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Aftercare for Patients with Transplanted Organs

Dtsch Arztebl Int 2009; 106(9): 148-55; DOI: 10.3238/arztebl.2009.0148

Schrem, H; Barg-Hock, H; Strassburg, C P; Schwarz, A; Klempnauer, J

Background: The postoperative management following solid organ transplantation requires close cooperation between family doctors, internists, the local hospital, and the transplant center.
Methods: Selective analysis of current national and international guidelines and relevant review articles.
Results/conclusion: In the early phase post transplantation, aftercare involves inpatient treatment and outpatient or inpatient rehabilitation with the aim of complete social and professional reintegration. Early diagnosis and treatment of typical general complications such as post-transplant diabetes, hyperlipidemia, arterial hypertension, osteoporosis, and kidney failure is essential. Early detection and treatment of malignant disease and opportunistic infections in patients with long-term immunosuppression is desirable. Moreover, organ-specific factors have to be taken into account. In the event of transplant dysfunction, recurrence of the underlying disease in the transplant, chronic or acute rejection, and organ-specific infections and drug toxicity have to be considered.
Dtsch Arztebl Int 2009; 106(9): 148–56
DOI: 10.3238/arztebl.2009.0148
Key words: organ transplantation, rehabilitation, quality of life, treatment outcome, cooperation
Physicians are increasingly having to deal with transplant patients in daily practice because of the generally growing number of transplants performed and the steadily improving prognosis (1). The aim of transplantation and subsequent rehabilitation is to achieve the fullest possible reintegration into normal life, including occupational and social rehabilitation. Long-term success of organ transplantation depends to a great extent on the ensuing interdisciplinary aftercare program (figure gif ppt).

The learning goals of this article are to equip the reader

- to ensure that the transplant patient achieves a good quality of life
- to apply essential therapeutic principles to produce a good long-term result regardless of the organ transplanted in long-term aftercare of organ transplant patients.

This paper is based on the current national and international guidelines and review articles from the last six years.

Immunosuppression in patients with transplanted organs
In addition to basic immunosuppression, depending on the transplant center and the transplanted organ, a so called induction therapy is often performed intraoperatively and during the first few days after transplantation. This therapy involves the center-specific use of mono- or polyclonal antibodies (such as antithymocyte globulin or antilymphocyte globulin) (2). Basic immunosuppression is a lifelong requirement aimed at eliminating the risk of transplant loss resulting from immunological rejection (2). In the initial phase, basic immunosuppression frequently consists in the use of corticosteroids (methylprednisolone or prednisolone) in decreasing doses. In the long-term course, a prednisolone dose between 5 and a maximum of 10 mg daily is often administered. In many cases, however, steroid-free immunosuppression is now a widely employed alternative (2).

Most immunosuppressive protocols are based on a combination of a calcineurin inhibitor (ciclosporin or tacrolimus) with steroids. m-TOR (mammalian target of rapamycin) inhibitors like sirolimus or everolimus—alone or in combination with a calcineurin inhibitor and/or corticosteroids—are gaining in clinical importance in various basic immunosuppressive protocols used in patients who have had transplants because of malignant disease or progressive renal failure. The purine synthesis inhibitor mycophenolate mofetil (MMF) has proved successful in many cases in combination with steroids and/or a calcineurin inhibitor (2). In patients with post-transplant renal failure, the nephrotoxic calcineurin inhibitors can also be replaced completely or partially by MMF or everolimus or sirolimus (3).

It is imperative to be aware of known interactions between calcineurin inhibitors and other drugs, since they may lead to relevant increases or decreases in the blood levels of calcineurin inhibitors with associated toxicity or the risk of graft rejection (4).

Calcineurin inhibitors, like m-TOR inhibitors, have to be administered in blood level adapted doses (2). It has been shown for ciclosporin that the value measured two hours after intake, the 'C2 level', accurately reflects the pharmacokinetic area under the curve (AUC) and allows optimized dose adjustment during drug monitoring (4). The optimal therapeutic trough and C2 levels depend on the organ transplanted, the time after transplantation, the inclusion of other immunosuppressive agents in the protocol (e.g. mycophenolate mofetil and/or corticosteroids), and the patient's medical history. The selection of an individualized immunosuppressive protocol should also be left to the transplant center during long-term aftercare. A comparative listing of the most commonly used immunosuppressive agents is provided in table 1 (gif ppt).

