Institutional Affiliations Chair Costanzo MR: Midwest Heart Foundation, Lombard Illinois, USA Task Force 1 Dipchand A: Hospital for Sick Children, Toronto Ontario, Canada; Starling R: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Anderson A: University of Chicago, Chicago, Illinois, USA; Chan M: University of Alberta, Edmonton, Alberta, Canada; Desai S: Inova Fairfax Hospital, Fairfax, Virginia, USA; Fedson S: University of Chicago, Chicago, Illinois, USA; Fisher P: Ochsner Clinic, New Orleans, Louisiana, USA; Gonzales-Stawinski G: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Martinelli L: Ospedale Niguarda, Milano, Italy; McGiffin D: University of Alabama, Birmingham, Alabama, USA; Parisi F: Ospedale Pediatrico Bambino Gesu, Rome, Italy; Smith J: Freeman Hospital, Newcastle upon Tyne, UK Task Force 2 Taylor D: Cleveland Clinic Foundation, Cleveland, Ohio, USA; Meiser B: University of Munich/Grosshaden, Munich, Germany; Baran D: Newark Beth Israel Medical Center, Newark, New Jersey, USA; Carboni M: Duke University Medical Center, Durham, North Carolina, USA; Dengler T: University of Hidelberg, Heidelberg, Germany; Feldman D: Minneapolis Heart Institute, Minneapolis, Minnesota, USA; Frigerio M: Ospedale Niguarda, Milano, Italy; Kfoury A: Intermountain Medical Center, Murray, Utah, USA; Kim D: University of Alberta, Edmonton, Alberta, Canada; Kobashigawa J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Shullo M: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Stehlik J: University of Utah, Salt Lake City, Utah, USA; Teuteberg J: University of Pittsburgh, Pittsburgh, Pennsylvania, USA; Uber P: University of Maryland, Baltimore, Maryland, USA; Zuckermann A: University of Vienna, Vienna, Austria. Task Force 3 Hunt S: Stanford University, Palo Alto, California, USA; Burch M: Great Ormond Street Hospital, London, UK; Bhat G: Advocate Christ Medical Center, Oak Lawn, Illinois, USA; Canter C: St. Louis Children Hospital, St. Louis, Missouri, USA; Chinnock R: Loma Linda University Children's Hospital, Loma Linda, California, USA; Crespo-Leiro M: Hospital Universitario A Coruna, La Coruna, Spain; Delgado R: Texas Heart Institute, Houston, Texas, USA; Dobbels F: Katholieke Universiteit Leuven, Leuven, Belgium; Grady K: Northwestern University, Chicago, Illlinois, USA; Kao W: University of Wisconsin, Madison Wisconsin, USA; Lamour J: Montefiore Medical Center, New York, New York, USA; Parry G: Freeman Hospital, Newcastle upon Tyne, UK; Patel J: Cedar-Sinai Heart Institute, Los Angeles, California, USA; Pini D: Istituto Clinico Humanitas, Rozzano, Italy; Pinney S: Mount Sinai Medical Center, New York, New York, USA; Towbin J: Cincinnati Children's Hospital, Cincinnati, Ohio, USA; Wolfel G: University of Colorado, Denver, Colorado, USA Independent Reviewers Delgado D: University of Toronto, Toronto, Ontario, Canada; Eisen H: Drexler University College of Medicine, Philadelphia, Pennsylvania, USA; Goldberg L: University of Pennsylvania, Philadelphia, Pennsylvania, USA; Hosenpud J: Mayo Clinic, Jacksonville, Florida, USA; Johnson M: University of Wisconsin, Madison, Wisconsin, USA; Keogh A: St Vincent Hospital, Sidney, New South Wales, Australia; Lewis C: Papworth Hospital Cambridge, UK; O'Connell J: St. Joseph Hospital, Atlanta, Georgia, USA; Rogers J: Duke University Medical Center, Durham, North Carolina, USA; Ross H: University of Toronto, Toronto, Ontario, Canada; Russell S: Johns Hopkins Hospital, Baltimore, Maryland, USA; Vanhaecke J: University Hospital Gasthuisberg, Leuven, Belgium.

http://www.jsht.jp/uploads/ISHLT_GL_TaskForce2_110810.pdf

The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients

Background:  The calcineurin inhibitors (CNIs), cyclosporine and tacrolimus, have had a revolutionary effect on the overall success of renal transplantation through reduction in early immunologic injury and acute rejection rates. However, the CNIs have a significant adverse impact on renal function and cardiovascular disease, and extended long-term graft survival has not been achieved. The recognition of these effects sparked interest in CNI-sparing strategies. Strategies to limit CNI exposure include CNI minimization, avoidance, and withdrawal. We sought to review the impact of CNI-sparing strategies in kidney, liver, and heart transplantation.

