The D&T Report

Abstract

As the worldwide burden of renal disease increases, it appears that the public's willingness to donate their organs is also growing: According to a 2009 survey by L.D. Horvat, MD and colleagues in the Donor Nephrectomy Outcomes Re-search (DONOR) Network, rates of living donor kidney transplantation have steadily risen in most regions of the world, increasing its global significance as a treatment option for kidney failure. In 2006, the latest year for which numbers are available, 27,000 live-donor transplants were performed around the world. As shown in Table I, Americans donated the greatest number of kidneys in absolute terms, but Saudi Arabians were most altruistic on a perpopulation basis.1

However, the supply of available kidneys from both live and deceased donors still falls greatly short of demand. In 2006, there were roughly 70,000 people on the wait list for organ donors in the United States alone, according to the U.S Renal Data Service. Similar scenarios exist in other countries. Currently, more than 50% of transplanted kidneys in the U.S. are from deceased donors and approximately 90% of these recipients would have undergone dialysis for three to five years prior to receiving that deceased- donor organ. 2

Many of the attempts to increase organ availability focus on broadening the donor pool. In trends such as expanded-criteria donors (ECD) and donation after cardiac death (DCD), kidneys are taken from people who are older and whose health may not be as good as standard-criteria donors (SCD), but whose organsmight still be viable for patients who are themselves older or sicker than average. The blessings associated with ECD kidneys are mixed: Patients who receive those organs live longer than people who remain on dialysis, but not as long as patients transplanted with SCD kidneys. In fact, compared with dialysis, the projected average number of added life-years associated with an SCD kidney is 10 years, but only 5.1 years for an ECD organ. The differences become especially stark with the passage of time: at 5 years post-transplant, average patient survival is 82% with SCD organs and only 70% with ECD organs, and graft survival is 65% and 49%, respectively. No such differences exist in comparisons between donation after brain death (DBD) and DCDkidneys. 2

Since 1996, some surgeons have transplanted both kidneys from donors who are particularly marginal. Dualkidney transplants (DKTs) now account for about 2% of all renal transplants performed in the U.S., or about 320 transplants per year. The criteria for a DKT donor is relatively loose, as long as the donor does not have cancer orAIDS. For example, in a DKT procedure performed at the University of Kansas Hospital in Kansas City last November, the donor was 75 at the time of death and had a history of hypertension and stroke. In this case, the recipient was 88 years old and also hypertensive. Such a patient would probably never have had a chance at a transplant otherwise, yet the patient was up and around within days and no longer needed dialysis. 3

In a study of long-term outcomes, Sacha de Serres, MD, at the Universite Laval in Quebec, Canada, and colleagues found that patient and graft survival were similar amongDKT, ECD, and SCD recipients followed for a median of 56 months. Creatinine clearance was similar for DKT and ECD recipients evaluated at 12, 36, and 84 months. The investigators concluded that “DKT patients can expect long-term results comparable with singlekidney ECD.” As a result, the University of Kansas Hospital increased transplants from donors older than 50 by nearly 50%. 4

While ECD, DKT, and DCD offer clear benefits to patients who might otherwise have no options other than dialysis, they still have their drawbacks. After following patients for a mean of 50 months, Reza Saidi, MD, and colleagues at Massachusetts General Hospital in Boston observed a higher incidence of delayed graft function, longer time to reach serum creatinine levels below 3 mg/dL, longer length of hospital stay, and a higher risk of readmission among patients receiving ECD, DCD, or ECD/DCD kidneys when compared with SCD recipients. The hospital charges associated with non-SCD transplants ranged from $70,030 to $72,789, compared with $47,462 for the SCD cases (p <0.001). Early graft survival was comparable among all groups, but ECD recipients had a significantly lower long-term survival than patients in the other groups. “These transplants are associated with increased costs and resource utilization,” the authors warn. “Revised reimbursement guidelines will be required for centers that utilize these organs.” 5

In recent years, paired exchange donation has become a popular way of expanding the donor pool beyond relatives, friends, and spouses. People can now exchange their live donor with another transplant candidate when there is biologic incompatibility with the original donor, opening the door for multiple paired exchanges.

Patient criteria also have come in for a closer look in recent years. As Silas Norman, MD, pointed out in a 2009 D&T paper, the average age of waitlisted patients has increased since 1997, with a particularly sharp increase in patients aged 50 or older. As a result, “there has been a marked increase in recipients dying with otherwise functional allografts, and a simultaneous decline in estimated post-transplant survival.” Current methods of allocation have not kept up with this reality, so that by 2007, the system was “inequitable, lacked predictability, and did not effectively utilize the potential life years available from donor kidneys.” The current system was also shown to be no longer consistent with sections of the National Organ Transplant Act (NOTA) of 1984 or the Organ Procurement and Transplant Network's (OPTN's) Final Rule, the two directives that guide organ allocation in the U.S. 6

In an effort to keep up with the changing patient profile, the OPTN's Kidney Transplant Committee proposed a Kidney Allocation Score (KAS) to replace the older system of allocation. Like the current system, the KAS would favor a certain level of panel reactive antibodies (PRA). However, where the present system allows mostly SCD or ECD organs, the KAS would use a donor profile index (DPI) calculated to determine the length of allograft survival. The KAS would also calculate waiting time from the beginning of maintenance dialysis, rather than when the patient is actively waitlisted, as is currently done.

