For those with advanced kidney disease, the treatment of choice is obvious: Recipients of kidney transplants have a higher quality of life, live longer, and cost less to treat than those on dialysis. Evidence is mounting, however, that transplantees could do even better, if patients would more often take their immunosuppressant drugs exactly as prescribed — and U.S. policymakers fix a loophole that abruptly cuts off insurance coverage for anti-rejection medications.

“We’re concerned that a significant percentage of [ failed kidney transplants] might be getting into trouble because of poor adherence to immunosuppressant drugs,” says Philip Halloran, a professor in the Departments of Medicine and Medical Microbiology & Immunology at the University of Alberta. Surveys of kidney recipients suggest roughly a quarter stray from the prescribed regimens even though they are much less intensive than the 12 or more hours of weekly treatment needed with dialysis.

The consequence of non-adherence can be severe. In a recent study, Halloran and his colleagues found that nearly half of late-stage kidney rejections were associated with patients who physicians suspected were non-adherent. Other recent work has found that less compliant patients face a 40% to 60% increased chance of graft failure and incur more than $12,000 in extra medical costs over three years. That jibes with earlier work that showed a 14-fold increase in the risk of acute rejection and a four-fold increased risk of graft failure five years after transplant.

Patients who lose their transplanted kidney must return to dialysis treatment or receive a second transplant, but they suffer from a double disadvantage: They do worse on dialysis than patients who have never received a transplant, with a quarter dying within two years, and they are more difficult to find organ matches for because the first transplant hypersensitizes their immune system.

The extent of the issue “is partly [the medical community’s] fault,” says Halloran, also director of the Alberta Transplant Applied Genomics Centre. “Asking patients to take drugs twice a day forever — it’s setup for failure. Patients are going to have a degree of noncompliance. We need to do better, to think about different ways to deliver drugs. This is largely a behavioral issue, and we need to address ourselves to modifying that behavior.”

Medicare reimbursement policy exacerbates the problem. Currently, Medicare covers long-term immunosuppressant therapy only for people 65 years or older or who have work-related disabilities. The remainder receive support for only three years following their transplants, leading many to abandon their drug treatments for financial reasons. Dialysis, however, is always covered, despite costing nearly three times as much annually. “This is a situation that clinicians, patients, and politicians cannot allow to persist,” Halloran says.

A Lifetime of Medication

Each preventable kidney transplant failure carries a high price. Nearly 100,000 people are on the U.S. transplant wait list with end-stage renal disease, an irreversible condition in which the kidneys lose their ability to filter blood. But only 16,000 to 17,000 kidney transplants take place each year, according to the Organ Procurement and Transplantation Network, which tracks organ transplant data. The remainder have to settle for the second-best solution: hemodialysis.

Not only do such patients need to visit a dialysis clinic thrice weekly for four to five hours each time, but they also tend to die sooner. “Life expectancy on dialysis is much worse, primarily due to cardiovascular disease,” says Thomas C. Pearson, a professor of surgery at Emory University School of Medicine and director of the Kidney Transplant Program at Emory University Hospital. “Although dialysis is life-sustaining, it doesn’t do as well as a functioning kidney in maintaining homeostasis.”

Although not as time-intensive as dialysis, keeping up with a post-transplant medical regimen comes with its own burdens. In addition to powerful immunosuppressant drugs given after surgery to prevent immediate rejection, patients take several “maintenance” anti-rejection drugs for life. The most common combination is tacrolimus, which blocks T-cell activity, and mycophenolate, an inhibitor of immune cell division, taken twice daily, along with a oncea-day dose of the steroid prednisone.

Tacrolimus has “a narrow therapeutic window,” Pearson says, necessitating regular blood monitoring. A standard schedule might be twice-weekly blood tests for the first month following a transplant, tapering down to once-a-month checkups. Adding to the complexity of home care, patients often are put on low-fat diets and might be prescribed a host of other medications — including antivirals, antibacterials, stomach-acid reducers, cholesterollowering drugs, and nutritional supplements — to help deal with side effects.

