Guidelines for Renal Transplantation

Guidelines for Renal Transplantation in Saudi Arabia 2006 1 Preface In the era of the evidence based medicine and the presence of guidelines for practice around the world, we started to formulate Saudi Guidelines for management of the important problems such as anemia and bone disease in the chronic kidney disease (CKD) patients. The publication of the guidelines for the management of anemia and bone disease in the CKD has encouraged the Saudi Center for Organ transplantation to prepare the guidelines for the management of transplant patients for the kidney disease centers in the kingdom of Saudi Arabia (KSA). In addition, the recent survey of attitudes of the physicians towards renal transplantation in the KSA has demonstrated deficiencies such as the unavailability of protocols that address the management of this important problem in the dialysis centers in the KSA. Currently, there are more than 7500 dialysis patients and 6000 renal transplant recipients in the KSA who require attention in terms of work-up and follow-up for renal transplantation Our guidelines aim at having a baseline for the development of sound practices in the context of the local experiences. We intend to develop and maintain these guidelines in order to support the local protocols in each dialysis unit, organ donating hospital and transplant center in the KSA. Such support may be fruitful in more quality care management by the providers of the CKD care such as the health planners, physicians and nursing staff. Faissal A.M. Shaheen MD., Muhammad Ziad Souqiyyeh MD., On behalf of the advisory committee for the management of mineral metabolism and bone disease in the CKD patients 2 Advisory Committee for the Renal Transplantation in Chronic Kidney Disease Patients Dr. Othman Alfureyh Department of Medicine King Faissal Specialist Hospital & Research Center Riyadh Dr. Saeed Alghamdi Division of Nephrology Department of Medicine King Faisal Specialist Hospital Jeddah Dr. Ali Alharbi Division of Nephrology Department of Medicine Security Forces Hospital Riyadh Dr. Khaled Almeshari Department of Medicine King Faissal Specialist Hospital & Research Center Riyadh Dr. Abdulla A. Al-Sayyari Division of Nephrology Department of Medicine King Fahd National Guard Hospital Dr. Mohammad Alsulaiman Division of Nephrology Department of Medicine Armed Forces Hospital Riyadh Prof. Jamal Al-Wakeel Division of Nephrology Department of Medicine King Kaled University Hospital Riyadh Dr. Ayman Karkar Division of Nephrology Department of Medicine Dammam Central Hospital Dammam Dr. Ali Lehbi Division of Nephrology Department of Medicine King Faissal Specialist Hospital & Research Center Riyadh Dr. Saadi Taher Department of Medicine King Fahd National Guard Hospital Riyadh Riyadh 3 Contents Topic Page Introduction …………………………………………..…………..… 6 Renal transplantation in CKD patients in Saudi Arabia ..………. 9 Guidelines statements …………………………………............…. 14 Section I: Preparation of the potential transplant recipient and donor……………………………………...……..… 15 General rules …………………….……………………..……...…. 16 Contra-indications for renal transplantation ………………...… 17 Immunologic work-up of Donor and recipient …..…………...… 23 Special situations and specific groups ………………………..… 25  Preemptive transplantation  Waiting list  Simultaneous transplantation of kidney and pancreas  Combined transplants with liver, heart and lung  Retransplants Donors selection and preparation …………..…..……………….. 28 Section II: Operation and early follow-up of transplant recipients ……………………………..…………...…… 33 Cross- matching donor/recipient …………………………….… 34 Pre-transplant dialysis/ volume correction ……..…..…….…… 36 Prophylactic induction immunosuppression with biological agents …………………………….………………...36 Initial and maintenance immunosuppressive treatment .............. 37 Evaluation of renal transplant patients and their grafts in the first post-transplant year …………………..…………...… 39 Evaluation of patients with delayed graft function..…………... 40 Evaluation of the patient with fever ……………...………….… 40 Infectious complications …………..………………………..…… 41 Rejection: Diagnosis and treatment ……………..……………... 44 Standards of graft and patient survival …………….…….…… 45 Section III: Long term management of the transplant recipient ……………………………………...… 46 Organization of follow-up of transplant recipients after the first year ……………………………...…………..……… 47 4 Graft dysfunction …………………..………………...…………… 48 Immunosuppressives modulation ……………….