Globally living donors provide 42% of all kidneys for renal transplantation. According to Global Observatory on Donation and Transplantation (GODT) annually > 33,000 living donors provide 95% of kidneys in Asia, 74% in Middle East, 42% in Australia, 32% in USA and 30% in Europe. Living donors also provide 20% of livers globally, 94% in Asia, 50% in Middle East and 33% in Australia [1]. Long-term consequences of the living donor is a concern to the transplant community and therefore efforts are made to optimize selection criteria, prevent adverse consequences and put in place effective measures to maximum donor safety. The Ethics Committee of the Transplantation Society Organized a Forum in Amsterdam in 2004 to develop an international standard of care [2] with a statement regarding the responsibility of the transplant community to the live kidney donor [3].

The forum made the following recommendations;

1. Prior to live kidney donation, the donor must receive a complete medical and psychological assessment.
2. Prior to donor nephrectomy, the potential donor must be informed of the nature of evaluation, the risk of nephrectomy, changes in health and renal function, effects on employability, family and social life.
3. The potential donor should be informed of alternative renal replacement therapy available for the recipient.
4. The donor should be capable of understanding the information presented in the consent form.
5. The decision to donate should be voluntary and the freedom to withdraw from the donation process at any time.
6. After kidney donation the transplantation center is responsible for care of the donor with long-term follow-up care and treatment of pre-existing or acquired medical conditions that represent a risk e.g. of hypertension, obesity, diabetes and proteinuria.

Short term care of the donor
Short term care relates to medical and social consequences of donation. Firstly, standard of care in donor assessment, surgical techniques, short term medical care and Secondly socio-economic factors in term of cost of care, lost wages, family support and psychological adjustments after donation.

Renal Function Assessment
Glomerular filtration rate (GFR) is one of the most important investigations of a kidney donor. The International Kidney Disease Improving Global Outcomes (KDIGO) group recommendation has set new guidelines regarding GFR evaluation [4]. These include two GFR thresholds for decision making. A high threshold (≥ 90ml/min per 1.73m2) to accept and a low threshold (<60ml/min/per 1.73m2) to decline with 60-89 ml/min per 1.73m2 as an intermediate range in which the decision to accept or decline is on the basis of factors in addition to GFR. GFR is evaluated using two stage testing. The initial test estimated GFR (eGFR) based on equations using creatinine (eGFRCr) or Cystatin C (eGFR Cys). Confirmation test to include measured GFR (mGFR) using clearance of exogenous filtration markers e.g. inulin, measured creatinine clearance (mClcr) indexed to 1.73m2 body surface area [5].

Surgical Techniques
A number of surgical techniques have developed to minimize morbidity for donors. Laparoscopic donor nephrectomy (LDN) has replaced open donor nephrectomy (ODN) and today over 80% of the nephrectomies are performed by LDN. LDN offers many benefits, firstly reduced hospital stay, less post-operative pain, short period of convalescence, less morbidity and much better cosmesis as compared to large scars in ODN. Indeed LDN has had a favorable impact on living donation rates [6-8]. A new addition in surgical technique is Robot-assisted donor nephrectomy (RADN). The benefits are similar to LDN however currently operative times are longer and increased costs as compared to LDN. The outcomes are similar with LDN and RADN [9].

Economics of donation
An important concern for the donors is the economics consequences of donation. In developed countries medical and surgical costs associated with living kidney donation are directly covered by health issues or paid by the state. However direct additional costs are borne by the donor including transportation, lodging, meals, outpatient medications and lost wages. A Canadian study on economic consequences for donors at 3 months and 1 year after donation showed that 96% experienced economic consequences with 94% reporting travel costs and 47% reporting lost pay. The majority, 83% reported inability to perform usual house hold activities [10]. A multicenter prospective Kidney Donor Outcome Cohort (KDOC) study on 186 donors from USA showed that 92% of the donor had one or more direct cost [11]. Transportation 86%, health care 41%, meals 53%, medications 36% and lodging 23%. Donors missed 33072 total work hours and this lead to $ 302175 in lost wages. Financial burden was higher for those with greater travel distance and lower house hold income. It is increasingly being recognized that to remove economic consequences to donation and to achieve a fair and successful living donation program – the gift of an organ must be financially neutral for the donor. The donor therefore need to be protected against health care costs associated with donation as well as long term care of conditions that may compromise renal function. Strategies that need to be developed vary within countries depending on their health care system and health expenditure. However such cover must not be such to induce donation and violate financial neutrality [12].

