|Year : 2016 | Volume
| Issue : 4 | Page : 109-118
An evidence-based protocol for a comprehensive assessment of living kidney donors: individualizing the long-term risk of living kidney donation
Brian Camilleri1, Bridson M Julie2, Ajay Sharma3, Ahmed Halawa4
1 Renal Unit, Ipswich Hospital NHS Trust, Ipswich; Institute of Learning and Teaching, Faculty of Health and Science, University of Liverpool, Liverpool, UK
2 Institute of Learning and Teaching, Faculty of Health and Science, University of Liverpool, Liverpool, UK
3 Institute of Learning and Teaching, Faculty of Health and Science, University of Liverpool; Royal Liverpool University Hospital, Liverpool, UK
4 Institute of Learning and Teaching, Faculty of Health and Science, University of Liverpool, Liverpool; Sheffield Teaching Hospitals, Sheffield, UK
|Date of Submission||05-Sep-2016|
|Date of Acceptance||30-Oct-2016|
|Date of Web Publication||20-Feb-2017|
Sheffield Teaching Hospitals, University of Sheffield, Sheffield, ZIB CODE S5 7AU
Source of Support: None, Conflict of Interest: None
Kidney transplantation is the treatment of choice for patients with end-stage renal failure. Living kidney donation has increased over the past few years and now accounts for 34% of the total kidney transplant programme in the UK. Reasons for the increase in living kidney donation include shortage of deceased donor organs and the possibility to perform pre-emptive kidney transplantation and antibody-incompatible transplantation. In addition, some prefer living kidney donation as this option is associated with better patient and graft survival. However, although kidney donation is considered safe in low-risk individuals, it is important to remember that the donor will have to undergo major surgery and lead a life with a solitary kidney with associated lifelong implications including reduction in renal function. Despite various national guidelines, several studies have shown significant variation in acceptance criteria among centres. This mirrors the controversies as to whether donors with certain characteristics can be accepted for donation. This is particularly important given recent publications regarding the long-term risks associated with donor nephrectomy. In view of this, it is essential that prospective living kidney donors are fully informed of the risks associated with donor nephrectomy. This ensures that the process of living kidney donation is underpinned by informed consent that is freely given to ensure donor autonomy is safeguarded. In this review, we discuss the short-term and long-term risks associated with donor nephrectomy with a view to proposing a protocol to help individualize the assessment of the potential living kidney donor.
Keywords: Kidney, transplantation, living, donation and guidelines
|How to cite this article:|
Camilleri B, Julie BM, Sharma A, Halawa A. An evidence-based protocol for a comprehensive assessment of living kidney donors: individualizing the long-term risk of living kidney donation. J Egypt Soc Nephrol Transplant 2016;16:109-18
|How to cite this URL:|
Camilleri B, Julie BM, Sharma A, Halawa A. An evidence-based protocol for a comprehensive assessment of living kidney donors: individualizing the long-term risk of living kidney donation. J Egypt Soc Nephrol Transplant [serial online] 2016 [cited 2017 Jun 29];16:109-18. Available from: http://www.jesnt.eg.net/text.asp?2016/16/4/109/200353
| Introduction|| |
Kidney transplantation is the treatment of choice for patients with end-stage renal disease (ESRD). Compared with dialysis, kidney transplantation is associated with better survival , is less expensive  and is associated with a better quality of life . Organs for transplantation can be obtained from deceased or living donors. Deceased organ donation does not meet the demand for kidney transplantation and this has led to an increase in the use of living kidney donation . In the UK, the number of living donor kidney transplants tripled between 2000 and 2010  and currently accounts for 34% of the total kidney transplant programme. This corresponds to a living donor rate of 15.9 per million population . Nearly 30 000 people become a living kidney donor annually worldwide .
Other reasons why living donation has increased include the possibility of performing pre-emptive and antibody-incompatible transplantation. In 2014–2015, pre-emptive kidney transplantation was achieved in 34% of living donor transplants and there were 60 human leucocyte antigen-incompatible and 72 ABO blood group-incompatible kidney transplants in the UK . In addition, living kidney transplantation is associated with better recipient and graft survival: in the UK, the 5-year patient and graft survival rates for living kidney transplantation are 95 and 92%, respectively, whereas the corresponding figures for deceased kidney transplantation are 89 and 86%, respectively .