In aftercare, the nephrotoxic, neurotoxic, and diabetogenic side effects are important factors in determining the long-term prognosis and quality of life, especially with the widely used calcineurin inhibitors ciclosporin and tacrolimus. Mycophenolate mofetil may be associated with diarrhea and/or clinically relevant bone marrow suppression that limit the use of this drug (2, 3).

Hyperlipidemia during immunosuppression
Almost all immunosuppressive agents cause hypercholesterolemia which often cannot be controlled by dietary management alone. In these cases statins should be used (5). In combination therapy with calcineurin inhibitors, pravastatin and fluvastatin are most suitable because these agents are so far the most thoroughly studied in combination with immunosuppressives and are not biotransformed mainly by the cytochrome P450 3A4 system like the calcineurin inhibitors (5). Dose increases should be based on the results of lipid electrophoretic monitoring and in conformity with the known target values for risk patients: LDL cholesterol below 2.6 mmol/L (6, 7, 8). Creatine kinase monitoring is important since statin and calcineurin inhibitor therapy has been associated with rhabdomyolysis which has occasionally been fatal when the symptoms were misinterpreted (5). Bezafibrate is contraindicated in kidney transplant patients with impaired renal function.

Post-transplant diabetes
Immunosuppression with steroids and/or a calcineurin inhibitor is associated with an increased incidence of diabetic metabolic derangements that can lead to insulin-dependent post-transplant diabetes (9). Diagnosing post-transplant diabetes requires the determination of fasting blood glucose, which is above 125 mg/dL. An oral glucose tolerance test (OGTT) is already required for transplant patients with a fasting blood glucose level between 110 mg/dL (6.1 mmol/L) and 125 mg/dL (6.9 mmol/L) to check for the presence of post-transplant diabetes or impaired glucose tolerance (7, 9). If post-transplant diabetes or impaired glucose tolerance is detected, it is essential to treat the condition because of the associated elevated cardiovascular risk (7, 9). During the further course, regular HbA1c monitoring every three to six months is advisable. If substantially reducing or tapering out steroids or replacing tacrolimus or ciclosporin in the immunosuppressive protocol as well as dietary measures fail to produce normoglycemia, oral antidiabetic therapy (e.g. with a sulfonylurea preparation) or insulin therapy should be initiated depending on the serum glucose level (7, 9).

Arterial hypertension in patients with transplanted organs
Many patients develop hypertension requiring treatment during immunosuppressive therapy. Corticosteroids and calcineurin inhibitors are known to have pressor effects. Arterial hypertension is a relevant risk factor for cardiovascular diseases with a significant influence on morbidity and mortality in transplant patients. Besides hyperlipidemia and post-transplant diabetes, arterial hypertension is one of the main prognostic factors for long-term survival in transplant patients (7, 10, 11).

Blood pressure management is essential in arterial hypertension to prevent long-term complications including renal insufficiency and cardiovascular events. The current guidelines of the German Hypertension League are based on the guidelines of the European Society of Hypertension and the European Society of Cardiology (www.hochdruckliga.info) (12).

This evidence-based guideline and the Guideline of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC-7 Guideline) (13) recommend target blood pressure values below 140/90 mm Hg and for diabetics below 130/80 mm Hg. The JNC-7 Guideline also proposes target blood pressure values below 130/80 mm Hg for renal insufficiency patients. For post renal transplant patients, the European guidelines recommend a target blood pressure below 130/80 mm Hg in patients without proteinuria and below 125/75 mm Hg in patients with proteinuria (10).

24-hour blood pressure monitoring is favored as a means of ruling out unrepresentative elevated values. Antihypertensive therapy can then be initiated and adjusted as required on this basis. The cardio- and nephroprotective ACE inhibitors and AT-1 blockers are usually preferred for transplant patients (8, 11).

Renal insufficiency in patients with transplanted organs
Monitoring of renal function during long-term therapy with calcineurin inhibitors should be based on determinations of serum creatinine and urea values, as well as glomerular filtration rate (GFR) or creatinine clearance. Protein excretion should be regularly determined in 24-hour pooled urine samples. Important renoprotective factors are an adequate daily fluid intake of at least two liters, optimal management of arterial blood pressure, avoidance of potentially nephrotoxic medications, especially non-steroidal anti-inflammatory drugs (NSAIDs), and elimination of an infectious focus if present (14). Supportive nephrological care is recommended for all patients after kidney transplant and for organ transplant patients with consecutive renal insufficiency. A change of immunosuppression to not primarily nephrotoxic drugs such as MMF, sirolimus or everolimus lies within the discretion of the transplant center (2, 3).

