Kidney Transplantation in Geriatric Patients

[okarol]

Kidney Transplantation in Geriatric Patients

Fidel Barrantes, MD, Milagros Samaniego-Picota, MD
November 15 2010

Individuals older than 65 years old constitute the fastest growing population group in America. According to the 2008 United States census bureau report, the number of elders grew from 29.6 million in 1990 to 36.8 million in 2008, representing a 20% incremental growth. (www.census.gov/compendia/statab/2010/tables/10s0034.pdf. Accessed on July 24, 2010). Furthermore, the number of individuals 60 years and older will increase from 56 million to 112 million from 2010 to 2050. This fast growth in the elderly population is not unique to the United States and results primarily from declines in fertility and mortality rates. Over the next quarter century, the growth of the elderly population is projected to be faster than any other segment of the population in all world regions, but especially in Eastern Europe and the developed world (www.census.gov/prod/2004pubs/wp-02.pdf. Accessed on July 25, 2010).

Consequent to the absolute increase of elderly individuals in the population pyramid, the prevalence and incidence of chronic diseases such as hypertension, diabetes, kidney disease, coronary artery disease, and heart failure have also risen in the overall population. This increase in the rate of chronic illnesses poses real challenges to the cost and resources of health care systems all over the world.
Epidemiology

The hazard risk (HR) of CKD stage IV and V among individuals older than 60 years is 26.3 and 1.8, respectively. According to the National Health and Nutrition Survey (NHANES) the prevalence of CKD (defined as glomerular filtration rate of 60 mL/min/1.73 m2 or less) has increased from 5.7% in 1988-1994 to 8.1% in 2003-2006, affecting particularly the old and diabetics. As the number of older patients with CKD increases, it is expected that the prevalence and incidence of renal replacement therapy in the elderly will increase accordingly. Indeed, the median age of incident dialysis patients is 64.4 years, and adjusted-incidence rate of end-stage renal disease (ESRD) in individuals older than 75 years has grown considerably when compared to subjects in the 20-44 or 45-64 age groups (11% vs. 2.4% vs. 6.1%, respectively) (www.usrds.org/2008/view/default.asp. Accessed on July 25, 2010).
Kidney transplantation

Kidney transplantation (KT) is the best form of renal replacement therapy. It is cost-effective and increases the projected life of patients with ESRD when compared with any form of dialysis. Notwithstanding its benefits, access to KT is limited by the imbalance between the offer and demand of transplantable organs. As a consequence of the limited availability of KT, the medical community has been biased towards the referral of “the fittest” for KT (N Engl J Med. 1999; 341: 1725-30). Thus, the growing prevalence and incidence of ESRD in the elderly poses both an ethical and clinical dilemma to referring physicians and transplant centers since older patients usually suffer of multiple co-morbidities, have limited social support, and are perceived as “unfit” and unable to enjoy the benefits of KT. There are 16,496 ESRD patients older than 65 years old waiting for a KT, representing 18.1% of all listed candidates (http://optn.transplant.hrsa.gov/latestData/step2.asp. Accessed on July 29, 2010).

The number of KT in recipients older than 65 years rose from 9% in 1998 to 16.8% in 2007, an increase of 86%. Of 23,754 KT performed between 1996 to 2005 in recipients aged 60 years or older, 29.5% were living donors (LD) transplants and 70.5% were from deceased donors (DD). A total of 73% of recipients who received kidneys from deceased donors received the organs from standard criteria donors (SCD) and 27% received organs from expanded criteria donors (ECD).

Access to KT for the elderly is limited by death while on the waiting list, which is more common among the elderly than any other age group. The number of deaths among wait-listed ESRD patients older than 65 years has increased from 11.2% in 1995 to 26.4% in 2009. Age is also a risk factor for delayed KT in other countries. Oniscu et al reported that Scottish ESRD patients aged 60-64 and older than 65 were 80% and 93% less likely to be wait listed and 34% and 45% less likely to have access to KT (BMJ. 2003; 327:1261). Patients older than 65 spent a longer time on dialysis before listing. They also had significantly longer median waiting times than the 18-34, 35-49, 50-59, 60-64 age groups (1,521 days vs. 446, 623, 738, and 800, respectively). Although these authors assumed that co-morbidities accounted for the observed differences, this hypothesis could not be tested due to insufficient data and physician bias could not be excluded.
Patient and graft outcomes