Following the introduction of the Human Tissue Act in September 2006 , it has been possible for recipients who have an incompatible donor to join a national live donor sharing scheme. This allows the possibility of paired or pooled donation  with a view to minimizing immunologic risk and avoiding intense immunosuppression associated with desensitization protocols . Compatible pairs can also be registered into the scheme to improve human leucocyte antigen or age matching for the recipient. The Human Tissue Act has also made it possible for nondirected altruistic donors to donate kidneys. The latter resulted in 107 living donor kidney transplants in the UK in 2014–2015 .
Despite the advantages associated with living kidney donation, and increasing rate of live donation, it is important to remember that the donor will have to undergo major surgery and lead a life with a solitary kidney. Although kidney donation is considered safe in low-risk individuals, it does have lifelong implications, including reduction in renal function. Several guidelines from across the world have been put forth to help guide the assessment of the living kidney donor in order to ensure that this is done in a safe manner ,,,. Despite these guidelines, there are significant variations regarding acceptance criteria among centres ,. These variations in practice reflect controversies as to whether donors with certain characteristics such as mildly reduced glomerular filtration rate (GFR), mild proteinuria, young age, obesity and hypertension can be accepted for donation. This is especially important given the more recent publications that have shaped our understanding of the long-term risks associated with donor nephrectomy ,,. These will be discussed in this review with a view to proposing a protocol to help individualize the assessment of long-term risk to the living kidney donor.
Current legal framework and ethical issues
In the UK, consent for the removal of organs from living donors must comply with the Human Tissue Act 2004  and with the Mental Capacity Act 2005 . The Human Tissue Authority was established as the regulatory body to oversee and enforce the working of the act. Various ethical principles are involved in living donor kidney transplantation, with autonomy being the main principle that provides the basis of living donation. This is reflected in the importance that is given to consent within this process.
Informed consent and risk associated with donor nephrectomy
For consent to be valid, it needs to be informed and freely given. In addition, the clinician must be satisfied that the prospective donor has the ability to make a competent and cogent decision . It is imperative to ensure that the process of living donor assessment is underpinned by informed consent. This requires information regarding donor nephrectomy to be passed on to the prospective donor in a form that allows them to make an informed decision. Ideally, both verbal and written information should be given to the donor to help this process. The information needs to include a full explanation of the short-term and long-term risks associated with donor nephrectomy. A critical reflection of the literature that forms the basis of this information will be reviewed next. Recommendations based on this reflection, which help formulate the living kidney donor assessment protocol presented in this review [Appendix 1 [Additional file 1]], are included.
Perioperative morbidity and mortality
Donor nephrectomy is associated with a small risk for death. Living donor nephrectomy was performed as an open procedure in the 1990s and mortality was around one in 3000 procedures ,. Matas et al.  reported on around 10 828 living donor nephrectomies performed in the USA. In this retrospective survey, 52.3% of nephrectomies were performed by an open approach and the rest were laparoscopic nephrectomies. Two donors (0.02%) died from surgical complications, and one was in a persistent vegetative state and reoperation was necessary between 0.4 and 1% of cases. More recently, in another study from the USA of more than 80 000 donors derived from a mandated national registry between 1994 and 2009, a period in which laparoscopic nephrectomy became more common than open nephrectomy, the 90-day mortality was 3.1 in 10 000 donations .
A study from the UK on more than 2000 donors, including 601 laparoscopic donor nephrectomies, showed no perioperative mortality . In this study, the rate of major morbidity (splenectomy, reoperation, thromboembolism, pneumothorax, pneumonia, or haemorrhage requiring blood transfusion) for laparoscopic and open donor nephrectomy was 4.5 and 5.1%, respectively. The rate of any morbidity (examples included constipation, diarrhoea, postoperative ileus, urinary tract infection, urinary retention requiring catheterization, wound complications and others) was 14% (10% laparoscopic and 16% open).
The short-term risks associated with donor nephrectomy need to be clearly discussed with the potential living kidney donor. A checklist has been provided to help with this process (see Section A of Appendix 1).
