ITS 2012 Report – Difficult donor issues in the time of donor shortages

by Maria Dalby – Introduction – In many ways waiting lists to receive an organ transplantation look very much the same today as they did a decade ago – such as gender, blood type, and even the underlying cause of end-stage renal disease (ESRD) to some extent. However, some aspects have changed dramatically. Today, patients going on the waiting list to receive an organ are likely to be older and heavier, can expect to spend longer time on the list, and are more likely to receive an extended-criteria organ than a decade ago. This reflects and is reflected in a changing donor population, with fewer optimal donors and instead an increasing donor population with a body mass index of over 40 or with undiagnosed HIV or hepatitis infection

For the 12^th year, Astellas Pharma Inc sponsored an educational satellite symposium to explore the donor-related challenges faced by clinicians against a background of continued organ shortage. The first part of the symposium, chaired by Professor Robert S Gaston from the Univeristy of Birmingham at Alabama, USA, focused on the challenges associated with deceased donors. The second part was chaired by Professor Jonas Wadström from Karolinska Hospital in Stockholm, Sweden, and dealt with the complex field of organ transplantation using living donors.

Part 1: Deceased donors

Acceptance: improving best practice

Rutger J Ploeg, University of Oxford, UK

Every transplant healthcare professional knows only too well that the demand for organs for transplantation far exceeds availability. The shortage of organs is pushing transplant teams to use organs from marginal donors after brain death (DBD) and circulatory death (DCD) to an increasing extent, with increased risk of graft failure and postoperative complications due to ischaemia and reperfusion injury.^1,2  Professor Rutger J Ploeg from Oxford, UK, stressed that whilst this poses significant clinical challenges, there is also an opportunity for intervention and improved best practice, not least in terms of the preservation and reconditioning of damaged organs.

In the early days of transplantation, machine perfusion was the norm for preserving organs prior to transplantation. This required complex and bulky technology, and as the cold storage ‘box’ became available this became the predominant option. However, recent advances in mapping the systemic inflammatory and coagulatory response following cerebral injury and circulatory arrest suggest that continuous hypothermic machine perfusion^3-5 and/or temporary normothermic recirculation⁶ can improve organ viability in organs that would otherwise have been discarded. The European Multicentre Trial on Kidney Preservation is a large prospective clinical trial programme to compare machine perfusion with cold storage in kidney transplantation. In 2009, the initial results of the study showed that machine perfusion of deceased-donor kidneys significantly reduced the risk of delayed graft function versus cold-storage preservation, with significantly higher graft survival at one year post-transplant in the machine perfusion group.⁴ A 3-year follow-up analysis was published in February 2012 and showed that survival of machine-perfused DBD kidneys remained significantly greater than after cold-storage preservation at 3 years post-transplant (91% vs 87%; adjusted hazard ratio for graft failure 0.60; p=0.04). The benefit of machine perfusion was especially evident in kidneys recovered from extended-criteria donors.

Controlled clinical studies are currently in progress to determine whether machine perfusion at normothermic conditions may be an option for preserving severely damaged kidneys and to validate machine technology for liver perfusion. There are also a number of studies looking to identify biomarkers during machine perfusion to predict delayed graft function due to reperfusion injury. Professor Ploeg concluded with the prediction that machine perfusion will help to provide a way forward for using marginal donors to close the gap between organ supply and demand.

References:

1. Morariu AM et al. Am J Transplant 2008; 8: 933–941
2. Snoeijs MG et al. J Am Soc Nephrol 2010; 21: 1015–1021
3. Jochmans I et al. Ann Surg 2010; 252: 756–764
4. Moers C et al. N Engl J Med 2009; 360: 7–19
5. Treckmann J et al. Transpl Int 2011; 24: 548–554
6. Fondevila C et al. Am J Transplant 2012; 12: 162–170
7. Moers C et al. N Engl J Med 2012; 366: 770-771

 

Allocation: maximising donor-recipient matching

John J Friedewald, Northwestern University Feinberg School of Medicine, Chicago, USA

As the mismatch between organ supply and demand continues to widen, fair and equitable organ allocation is becoming an issue for transplant centres all over the world. At the moment, most centres allocate their available organs almost exclusively based on the time the recipient has spent on the waiting list.¹ However, as Professor John J Friedewald from Chicago pointed out in his presentation, with a resource as scarce and valuable as donated organs and with the increasing number of older and less fit patients on the waiting list, allocation should involve a greater degree of utility to ensure the maximum benefit in terms of life years for the recipient as well as for society as a whole.

