LIVING DONOR RENAL TRANSPLANT- WHAT DO THE GUIDELINES SAY?

Renal transplant (RT) is the treatment of choice for patients with end stage renal disease. The use of grafts from living donors (LD) has been increasing over time. Living donor RT is a unique situation as it allows optimum graft survival (as compared to deceased donor transplants) and also allows complex transplants (for example in the antibody incompatible setting). In the UK , according to annual NHS blood and Transplant activity report (201-2017), living donor kidney transplants made up 30% of  all the RT(1). Living donor activity in that period comprised directed donation (80%), non directed/altruistic (6.5%), paired/pooled exchanges (7.5%) and altruistic donor chain (6%)(1).

The kidney donor is paramount to the success of any LD transplant  program and in the UK setting, the British Transplant Society /Renal Association (BTS) have published best practice guidelines for living donor transplant in an effort to set standards, ensure safety of donor patients and as a resource for transplant clinicians(2). The ‘Kidney Disease Improving Global Outcomes (KDIGO)’ guidelines also discuss the evaluation and care of living kidney donors (3). Further guidelines from the European Association of Urology (EAU) cover renal transplantation and deal mainly with technical aspects of donor assessment and surgery(4). In this report, key recommendations from those three guideline bodies will be reviewed. The local transplant protocol (Newcastle Upon Tyne,UK) and donor assessment process will also be discussed highlighting differences between the published guidelines and local practice. Finally, an evidence based protocol for living donor RT will be presented.

Local transplant experience and living donor assessment

Annual reports from NHSBT and the United Kingdom Renal Registry (UKRR) provide data on the burden of chronic kidney disease and RT activity at a local and UK level. According to the UKRR 19

^th

Annual report (2016), the prevalence of patients on renal replacement therapy (RRT) in the Newcastle Upon Tyne area was 865 per million population (pmp) compared to 924pmp for the whole of the UK(5). Incidence rates for patients starting RRT in Newcastle Upon Tyne was 98pmp (vs. 119pmp for whole of UK)(6). For local patients on RRT, 66% had RT, 29% had haemodialysis and 5% had peritoneal dialysis(7). The NHSBT 2016/17 report indicated that there were 395 patients on the RT waiting list with 170 transplants having been performed over the 12-month period in Newcastle Upon Tyne(1). RT performed comprised 111 cadaveric transplants (63 DBD, 48 DCD) and 59 living donor transplants in 12 months. In addition 29% of all living donor transplants performed between 2009-2013 were ABO or HLA incompatible (compared to 15% whole of UK). For living donor transplants locally, one-year and five-year graft survival rate was 100% and 90% respectively compared to 97% and 91% for the whole of UK(1).

The local living donor transplant assessment is undertaken in a dedicated transplant clinic. The potential donor has to go through a rigorous assessment process and have a good understanding of the risks and benefits of the surgery. After an initial appointment with a live donor transplant coordinator, a potential donor is seen by a consultant nephrologist for a full medical assessment and initial investigations (including imaging, crossmatch) to ensure suitability for donation. Following this assessment and initial tests, the potential donor is then seen by the consultant transplant surgeon to ensure donation is surgically possible and to be counselled about the surgical risks. Laparoscopic donor nephrectomy is the technique of choice in our unit. As it is a legal requirement, an independent assessor reviews each case put forward for living donation. Following comprehensive assessment, all living donor cases are reviewed at a multidisciplinary meeting once all the investigations are available to ensure safe donation and final decision to proceed is made at the time.