Materials and methods:  A PubMed search 1966 to August 2006 was conducted to identify relevant research articles, and the references of these articles as well as the authors’ personal files were reviewed.

Results:  Calcineurin inhibitor minimization using mycophenolate mofetil or sirolimus may be associated with a modest increase in creatinine clearance (CrCl) and a decrease in serum creatinine (SCr) in the short term. Despite improvement in CrCl or SCr, CNI nephrotoxicity and chronic allograft nephrotoxicity are progressive over time when CNI exposure is maintained. In kidney transplantation, the tubulo-interstitial and glomerular damage are irreversible. Mycophenolate mofetil may improve renal outcomes during CNI minimization more than sirolimus, and antibody induction may be effective to limit CNI exposure, but longer-term follow-up data are required. Use of sirolimus with mycophenolate mofetil or azathioprine to avoid CNI exposure de novo has improved glomerular filtration rate for at least two yr in most studies in kidney transplantation; however, experience is limited in liver and heart transplantation, and reports of delayed graft function and wound healing with sirolimus may have dampened enthusiasm for de novo use. Late CNI withdrawal has achieved variable results, possibly because withdrawal was attempted after the kidney damage was too extensive. Early CNI withdrawal, prior to significant graft damage, has generally improved CrCl and markers of fibrosis and decreased chronic allograft lesions, a finding also observed with sirolimus in most CNI avoidance studies. Successful withdrawal appears to be more effective than CNI minimization.

Conclusions:  Calcineurin inhibitors are associated with significant nephrotoxicity and chronic kidney damage. Minimization is associated with a modest increase in renal function, but persistent damage is observed on biopsies as long as the CNIs are continued. Avoidance is hampered by lack of experience and possible sirolimus-induced side effects. CNI withdrawal may be the best option by delivering CNIs during the early period of immunologic graft injury and then converting them to less nephrotoxic agents before significant renal damage occurs.

Calcineurin inhibitor-sparing regimens in solid organ transplantation: focus on improving renal function and nephrotoxicity.

Received March 16, 2004; revision received July 23, 2004; accepted September 30, 2004. 

Part I of this series describes the mechanisms and types of rejection and the intravenous immunosuppressive drugs commonly used for induction or antirejection therapy. In this article, we review the commonly used oral immunosuppressive drugs. Intravenous corticosteroid methylprednisolone is included in the discussion of corticosteroids. Table 1 gives trade names, pharmacology, necessary adjustments for renal or hepatic dysfunction, and dosing and general monitoring guidelines for drugs described in this section. Table 2 lists the major adverse effects of immunosuppressive drugs described in Parts I and II of this review and provides an estimate of their relative frequency. 

View this table:

TABLE 1. Commonly Used Oral (and Intravenous) Immunosuppressive Drugs 



View this table:

TABLE 2. Major Adverse Effects of Immunosuppressive Drugs 



Steroids, among the first immunosuppressive agents used in clinical transplantation, have remained an important component of induction, maintenance, and rejection regimens.

### Mechanism of Action

Glucocorticoids are potent immunosuppressive and antiinflammatory agents (the Figure). They diffuse freely across cell membranes and bind to high-affinity cytoplasmic glucocorticoid receptors. The glucocorticoid receptor–steroid complex translocates to the nucleus, where it binds to a glucocorticoid response element within the DNA.1 The glucocorticoid receptor–steroid complex may also bind to other regulatory elements, inhibiting their binding to DNA. Both actions cause transcriptional regulation, thereby altering the expression of genes involved in immune and inflammatory response. Glucocorticoids affect the number, distribution, and function of all types of leukocytes (T and B lymphocytes, granulocytes, macrophages, and monocytes), as well as endothelial cells.2 The major effect on lymphocytes appears to be mediated by inhibition of 2 transcription factors, activator protein-1 and nuclear factor (NF) κ-B.3,4 This affects the expression of a number of genes, including those for growth factors, cytokines, CD40 ligand, GM-CSF, and adhesion and myosin heavy chain molecules.2 In nonlymphoid …

Drug therapy in the heart transplant recipient: part II: immunosuppressive drugs.