Long-term care of donors
End-Stage Renal Disease in Donors
Safety of living kidney donors is achieved by devoting and investing in a thorough pre-donation assessment to select donors who are at a low risk of developing medical or psychological problems. Long-term studies mostly retrospective in nature have shown that selected donors are at low risk of developing medical complications and all-cause mortality [13]. Ibrahim et al reported an ESRD rate of 180 cases per million persons per year as compared to 268 in general population [13]. On the other hand studies where donors have been compared with healthily non-donor populations have shown more than 7-10% increased risk of ESRD and increase in all-cause mortality [14-15]. Unfortunately many studies are affected by an information bias by the non-inclusion of data from a substantial percentage of donors who are lost to follow-up. The donors lost to follow-up may be due to their own health, health of their recipients or may be healthy enough not to attend follow-up assessment. Retrospective studies show absence of regular yearly follow-up in about a quarter of donors, none response to surveys in about 50% and 10% in a prospective study of upto 3 years [16-18].

Long-term risk assessment
A recent study by Grams and Colleagues from data collected by the Chronic Kidney Disease Prognosis Consortium identified risk for developing renal failure [19]. The authors computed association between 13 health characteristics and development of End-Stage Renal Disease (ESRD). These included age, race, sex, estimated GFR (eGFR), album creatinine ratio, systolic blood pressure, presence of non-insulin dependent diabetes mellitus (NIDDM), use of antihypertensive drugs, smoking status, body mass index, low density lipoprotein (LDL) cholesterol and history of kidney stones. They found that risk of developing ESRD among donors was 3.5 – 5.3 times higher than those who did not donate but were eligible to donate. Diabetes conferred the highest risk.

Obesity and ESRD
Obesity, a body mass index (BMI) of more than 30kg/m2 has been linked with increased risk for cardiovascular disease, diabetes mellitus and ESRD [20-22]. Currently more than 25% of the living donors in USA are obese at the time of donation [23]. A report by Locke and colleagues has shown that estimated risk of ESRD 20 years after donation was 93.9 per 10,000 for obese as compared to 39.7 per 10,000 for none observe donors. For each unit increase in BMI above 27 kg/m2 there was an associated significant 7% increase in ESRD risk [24].

Prospective Follow-up of donors
Rizvi et al in a prospective study have followed 2696 living donors yearly in a dedicated donor clinic where all investigations and medication were provided free of cost life-long [25]. In this study 72% of all donors were in regular yearly follow-up for upto 27 years. In follow-up period proteinuria > 1000 mg/24 hour developed in 1%, hypertension in 13.7%, diabetes in 3.6%, creatinine clearance < 45ml/min/1.73m2 in 0.9% at mean follow-up of 8.9±4.7 years. In the follow-up period 20% of donors become overweight and 5% became obese. These donors had higher rates of hypertension 42% and diabetes 12%. Overall 6 (0.2%) developed ESRD at 2.7/10,000 person years and 11 (0.4%) died at 4.0/10,000 person years. Therapeutic intervention was given to all these donors. This study has shown that timely diagnosis and intervention can modify risk factors and prevent adverse outcomes.

Conclusion
Long-term follow-up and assessment of living donor remains one of the important responsibilities of the transplant community. The donors are likely to attend assessment and follow-up care when the expenses for care are provided for by developing policies appropriate to the economic state of nations, keeping in mind financial neutrality. There is indeed on urgent need to develop international guidelines for care of the donors to insure best outcomes of these honourable individuals.