……………….. 51 Cardiovascular disease after renal transplantation …………..….53 Post-transplant malignancy ….………………………………….... 56 Late infections …………….……………….………………….…… 58 Bone disease …………………………..……………………...…… 60 Hematological complications ………………………..……….… 62 Pregnancy in renal transplant recipients ……………...........…… 63 Pediatrics (specific problems) ……………….……………………. 65 Elderly (specific problems) ……………….………………….…… 67 Analysis of patient and graft survival …………………….….…... 68 References ………..…………………………….………….………. 70 5 Introduction Since transplantation offers better quality of life, it should be offered to all end-stage renal disease patients who should be evaluated for any physical or psychological relative or absolute contraindication of transplantation. 1-5 The patients should be informed about their options and available modalities of therapy including transplantation. 6 There are few contra-indications to renal transplantation. These include uncontrolled cancer, 7-10 HIV positivity 11 active systemic infections (such as hepatitis B or C) 12,13 and/or any condition with a life expectancy <2 years. Primary glomerulonephritis may recur after transplantation such as focal and segmental glomerulosclerosis,14-16 membranous glomerulonephritis (GN),17 membranoproliferative GN,18,19 IgA GN,20,21 and antiglomerular basement membrane GN 19 Furthermore, systemic diseases may recur after transplantation such as lupus nephritis, 22 Henoch-Schonlein purpura,23 fibrillary/immunotactoid glomerulopathy ,24 renal amyloidosis associated with Familial Mediterranean fever, 25 hemolytic-uremic syndrome, 26 anti-neutrophilic cytoplasmic antibody-associated (ANCA) vasculitis,27 and idiopathic mixed cryoglobulinemic nephritis. 28 However, all these conditions are not contraindications to transplantation in comparison to the light-chain deposition disease.29 Metabolic disease may recur after transplantation such as diabetic nephropathy,30,31 type 1 primary hyperoxaluria,32 cystinosis ,33 and Fabry's disease,34 but transplantation is a viable option to the patients with these conditions. Specific and non specific measures to reduce the risk of vascular thrombosis of the graft after renal transplant surgery are recommended . 35-37 Diabetes mellitus, cardiovascular disease are comorbid conditions that affect the outcome of transplantation.38-41 The patients who have these conditions should be thoroughly evaluated. Age alone is not a limiting factor. 42,43 ABO blood grouping and HLA typing are indispensable in the evaluation of the prospective recipients.44,45 Antibody screening to evaluate sensitization status should be defined in the recipients. 46,47 Pre-emptive transplantation is preferable for the potential transplant candidates than after initiation of dialysis. 48,49 Assignment to the transplant waiting list is important to consider the readiness for the transplantation and all transplant centers should have such list. 50,51 Regular check-up while on the waiting list should be exercised. There are principles of organ sharing that can be applied for better use of donor resources. 52 Pre-operative specific transfusions are almost abandoned due to the negative impact on the outcome of transplantation. 53-55 6 Specific groups such as simultaneous transplantation of kidney and pancreas should be defined, 56-58 as well as the combined transplants with liver, 59,60 heart and lung 60-62 and retransplantation. 63,64 Renal allograft donation is indispensable and the main sources are the living and cadaveric donors. The determination of brain death and the care of the cadaveric donors have been defined.65-67 Marginal and non-heart beating cadaveric donors still form alternative sources for renal allograft donation. 68,69 Living related and unrelated allograft donation has been attracting more attention recently than ever. 70-73 Follow-up of transplant recipients from initial hospitalization to one year post transplant is crucial for the long-term survival of patients and allografts. At the time of the operation, the cross-matching of the donor/ recipient for ABO blood groups 74,75 and HLA tissue typing.76,77 are of first priority. Pretransplant antibody crossmatching is also crucial to avoid hyperacute rejection 47,78 and post-transplant antibody monitoring to avoid antibody mediated rejection. 