The greatest degree of mismatch is seen in the age of the donor versus the recipient, with older transplant patients receiving younger organs to a significant extent.² Age is widely known to be a good predictor of post-transplant outcome in renal transplantation; however, matching organs based on age alone is not feasible as this would contravene laws against age discrimination in the US and most other Western countries. Instead, Professor Friedewald’s centre in Chicago has introduced a scheme of ‘longevity matching’ of donated kidneys based on a composite risk index, the Kidney Donor Risk Index (KDRI). This index provides an estimate of the relative risk of post-transplant graft failure in an adult recipient from a particular deceased donor, compared with the median (50^th percentile) donor, and takes into account 10 key donor characteristics including age, weight, any history of hypertension and/or diabetes, and also the cause of death.³

The KDRI will be implemented as an allocation tool in the form of the Kidney Donor Profile Index (KDPI). The KDPI expresses the quality of the donated organ as a percentage, where a higher percentage indicates lower organ quality and a greater risk of graft failure. Under the proposed model, the top 20% of kidneys in terms of quality (low KDPI and high estimated post-transplant survival [EPTS] will be allocated using the new tool. At the other end of the scale, kidneys with the highest 15% KDPI scores will be allocated within an opt-in scheme with the goal of improving the use of extended-criteria kidneys and preventing usable organs from being discarded. Professor Friedewald stressed in his conclusion that whilst the top priority should remain to provide access to organs for transplantation for all patients on the waiting list, longevity matching can be a useful strategy for maximising the survival benefit from each donated organ in a fair and equitable way.

References:

1. US Organ Procurement and Transplantation Network Concepts for Kidney Allocation. 2011. http://optn.transplant.hrsa.gov/SharedContentDocuments/KidneyConceptDocument.PDF
2. Scientific Registry of Transplant Recipients Kidney-Pancreas Simulated Model. 2010 results. Available at: http://www.docstoc.com/docs/74697927/Kidney-Allocation-Concepts
3. Rao et al. Transplantation 2009; 88:231-236

 

The risk-benefit balance: minimising transmission and acquisition of infection and malignancy

Elmi Muller, Groote Schuur Hospital, Cape Town, South Africa

John Dark, Freeman Hospital, Newcastle upon Tyne, UK 

Expanding the deceased donor pool by extending the criteria for donation is of critical importance to overcome the shortage of available organs. Viral infection and malignancy have traditionally been regarded as contraindications for organ donation; however, there is now increasing evidence that there may be circumstances in which organs from high-risk donors can be used to increase the number of transplants and reduce waiting times. Dr Elmi Muller from the Groote Schuur Hospital in Cape Town, South Africa, shared her extensive experience with transplanting organs from donors with HIV and/or tuberculosis (TB). Dr Muller was followed by Professor John Dark who presented a wider overview of the field of donor-derived risk in transplantation.

HIV

HIV and TB are both endemic in South Africa, to the extent that donors are routinely screened for TB based on clinical features and chest X-rays, and recipients receive TB prophylaxis. HIV-associated nephropathy is one of the most common indications for renal replacement therapy in South Africa¹ which puts transplantation services under significant pressure as very few patients have access to dialysis under the South African healthcare system. Studies suggest that using kidneys from HIV-positive donors could be a suitable approach for these candidates to improve compared with continued dialysis.^2,3 Dr Muller stressed that obtaining informed consent from the recipient is absolutely essential. To date, a total of 14 HIV-positive patients have been transplanted with HIV-positive kidneys at the Groote Schuur Hospital. The outcomes have so far been excellent, with graft survival of 92% at 1 and 2 years and 86% at 3 years. No problems with donor-derived second viral strain infection have been reported. Dr Muller concluded that the risk associated with using high-risk donors with chronic infections is relative to the ethical context, and that these donors provide a means of giving patients on the waiting list access to organs provided the pathology is known and informed consent is given.