Living donation guidelines and local practice

This section reviews the existing guidelines and compares them to the local protocol as follows:

BTS guidelines


(2)

The BTS guidelines stress the importance of centres complying with a strong legal framework for LD RT including the Human Tissue Act 2004 and European Union Organ Donation Directive(8).  In addition, the ethics of organ donation and principles of confidentiality should be adhered to(9). Discussion for potential donors should start when recipient estimated glomerular filtration rate (GFR) is around 20ml/min or when the recipient is within 12-18mo of requiring dialysis. An 18 week timeline is suggested for working up a potential donor comprising: donor identification (week 0-2), crossmatch tests (week 2-4), donor investigations including infection screening/imaging (week 4-8), MDT review (week 8-10), consultant surgeon nephrologist/surgeon/HTA approval (week 11-12) and listing for surgery (up to week 18).Regarding crossmatch, a compatible ABO blood group and HLA transplant is associated with better graft outcomes and if ABO or HLA incompatibility is present, antibody incompatible transplant or paired/pooled donation should be considered in centres with appropriate experience(10, 11). Renal function assessment should be undertaken using GFR measured by

⁵¹

Cr EDTA or 125iothalamate and differential function by DMSA should be considered when there is a >10% variation in renal size or significant renal abnormality(12).  Whilst age alone should not be a contraindication for donation, door age>60yrs is associated with higher perioperative complications and  reduced graft survival(13).  As regards BMI, donation for BMI >35 should be discouraged, whilst moderately obese (BMI 30-35) should be counselled about increased risk of perioperative complications and advised to lose weight – those with BMI 25-30 may safely proceed to donation(14). Blood pressure <140/90mmHg normally (or at that level on up to 2 antihypertensives) is considered safe for donation(15).  Diabetic donors have traditionally been discouraged from donation but the updated guidelines suggest that in the absence of target organ damage and cardiovascular risk factors, donation can be considered(16). As part of cardiovascular workup, patients at increased risk (history of cardiovascular disease or METS<4) should have further evaluation by stress testing or CT calcium scoring. From a urological perspective, haematuria and presence of calculi should be further evaluated prior to donation. All donors should also be evaluated for infection. Careful history taking, clinical examination and investigation are required to exclude infection and occult malignancy before kidney donation (particularly in donors >50yrs).Laparoscopic donor surgery (fully laparoscopic or hand-assisted) is the preferred technique for living donor nephrectomy, offering a shorter length of stay and reduced post-operative pain(17).

KDIGO guidelines


(3)

KDIGO emphasise the importance of a good legal and ethical framework for living donation. Compatibility testing (ABO/HLA) should be performed twice before donation. Predonation renal function should be assessed by GFR measurement using a nuclear medicine method (such as

⁵¹

Cr EDTA) and DMSA should be used if there are parenchymal, vascular, urological concerns or asymmetry of kidney size on imaging. The finding of haematuria or renal stones should be further evaluated for underlying causes. As regards blood pressure, donor candidates with hypertension that can be controlled to <140/90mmHg using up to two antihypertensive agents and who do not have evidence of target organ damage, may be acceptable for donation.  The decision to approve donor candidates with obesity and BMI >30 kg/m

²

or diabetic subjects should be individualized based on demographic and health profile. Smoking cessation advice should be given to donors(18). Risk for HIV, HBV,HCV infections should be assessed before donation. Donor candidates should undergo cancer screening consistent with local clinical practice with active malignancy being contraindication for donation. Donor candidates should receive in-person psychosocial evaluation, education and planning from health professionals experienced in the psychosocial concerns of donor candidates and donors(19). Mini-open laparoscopy or hand-assisted laparoscopy by trained surgeons should be offered as optimal approaches to donor nephrectomy. Personalised follow-up for donors should include at least annual check of BP, BMI, eGFR, albuminuria and review of psychosocial health.

EAU guidelines


(4)

Recommendations on living donor nephrectomy are made in those guidelines. They recommend a laparoscopic approach as primary donation method although open surgery by mini incision is a valid alternative. Options for laparoscopic donation include  pure or hand -assisted transperitoneal or retroperitoneal approach. A strong recommendation is made for long-term follow-up of all donors post nephrectomy.