References

1. Global Observatory on Donation and Transplantation. http://www.transplant-observatory.org/.
2. Delmonico F; Council of the Transplantation Society. A Report of the Amsterdam Forum On the Care of the Live Kidney Donor: Data and Medical Guidelines. Transplantation. 2005 Mar 27;79 (6 Suppl): S53-66. Review.
3. Ethics Committee of the Transplantation Society. The consensus statement of the Amsterdam Forum on the Care of the Live Kidney Donor. Transplantation. 2004 Aug 27;78(4):491-2.
4. Levey AS, Inker LA. GFR Evaluation in Living Kidney Donor Candidates. J Am Soc Nephrol. 2017 Apr;28(4):1062-1071. doi: 10.1681/ASN.2016070790. Epub 2017 Mar 15.
5. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group: KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 3: 1-150, 2013.
6. Rampersad C, Patel P, Koulack J, McGregor T. Back-to-back comparison of mini-open vs. laparoscopic technique for living kidney donation. Can Urol Assoc J. 2016 Aug;10(7-8):253-257.
7. Fonouni H, Mehrabi A, Golriz M, Zeier M, Müller-Stich BP, Schemmer P, Werner J. Comparison of the laparoscopic versus open live donor nephrectomy: an overview of surgical complications and outcome. Langenbecks Arch Surg. 2014 Jun;399(5):543-51. doi: 10.1007/s00423-014-1196-4. Epub 2014 Apr 28. Review.
8. Antcliffe D, Nanidis TG, Darzi AW, Tekkis PP, Papalois VE. A meta-analysis of mini-open versus standard open and laparoscopic living donor nephrectomy. Transpl Int. 2009 Apr;22(4):463-74. doi: 10.1111/j.1432-2277.2008.00828.x. Epub 2009 Jan 20.
9. Giacomoni A, Di Sandro S, Lauterio A, Concone G, Buscemi V, Rossetti O, De Carlis L. Robotic nephrectomy for living donation: surgical technique and literature systematic review. Am J Surg. 2016 Jun;211(6):1135-42. doi: 10.1016/j.amjsurg.2015.08.019. Epub 2015 Oct 21. Review.
10. Klarenbach S, Gill JS, Knoll G, Caulfield T, Boudville N, Prasad GV, Karpinski M, Storsley L, Treleaven D, Arnold J, Cuerden M, Jacobs P, Garg AX; Donor Nephrectomy Outcomes Research (DONOR) Network. Economic consequences incurred by living kidney donors: a Canadian multi-center prospective study. Am J Transplant. 2014 Apr;14(4):916-22.
11. Rodrigue JR, Schold JD, Morrissey P, Whiting J, Vella J, Kayler LK, Katz D, Jones J, Kaplan B, Fleishman A, Pavlakis M, Mandelbrot DA; KDOC Study Group. Direct and Indirect Costs Following Living Kidney Donation: Findings From the KDOC Study. Am J Transplant. 2016 Mar;16(3):869-76. doi: 10.1111/ajt.13591. Epub 2016 Feb 4.
12. Gill JS, Delmonico F, Klarenbach S, Capron AM. Providing Coverage for the Unique Lifelong Health Care Needs of Living Kidney Donors Within the Framework of Financial Neutrality. Am J Transplant. 2017 May;17(5):1176-1181. doi: 10.1111/ajt.14147. Epub 2017 Jan 9.
13. Ibrahim HN, Foley R, Tan L, Rogers T, Bailey RF, Guo H, Gross CR, Matas AJ. Long-term consequences of kidney donation. N Engl J Med. 2009 Jan 29;360(5):459-69. doi: 10.1056/NEJMoa0804883.
14. 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; 3119(6): 579-86.
15. Mjoen G, Hallan S, Hartmann A, Foss A, Midtvedt K, Oyen O, et al. Long-term risks for kidney donors. Kidney Int. 2014; 86(1): 162-7.
16. Steiner RW. The Risks of Living Kidney Donation. N Eng; J Med. 2016; 374(5): 479-80.
17. Rodrigue JR, Vishnevsky T, Fleishman A, Brann T, Evenson AR, Pavlakis M, Mandelbrot DA. Patient-Reported Outcomes Following Living Kidney Donation: A Single Center Experience. J Clin Psychol Med Settings. 2015 Sep;22(2-3):160-8.
18. Kasiske BL, Anderson-Haag T, Israni AK, Kalil RS, Kimmel PL, Kraus ES, Kumar R, Posselt AA, Pesavento TE, Rabb H, Steffes MW, Snyder JJ, Weir MR. A prospective controlled study of living kidney donors: three-year follow-up. Am J Kidney Dis. 2015 Jul;66(1):114-24.
19. Grams ME, Sang Y, Levey AS, Matsushita K, Ballew S, Chang AR, Chow EK, Kasiske BL, Kovesdy CP, Nadkarni GN, Shalev V, Segev DL, Coresh J, Lentine KL, Garg AX; Chronic Kidney Disease Prognosis Consortium.. Kidney-Failure Risk Projection for the Living Kidney-Donor Candidate. N Engl J Med. 2016 Feb 4;374(5):411-21.
20. Chertow GM, Hsu CY, Johansen KL. The enlarging body of evidence: obesity and chronic kidney disease. J Am Soc Nephrol. 2006 Jun;17(6):1501-2. Epub 2006 May 3. No abstract available.
21. Abdullah A, Amin FA, Hanum F, Stoelwinder J, Tanamas S, Wolf R, Wong E, Peeters A. Estimating the risk of type-2 diabetes using obese-years in a contemporary population of the Framingham Study. Glob Health Action. 2016 Jan;9(1):30421. doi: 10.3402/gha.v9.30421.
22. Poirier P, Giles TD, Bray GA, Hong Y, Stern JS, Pi-Sunyer FX, Eckel RH; American Heart Association.; Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism.. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006 Feb 14;113(6):898-918. Epub 2005 Dec 27. Review.
23. Taler SJ, Messersmith EE, Leichtman AB, Gillespie BW, Kew CE, Stegall MD, Merion RM, Matas AJ, Ibrahim HN; RELIVE Study Group. Demographic, metabolic, and blood pressure characteristics of living kidney donors spanning five decades. Am J Transplant. 2013 Feb;13(2):390-8. doi: 10.1111/j.1600-6143.2012.04321.x. Epub 2012 Nov 8.
24. Locke JE, Reed RD, Massie A, MacLennan PA, Sawinski D, Kumar V, Mehta S, Mannon RB, Gaston R, Lewis CE, Segev DL. Obesity increases the risk of end-stage renal disease among living kidney donors. Kidney Int. 2017 Mar;91(3):699-703. doi: 10.1016/j.kint.2016.10.014. Epub 2016 Dec 29.
25. Rizvi SA, Zafar MN, Jawad F, Aziz T, Hussain Z, Hashmi A, Hussain M, Akhtar F, Ahmed E, Naqvi R, Naqvi SA. Long-term Safety of Living Kidney Donation in an Emerging Economy. Transplantation. 2016 Jun;100(6):1284-93.