Long-term renal risks
Following kidney donation, there is an initial decrement in the GFR, but by 3 months the remnant kidney clearance increases to a mean GFR of around 70% of predonation renal function . In the systematic review and meta-analysis by Garg et al. , the average decrement in GFR after donation was 26 ml/min/1.73 m2 (range=8–50). Patients with chronic kidney disease have an increased risk for ESRD and death. In the study of more than one million adults in the USA (2004) , there was an independent graded association between an estimated GFR below 60 ml/min/1.73 m2and the risk for death, cardiovascular events and hospitalization. In view of this, it is reasonable to ask whether donor nephrectomy increases the risk for ESRD and poor outcomes in an otherwise healthy living kidney donor.
The overall incidence of ESRD among living kidney donors remains low at 0.2–0.5% in the first decade after kidney donation ,. In the study by Ibrahim et al. , the rate of ESRD was 180 and 268 cases per million persons per year in donors and controls, respectively. However, the controls in this study were selected from the general population. Although they were matched for age, sex, race and ethnic group, this control group included adults with medical conditions not eligible for kidney donation, resulting in a less healthy cohort.
Two recent studies addressed this problem by comparing the risk for ESRD in donors with that in selected healthy nondonors. Mjøen et al.  reported on the long-term renal function in 1901 patients who donated a kidney in Norway between 1963 and 2007. The outcomes were compared with those in 32 621 nondonors who would have been considered for donation over this period. The median follow-up period was 15.1 years for the donors and 24.9 years for nondonors. In this study, 0.47% of donors and 0.07% of nondonors developed ESRD. This may have been influenced by the fact that 80% of donors were first-degree relatives of the kidney recipient. Of the nine donors who developed ESRD, seven were secondary to immunological causes. Despite an 11-fold increased risk for ESRD in the donors compared with healthy nondonors, the absolute incidence of ESRD among donors remained low. There are limitations to this study, such as a difference in the commencement dates for the observation of the living donor cohort and controls (1963 to 2007 for donors and 1984 to 1987 for controls) that led to a longer observation period for donors, which in turn may have led to a higher incidence of ESRD in the donors. Other limitations include lack of measurement of kidney function or proteinuria in the control group at baseline, and a difference in baseline age, which was higher for donors. Finally, an exclusion criterion for donors was an estimated GFR of below 70 ml/min/1.73 m2, which meant that donors were accepted with an estimated GFR as low as 70, which may be associated with a worse outcome.
In another study by Muzaale et al. , 96 217 patients who had donated a kidney in the USA between 1994 and 2011 were studied and compared with 9364 healthy matched controls derived from the NHANES III study. The donor population was 75% white and 25% obese, and 22% had a predonation estimated GFR below 80 ml/min. The estimated risk of developing ESRD was 30.8 per 10 000 patients at 15 years after donation and 3.9 per 10 000 patients in the control group. The risk was higher in black donors (74.7). The estimated lifetime risk per 10 000 individuals was 14 for healthy nondonors, 90 for donors and 326 for the general population ([Figure 1]).
|Figure 1: Estimated lifetime risk for end-stage renal disease in a matched but unscreened general population, matched healthy general population and live kidney donors (from Muzaale et al. ).|
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These studies therefore suggest that the risk for renal failure in donors remains lower when compared with that in the general population but higher when compared with that of healthy individuals in the general population who did not donate. The overall risk of developing ESRD after kidney donation remains very low however, occurring in less than 0.5% donors. However, the absolute risk for young donors over a lifetime, especially in the presence of risk factors for ESRD, is likely to be more significant. In addition, the increased risk for kidney failure among living donors is almost exclusively due to genetic and immunological factors.
The small absolute risk for ESRD should be communicated to the prospective living kidney donor. This is important information when assessing and informing potential donors of the risks associated with donation. It still leaves living donation a potential option for transplantation, but particular care should be given to young donors, donors with relatives having ESRD secondary to immunological disease, and non-Caucasian donors.