Local donor assessment protocol

The local donor assessment is generally in line with BTS guidelines. Local donor assessment is undertaken in a dedicated clinic but the timeline for completing workup is up to 6 months. All potential donors undergo DMSA assessment. Pure laparoscopic donor nephrectomy is the technique of choice for graft harvesting and there is local preference for using the left donor kidney. Patients with BMI>30 are generally not encouraged to donate although this is very much dependant on the counselling with the donor surgeon. Donors are only seen once at 3 months post-donation and have ongoing follow-up in primary care or in their local nephrology unit. Table 1 summarises the key recommendations of the different guidelines and their relevance to the local practice.

	BTS guidelines	KDIGO Guidelines	EAU guidelines	Local practice
Recommendation
Time line for donor workup	Up to 18 weeks	–	–	Up to 6months
Perform crossmatch	ABO / HLA	ABO / HLA (Twice)	ABO / HLA	ABO / HLA
Renal function	Measure GFR DMSA if >10% variation in size	Measure GFR DMSA in selected cases	–	51 Cr EDTA DMSA always done
Age	No age cut-off	–	–	30-75 yrs
BMI	>35 discouraged 30-35 : higher complications	>30 done on cases by case basis	–	<30
BP	<140/90	<140/90	–	<140/90
Cardiovascular (for high risk)	Stress testing or CT calcium score	–	–	Myocardial perfusion scan
Donor surgery	Laparoscopic	Mini open Laparoscopic or Hand assited lap	Laparoscopic (option mini-open)	Pure laparoscopic
Donor follow-up	Life-long	Life long	Long-term	GP follow-up

Table 1: Living donor guidelines and local practice

An evidence-based living donor transplant protocol

• Potential living donors will be seen for an initial appointment by a dedicated living donor transplant coordinator for initial assessment and if suitable to proceed will be reviewed in a joint clinic with a nephrologist and transplant surgeon for comprehensive assessment
  
  

Rationale: Donor assessment should be undertaken in an efficient manner to reduce the number of hospital visit and allow flexibility to perform all required investigations. A recent postal survey of UK units a showed that only 81% of transplant centres had a dedicated live donor clinic and that having a dedicated clinic streamlines the assessment process and ensures efficiency


(20)


.

• All living donor transplants must comply with legislation (Human Tissue act 2004) and health professionals must ensure good ethical practice.

Rationale: The Human Tissue Authority (HTA) regulates the removal, storage and use of organs from the deceased and living and is responsible for all applications for organ donation from living subjects. Living organ donation leads to complex ethical issues – one of those is altruism where organ donation is often from a stranger and seen as a selfless gift to others


(8, 9)


.

• A thorough medical history of the donor should be undertaken to identify any contraindications for transplantation or any disease process that could have an impact post nephrectomy as well as any transmissible infection or malignancy risk.

• A thorough clinical assessment including cardiorespiratory, abdominal and psychosocial evaluation should be undertaken

• Donor renal function measurement should include an initial estimated GFR, then formal GFR measurement (using nuclear medicine technique e.g
  
  ⁵¹
  
  Cr EDTA) as well as differential function by DMSA. Advisory threshold GFR levels considered acceptable for living donation should be adhered to. CT angiogram should be used for imaging of vessel anatomy.

Rationale: Divided renal function, measured by combining 51Cr-EDTA and DMSA, can be helpful in decision-making where there is a size disparity between the two kidneys (>10%) in a potential donor, if renal function is close to the acceptable threshold for donation, or when there is anatomical abnormality or complexity. Evidence for routine use of DMSA is limited


(2, 3)


. Recent data accurately define gender and age-specific mean and normal ranges for measured GFR in over 3000 healthy potential UK living kidney donors


(21)


. Practice across transplant units vary greatly with 75% always doing DMSA and 61% using CT angiogram


(20)


.

• Donor age should not be a barrier to transplant although those above 60yrs should be warned of  higher risk of perioperative complications and rigorous assessment is required particularly in this age group.
  