The most controversial aspect of the KAS involves a change in the major medical consideration, which currently is HLA matching.With the KAS, thatwould be replaced by a calculation of life-years from transplant (LYFT): the difference between the patient's life expectancy with a kidney from a specific deceased donor, and his or her life expectancy without the transplant. LYFT would be derived from a complex equation that included both donor and recipient factors, plus an adjustment for quality of life.

LYFT has drawn criticism from physicians and patient advocate groups because it appears to recommend matching older, sicker patients with older, sicker donors, eliciting fears that those patients would get kidneys of lesser quality. However, Larry Melton,MD, D&T's coeditor- in-chief points out that some younger patients have so many comorbidities that their life expectancy may be the same or less than that of an older personwho is relatively healthy. 7

Officials at the U.S. Department of Health and Human Services Office of Civil Rights are reviewing the KAS to determine whether it violates laws against age discrimination. In the meantime, the search continues for an ethical, equitable way to expand the supply of organs.

Patients who undergo a kidney transplant after months or years on dialysis enjoy the independence and the return to a (nearly) normal life that the graft provides. Not surprisingly, a graft failure can take an enormous psychological and clinical toll. “It can be devastating to the patient, as they go through similar steps of denial and anger initially, akin to when a person is told of the death of a loved one,” says Kenneth Bodziak, MD, assistant professor of nephrology and hypertension at Case Western Reserve University in Cleveland, Ohio.

In general, people returning to dialysis after graft loss (DAGL) experience reduced survival and quality of life, compared with patients who have remained on dialysis or to those whose grafts remain viable. Most DAGL patients have already been on dialysis for an extended period before their transplant, so they have a long exposure to uremia and its related complications. Following graft failure, added to that are the inflammatory consequences of organ rejection. These patients experience high rates of infection- related sepsis, and they often require catheters for venous access. All of this is in addition to the emotional toll the return to dialysis takes.

Diana Headlee-Bell knows something about this process. She received a deceased-donor transplant in 1981 and enjoyed 18 years with her kidney. In 1999 she contracted pneumonia, and the powerful antibiotics she needed caused the graft to fail. Reluctantly, she returned to in-center dialysis.At the time of the transplant failure her husband also was ill and she was raising their 13-year-old son almost on her own; her day-to-day life was already stressful, and the change in her lifestyle and health due to the return to dialysis made for an almost unbearable transition.

It is perhaps not surprising that mortality spikes sharply in this patient population within the first year of resuming dialysis. 1

One of the appeals of peritoneal dialysis (PD) is that it offers patients much of the same independence and freedom they experience with a renal graft. Until recently, however, clinicians have been reluctant to offer that option to DAGLpatients, due to fears of adverse side effects such as peritonitis. In January, Jeffrey Perl, MD, and colleagues at St. Michael's Hospital at the University of Toronto, Ontario, published data showing that mortality is similar among DAGL patients regardless of the dialysismodality they use. 2

The authors combed the Canadian Organ Replacement Register to identify 2,110 patients who returned to hemodialysis (HD) or peritoneal dialysis after a failed transplant between January 1991 and December 2005. They studied the relationship between dialysis modality on mortality at two years (early mortality), after two years (late mortality), and overall. The hazard ratio of overall mortality for HD compared with PD was 1.05 (95% CI, 0.85 to 1.31), suggesting that there was no difference in survival associated with HD or PD following graft failure. Similar findings were obtained for early and late survival.

Transplant-naïve dialysis patients who choose PD have an early survival advantage over those on HD, but the investigators found this advantage diminishes over time. The study suggests that “the use of PD compared with HD is associated with similar early and overall survival among patients initiating DAGL. Differences in both patient characteristics and pre-dialysis management between patients returning to DAGL and transplant- naïve incident dialysis patients may be responsible for the absence of an early survival advantage with the use of PD in DAGLpatients.”

Of course, many factors figure in the choice of dialysis modality when a transplanted kidney fails. “The key issues that need to be addressed are the timing of when to return to dialysis, the degree of immunosuppression the patient is on once he or she returns to dialysis, and whether or not the patient is a candidate for re-transplantation,” says Dr. Bodziak. In general, the proportions of DAGL and pre-transplant patients undergoing HD or PD are similar. “For people choosing PD, it is important to ascertain that the peritoneal membrane was left intact at the time of transplant surgery, and that there is adequate volume in the peritoneal cavity in which to instill the PD fluid,” he says.

The findings by Perl and colleagues may offer more options to DAGLpatients who have grown accustomed to living with their transplants. But the decision is not that simple—many factors must be taken into account when determining to which modality to return. Headlee-Bell, for example, was never a candidate for PD, because previous operations had left her with extensive abdominal adhesions. After 12 years on HD (and she now receives in-center nocturnal dialysis), she is hoping for another transplant because “I've come to the point where I'm just tired of dialysis,” she says.