Malignant diseases in patients with transplanted organs
The risk of malignant diseases of all kinds is significantly increased by the long-term immunosuppression necessary after organ transplant (table 2 gif ppt). Put simply: the higher the total dose of immunosuppression, the more likely malignancy becomes. All malignant diseases show more aggressive biological behavior during long-term immunosuppression (1517). Regular cancer screening is therefore vitally important during aftercare (table 3 gif ppt).

Table 4 (gif ppt) shows how much higher the estimated incidence of various malignant skin tumors is in patients after organ transplantation compared to the general population.

The risk of malignant skin tumors is further increased in transplant patients (15, 17) by

- advanced age
- increased exposure to ultraviolet light
- stronger immunosuppression
- infections with human papillomavirus (HPV)
- a history of malignant skin tumors
- Fitzpatrick I, II and III skin types.

Immunosuppressed patients should undergo a dermatological assessment once a year. Sunbathing and solarium use should be avoided during immunosuppressive therapy. Skin exposed to the sun should be protected with a lotion with a very high sun protection factor (at least SPF 30, the higher the better) (15, 17). Relevant patient education is essential.

Besides malignant skin tumors, post-transplant lymphoproliferative disorder (PTLD), which is usually induced by the Epstein-Barr virus (EBV), also plays a leading role in post transplant malignancies. Post-transplant lymphomas usually develop in patients with serological evidence of EBV infection during childhood or adolescence or when there is the constellation of an EBV seropositive organ donor with an EBV seronegative organ recipient. Monitoring for the lifelong latent infection of the B cells with EBV is based on cytotoxic T-cells whose function is specifically impaired, depending on the immunosuppressive protocol, by polyclonal (e.g. antithymocyte globulin) or monoclonal antibodies (e.g. muromonab-CD3; also known as OKT3) during induction therapy in organ transplant patients. As a result, the risk of monoclonal B-cell non-Hodgkin lymphoma increases after transplantation. The cumulative incidence is also linked to the nature and intensity of the immunosuppression (16).

Malignant gastrointestinal diseases such as colon cancer, especially in patients with chronic inflammatory bowel disease or a positive family history, must be ruled out or detected by regular colonoscopy and treated in a timely manner (18). If malignancy is detected during long-term immunosuppression, a modification of the immunosuppressive protocol should be discussed. It should then also be considered, as appropriate, whether the intensity of the immunosuppression should be reduced and/or whether to use everolimus or sirolimus for immunosuppression, since these m-TOR inhibitors have been observed to exert antiproliferative effects against tumor cells in vitro.

Osteoprotection in patients with transplanted organs
The risk of steroid-induced osteoporosis is increased in transplant patients by the administration of prednisolone for immunosuppression. To exclude or detect osteoporosis during glucocorticoid therapy of more than three months' duration or in the event of a typically osteoporotic fracture, bone density measurement by dual x-ray absorptiometry (DXA) of the lumbar spine and total hip is recommended during the course (19). With clinically apparent osteoporosis it is essential to consider changing the basic immunosuppression to a steroid-free protocol or at least reducing the prednisolone dose as far as possible (2).

A markedly increased fracture risk is already apparent from a daily dose of less than 2.5 mg prednisolone equivalent (21). Several studies have shown that bone density loss is particularly pronounced in the first 3 to 12 months of glucocorticoid therapy, then passing into a phase characterized by a much slower demineralization process (21). In patients receiving prednisolone therapy over a period exceeding three months, the current Guideline of the DVD (Dachverband Osteologie), which is the joint organization of the scientific German-language societies for osteology, recommends osteoporosis prophylaxis with vitamin D3 (400 to 1200 IU/d) and calcium (1000 to 1500 mg/d) from the outset (www.lutherhaus-essen.de/osteo/leitlinien-dvo). This guideline proposes drug therapy with bisphosphonates during steroid therapy exceeding three months in the presence of a DXA-T value of less than -1.5 or in the event of osteoporotic fracture. Patients with esophageal varices or a history of ulceration, however, should only receive bisphosphonates intravenously (e.g. pamidronate or ibandronate intravenously every three months). As with the oral administration of alendronate, adequate pharmacological gastroprotection with a proton pump inhibitor should also be provided to counteract the increased risk of developing bisphosphonate-associated peptic and duodenal ulcers (22).

