts.
Commentary on Chapter 14: Evaluation of Genetic Kidney Disease
The recommendations in Chapter 14 are based on expert opinion and are “Not Graded.” We agree with the KDIGO Guideline recommendations regarding the evaluation, selection, and counseling of donor candidates with potential genetic kidney diseases. 3 The KDIGO Guideline recommendations align with the KPD Protocol, particularly in the diagnostic testing of donor candidates with a family history of autosomal dominant polycystic kidney disease (ADPKD).2,3
There are some notable considerations and exceptions. First, the KPD Protocol does not address the impact on obtaining health or life insurance in the event of a diagnosed genetic kidney disease. Second, the KDIGO Guideline and KPD Protocol disagree in their recommendations regarding cases where there is uncertainty whether the donor candidate has a genetic kidney disease that can cause kidney failure. The KPD Protocol recommends that in these cases, donor candidates should not proceed with donation in the interest of their own safety. 2 In contrast, we agree with the KDIGO Guideline that, in this situation, donation should only proceed after informing the donor candidate of the risks of donation, if the disease occurs later in life. 3 The donor candidate should also be informed of any potential impact of the genetic disease on survival and function of the graft. Lastly, the KPD Protocol does not make any comments on the utility of apolipoprotein L1 (APOL1) genotyping in donor candidates of sub-Saharan African ancestry. We agree with the KDIGO Guideline recommendations that these donor candidates be offered APOL1 genotyping and informed of the increased risk of kidney failure associated with having 2 APOL1 risk alleles; however, the precise kidney failure risk for an affected individual after donation is unknown.
Commentary on Chapter 15: Pregnancy
Most of the recommendations in Chapter 15 are based on expert opinion and are “Not Graded,” except for recommendation 15.9 which is graded as 2C. We agree with the KDIGO Guideline recommendations surrounding pregnancy considerations. For female donor candidates with a history of a hypertensive disorder of pregnancy, a detailed description should be obtained and documented. This includes the number of pregnancies, episodes of hypertensive or other disorders of pregnancy, and any clinical sequelae. The evidence suggests that a prior history of hypertensive disorder during pregnancy (particularly preeclampsia/eclampsia) is associated with a higher risk of ESRD.82-84 Donor candidates with a mild hypertensive disorder during pregnancy, or a single event that occurred more than 10 years ago who have normal eGFR, normal blood pressure, and no microalbuminuria and who have completed their families are likely at lower risk of postdonation ESRD and can be considered for living kidney donation. Female donor candidates with recurrent episodes of preeclampsia/eclampsia during subsequent pregnancies have a higher risk of ESRD and should be excluded from donation. 83
Three retrospective cohort studies (from Norway, 85 United States, 86 and Canada) 47 suggest a greater likelihood of being diagnosed with gestational hypertension or preeclampsia after kidney donation although the overall risk remains low. In the Canadian study, the risk of gestational hypertension or preeclampsia was twofold higher in living kidney donors compared to matched female nondonors over a median follow-up 11 years (Table 2; 11% vs. 5%; odds ratio 2.4, 95% CI = 1.2.-5.0; P = .01). 47 To reduce the risk of complications in postdonation pregnancies, female donors should be counseled to maintain general good health, ensure adequate follow-up, and receive proper prepregnancy counseling and prenatal care.
Commentary Chapter 16: Psychosocial Evaluation
Most of the recommendations in Chapter 16 are based on expert opinion and are “Not Graded,” except for recommendation 16.6 which is graded as 2D. Both the KDIGO Guideline and the KPD Protocol recommend a comprehensive psychosocial evaluation for donor candidates.2,3 The KPD Protocol further specifies that the psychosocial evaluation should be conducted by a trained health care professional, such as a social worker or psychologist. 2 This role may vary across transplant centers according to resources and expertise. We agree that the psychosocial assessment of the donor candidate should occur in the absence of other people to minimize the risk of potential coercion and be performed by members of the health care team who are not directly involved in the care of the intended recipient. 87 Currently, there is no evidence-based tool or systemic protocol for assessing a donor candidate’s psychosocial suitability and further research is needed.88,89
The KPD Protocol does not have recommendations regarding postdonation quality of life. 2 One retrospective study involving 7 centers in Canada found that the quality of life scores (using 15D) was high and similar between living kidney donors and healthy nondonors (Table 2). 40 Donor candidates should be informed about the benefits of living kidney donation but also the potential psychological impact after transplantation, particularly if they or their intended recipient suffers complications. Transplant programs have a responsibility to ensure the long-term medical and psychosocial well-being of living kidney donors.
Commentary on Chapter 17: Acceptable Surgical Approaches for Donor Nephrectomy
Most of the recommendations in Chapter 17 are based on expert opinion and are “Not Graded,” except for recommendations 17.3 and 17.7 which are graded as 2D. Both the KDIGO Guideline and the KPD Protocol appropriately recommend renal imaging for assessment of renal anatomy, which is essential prior to undertaking donor nephrectomy.2,3 The KDIGO Guideline contains a number of prescriptive statements about the surgical technique to be utilized for donor nephrectomy, while the KPD Protocol does not make any specific recommendations.