Infection/malignancy

The risk associated with donor factors such as age, obesity and smoking is an example of continuous risk. In contrast, the risk of transmission of a chronic infection or malignancy is a binary risk – either it is present or it is not. In his overview, Professor John Dark reminded the audience that all risks must be considered against the alternative of no transplant.

A prime example of progress in this area is cytomegalovirus (CMV) infection which is present in 50% of the population and used to pose a significant challenge, especially in lung transplantation. However, advances in detection and therapies have now meant the acute and long-term consequences can be prevented and clinicians have been able to more or less forget about CMV as a risk.⁴

Another binary risk where there is recent good-quality data to support the clinical decision-making is transmission of malignancy. This is a highly topical issue in that whilst a sustained large proportion of donors in the UK are smokers, many candidates will refuse organs from a smoker for fear of developing cancer. However, a recent prospective analysis clearly showed that although lungs from smoking donors are associated with poorer outcomes, these lungs still improve overall survival compared with holding out on the waiting list for a non-smoking donor.⁵

Another form of malignancy that has previously been labelled as associated with high risk of transmission is cerebral tumours. A recent analysis of UK transplant and cancer registries showed, however, that the risk of transmission was much lower than previously estimated, suggesting that these organs can be safely used.^6,7 Professor Dark finished by stressing that whilst some risk is unavoidable, it is important to base any decision or advice on whether to accept or refuse an organ on the best available data.

References:

1. UNAIDS. Report on the global AIDS epidemic 2010. http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2010/20101123_globalreport_en.pdf
2. Mysore S et al. Am J Transplant 2008; 8(Suppl S2): 179
3. Muller E et al. N Engl J Med 2010; 362: 2336–7
4. Snydman. Clin Infect Dis 2001; 33 (Suppl 1): S5-S8
5. Bonser RS, et al. Lancet 2012 [Epub ahead of print]
6. Watson CJ, et al. Am J Transplant 2010; 10: 1–8
7. Warrens AN, et al. Transplantation 2012; 93: 348–53

 

Part 2: Living donors

Donor outcomes

Jonas Wadström, Karolinska University Hospital, Stockholm, Sweden

The increasing use of organs from living donors poses unique medical and ethical challenges which transplant clinicians need to be aware of in all situations. Chairman Professor Jonas Wadström from Stockholm, Sweden introduced the second part of the symposium with a series of interactive keypad questions to the audience. The majority (59%) thought that live kidney donation should be actively promoted and all potential donors should be considered, including anonymous donors, cross-over donation etc. Professor Wadström also presented two hypothetical patient cases, chosen to highlight the often difficult risk-benefit considerations associated with transplantation using living donors.

The first case involved a 58-year old mother keen to donate a kidney to her son with ESRD; The mother’s BMI is 32, she has a history of kidney stone, and she presents with a blood pressure of 145/90mmHg on repeated measurements and microscopic haematuria. Only 16% felt that donation would be contraindicated; 30% thought the mother should be allowed to donate if she could lose weight and her blood pressure could be reduced, and 32% thought that she should be allowed to donate with information on the risks and the need for life-long medication.

The second case involved a wife wanting to donate a kidney to her husband who is 69, has ESRD due to nephrosclerosis and type 2 diabetes, a BMI of 35, HBA1c 11mmol/l, blood pressure at 180/95mmHg, and stage T2 prostate cancer. In this case, 41% replied that the donoation was contraindicated due to too many risk factors, although 31% felt the donation could go ahead following prostatectomy and provided PSA remains normal for at least two years.

 

 Difficult donor decisions

Arthur J Matas, University of Minnesota, Minneapolis, USA

Preparing for transplantation of an organ from a living donor puts the transplant team in a position of competing priorities. The wish to transplant the candidate and relieve him/her of the burden of continued dialysis on the waiting list must be balanced against the need to protect the donor from potential harm. Professor Arthur Matas from the University of Minnesota gave an insight into the most challenging donor and recipient issues; whilst these are numerous, most can be addressed by having in-depth discussions with both the donor and recipient, separately or together, and ensuring that informed consent is obtained.