Corticosteroids are also a risk factor for avascular bone necrosis. In 90% of cases the femoral head is affected. The total incidence after organ transplantation is estimated as about 5%. In these cases, the implantation of a total hip replacement is unavoidable during the further course (23).

The treatment of persistent renal osteopathy following renal transplantation with or without hypercalcemia should remain the exclusive preserve of the nephrologist in cooperation with the transplant center. Especially parathyroidectomy, which may become necessary after renal transplant and which in 50% of cases results in a deterioration of renal function, should under all circumstances be decided in consultation with the transplant center. We refer readers particularly interested in this topic to the Guideline of the National Kidney Foundation for the diagnosis and treatment of renal osteopathy (20).

Infections in patients with transplanted organs
Organ transplant patients with infections represent a major challenge for the managing physician. While the presence of fever may prompt differential diagnostic consideration of possible graft rejection, the symptoms of an infection may be less pronounced in transplant patients than in non-immunosuppressed patients.

An early-stage microbiological diagnostic program including microbial identification and an antibiogram is essential for the successful treatment of bacterial infections. After obtaining material for microbiological diagnosis, however, calculated antibiotic therapy should be initiated as rigorously and rapidly as possible. Viral infections should be included in the differential diagnostic evaluations and should be diagnosed or excluded accordingly. The risk of certain infections depends on the intensity of immunosuppression and the further post-transplant course. Urinary tract infections and upper airway infections predominate in the long-term course (box gif ppt) (8, 24).

Transplantation may be followed by infections transmitted by the organ donor via the graft, nosocomial infections, or community-acquired infections. Immunosuppressed transplant patients may also be expected to exhibit reactivation of latent, clinically inapparent infections such as tuberculosis or latent cytomegalovirus (CMV) infections. Most infections transmitted by organ donors are caused by CMV, tuberculosis, and Trypanosoma cruzi (24). Donors may also transmit Epstein-Barr virus (EBV) and other viruses. As regards donor-derived infections it should also be considered that these persons may also be infected or colonized with multi-resistant nosocomial microorganisms. Microbiological and virological screening of organ donors is limited by the short time elapsing between the onset of brain death and organ harvest (24).

When initiating immunosuppression, prophylactic antibiotic, antiviral and antimycotic pharmacological interventions are necessary, in some cases restricted to a period of three to six months. These include Pneumocystitis carinii prophylaxis with cotrimoxazole and, for CMV-IgG-positive organ donors and non-immunized patients, the administration of valganciclovir in creatinine clearance based dosage. Amphotericin B suspension is given to prevent stomatitis or esophagitis caused by candidiasis (8, 24). The combined use of valganciclovir and mycophenolate mofetil may be expected to cause leukocytopenia. Regular blood count monitoring is therefore strongly advised (24). An increased incidence of infections with herpes zoster and herpes simplex viruses is quite often seen with mycophenolate mofetil (MMF) because of the pronounced B-cell inhibition. Oral therapy with aciclovir or valaciclovir and a temporary reduction of the MMF dosage are usually sufficient. In severe cases, the immunosuppression should be changed to an MMF-free regimen and initiated with intravenous aciclovir therapy (24).

In immunosuppressed transplant patients, perioperative antibiotic prophylaxis is recommended for all surgical interventions. The current guidelines for heart transplant patients, however, no longer recommend the general use of antibiotic prophylaxis unless a defect is present (25). If the heart valves are sclerotic, which is frequently the case in kidney transplant patients after prolonged periods of dialysis, the need for peri-interventional endocarditis prophylaxis should be decided on the basis of echocardiographic evidence.

Conflict of interest statement
The authors declare that no conflict of interest exists according to the guidelines of the International Committee of Medical Journal Editors.

Manuscript received on 5 November 2007; revised version accepted on
30 October 2008.

Translated from the original German by mt-g.