Wolf and colleagues performed one of the most comprehensive studies comparing the survival of patients on dialysis versus that of primary DD-KT recipients. Among patients aged 60-74 years who received a primary DD-KT, the cumulative survival rate improved after the first year post-KT, with a projected four-year increase in life span and a 61% decrease in the long-term risk of death. When the elderly subgroup was further subdivided into patients aged 60-64 years, 65-69 years, and 70-74 years, the projected increase in life span was 4.3, 2.8, and 1.0 years, respectively.1 More recently, Rao et al found that KT recipients older than 70 years old were about 40% less likely to die when compared with their counterparts who remained on dialysis (Figure 1 and 2).3

Concerning the end-point of graft survival in the elderly KT recipient, in an analysis of data reported to the Scientific Renal Transplant Registry (SRTR) in 1994-1998, Cecka found that recipient's age affected both graft survival and cause of graft loss. Recipients aged 19-25 had a 78% three-year graft survival rate compared with 72% for recipients over age 60, a significant difference between the groups. In the elderly, 65% of graft losses after the first year post-KT were due to death with a functioning graft compared with 18% among 19-45 years old. Although immunologic graft loss was more frequent among younger recipients.4 Using the same analytical approach, Meier-Kriesche et al showed that the actuarial eight-year death censored graft survival was significantly worse in older patients (older than 65 years) than in recipients aged 18-49 years (50.7% vs. 67%, respectively).5

The choice of KT donor may impact graft and patient survival of elderly KT recipients. To improve access of the elderly to KT and shorten waiting times, the use of kidneys from older donors in older recipients has been advocated. Gill et al found that elderly recipients of KT from older LD (those older than 55 years) had inferior three-year graft survival rates (85.7%) but similar three-year patient survival rates (88.4%) when compared with their counterparts transplanted with younger LD (aged 55 or younger). In comparison, recipients of older LD organs had superior graft survival compared with all DD options. Compared with recipients of kidneys from donors older than 55 years, those who received ECD kidneys had a 2.36 times increased risk of graft loss.6

Between 1995 and 2002, 32.3% of KT recipients aged 60 years and older received an ECD KT.  In elderly patients facing long-waiting times and high mortality, inferior graft outcomes from ECD transplants may represent an acceptable trade-off if they offer improved overall patient survival. Recipients aged 60 years or older of an ECD kidney experienced a significant 22% reduction in the three-year relative risk of mortality when compared with patients wait-listed. Elderly recipients with long wait times (ie, 1,350 days) had a 37% decreased relative risk.

When recommending ECD KT to elderly recipients, one must consider that the perioperative mortality risk of ECD recipients is 5.2-fold higher during the first two weeks post-KT than that of SCD KT recipients or waitlisted patients.7 Therefore, recipient selection is pivotal to ensure success.
Complications

Transplantation is not exempt from complications, and the elderly are particularly vulnerable. In this group, early surgical complications are associated to significant morbidity. Wolfe et al found that, regardless of age, the risk of death after KT is 2.8 times higher in KT recipients than in waitlisted patients during the first trimester, a risk that remains elevated until day 106 post-KT.

Bentas et al compared the rates of surgical complications in recipients from the Euro-Transplant Senior Program and those of patients in the Euro-Transplant Kidney Allocation System. The mean donor/recipient age in these groups was 71.1/67.1 and 49.7/63.6 years, respectively. Forty-seven percent of KT recipients in the Senior Program had complications versus 28% in the control group. Arterial anastomosis issues and lymphoceles were most common among the candidates from the senior program, but both groups had similar rates of secondary hemorrhage, wound infection, wound dehiscence, urinomas, and ureteral strictures. Gill et al found that in elderly KT recipients, death with a functioning graft due to cardiovascular disease, infection, or malignancy was the most common cause of graft loss. In addition, death was more prevalent among older KT recipients of younger LD transplants (ie, younger than 55 years).
The impact of KT on the quality of life (QOL) among elderly ESRD patients has been poorly studied. Depression seems to be less common in elderly KT recipients than in KT recipients aged 18-34. Although it has been speculated that elderly patients are better able to cope with critical illness and accept it as part of the aging process, they are also more likely to underreport depression because of the fear of the stigma of psychiatric disease.8