Survival after heart transplantation has improved considerably over the past 20 years. Half of all patients now live >9 years, and ≈25% live ≥17 years.1 Currently, ≈20 000 heart transplant recipients live in the United States.2 Improved longevity means prolonged immunosuppression and the concomitant use of drugs to prevent or treat the long-term complications of immunosuppressive agents, such as infection, obesity, hypertension, hyperlipidemia, renal insufficiency, diabetes, osteoporosis, gout, and malignancies. In 1989, heart transplant recipients surviving 1 year were reported to be taking 16±6 drug doses per day (prescription and nonprescription).3 In 2001, heart transplant recipients surviving an average of 76 months were taking 7 prescription drugs (range, 2 to 14), along with a number of nonprescription drugs.4 Thus, despite prolonged survival, heart transplant recipients continue to take multiple medications. With the large number of heart transplant recipients in the community and the increasing number of immunosuppressive and nonimmunosuppressive drugs used by these patients, it is important that the general cardiologist understand these drugs, their side effects, and the very real potential for drug–drug interactions. These interactions may result in adverse events caused by supratherapeutic and subtherapeutic drug concentrations. In this series, we review mechanisms and types of rejection, immunosuppressive drugs commonly used in the heart transplant recipient, common medical problems after transplantation, and clinically significant drug–drug interactions.

A brief review of known immunologic mechanisms leading to graft rejection highlights the action of individual immunosuppressive drugs, as well as the rationale for combination therapy5–8 (Figure). The rejection of a transplanted organ is primarily a T-lymphocyte (T-cell)–mediated event, although humoral (B-cell) responses also contribute. The exception is hyperacute rejection, which occurs when preformed antibodies to human leukocyte antigens (HLA) result in an immediate and catastrophic rejection. Immune recognition of donor antigens that differ from those of …

Drug therapy in the heart transplant recipient part I: Cardiac rejection and immunosuppressive drugs

Liver transplant recipients are at increasingly high risk for suffering from impaired renal function and probable need of renal replacement therapy. Extended criteria organs and transplantation of patients with higher model for end-stage liver disease scores further increase this problem. Acute and chronic nephrotoxicity are the trade-off in immunosuppression with potent calcineurin inhibitors (CNIs). As a good renal function is associated with better graft and patient survival, CNI minimization protocols have been developed. Current strategies to overcome CNI toxicity include reduction or withdrawal of CNIs concurrently with switching over to mammalian target of rapamycin inhibitor or mycophenolate mofetil (MMF)-based regimens. This strategy caused an improvement in renal function in a significant number of liver transplantation patients according to several studies. However, total CNI avoidance seems to result in higher rejection rates. To prevent chronic renal dysfunction in patients prone to or with acute renal failure, CNI delay - with induction therapy for bridging - followed by low-dose CNI in combination with MMF are proven strategies without risking higher rejection rates. An individualized, tailor-made immunosuppressive regime, with a special focus on renal function is recommended. This review gave an overview on CNI minimization protocols in liver transplantation also focusing on recently analyzed studies.

Calcineurin‐inhibitor minimization protocols in heart transplantation

BACKGROUND Cyclosporine (CsA) nephrotoxicity is a common problem after cardiac transplantation. We have studied the impact of CsA dose reduction in association with mycophenolate mofetil (MMF) treatment on renal function in heart transplant recipients with suspected CsA nephrotoxicity (serum creatinine level >2 mg/dl). METHODS Twelve heart transplant recipients (11 men, 1 woman; 111 to 1813 days after transplantation) with CsA-based immunosuppression (plus azathioprine and/or steroids) and a serum creatinine level >2.0 mg/dl were started on a daily dose of 2000 mg of MMF. Dilated cardiomyopathy was the underlying disease in nine patients, ischemic cardiomyopathy in three patients. Mean patient age was 57 years (range 44-69 years). Azathioprine was discontinued and CsA slowly tapered. Creatinine clearance, serum creatinine level, urea nitrogen, and uric acid were monitored. CsA levels were measured, and CsA dose was adjusted for whole blood levels of 70-120 microg/L. Ten patients still had endomyocardial biopsies, whereas one had echocardiographic controls only. RESULTS One grade 1B rejection episode according to ISHLT (International Society for Heart and Lung Transplantation) was observed until 1 year after the switch to MMF. One patient was excluded due to gastrointestinal side effects. CONCLUSIONS Conversion from azathioprine to MMF with consecutive reduction of CsA in heart transplant recipients with CsA-impaired renal function improves renal function as evidenced by lower serum creatinine, urea nitrogen, uric acid, and higher creatinine clearance.

Baryalei M

Papers

Improvement of impaired renal function in heart transplant recipients treated with mycophenolate mofetil and low-dose cyclosporine.