|
Organ transplant
Patient Information
|
Transplant Update
April 2005
Issue No.2
Dinesh Ranjan, MD
Chief, Transplant Section
Professor of Surgery
UK College of Medicine
dranj1@email.uky.edu
We are pleased to bring you this second issue of Transplant Update. Before introducing the intriguing discussions on liver allocation algorithms, pancreas transplantation and immunosuppressant drug interactions, I would again like to emphasize the importance of the involvement of our referring physicians in the transplant process. The referring physician holds the key to the pre-transplant and post-transplant care, as is obvious from the two discussions presented in this newsletter.
The MELD (modified end-stage liver disease) score system assigns computed scores based on a patient’s serum creatinine, INR and bilirubin, as these were found to most accurately correlate with probability of mortality within the three months’ period. Other than hepatorenal syndrome, a patient on high dose diuretic requirement due to ascites and/or edema may present to you with high serum creatinine. Similarly antibiotic therapy in face of advancing liver disease may induce coagulopathy due to Vitamin K dependent factor deficiency, and increased INR. These patients have been reported to have the highest risk of mortality before transplantation, and the referring physician often finds himself or herself on the front-line, handling these issues. On the flip side, however, there are problems with the MELD allocation scheme, as it places too heavy an emphasis on serum creatinine (not even creatinine clearance) which is not a direct measurement of liver dysfunction, while ignoring other time-honored parameters such as serum albumin, ascites, encephalopathy, spontaneous peritonitis, etc.
There is no patient more grateful than a diabetic that you have cured. The landmark article in the New England Journal in 1991 validated the fact that to prevent complications of diabetes, we need keep the blood sugar normal at all times. The only proven therapy that achieves this goal is whole organ pancreas transplantation. Despite some improvement in islet cell infusion therapy, the success rate of this therapy is not even close to the one achieved with pancreas transplantation. Currently pancreas transplantation is the standard therapy for brittle type I diabetics. The results of simultaneous kidney-pancreas transplantation are usually better than pancreas transplant alone, but the difference is narrowing rapidly due to a significant improvement in the results. Please keep this option in mind when you see an insulin dependent diabetic suffering through swings in blood sugar and stigmata of diabetes such as impending blindness, neuropathy or renal failure.
Our routine protocol dictates that a stable patient approximately 12 weeks post-transplant is released to the care of the referring physician. These patients are always on multiple immunosuppressing agents and are at risk for experiencing drug interactions. Therefore, as I am sure, you must have noted in our notes of caution when post-transplant patients are released back to you, special attention is necessary whenever prescribing a new medication. The commonly known drugs that may pose this problem are discussed in the accompanying article and therefore this article is worth noting. I must mention though, these patients are now healthier than they were when you sent them to us: the disease organ, be it liver or kidney, has been replaced with a healthy one. WE therefore request you to take over the care of their routine medical problems.
As you can see, pre-transplant or post-transplant, you remain an important member of our team.
Hoonbae Jeon, MD
Assistant Professor of Surgery
jhoon2@email.uky.edu
After an exponential increase of liver transplantation volume in early 1990’s, liver transplantation has soon become a victim of its own brilliant success due to the shortage of organs from cadaveric donors. The severe discrepancy between the number of patients on the waiting list and the number organs requires fair and evidence-based organ allocation system.
The prime principle underlying liver allocation is to offer donor livers to recipients in greatest need who have a substantial risk of dying. The initial allocation scheme of UNOS(United Network for Organ Sharing) status, before 1997, stratified urgency according to hospital status and waiting time. In the patient with end-stage liver disease, highest status was awarded to the patient in the ICU, and the next was given to hospitalized, non-ICU patients. “At-home” patients were given the lowest priority. In this situation, due to the large numbers of patients in each priority group, waiting time served as the tiebraker. In 1997, UNOS adopted minimal listing criteria in an attempt to stem the tide of patients being listed at early stages of disease. In 1998, UNOS redefined UNOS status based on disease severity using Child-Turcotte-Pugh score and estimated short survival. But UNOS categories still remained broad with large numbers of patients within each status. In addition, the determination of short term survival, severity of ascites and encephalopathy were arbitrary and based on subjective clinical assessment. In 1999, the US Department of Health and Human Services issued a “Final Rule” under the National Organ Transplant Act the transplant community to resolve the perceived inequities in liver allocation. As a result, MELD(model of end stage liver disease) was instituted by UNOS for organ allocation in February 2002. MELD scores are rounded to the nearest integer and range from 6 to 40, yielding 34 scores for severity of illness. Waiting time is still used as a tiebreaker in case of identical MELD score. This model has underwent validation before implementation for a few years this mainly assigns priority to patients with higher risk of mortality within next three months.