Exercise intolerance is common in dialysis patients and elderly KT recipients. Older age is associated to poor functional performance after KT especially when pre-KT functional status is sub-optimal.  Van den Ham et al evaluated the VO2 –peak as indicator of exercise capacity in a small cohort of KT recipients and patients on dialysis with a mean age of 54 years. They found that both groups had comparable exercise tolerance and muscle strength, but higher age was associated with less strength and exercise capacity.9

Chisholm et al evaluated the influence of economic and demographic factors on QOL of KT recipients with a mean age of 50.6 years. Increasing age was a predictor of poorer physical dimension health-related QOL scores, a compound metric of physical functioning, bodily pain, and general health and vitality.10
Transplant management

The immune system of older KT recipients is less efficient at generating primary responses to neoantigens yet able to elicit strong T- and B-cell anamnestic responses.  Older individuals previously exposed to HLA antigens through transplantation, blood transfusions, pregnancies, or ventricular-assisted devices are theoretically at a high risk for developing T-cell and antibody-mediated rejection.

Although the bioavailability of drugs in older individuals can be affected by many factors, it appears that variables such as higher gastric pH, reduced gastric emptying, decreased splanchnic circulation, and changes in fat distribution have little influence in the pharmacodynamics of immunosuppressants in elderly KT recipients.

Immunosuppression in transplantation is divided in two phases: induction therapy and long-term maintenance immunosuppression. Induction involves the use of lymphocyte depleting agents or non-depleting interleukin-2 receptor antagonists (IL2-RA). Rabbit anti-thymocyte globulin (rATG) and alemtuzumab are potent depleting agents associated with lower rates of acute rejection but higher incidences of infections and malignancy. Non-depleting agents, such as IL2-RA although less efficient in preventing acute rejection have a lower risk of post transplant malignancies and infection.11

With regard to maintenance immunosuppression, the standard combination includes permutations of calcineurin inhibitors, antiproliferative agents and prednisone. As suggested by Danovitch and colleagues, immune risk stratification is pivotal in the choice of immunosuppression in the elderly. In elderly KT recipients with low immunologic risk profile and receiving a kidney from young donor, clinicians should consider IL2-RA for induction as well as steroid withdrawal or minimization protocols. In elderly KT recipients with a high risk of rejection, standard induction with lymphocyte depleting agents and standard immunosuppression are recommended. For elder KT recipients of an ECD kidney or older living donor, the choice of induction should primarily depend on the immunological risk. Given the high risk of calcineurin inhibitor (CNI) nephrotoxicity in these grafts, clinicians should consider using CNI avoidance or minimization protocols.

Despite these general guidelines, immunosuppression in KT recipients should be tailored and individualized. Careful institutional protocols should be adapted to the elderly population and a customized rather than a “one size fits all” approach should be sought.
Predicting outcomes

Several studies have attempted to identify variables that would predict outcomes in elderly KT recipients. Doyle et al found that a pre-KT history of non-skin malignancy, vascular disease, and current smoking were risk factors for decreased graft and patient survival.12 In a single-center cohort study, Yango and coworkers found that a history of chronic obstructive pulmonary disease and peripheral vascular disease also predicted higher mortality among older recipients. Most recently, Heldal found that acute rejection in the first 90 days and a donor age of 60 years and older predicted lower patient survival whereas delayed graft function, donor age of 60 or older, and HLA antibodies were associated with death-censored graft loss.13

In a cohort of 436 KT patients, Kutner et al found that patients older than 55 years were more likely to have lower physical functioning score. In multivariate analysis, age older than 55 years and lower pre-KT physical functioning were the only predictors of hospitalization or death post-KT. All these studies highlight the importance of adequate patient selection of older KT candidates (Table 1).
Improving outcomes