  

Rationale: A recent study of over 80,000 living donors in the US highlighted a worse 12 year survival in donors >60yrs compared to those <60 yrs.

However, the long-term risk of death was no higher for older living donors than for age- and comorbidity-matched participants suggesting that the poorer survival could not be attributable solely to donation


(22)


. A further study of over 700 laparoscopic donor nephrectomies showed no difference in complications and donor outcomes based on age alone


(23)


. Based on a UK survey, 86% of transplant units have no upper age limit for donation




and 7% exclude donors >70yrs


(20)


.

• Patients with BMI>35kg/m2 should be discouraged from donation. Donors with BMI 30-35 should be counseled regarding increased risk of donation. Donors with BMI 25-30 can safely donate.

Rationale: The landmark meta-analysis of ten studies (484 obese living donors with a mean BMI of 34.5 kg/m2) reported statistically significant differences in operative time, blood loss and hospital stay between obese and non-obese donors


(24)


. A more recent metanalysis looking at over 5000 laparoscopic donor nephrectomies showed a significant increase in conversion to open surgery as the only morbidity risk that was significantly increased in the obese donor


(25)


.




22% of UK transplant units accept BMI up to 35 and 9% have no upper limit for BMI


(20)


.

• BP <140/90 acceptable for donation (having this target BP with up to 2 antihypertensives is permissible)
  
  

Rationale: A database analysis of over 3600 donors in the US showed that the rate of hypertension in donors was similar to that of the general population


(26)


. Boudville et al performed a metanalysis of the risk of hypertension in living kidney donors and reported a mean increase in blood pressure of 7 mmHg systolic and 5 mmHg diastolic post nephrectomy


(27)


.

In a further small series of 58 patients with hypertension (controlled with up two agents) undergoing nephrectomy, there were no increased risks to the donor identified


(28)


.

• All potential donors should have fasting blood sugar done and if impaired fasting glucose  (6.1-6.9) detected, an OGTT performed. Diabetics should generally be discouraged from donation although a well informed group with no diabetes-related complications and no other risk factors may donate

Rationale: Traditional guidance has suggested that individuals with diabetes should not donate a kidney. However, in an observational study of 444 donors from a single Japanese centre that has accepted subjects with an abnormal OGTT, including a small number with diabetes, no difference was found in the rate of immediate post-operative complications or survival at 20 years between the glucose tolerant and intolerant groups


(29)


.

• For cardiovascular assessment, high risk patients should undergo cardiac stress testing.

• Donors with visible or non visible haematuria should be referred to urology services for further investigations. For persistent non visible haematuria and normal urological investigations, consider renal biopsy if family history of renal disease

• Screening of donor for infection should include in all cases HbsAg, HBcAb, HCV Ig, HIV, HTLV, CMV, EBV, treponemal pallidum Ab and Toxoplasma gondii IgG. Depending on selected history further serological testing should be undertaken (e.g malaria, schistosomiasis, TB)

• Patients with history of urolithiasis or calculi detected on imaging should be referred to urology for further evaluation. In the absence of metabolic problems, donors with limited history of previous stones or small stones on imaging may still be eligible for donation.

• Anaemia should be fully investigated and treated prior to donation

• Active malignancy is a contraindication to donor nephrectomy but donors with certain types of low grade tumours and certain types of successfully treated tumours can be considered after careful counseling ( the Israel Penn registry can be consulted for this)

Rationale:




In a US registry review of 154 cadaveric donors with known cancer, transmission occurred in 45% of recipients


(30)


. To minimise this risk, care must be taken during evaluation of the potential living donor to ensure that a past medical history of malignant disease is recorded and that symptoms consistent with undiagnosed malignancy are identified


(31)


.