Recipient factors that may affect the donor’s preparedness to donate a kidney include:

• Limited life span. Transplantation is likely to improve the recipient’s quality of life and may potentially prolong survival, but it is important that the donor is informed.
• Potentially recurrent disease, such as focal segmental glomerulosclerosis, with increased risk of early graft loss. In most cases, however, the risk of recurrence can only be estimated and the best test is to actually do the transplantation.
• History of non-compliance – non-compliance with immunosuppressive medication is a common cause of graft loss. At Professor Matas’ centre, the donor will be informed of the recipient’s history of non-compliance (although this actually contravenes US federal patient confidentiality legislation) and asked to discuss this with the recipient before making a final decision.
• Strong family history of hypertension or diabetes, as donors who are younger siblings or children may be at increased risk later in life. Again, donor counselling is essential, and annual screening is recommended if the donation goes ahead.

On the other hand, there may be donor factors that increase the risk to both the donor and the recipient:^1-6

• Young donors (children or grandchildren) may be highly motivated, but may lack the necessary mental maturity to make the decision. There is also the risk that a young individual may develop disease later in life which may be aggravated by the donation.
• Borderline or low kidney function – glomerular filtration rate (GFR) can be difficult to measure precisely, and there is also a lack of consensus as to what is an acceptable GFR with increasing age.
• Obesity, which carries a double risk – obese individuals are more likely to suffer surgical complications, and there is also a greater risk of graft loss in the longer term. Obese individuals presenting as living donors at Professor Matas’ centre will not even be evaluated unless weight loss to BMI below 35 can be achieved.
• Hypertension, although ESRD due to hypertension is uncommon amongst Caucasians.
• Haematuria, which may have natural causes.
• History of kidney stones and/or thrombosis, depending on frequency and severity.
• Arterial lesions, depending on their location.

In many cases, the most attractive option may be to find another living donor or wait for a deceased donor, although this is likely to prolong the recipient’s time of the waiting list with poorer outcomes as a consequence.¹ Professor Matas advised that if no other living donor candidates are available, the option of going ahead with the transplant despite the risks should be considered; in such cases, informed consent and long-term follow-up are essential.

References:

1. Matas AJ, Sutherland DER. JAMA 2005; 294: 1691–3
2. Davis CL, Delmonico FL. J Am Soc Nephrol 2005; 16: 2098–110
3. Sachdeva M et al. J Transplant 2011; article ID 245738
4. Ramcharan T et al. Transplant Rev 2003; 17: 3–10
5. Koushik R et al. Transplantation 2005; 80: 1425–9
6. Steiner RW. Am J Transplant 2010; 10: 737–41

 

Difficult recipient decisions

Robert S Gaston, University of Alabama, Birmingham, USA

Some absolute contraindications to kidney transplantation remain, although the definition of what constitutes a high-risk transplant recipient has changed dramatically since the 1970s when kidney transplantation was in its infancy. Chairman Professor Robert Gaston pointed out that using living donors to mitigate risk is an accepted practice that requires ongoing re-evaluation with focus on donor risk and, not least, informed consent – as Professor Gaston put it: “informed consent is the 8,000 lb elephant in the room”.

In the 1970s, kidney transplant patients were considered high-risk if they had diabetes or had a history of gastrointestinal bleeding or were aged over about 50 years – today, these patients are considered to be fairly standard candidates.^1-4 The University of Birmingham at Alabama currently lists a number of risk factors as absolute contraindications to kidney transplantation, including recent invasive malignancy, active infection, advance cardiopulmonary disease or BMI over 40. In contrast, a number of risk factors are regarded as relative contraindications depending on the circumstances, such as coronary disease and peripheral vascular disease, HIV infection, obesity and age over 70 years. Professor Gaston hypothesised that the changes to come over the next 30-40 years are likely to occur on this list as our ability to prevent complications and manage issues such as non-compliance with immunosuppressive medication improves.^5-9

For most recipients, kidney transplantation offers substantial benefit over maintenance dialysis both in terms of survival and quality of life.^10-12 Summing up, Professor Gaston concluded that saying no is still appropriate under some circumstances, but the underlying evidence base and rationale is changing rapidly before our eyes. Any clinical decision regarding organ donation from a living donor must consider the risk and benefit to the donor as well as to the recipient – donors must be an end to themselves, as opposed to merely a means to the ends of others.