Corresponding author
Dr. med. Harald Schrem
Klinik für Allgemein-, Viszeral- und Transplantationschirurgie
Medizinische Hochschule Hannover,
Carl-Neuberg-Str. 1
30625 Hannover, Germany
schrem.harald@mh-hannover.de


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1.
Schrem H, Till N, Becker T et al.: Langzeit-Outcome nach Lebertransplantation. Chirurg 2008; 79(2): 121–9. MEDLINE
2.
Taylor AL, Watson CJ, Bradley JA: Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol 2005; 56(1): 23–46. MEDLINE
3.
Schlitt HJ, Barkmann A, Böker KH: Replacement of calcineurin inhibitors with mycophenolate mofetil in liver-transplant patients with renal dysfunction: a randomised controlled study. Lancet. 2001; 357: 587–91. MEDLINE
4.
Schrem H, Lück R, Becker T, Nashan B, Klempnauer J: Update on liver transplantation using cyclosporine. Transplant Proc 2004; 36: 2525–31. MEDLINE
5.
Kobashigawa JA: Statins in solid organ transplantation: Is there an immunsosuppressive effect? Am J Transplant 2004; 4: 1013–8. MEDLINE
6.
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106: 3143–421. MEDLINE
7.
Wilkinson A, Davidson J, Dotta F et al.: Guidelines for the treatment and management of new-onset diabetes after transplantation. Clin Transplant 2005; 19: 291–8. MEDLINE
8.
Mayr M: Management nach Transplantation. Ther Umschau 2005; 62: 487–501. MEDLINE
9.
Pham PT, Pham PC, Lipshutz GS, Wilkinson AH: New onset diabetes mellitus after solid organ transplantation. Endocrinol Metab Clin North Am 2007; 36: 873–90. MEDLINE
10.
EBPG Expert Group on Renal Transplantation: European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.5.2. Cardiovascular risks. Arterial hypertension. Nephrol Dial Transplant 2002; 4: 25–6. MEDLINE
11.
Mells G, Neuberger J: Reducing the risks of cardiovascular disease in liver allograft recipients. Transplantation 2007; 83:1141–50. MEDLINE
12.
European Society of Hypertension—European Society of Cardiology Guidelines Committee: 2003 European Society of Hypertension—European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003; 21:1011–53.
13.
Chobanian AV, Bakris GL, Black HR, et al.: National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560–72. MEDLINE
14.
Ojo AO: Renal disease in recipients of nonrenal solid organ transplantation. Semin Nephrol 2007; 27: 498–507. MEDLINE
15.
Euvrard S, Kanitakis J, Claudy A: Skin cancers after organ transplantation. N Engl J Med 2003; 348: 1681–91. MEDLINE
16.
Birkeland SA, Hamilton-Dutoit S: Is posttransplant lymphoproliferative disorder (PTLD) caused by any specific immunosuppressive drug or by the transplantation per se? Transplantation 2003; 76: 984–8. MEDLINE
17.
Traywick C, O'Reilly FM: Management of skin cancer in solid organ transplant recipients. Dermatol Ther 2005; 18: 12–8. MEDLINE
18.
Morath C, Mueller M, Goldschmidt H, Schwenger V, Opelz G, Zeier M: Malignancy in renal transplantation. J Am Soc Nephrol 2004; 15: 1582–8. MEDLINE
19.
Torres A, Lorenzo V, Salido E: Calcium metabolism and skeletal problems after transplantation. J Am Soc Nephrol 2002; 13: 551–8. MEDLINE
20.
National Kidney Foundation: K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003; 42: S1–201. MEDLINE
21.
Kanis JA, Johansson H, Oden A, et al.: A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 2004; 19: 893–9. MEDLINE
22.
Cruz DN, Brickel HM, Wysolmerski JJ, et al.: Treatment of osteoporosis and osteopenia in long-term renal transplant patients with alendronate. Am J Transplant 2002; 2: 62–7. MEDLINE
23.
Abbott KC, Oglesby RJ, Agodoa LY: Hospitalized avascular necrosis after renal transplantation in the United States. Kidney Int. 2002; 62: 2250–6. MEDLINE
24.
Fishman JA: Infection in solid-organ transplant recipients. N Engl J Med 2007; 357: 2601–14. MEDLINE
25.
Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116: 1736–54. MEDLINE
Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Medizinische Hochschule Hannover: Dr. med. Schrem, Dr. med. Barg-Hock, Prof. Dr. med. Klempnauer Abteilung Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover: Prof. Dr. med. Strassburg Abteilung Nephrologie, Medizinische Hochschule Hannover: Prof. Dr. med. Schwarz