ABOUT OUR GUEST EDITOR

Prof. Mirza Naqi Zafar

Professor of Pathology
Sindh Institute of Urology and Transplantation (SIUT)
Civil Hospital
Karachi – 74200, Pakistan

Dr. Mirza Naqi Zafar is Professor of Pathology and Head of Laboratories at the Sindh Institute of Urology and Transplantation, Karachi Pakistan. He graduated from University of London in 1975 and obtained his doctorate in 1979. He has extensive research experience in histocompatibility testing, transplant outcomes and donor follow-up care. He has published over 100 papers on these subjects in international and national journals. He has also contributed to four chapters in books on transplantation. He is a member of a number of Societies and Pathology Associations. He is the General Secretary of the Transplantation Society of Pakistan and Councilor of Asian Region for International Society of Organ Donation and Procurement. He serves on the editorial boards of a number of national journals.

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Associate Professor of Clinical Medicine
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WIT Initiative on Sex and Gender Issues in Transplantation

Did you know that both donor and recipient sex may have important independent impacts on graft outcomes? Did you know that gender may influence access to transplant, and may have important effects on the way potential donors are solicited? Enhanced understanding of these issues will improve access to transplantation as well as graft outcomes. A new TTS initiative aims to promote research and advocacy in this area, with the broad goal of improving transplant outcomes for all. Activities of the working group will include directing scoping reviews to catalogue existing research in this area, organizing symposia focusing on sex and gender issues in transplantation at conferences, and eventually organizing a consensus conference.

If you are interested in joining the working group, please contact committees@tts.org. Membership is open to both sexes and all genders.

Young Members Corner

THE ROLE OF LIVING DONOR LIVER TRANSPLANTATION IN THE WESTERN WORLD

Arzu Oezcelik, MD

Living donor liver transplantation (LDLT) was performed to circumvent the organ shortage, especially for pediatric liver transplantation. With increasing experience, it became an accepted treatment for end stage liver disease. The main limitation of the procedure is the risk for donor morbidity and of course, the availability of a suitable living donor. The right liver lobe is the graft of choice in adult LDLT. Several studies in the past have shown that the right donor hepatectomy is associated with significant risk for morbidity, which has led to decreasing number of adult LDLT in the western world. The donor risk cannot be justified if the patient has a realistic chance for a deceased donor organ. However, there are some indications where LDLT can still be a better option. One of the justified indications for LDLT - even in the western world with higher number of deceased donors - is the hepatocellular carcinoma of the liver. Between October 2004 and June 2015, 841 patients underwent liver transplantation at our Center. Out of these patients, 212 were diagnosed with HCC and 160 of them underwent LDLT. The overall 5-year-survival rate was 75.4% after LDLT (unpublished data: Florence Nightingale Hospital/Istanbul). The main advantage is the chance to perform liver transplantation without waiting time to avoid tumor progress on the waiting list. The left lobe LDLT in children is widely accepted also in the western world as the treatment of choice since the chance to find a suitable deceased donor for children is very low. Although the DDLT should be preferred in order to avoid donor morbidity, in some indications LDLT is the treatment of choice prior to DDLT.

Arzu Oezcelik is part of the TTS Young Members Committee. Want to know more about this? Email the Committee at ymc@tts.org.

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