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The Ultimate Gift
A
newsletter from the transplant team
at Rhode Island Hospital
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Noncompliance After Transplantation
by Paul Morrissey, MD
Approximately 75-80% of renal transplant patients have a functioning
allograft after two years. The major causes of allograft beyond
2 years are chronic rejection (36%), noncompliance (28%), patient
death (22%), and acute rejection (10%) (Transplantation 1990; 49:349).
In this issue of The Ultimate Gift, I will address noncompliance
and late acute rejection and there impact on renal allograft outcomes
with particular reference to our patient population at Rhode Island
Hospital.
Patient noncompliance with immunosuppressive drug therapy is a
common problem with an incidence of 15-22% (Transplantation 1998;
66:1718). Reasons for noncompliance include drug side effects, requirements
for co-medications, cost, and psychosocial factors - predominantly
illicit drug use and depression. Noncompliance ranges from willful
discontinuation of immunosuppressive therapy (either abruptly or
by self-weaning) to frequent missed doses ("I was too busy
to take my medications"). Some patients perceive an inability
to take medications due to illness or cost. In the latter case,
I emphasize perceive, because in reality with the assistance of
Kathy Rosener, MSW, there has never been a patient for whom immunosuppressive
medications could not be obtained through a variety of patient assistance
programs (Novartis, Roche, NKF, etc.).
After renal transplantation patients require high doses of immunosuppressive
medications, particularly in the first 3-6 months, until the host
adapts to the allograft. The immunologic basis of host adaptation
is not understood, but the phenomenon of progressively lower requirements
for immunosuppression is reproducible in all solid organ transplants.
In this initial period the phrase "it's the medications"
often becomes a mantra. It is the explanation for every patient
problem (edema, tremor, nausea, diarrhea, hirsuitism, alopecia,
proximal muscle weakness, moon face, bruising, elevated blood sugars,
hyperlipidemia, hypertension, etc.). While this is often true, we
may be fostering noncompliance by emphasizing the adverse effects
of the immunosuppressive drugs. Most of these issues, particularly
the cosmetic effects resolve as medication doses are reduced. A
better explanation may be a reassuring "we see this effect
in the early period after transplantation - it usually disappears
after the first few months". If the issue of drug-related side
effects is brought up directly I respond, "I know that is a
problem now, however, this dose is required at this point to protect
the health of the kidney; in a few months the dose will be reduced
and this problem usually goes away."
We have instituted two recent changes to address some of
these issues at Rhode Island Hospital. First, we have changed our
steroid taper to target a dose of 10 mg/d by postoperative day 32,
rather than at 6 months. For patients considered at "high medical
risk" for transplantation, we have instituted a 7-day taper
to 10 mg/d. Secondly, we have decided to increase our use of tacrolimus
(Prograf) as the primary immunosuppressive agent. Most of our patients
receive induction therapy with Thymoglobulin or Simulect. Combined
with tacrolimus and Cellcept, it should be possible to taper steroids
rapidly with no increased risk of acute rejection. Indeed this has
been our early experience and the experience of others (Transplantation
2005: 69: 875). This regimen minimizes adverse effects of immunosuppression
by substituting tacrolimus for cyclosporine (no hirsuitism, gingival
hyperplasia or hyperlipidemia) and reduces steroid therapy to a
supportive rather than leading role.
Several recent cases of late acute rejection highlight many of
these issues (see chart below). We currently have 290 patients with
over 3 months of follow-up. There have been 88 cases of acute rejection
in 71 of these patients (25% of patients experienced rejection).
In fifteen of these cases, all late rejections, the patient admitted
to noncompliance. Despite treatment, several grafts were lost and
most patients with late rejection developed a significant decline
in renal function compared with their previous baseline. Cosmetic
side effects and depression accounted for the majority of this noncompliance.
Of note, none of the last 34 patients transplanted has experienced
acute rejection (knock on wood). Although some will, we anticipate
a lower incidence of noncompliance and late acute rejection with
our new immunosuppressive regimen.
On a final note, some episodes of acute rejection are the consequence
of our best intentions. Four patients suffered acute rejection during
a steroid taper 11-28 months after transplantation. The taper schedule
was 1 mg per month and despite monthly lab testing during the taper
the rejection episodes were moderate to severe and resulted in a
permanent decrement in renal function in 2/4 patients. Another two
patients experienced acute rejection after discontinuing ketoconazole.
Recall that the administration of ketoconazole with Neoral leads
to an 80% dose reduction in cyclosporine to maintain therapeutic
trough levels. Discontinuing ketoconazole with no upward dose adjustment
in cyclosporine led to undetectable cyclosporine levels in both
patients, followed by acute rejection.
The face of immunosuppressive therapy is always changing. Using
these drugs effectively is both science and art. New drugs are in
the pipeline. Some patients are currently enrolled in a study of
Certican (hydroxy-sirolimus) and others are being recruited for
a randomized, double blind trial of steroid withdrawal after 7 days.
Immunosuppressive drug regimens are increasingly varied and complex.
The possible permutations of immunosuppressive therapy to prolong
allograft function and improve patient satisfaction (compliance)
mandate a lifetime of follow-up and cooperation between the patient's
nephrologist and the transplant clinic.
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