We disagree with the surgical recommendations 17.3, 17.4, 17.6, and 17.7. In Canada, there is discrepancy in the number of surgeons and clinical volumes between transplant centers participating in KPD. Due to limitations on the shipping of live donor kidneys in Canada, donors may need to travel to the center of their matched recipient in order to donate, which may incur additional costs and out-of-pocket expenses to the donor. Given that the priority for the surgeons is to achieve the safest possible outcome for the donor, the decisions about surgical technique (open, mini-open, hand-assist laparoscopic, pure laparoscopic, robotic, etc.) and which kidney to remove (right vs. left) should be at the discretion of the surgeon. The surgical experience in Canada suggests that compared to the open technique, laparoscopic donor nephrectomies have longer operative times but are associated with lower blood loss, reduced intraoperative complication rates, and shorter hospital stays.26,28-30 We also agree with the recommendation 17.5, but would modify this to state that Weck Hem-o-lok clips should not be used as the sole method for control of the main renal artery during donor nephrectomy.
Commentary on Chapter 18: Ethical, Legal and Policy Considerations
The recommendations in Chapter 18 are based on expert opinion and are “Not Graded.” Many of these recommendations are not considered in the KPD Protocol. 2 In Canada, provincial and federal laws state that organ donation should be gratuitous and organs should not be sold and bought in exchange of valuable consideration. 90 Moreover, living organ donation should be done in compliance with Health Canada standards. 76 Currently, there are no laws or policies that impede the ethical practice of living donation and every effort should be made to remove all disincentives for living kidney donors. Autonomy should always be respected in the process of living organ donation; however, relational autonomy should also be taken into account. Relational autonomy considers the social context, social relationships, and emotions that are embedded in decision making.
In 2017, the CST published a position statement on the issue of public solicitation. 91 It is legally and ethically acceptable for transplant centers to consider potential living organ donor from public solicitation provided that it is made in compliance with the Canadian laws; however, it is not mandatory for transplant programs to assess these donors. Transplant professionals could have conscientious objection towards public solicitation. In such cases, transplant centers should be transparent in disclosing the reasons for declining to evaluate these donors and should refer them to another center for evaluation.
A 2014 prospective study of 7 Canadian transplant centers found that the average overall cost incurred by donor candidates was $3268 with 15% of donors spending >$8000 (Table 2). 15 While there is some credit at the Canadian federal level, reimbursement programs for living kidney donors vary in their policies across the provinces. 92 One study from Ontario’s reimbursement program found that the average financial gap between costs incurred and costs reimbursed to donors was $3115 CAD. 18 Transplant centers should continue to advocate for financial neutrality for the donor during the evaluation and donation process.
Canadian Blood Services recommends that anonymity be maintained between nondirected donors and donors participating in paired donation to prevent unwanted requests from the donor or the recipient. In the rare event that a living kidney donor develops ESRD, most programs have allocation policies that allow for certain priority for living donors on the deceased donor kidney transplant waiting list.
Commentary on Chapter 19: Postdonation Follow-Up Care
The recommendations in Chapter 19 are based on expert opinion and are “Not Graded.” We agree with the KDIGO Guideline recommendations as an essential component of the donor evaluation process. 3 The KPD Protocol does not address postdonation follow-up care. 2 Since the publication of the KPD Protocol in 2014, there has been increasing literature to further our understanding of long-term postdonation outcomes. Two studies, 1 from Norway and 1 from the United States, have shown that the relative risk of ESRD in living kidney donors is higher than in selected nondonors of similar baseline health; however, the absolute estimates are small (<0.5% over 15 years for most donors).58,93,94 In addition to this, over a follow-up of ~10 years in Ontario, the risk of gestational hypertension or preeclampsia and gout was higher in donors compared to matched, healthy nondonors,47,48 whereas the risk of cardiovascular disease, acute dialysis, kidney stones with surgical intervention, gastrointestinal bleeding, and fractures was similar (Table 2).41,42,44-46,95
There are many potential benefits of postdonation follow-up care. It allows for prevention, early detection, and management of diseases and is an opportunity to inform and educate prior donors on new research on long-term outcomes. 32 It can also promote the transplant center’s collaborative role in the long-term care of donors, rather than leaving them with a sense of abandonment. Although all Canadian center’s perform short-term follow-up as part of the surgical postoperative care, there is wide variability in the involvement of centers in the longer-term follow-up. This is mainly due to the role of the primary care physician in follow-up care, donor or professional opinion of well-being, and lack of proven efficacy that close surveillance and monitoring results in improved outcomes. 31 One study from Alberta found that, over a median follow-up of 7 years, only 25% of donors had all 3 markers of care recommended in the KDIGO Guideline (physician visit, serum creatinine, albuminuria measurement) in each year of follow-up (Table 2). 32
While the United States has mandatory reporting by transplant centers to the national transplant registry, it is limited to 2 years postdonation, and has high rates of missing data and loss-to-follow-up.96,97 No such policy exists in Canada and while there is enthusiasm for living donor registries in Canada and the United States, there are challenges including limited resources, infrastructure, and funds. 98
Conclusion
Overall, the recommendations in the 2017 KDIGO Guideline on the Evaluation and Care of Living Kidney Donors aligns with our national 2014 KPD Protocol for Participating Donors. There are some notable differences that we have highlighted in our review, including considerations of our ethnically diverse population, such as the Indigenous population.
Footnotes
Acknowledgements
We would like to thank Canadian Blood Services and Dr. S.K. Singh for their contributory work on the “Evaluation of KPD Protocol Alignment with KDIGO Living Kidney Donor Guidelines.”
Authors’ Note
Text from the KDIGO Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors in the boxes of this commentary is reproduced with permission from KDIGO.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