Risk for loss of glomerular filtration rate after donation
In view of the information presented above, it is proposed that the threshold for the acceptable predonation GFR should be changed. It is important to ensure that the donor is left with adequate renal function after donation that is sufficient to maintain normal health without affecting the lifespan. In the current UK guidelines, it is recommended that donors have a GFR of at least 37.5 ml/min/1.73 m2 at the age of 80 in order to proceed with donation . However, this will need to be revised in view of the evidence presented above.
When determining a safe predonation level of kidney function, one needs to consider the difference in kidney function between men and women, the normal physiological changes associated with ageing and the rate of decline in GFR following living donation. In the study of 1878 potential donors from 15 UK centres , renal function was significantly higher in men than in women after the age of 40 years. GFR remained stable in this normal population in both sexes until age 40 and then declined each decade at a rate of 6.5 ml/min/1.73 m2 for men and 7.9 ml/min/1.73 m2 for women. In the study by Ibrahim et al.  of predominantly Caucasian donors, the rate of decline of renal function measured over 12 years after donation was very similar (0.6±3.8 ml/min/1.73 m2/year).
In light of the new evidence regarding the risk for ESRD, it is proposed that predonation measured GFR should be such that postdonation GFR remains within the sex-specific and age-specific normal range within the donor’s lifetime. [Table 1] shows possible recommended thresholds as proposed by the British Transplantation Society and the Renal Association. It should be noted that the younger the donor, the higher the threshold GFR in view of the extended expected lifetime risk.
|Table 1: Normal GFR and acceptable (threshold) GFR levels for live kidney donation (as proposed by the British Transplantation Society/Renal Association)|
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Risk of proteinuria
Proteinuria in the general population is associated with an increased risk for chronic kidney disease and cardiovascular disease ,. After kidney donation, many donors show a small increase in urine protein excretion after nephrectomy . In the study by Garg et al. , after an average of 7 years after donation, the average 24 h urine protein level was 154 mg/day.
The current UK guidelines recommend that significant proteinuria, defined as an albumin–creatinine ratio (ACR) of more than 30 mg/mmol, a urine protein–creatinine ratio (PCR) of more than 50 mg/mmol, or a 24 h urine total protein of more than 300 mg/day, contraindicates donation . Careful evaluation and counselling is recommended for those with microalbuminuria. The latter is defined as ACR between 3.5 and 30 mg/mmol, PCR between 15 and 30 mg/mmol, or a 24 h urine protein of 150–300 mg.
Urine protein excretion should be carefully assessed in the prospective living kidney donor. On the basis of the recent evidence on increased long-term renal risk, it is proposed that an ACR above 3.5 mg/mmol, PCR above 15 mg/mmol or a 24 h urine protein above 150 mg/day would be a contraindication for live donation. A kidney biopsy could be considered, especially in prospective donors who are relatives of recipients with a background history of ESRD secondary to immunological disease. However, the risks associated with a kidney biopsy should not be underestimated, and this would need to be discussed with the donor. In addition, it would need to be specified that this may not alter management in the donor who may not be willing to take the risk associated with the procedure.
Long-term risk for all-cause and cardiovascular mortality
In the study by Ibrahim et al. , mortality was lower among donors than in the unscreened general population. This is not surprising given the rigorous screening and selection process for donors. In the study by Garg et al.  comparing more than 2000 donors who underwent nephrectomy between 1992 and 2009 with more than 20 000 healthy matched nondonors, there was a lower risk for death or major cardiovascular events among donors versus nondonors after a median follow-up of 6.5 years. The risk for a major cardiovascular event was similar among donors and nondonors.
However, in the study by Mjøen et al.  from Norway mentioned above, the survival curves between donors and healthy nondonors started to separate after 10 years ([Figure 2]). At 25 years after donation, cumulative all-cause mortality was 18% among donors and 13% among healthy nondonors (hazard ratio of 1.3, P<0.001). The hazard ratio for cardiovascular death was 1.4 (P=0.003) in the donor group.
|Figure 2: Cumulative mortality risk in kidney donors and controls, adjusted for year of donation. Controls are matched to donors for age, sex, systolic blood pressure, BMI and smoking status (from Mjøen et al. ).|
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Reasons that may explain these increased risks include a small increase in blood pressure of about 5 mm Hg  and a slightly higher incidence of hypertension diagnosis  after donation. Small increases in proteinuria and a reduced GFR after donation  have both been associated with increased cardiovascular and all-cause mortality in the general population, especially in those with an estimated GFR below 70 ml/min/1.73 m2 ,. It is difficult to extrapolate this directly to a reduced GFR after donation. A reduced GFR in the general population may be a reflection of other disease associations such as hypertension and vascular disease.