Transplant programs should perform a comprehensive evaluation of older KT candidates, including assessment of cardiovascular, infection, and malignancy risk and evaluation of patients' psychosocial network and support, mobility and functional status, cognition, immune system reactivity, and patient and family expectations. Older patients have more comorbidities than younger recipients, so they should be warned about the risks and likelihood of delisting after initial clearance for KT. As suggested by Danovitch and Savransky, older waitlisted patients should be seen at least twice a year to optimize their status. Geriatricians should participate in both the initial evaluation and subsequent follow-up pre-KT visits as they can provide insights into the functional and mental status of the elderly candidates by picking-up subtle cues indicative of declining performance.14
Conclusions

Altogether, the current literature supports KT in elderly recipients. Survival of older patients undergoing KT is substantially better than that of those who remain on dialysis.  This benefit persists even in individuals older than 70 years old. Elderly recipients transplanted with LD kidneys have better graft and patient survival than those who receive an SCD or ECD KT.  Among recipients of LD kidneys, those transplanted with organs from donors younger than 55 have the best outcomes. For selected elderly candidates facing long waiting times, ECD transplantation is a more suitable alternative than continuation of dialysis.

The success of transplantation in any KT recipient is incumbent upon strict and thorough selection criteria. The selection of older candidates for KT is a complex task that should be customized to each patient and should involve a formal geriatric evaluation. Management of immunosuppression in older KT should be tailored to avoid acute rejection while minimizing the risk of infection and malignancy. To that end, standard immunosuppression protocols may not fulfill the needs of elderly KT recipients, and biological rather than chronological age should be used as frame of reference when designing immunosuppressive regimens for the elderly.

Dr. Barrantes is a clinical lecturer and Dr. Samaniego-Picota is an associate professor in the Department of Internal Medicine at the University of Michigan in Ann Arbor, where also is Medical Director of Kidney and Kidney-Pancreas Transplantation.
REFERENCES

1. Wolfe RA, Ashby VB, Milford EL et al. Comparison of mortality in all patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999;341:1725-1730.

2. Oniscu GC, Schalkwijk AA, Johnson RJ, et al. Equity of access to renal transplant waiting list and renal transplantation in Scotland: cohort study. BMJ. 2003;327:1261.

3. Rao PS, Merion RM, Ashby VB, et al. Renal transplantation in elderly patients older than 70 years of age: results from the Scientific Registry of Transplant Recipients. Transplantation. 2007;83:1069-1074.
4. Cecka JM. Outcomes statistics of renal transplants with an emphasis on long-term survival. Clin Transplant. 1994;8:324-327.

5. Meier-Kriesche HU, Ojo AO, Cibrik DM et al. Relationship of recipient age and development of chronic allograft failure. Transplantation. 2000;70:306-310.

6. Gill J, Bunnapradist S, Danovitch GM et al. Outcomes of kidney transplantation from older living donors to older recipients. Am J Kidney Dis. 2008;52:541-552.

7. Merion RM, Ashby VB, Wolfe RA, et al. Deceased-donor characteristics and the survival benefit of kidney transplantation. JAMA. 2005;294:2726-2733.

8. Dobbels F, Skeans MA, Snyder JJ, et al. Depressive disorder in renal transplantation: an analysis of Medicare claims. Am J Kidney Dis. 2008;51:819-828.

9. van den Ham EC, Kooman JP, Schols AM. Similarities in skeletal muscle strength and exercise capacity between renal transplant and hemodialysis patients. Am J Transplant. 2005;5:1957-1965.

10. Chisholm MA, Spivey CA, Nus AV. Influence of economic and demographic factors on quality of life in renal transplant recipients. Clin Transplant. 2007;21:285-293.
11. Lebranchu Y, Bridoux F, Büchler M, et al. Immunoprophylaxis with basiliximab compared with antithymocyte globulin in renal transplant patients receiving MMF-containing triple therapy. Am J Transplant. 2002;2:48-56.

12. Doyle SE, Matas AJ, Gillingham K, Rosenberg ME. Predicting clinical outcome in the elderly renal transplant recipients. Kidney Int. 2000;57:2144-2150.
13. Heldal K, Hartmann A, Leivestad T, et al. Clinical outcomes in elderly kidney transplant recipients are related to acute rejection episodes rather than pretransplant comorbidity. Transplantation. 2009;87:1045-1051.

14. Danovitch G, Savransky E. Challenges in the counseling and management of older kidney transplant candidates. Am J Kidney Dis. 2006;47 (4 Suppl 2):S86-S97.

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