1. Schrem H, Till N, Becker T et al.: Langzeit-Outcome nach Lebertransplantation. Chirurg 2008; 79(2): 121–9. MEDLINE
2. Taylor AL, Watson CJ, Bradley JA: Immunosuppressive agents in solid organ transplantation: Mechanisms of action and therapeutic efficacy. Crit Rev Oncol Hematol 2005; 56(1): 23–46. MEDLINE
3. Schlitt HJ, Barkmann A, Böker KH: Replacement of calcineurin inhibitors with mycophenolate mofetil in liver-transplant patients with renal dysfunction: a randomised controlled study. Lancet. 2001; 357: 587–91. MEDLINE
4. Schrem H, Lück R, Becker T, Nashan B, Klempnauer J: Update on liver transplantation using cyclosporine. Transplant Proc 2004; 36: 2525–31. MEDLINE
5. Kobashigawa JA: Statins in solid organ transplantation: Is there an immunsosuppressive effect? Am J Transplant 2004; 4: 1013–8. MEDLINE
6. National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III): Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation 2002; 106: 3143–421. MEDLINE
7. Wilkinson A, Davidson J, Dotta F et al.: Guidelines for the treatment and management of new-onset diabetes after transplantation. Clin Transplant 2005; 19: 291–8. MEDLINE
8. Mayr M: Management nach Transplantation. Ther Umschau 2005; 62: 487–501. MEDLINE
9. Pham PT, Pham PC, Lipshutz GS, Wilkinson AH: New onset diabetes mellitus after solid organ transplantation. Endocrinol Metab Clin North Am 2007; 36: 873–90. MEDLINE
10. EBPG Expert Group on Renal Transplantation: European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.5.2. Cardiovascular risks. Arterial hypertension. Nephrol Dial Transplant 2002; 4: 25–6. MEDLINE
11. Mells G, Neuberger J: Reducing the risks of cardiovascular disease in liver allograft recipients. Transplantation 2007; 83:1141–50. MEDLINE
12. European Society of Hypertension—European Society of Cardiology Guidelines Committee: 2003 European Society of Hypertension—European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertens 2003; 21:1011–53.
13. Chobanian AV, Bakris GL, Black HR, et al.: National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289: 2560–72. MEDLINE
14. Ojo AO: Renal disease in recipients of nonrenal solid organ transplantation. Semin Nephrol 2007; 27: 498–507. MEDLINE
15. Euvrard S, Kanitakis J, Claudy A: Skin cancers after organ transplantation. N Engl J Med 2003; 348: 1681–91. MEDLINE
16. Birkeland SA, Hamilton-Dutoit S: Is posttransplant lymphoproliferative disorder (PTLD) caused by any specific immunosuppressive drug or by the transplantation per se? Transplantation 2003; 76: 984–8. MEDLINE
17. Traywick C, O'Reilly FM: Management of skin cancer in solid organ transplant recipients. Dermatol Ther 2005; 18: 12–8. MEDLINE
18. Morath C, Mueller M, Goldschmidt H, Schwenger V, Opelz G, Zeier M: Malignancy in renal transplantation. J Am Soc Nephrol 2004; 15: 1582–8. MEDLINE
19. Torres A, Lorenzo V, Salido E: Calcium metabolism and skeletal problems after transplantation. J Am Soc Nephrol 2002; 13: 551–8. MEDLINE
20. National Kidney Foundation: K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. Am J Kidney Dis 2003; 42: S1–201. MEDLINE
21. Kanis JA, Johansson H, Oden A, et al.: A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res 2004; 19: 893–9. MEDLINE
22. Cruz DN, Brickel HM, Wysolmerski JJ, et al.: Treatment of osteoporosis and osteopenia in long-term renal transplant patients with alendronate. Am J Transplant 2002; 2: 62–7. MEDLINE
23. Abbott KC, Oglesby RJ, Agodoa LY: Hospitalized avascular necrosis after renal transplantation in the United States. Kidney Int. 2002; 62: 2250–6. MEDLINE
24. Fishman JA: Infection in solid-organ transplant recipients. N Engl J Med 2007; 357: 2601–14. MEDLINE
25. Prevention of infective endocarditis: guidelines from the American Heart Association: a guideline from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2007; 116: 1736–54. MEDLINE

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