These findings are relevant, especially as a recent study from Australia and New Zealand has shown that about a third of kidney donors had an absolute or relative contraindication to donation when compared with national guidelines . These contraindications included one or more renal or cardiovascular risk factor such as hypertension, obesity and smoking.
Age is also an important consideration. Younger donors have a longer time to develop complications from risk factors. A recent study of more than 3000 donors above 55 years of age who underwent nephrectomy in the USA between 1996 and 2006 were compared with healthy matched nondonors . After a median follow-up of 8 years there was no difference in all-cause mortality or in the composite outcome of death or cardiovascular disease.
These data should not deter from pursuing living kidney donation but it is very important to ensure that donor evaluation includes assessment of risk factors such as BMI, blood pressure, blood glucose and risk for diabetes mellitus. Screening for cardiovascular disease should also be included. In our unit, all potential donors undergo an exercise treadmill test to assess the functional status and screen for cardiovascular disease. It may be reasonable to have a lower threshold for accepting older donors with one or two mild risk factors.
Potential donors of childbearing age
Three main studies have assessed the impact of kidney donation on pregnancy outcomes. The first two studies, one from Norway  and the other from Minnesota, USA , were published in 2009. Outcomes of pregnancies before and after donation were compared in these studies. In the study from Norway, pre-eclampsia occurred in 5.7% after donation compared with 2.6% before donation (P=0.026). In the US study, there was a higher incidence after donation of foetal loss (19.2 vs. 11.3%, P<0.0001), gestational hypertension (5.7 vs. 0.6%, P<0.0001) and pre-eclampsia (5.5 vs. 0.8%, P<0.0001). The problem with these studies is that the risk for complications increases inherently with maternal age, making it difficult to clearly attribute the increased risk associated with donation.
A more recent study from Ontario, Canada, by Garg et al.  compared 131 pregnancies in 85 women who were kidney donors with 788 pregnancies in 510 healthy matched nondonors from the general population. The primary outcome of gestational hypertension or pre-eclampsia was more common among kidney donors (11 vs. 5%; odds ratio for donors 2.4, P=0.01). Odds ratio was 2.5 for gestational hypertension and 2.4 for pre-eclampsia in donors. Although this study showed that gestational hypertension and pre-eclampsia were more likely in kidney donors than in matched nondonors, it is important to point out that the absolute risk was still very small. In this study, 2% of nondonors had gestational hypertension and this increased to 5% in donors. Similarly, 3% of nondonors had pre-eclampsia versus 6% of donors. These results are comparable to the Norway study (3% gestational hypertension and 6% pre-eclampsia) and the US study (6% for each). In the Ontario study, there was no difference with respect to preterm birth rates or low birth weight. There were no maternal deaths, stillbirths or neonatal deaths, and most women experienced uncomplicated pregnancies after donation.
The Ontario study has some limitations, which include applicability of these data to non-White people as White people accounted for 70% of the cohort. In addition, the median maternal age for pregnancies in the donors was 32 years, which raises the question as to whether these findings are applicable to women of lower or higher age. It is possible that gestational hypertension and pre-eclampsia were diagnosed more likely in donors than in nondonors as these depended on clinical judgement by physicians. Finally, 65% of donors had a first-degree relative with kidney failure, raising the possibility that some donors may have had a genetic predisposition to kidney disease. However, this study helps in informing a potential donor of childbearing age that should they become pregnant there is a two-fold increase in the risk for gestational hypertension or pre-eclampsia but with a small increase in absolute risk of about 2–3%.
This information needs to be clearly communicated to potential living kidney donors of childbearing age. In addition, it may be advisable to recommend young female prospective donors who plan on future pregnancies to defer donation until they have had a family. This option may be relevant especially if there are other potential donors who may be preferred on the basis of this increased risk.
For those who become pregnant after donation, close monitoring is advisable during pregnancy for blood pressure, creatinine levels, and foetal well-being.