Questions and Answers

Despite the importance of keeping patients on these medications, however, physicians still remain in the dark about many aspects of nonadherence. Part of that is the inherent difficulty of collecting reliable data. Not only do patients have social reasons to lie, but admitting noncompliance can have medical consequences, such as reducing eligibility for a second kidney transplant. For example, attendance records for dialysis treatment are often a screening factor for transplant eligibility. “Surgery is the tip of the iceberg,” Pearson says. “It’s just a beginning. If a patient is not capable of maintaining the needed regimen, then we delay or defer on a transplant.”

For these reasons, clinicians will oftentimes rely on their experience to identify suspected non-adherent patients, Halloran says. More objective methods range from counting pills and tracking prescription refills to using electronic sensors to detect when a pill bottle is opened, but none can reliably check that the patient is actually taking medication at the right dose. Even blood or urine testing can be misleading, since patients will often improve adherence right before a clinical visit. Thus, although numerous studies suggest that between 20% and 30% of patients don’t take their medications as prescribed, questions remain about the true rate of non-adherence.

Still, scientists have identified several patterns in kidney transplants and other diseases requiring long-term treatment. For example, younger patients, men, and non-U.S. residents, along with those who have poor social support systems, poor knowledge about the disease, and a lackluster patient-physician relationship, tend to do worse. Patients with diabetes and those with simpler drug regimens fare better. Almost everyone declines over time.

One clear predictor, however, is financial wherewithal, particularly insurance. By one estimate, more than 40,000 kidney recipients in the U.S. are currently at risk of stopping drug treatment because of cost, as even the most affordable immunosuppressant treatments still run at least $10,000 yearly. This would cause between 1,300 and 1,500 transplanted organs to be lost each year. The consequences are severe: In countries with lifetime government-funded immunosuppressant coverage, such as Australia, Canada, and the United Kingdom, kidney transplant patients have much higher five- and 10-year survival rates than in the U.S.

According to the authors of a recent policy paper assessing the state of the U.S. system, “to pay for the transplants but not the care necessary to ensure their survival is misguided and counterproductive.” Bekir Tanriover, a nephrologist at the Columbia University College of Physicians and Surgeons and lead author of the paper, says that several recent attempts to change the policy, including a provision in the Affordable Care Act, have failed to pass Congress despite evidence showing that the government will ultimately save money. “If you’re not eligible for Medicare, you’re on your own,” he says. But “we have to continue to support these people. [Covering immunosuppressant drugs] gives hope for the long term, and quality of life will be better. It’s our ethical responsibility.”

But non-adherence runs much deeper than just a matter of access to drugs. Researchers have found that non-adherence appears early — within 90 days of a transplant. Moreover, while everyone’s compliance tends to ebb as time passes, people tend to decline in lockstep, so that those who do worse at the beginning are likely to continue the pattern. Nor is education a panacea, with doctors and nurses also slipping up at high rates. “Part of solving this issue is admitting we’re part of the problem,” Halloran says. “Health care professionals probably don’t do much better than anyone else [when asked to take medication].”

Small Steps

So what can be done to help patients stick to prescribed treatments? A simpler regimen is one option. Belatacept, an immunosuppressant approved by the FDA in 2011, is administered intravenously once a month and offers similar or better outcomes to using tacrolimus, Pearson says. However, uptake has been slow due to cost, and it’s still too early to tell to what extent it might improve patient adherence, he adds. Other extended-release formulations, such as a once-daily version of tacrolimus, are also being assessed. Alternate options include better screening for high-risk patients; more stringent guidelines on how well patients must do with dialysis before being approved for a transplant; improved education about the importance of drugs; repetitive teaching techniques; schedules, calendars, pillboxes, and other mnemonic devices to aid memory; and more open-ended discussions with patients to facilitate discussion about drug adherence issues.

Ultimately, however, more research is needed into the underlying psychology of nonadherence and better methods for directly dealing with the resulting behavior, Halloran says. More interdepartmental collaboration is key, he adds, with the upshot that any new findings may dramatically improve many medical disciplines simultaneously. “In general, noncompliance is the elephant in the room, in many areas of medicine, that is seldom discussed,” he says. “It’s been very understudied in relation to its importance.

“It’s one aspect of a larger behavioral problem: How you get people to do things that are good for them and stop doing things that are bad for them, like smoking?”

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