References:

1. Simmons RL et al. Arch Surg 1971; 103: 290–8
2. Woods JE et al. Surg Gynecol Obstet 1973: 137: 393–8
3. Knoll G et al. CMAJ 2005;173: 1181–4
4. European Best Practice Guidelines Expert Group on Renal Transplantation. Nephrol Dial Transplant 2000; 15(Suppl 7): 3–38
5. Kasiske B et al. Am J Transplant 2001; 1(Suppl 2): 3–95
6. Stock PG et al. N Engl J Med 2010; 363: 2004–14
7. Dudley C, Harden P. Nephron Clin Pract 2011; 118(Suppl 1): c209–24
8. Lynch R et al. Ann Surg 2009; 250: 1014–20
9. Sellares J et al. Am J Transplant 2012; 12: 388–99
10. Schold JD et al. Am J Transplant 2010; 10: 2008–16
11. Wolfe RA et al. N Eng J Med 1999; 341: 1725–30
12. Oniscu GC et al. J Am Soc Nephrol 2005; 16: 1859–65

 

Increasing donation: removing disincentives and adding incentives

Willem Weimar, Erasmus Medical Centre, Rotterdam, The Netherlands

Living donation is regarded by many as the answer to the transplantation waiting list dilemma in Europe, where between 5,000 and 6,000 patients die on the waiting list for a kidney transplantation every year, and a similar number are delisted due to deterioration.¹ Of patients older than 60 years who are put on the waiting list, only just over 50% will actually receive a kidney.² Professor Willem Weimar from Rotterdam argued the case for promoting living donation through education and public awareness programmes to tap into this potentially huge donor resource and reduce attrition rates on the waiting list.

Although the living donor pool has expanded in recent years to include genetically unrelated donors such as spouses and anonymous so-called ‘Samaritan’ donors, a number of disincentives and misconceptions still exist. Many countries in the European Union do not have provision for living donation in their national healthcare systems and the costs and practical hurdles associated with, for example, travel, loss of income or childcare may be considerable. Common misconceptions around living donation include the belief that it increases the risk of renal failure and death, that it takes months to recover from the surgery, that it causes infertility, or that it is against certain religions.

The key to overcoming these misconceptions and hurdles is to educate patients and families on the benefits of living donation, particularly pre-emptively, in terms of prolonged survival and improved quality of life.³ The aim should be to establish living donation as the norm for renal replacement therapy in each European country. Exchange programmes and domino-paired translations should be used to overcome incompatible blood types and positive cross-matches.^4-5 In Rotterdam to date, 86 living donor kidneys donated under such programmes have enabled a total of 148 transplants.

Professor Weimar also suggested that the clinical benefits of living donor kidney transplantation are sufficient to justify some form of monetary incentive scheme. Not only does the individual recipient benefit, but society as a whole gains both in terms of reduced dialysis costs and quality-adjusted life years gained. The issue of organ selling raises difficult ethical and philosophical questions regarding the ownership of an organ and the price of life; Professor Weimar advised that the best way forward on this issue is to keep an open mind and stay clear of paternalism.

References:

1. US Organ Procurement and Transplantation Network and Scientific Registry of Transplant Recipients. 2010 Annual Data Report. Available at: http://www.srtr.org/annual_reports/2010/pdf/01_kidney_11.pdf.
2. Schold J et al. Clin J Am Soc Nephrol 2009; 4: 1239–45
3. Rodrigue JR et al. Am J Transplant 2007; 7: 394–401
4. Davis CL, Delmonico FL. J Am Soc Nephrol 2005; 16: 2098–110
5. Roodnat JI et al. Am J Transplant 2010; 10: 821–7