• Laparoscopic donor nephrectomy is the technique of choice for donation and should be performed or supervised directly by a consultant surgeon with appropriate training
  
  

Rationale: Lentine et al examined date from 14,964 living donors and found an overall incidence of 16.8% for any perioperative complication. Complications were formally graded using the Clavien-Dindo classification (22) with 8.8% of donors manifesting a Clavien 2 complication, 7.3% a Clavien 3 and 2.5% a Clavien 4


(32)


. Matas et al reviewed




over 10,000 living donor nephrectomies performed in the USA and reported reoperation rates of 0.4% for open donors and 1% and 0.9% for hand-assisted and non-hand-assisted laparoscopic surgery respectively. Complications not requiring reoperation were 0.3%, 1% and 0.8% respectively


(33)


. These data show the safety of the laparoscopic approach for living donation.

• Donor and recipient histocompatibility testing should be performed at an early stage of assessment to avoid unnecessary investigations. HLA and ABO compatibility testing are vital with best outcomes achieved with antibody compatible donation. If incompatibility is present, alternative options including paired/pooled donation should be discussed.

• Donors should be counseled of the risk of donation, expected graft outcomes and long-term renal function. Long-term follow-up for donors should be undertaken.

Rationale: Muzaale et al. compared the outcome of 96,000 kidney donors in the USA over a maximum follow-up of 15 years with matched healthy controls. The donor population was 75% white, 25% obese and 22% had a pre-donation eGFR <80 mL/min. The estimated risk of ESRD 15 years post-donation was 31 per 10,000 compared to 4 per 10,000 in matched controls. The increased risk was far greater in high risk donor populations. The estimated lifetime risk of ESRD was 90 per 10,000 in donors, 326 per 10,000 in the general population, and 14 per 10,000 in matched healthy non-donor controls


(34)


. Therefore, for potential donors, the absolute increase life time risk of GFR <30 mL/min/1.73m2 or ESRD is very small (<1%). The absolute risk for young donors over a lifetime, particularly with additional risk factors for ESRD is likely to be more significant.

In line with this protocol and existing guidelines, changes to local practice would include a more streamlined donor assessment (using an 18-weelk target), limiting DMSA measurement only to cases with abnormal renal imaging, considering donors up to BMI of 35 and setting up a dedicated post-donation follow-up clinic.

Conclusions

A comprehensive assessment of a potential donor is critical to the success of any RT programme. Donors should be well informed of the risks of donation including surgical risk and long-term effects on renal function. Long-term follow-up for donors is important.

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3. Lentine KL, Kasiske BL, Levey AS, Adams PL, Alberu J, Bakr MA, et al. KDIGO Clinical Practice Guideline on the Evaluation and Care of Living Kidney Donors. Transplantation. 2017;101(8S Suppl 1):S1-S109.

4. Kalble T, Lucan M, Nicita G, Sells R, Burgos Revilla FJ, Wiesel M, et al. EAU guidelines on renal transplantation. Eur Urol. 2005;47(2):156-66.

5. MacNeill SJ, Ford D. UK Renal Registry 19th Annual Report: Chapter 2 UK Renal Replacement Therapy Prevalence in 2015: National and Centre-specific Analyses. Nephron. 2017;137 Suppl 1:45-72.

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8. Human Tissue Act. 2004.

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11. Pankhurst L, Hudson A, Mumford L, Willicombe M, Galliford J, Shaw O, et al. The UK National Registry of ABO and HLA Antibody Incompatible Renal Transplantation: Pretransplant Factors Associated With Outcome in 879 Transplants. Transplant Direct. 2017;3(7):e181.

12. Even-Sapir E, Gutman M, Lerman H, Kaplan E, Ravid A, Livshitz G, et al. Kidney allografts and remaining contralateral donor kidneys before and after transplantation: assessment by quantitative (99m)Tc-DMSA SPECT. J Nucl Med. 2002;43(5):584-8.