Aspirin 75 mg daily is recommended for use in the general population at high risk for pre-eclampsia and this is also advisable in kidney transplant recipients who plan a pregnancy . It is acknowledged, however, that there is no evidence to support this in living kidney donors.
Protocol for living kidney donation and individualized long-term risk
Protocol for living donor assessment
On the basis of the evidence presented above, a protocol is proposed in Appendix 1. This protocol has been devised using guidance from the Quality and Service Improvement Tools of the NHS Institute for Innovation and Improvement . The protocol is not intended to replace the national guidelines and it is advised that the user should refer to these guidelines for more information, especially if further guidance is required regarding abnormal investigations. The aim of this protocol is to enable the implementation of these national recommendations and to incorporate the new evidence with regard to long-term risks associated with donor nephrectomy. The protocol is divided into three sections: a checklist on the risks of donor nephrectomy, a list of investigations and parameters to help guide selection and/or exclusion of donors, and a table showing acceptable GFR levels based on age and gender.
Estimating the long-term risk for end-stage renal disease
A study from the USA has sought to develop a tool to estimate a person’s probable long-term risk for ESRD if that person does not donate a kidney . This online tool (http://www.transplantmodels.com/esrdrisk) uses 10 demographic and health characteristics to enable the 15-year and lifetime risk projections for the incidence of ESRD in nondonors. This study showed that hypertension, obesity (BMI>30), smoking, estimated GFR between 60 and 90 ml/min/1.73 m2 and abnormal urine albumin excretion independently increased the long-term risk for ESRD by 1.35-, 1.16-, 1.76-, 1.63- and 2.94-fold, respectively. In this model, the highest 15-year risks were among middle-aged black men and the highest lifetime projections were among young black persons ([Figure 3]a and [Figure 3]b). Older persons, even in the presence of low estimated GFR and mild hypertension, had a low estimate of the long-term risk of ESRD. This tool can be used to help individualize risk in a prospective donor, although it is important to emphasize that the projections were calibrated on US population cohorts.
|Figure 3: (a) Projections of the 15-year projected incidence of end-stage renal disease (ESRD) in the USA according to age, race and sex for the average kidney donor (from Grams et al. ). (b) Lifetime projected incidence of ESRD in the USA according to age, race and sex for the average kidney donor (from Grams et al. ).|
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Lifelong monitoring post-donation
Lifelong follow-up is recommended in view of the long-term medical risks discussed above. Investigations required are shown in Section B of Appendix 1.
| Conclusion|| |
Living kidney donation remains an important option for the treatment of ESRD. Living kidney donation benefits patients, their families and society. From a donor’s perspective, autonomy should be respected, and integral to this key ethical principle is informed consent that is freely given. This can only be achieved by ensuring that information regarding the risks and the uncertainties of donation are shared with the donor during the informed consent process. Recent data regarding long-term medical risks have shaped this process, and updated guidance from national bodies is awaited. In the meantime, this protocol is aimed at individualizing the process of living kidney donor assessment. The user must refer to the national guidelines with regard to determining suitability of a donor in case of abnormal findings during this assessment. The following key messages should also be borne in mind:
Risk for all-cause mortality
- Risk for ESRD
- The risk for ESRD in a living kidney donor is lower than that in the unscreened general population .
- The risk for ESRD in a living kidney donor is increased 11-fold when compared with that in a healthy nondonor. The absolute increased risk, however, is small and less than 1% ,.
- The lifetime risk for ESRD is higher in young and black persons .
The risk for all-cause mortality is lower for a living kidney donor when compared with the general population, although this is not surprising .Survival curves between donors and healthy nondonors start to separate after 10 years, and at 25 years after donation the cumulative mortality for donors is higher (18 vs. 13%, hazard ratio 1.3). The hazard ratio for cardiovascular death is 1.4 for the donor group . The absolute risk remains low.Donor of childbearing age
There is an increased risk for gestational hypertension and pre-eclampsia after donation but the absolute risk remains low. The risk for gestational hypertension is 2 and 5% for healthy matched nondonors and donors, respectively. The corresponding risks for pre-eclampsia are 3 and 6% .
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]