MELD is the proposed answer to the search for an objective, reliable, and clinically useful model for defining disease severity in patients on the liver waiting list. MELD score is being calculated based only on total bilirubin, creatinine and INR. UNOS has mandated frequent updates of MELD scores to combat the effect of transient fluctuations in laboratory results. There are, however, still several questions to be answered. The immediate effect of institution of MELD should be to reduce waiting list mortality. However, the effect of MELD on mortality must include posttransplant outcome because allocation of donor livers to the sickest patients or those renal failure may yield significant increase in posttransplant mortality. Thus, any gains in reduction of waiting list mortality may be offset by higher posttransplant mortality. Also, fewer patients are listed in the early stages of their disease because waiting time is of diminished importance in MELD-based allocation. Death in these unlisted patients, who in the past might have been listed, are not captured. Starting from January 15th 2005, organs will be regionally shared for patients with MELD score greater than 15 to increase the chance of liver transplantation for sicker patients. Of note, new MELD allocation algorithm assigns significant priority to transplant candidates with early-stage HCC (Single lesions 5 cm or less in diameter, or three or fewer lesions none >3 cm in diameter. No extrahepatic metastasis or vascular invasion). A diligent screening of HCC in every patients with cirrhosis can potentially help patients with early stage HCC’s. Even if the patient should exceed criteria to get extra priority, local ablative therapy such as radiofrequency ablation or transarterial chemoembolization can “downstage” the tumor to fulfill criteria to obtain priority. At UK Transplant Center, there multimodality treatment of HCC are all available in an orchestrated fashion to achieve the ultimately curative treatment, which is liver transplantation. For more information or to discuss your patient’s case, please contact UK Transplant Center at
859-231-9922, or toll free at 1-800-888-5533. Our transplant surgeons are available 24 hours a day, seven days a week.
Thomas Johnston, MD
Associate Professor of Surgery
tdjohn1@email.uky.edu
With the publication of the landmark Diabetes Control and Complication Trial* (DCCT) in 1993, it was confirmed that intensive therapy could indeed reduce the risk of the secondary complications, and intensive therapy has subsequently become the standard of care for virtually all type I diabetes patients. However, there are number of limitations exist despite the known benefits of intensive insulin therapy.
The ideal therapy for type I diabetes should provide regulated insulin delivery, respond to the everchanging insulin demand of the patient, and allow for sustained normalization of blood glucose without hypoglycemia. Exogenous insulin cannot, in general, achieve sustained normalization of blood sugar. While intensive insulin therapy can reduce the risk of complications, it does not eliminate this risk. In the DCCT, subjects in the intensive insulin treatment group still developed some microvascular complications including retinopathy. Further, insulin therapy still carries significant risk of hypoglycemia. This is arguably the most important risk associated with intensive insulin therapy. Data from DCCT found a threefold increase in the risk of severe hypoglycemia. The only therapy currently available that achieves sustained normoglycemia is the transplantation of functional islet tissue. An important clinical concern with the use of intensive insulin therapy is the tendency for patients to gain weight. This weight gain occurs despite a prescribed decrease in daily caloric intake. This weight gain can be associated with changes in plasma lipids, an increase in abdominal obesity, and higher rate of hypertension. The added cost of intensive therapy includes extensive use of self-monitored blood glucometer, increased supplies for exogenous insulin use, and increased interaction with healthcare providers. In a long run, intensive therapy may outcost pancreas transplantation.
At present, the use of transplant therapies will need to be carefully considered and the active participation of endocrinologist and primary care physician will be needed to assist in the selection and screening of subjects most suitable for transplant therapies.
Currently, the indications for transplant should include but are not limited to:
1. patients with previous renal transplantation
2. patients for whom exogenous insulin use is impractical due to severe complication such as visual impairment
3. patients with progressive and severe complication despite use of maximal intensive insulin
therapies
4. Recurrent hypoglycemia with symptom unawareness
At present, the role of the evaluating physician is to help identify individuals in whom
1. the risk of hypoglycemia exceeds the potential risk of transplantation procedures
2. the demand of intensive therapy cannot be satisfactorily met by the patient
3. progressive and severe complications such as worsening renal function are developing despite maximal intensive therapeutic effort.
* Diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent and progression of long-term complications in insulin-dependent diabetes mellitus. N Eng J med 1993;329;252-263
Tim Clifford, PharmD
Transplant Pharmacologist
timclif1@email.uky.edu
The advent of immunosuppression entered a new dawn on the treatment of end stage diseases of the heart, lung, liver, and kidney. As transplant becomes a more viable option for many patients, the risk of drug interactions has also increased. Patients are living longer with because of immunosuppressant agents. These agents have a narrow therapeutic concentration and are prone to drug interactions that can increase or decrease the effectiveness of these agents. The focus of this letter will be on selected drug interactions with tacrolimus (Prograf©). Many drugs can alter the pharmacokinetics of tacrolimus. Below is a summary of some common interactions and the effects on drug levels.
Agents known to increase tacrolimus concentrations by CYP 450 enzyme inhibition/competition:
Cimetidine
Clarithromycin
Diltiazem
Erythromycin
Fluconazole
Grapefruit juice
Itraconazole
Ketoconazole
Metronidazole
Nifedipine (competition)
Omeprazole
Telithromycin
Theophylline
Verapamil
Voriconazole
Agents known to decrease tacrolimus concentrations by CYP 450 enzyme induction:
Carbamazepine
Phenobarbital
Phenytoin
St. John’s Wort
Agents with other affects on tacrolimus effectiveness or toxicity:
Aminoglycosides (increased risk of nephrotoxicity)
Echinacea (decreased effectiveness of tacrolimus)
Metoclopramide (increased bioavailability of tacrolimus)
NSAIDS (increased risk for nephrotoxicity)
Although not an exhaustive list, these are agents that practitioners may encounter in the post transplant population. When any of these agents are initiated or discontinued, increased monitoring of tacrolimus may be necessary. This should be used as information about the effects of these agents on tacrolimus. For further interactions please consult a published drug reference guide or please check with one of transplant physicians at UK Transplant Center 859-231-9922 or toll free at 1-800-888-5533.
|
Academics | Service | Research | UK HealthCare | UK A-Z 