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16. Shinzato T, Kurosawa A, Kubo T, Shimizu T, Kimura T, Nanmoku K, et al. No significant differences in short-term renal prognosis between living kidney donors with and without diabetes. Clin Exp Nephrol. 2017.

17. Kortram K, Ijzermans JN, Dor FJ. Perioperative Events and Complications in Minimally Invasive Live Donor Nephrectomy: A Systematic Review and Meta-Analysis. Transplantation. 2016;100(11):2264-75.

18. Heldt J, Torrey R, Han D, Baron P, Tenggardjaja C, McLarty J, et al. Donor Smoking Negatively Affects Donor and Recipient Renal Function following Living Donor Nephrectomy. Adv Urol. 2011;2011:929263.

19. Jacobs CL, Gross CR, Messersmith EE, Hong BA, Gillespie BW, Hill-Callahan P, et al. Emotional and Financial Experiences of Kidney Donors over the Past 50 Years: The RELIVE Study. Clin J Am Soc Nephrol. 2015;10(12):2221-31.

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21. Peters AM, Perry L, Hooker CA, Howard B, Neilly MD, Seshadri N, et al. Extracellular fluid volume and glomerular filtration rate in 1878 healthy potential renal transplant donors: effects of age, gender, obesity and scaling. Nephrol Dial Transplant. 2012;27(4):1429-37.

22. Segev DL, Muzaale AD, Caffo BS, Mehta SH, Singer AL, Taranto SE, et al. Perioperative mortality and long-term survival following live kidney donation. JAMA. 2010;303(10):959-66.

23. Jacobs SC, Cho E, Foster C, Liao P, Bartlett ST. Laparoscopic donor nephrectomy: the University of Maryland 6-year experience. J Urol. 2004;171(1):47-51.

24. Heimbach JK, Taler SJ, Prieto M, Cosio FG, Textor SC, Kudva YC, et al. Obesity in living kidney donors: clinical characteristics and outcomes in the era of laparoscopic donor nephrectomy. Am J Transplant. 2005;5(5):1057-64.

25. Lafranca JA, Hagen SM, Dols LF, Arends LR, Weimar W, Ijzermans JN, et al. Systematic review and meta-analysis of the relation between body mass index and short-term donor outcome of laparoscopic donor nephrectomy. Kidney Int. 2013;83(5):931-9.

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27. Boudville N, Prasad GV, Knoll G, Muirhead N, Thiessen-Philbrook H, Yang RC, et al. Meta-analysis: risk for hypertension in living kidney donors. Ann Intern Med. 2006;145(3):185-96.

28. Textor SC. Hypertensive living renal donors have lower blood pressures and urinary microalbumin one year after nephrectomy. Am J Transplant. 2003;3.

29. Okamoto M, Suzuki T, Fujiki M, Nobori S, Ushigome H, Sakamoto S, et al. The consequences for live kidney donors with preexisting glucose intolerance without diabetic complication: analysis at a single Japanese center. Transplantation. 2010;89(11):1391-5.

30. Penn I. Transmission of cancer from organ donors. Ann Transplant. 1997;2(4):7-12.

31. Desai R, Collett D, Watson CJ, Johnson P, Evans T, Neuberger J. Estimated risk of cancer transmission from organ donor to graft recipient in a national transplantation registry. Br J Surg. 2014;101(7):768-74.

32. Lentine KL, Lam NN, Axelrod D, Schnitzler MA, Garg AX, Xiao H, et al. Perioperative Complications After Living Kidney Donation: A National Study. Am J Transplant. 2016;16(6):1848-57.

33. Matas AJ, Bartlett ST, Leichtman AB, Delmonico FL. Morbidity and mortality after living kidney donation, 1999-2001: survey of United States transplant centers. Am J Transplant. 2003;3(7):830-4.

34. Muzaale AD, Massie AB, Wang MC, Montgomery RA, McBride MA, Wainright JL, et al. Risk of end-stage renal disease following live kidney donation. JAMA. 2014;311(6):579-86.