79,80 Pre-transplant dialysis/volume correction should be guided by the clinical status.81,82 At present, immunosuppressive drugs are indispensable in renal transplantation. Induction therapy by biologic 83-86 and non-biologic agents at the time of transplantation followed by maintenance on non-biologic agents is still mandatory for the survival of renal allograft. 87-94 There should be continuous evaluation of renal transplant patients and their grafts in the first post-transplant year. After discharge, graft function should be assessed at least twice-weekly for 1 month and once-weekly for another month, and then at regular intervals.95,96 A more extensive evaluation is recommended before discharge, at 6 and 12 months after transplantation, and in patients with deterioration of graft function.97 Evaluation of patients with delayed graft function should be meticulous because of the risk of graft loss .97 Evaluation of the recipient of renal allograft with fever as well is also important because of the risk of morbidity and mortality of the patient. 98,99 The infectious complications such as cytomegalovirus (CMV) infection, 100103 Hepatitis B 12,104 and C virus infection 105,106 should be monitored carefully during the follow-up of the patients during the first year an thereafter. There should be a protocol for the clinical and pathological diagnosis of acute rejection and a protocol for aggressive treatment since there is association between acute and chronic rejection and graft loss. 108-113 Each transplant or follow-up center should standarize the graft and patient survival curves in order to have close follow-up of the results and evaluate the 7 quality of performance. 114-117 Regular follow-up of transplant recipients after the first year should be organized to monitor several areas such as the graft function, infection, cardiovascular hematological and bone complications, and cancer. Allograft dysfunction should be evaluated and addressed carefully in each patient.118 The immunological 119-121 and non immunological factors 122-130 of the renal allograft dysfunction may be equally important in the contribution to the long term prognosis of the patient and the graft. De novo and recurrent renal disease after transplantation may also contribute to the graft dysfunction and loss. 131-138 Late steroid or cyclosporine withdrawal may be attempted but patients should be closely monitored .139-143 Non compliance is a significant problem in causing renal allograft dysfunction and affects the long-term graft and patients prognosis.144,145 The cardiovascular disease after renal transplantation is a major cause of mortality.146 The risk factors for cardiac disease include arterial hypertension,147-150 hyperlipidemia,151,152 diabetes,153 smoking, 123-124 weight gain and obesity 150 and immunosuppressive agents. 151-153 Monitoring post-transplant cancer 154 such as lymphoproliferative disease (PTLD), 155-158 skin 159-161 and solid cancer 162-,164 should be addressed in the guidelines since their incidence is not common but affect the survival of the patients. Late infections such as Pneumocystis carinii pneumonia 165,166 and tuberculosis 167 should be monitored. Prophylactic therapy should be administered in the high risk patients. 168-172 Bone disease, 173-181 hematological disease such as anemia 182-184 and leucopenia 183,185 and erythrocytosis 182 parameters should also be monitored. They have their impact on the morbidity and the patients' long-term prognosis. Pregnancy after transplantation imposes a special problem. Women who are willing to become pregnant should be monitored carefully in a multidisciplinary manner. 186-191 Special subgroups such as the pediatric and elderly patients should have careful attention due to the concern about attainment of growth of the first 192195 and the increased mortality in the second due to multiple medical problems and aging. 196-201 Finally, long term survival of patient and grafts should be monitored in each transplant follow-up unit to evaluate the quality of care rendered to the patients. 202-207 8 Saudi Experience in Renal Transplantation 1. In 1986, Hefty et al 208 reported about the renal transplantation in Saudi Arabia. The authors concluded that this would give a chance to proper statistical reports graphs and better coordination in renal transplantation. 3. In 1988, Qunibi et al 210 reported about Kaposi's sarcoma: the most common tumor after renal transplantation in Saudi Arabia.. 4. In 1989, Nezamuddin et al 211 reported about the en-bloc anencephalic cadaver donor renal transplantation. 5. In 1990, Qunibi et al 212 reported about mycobacterial infection after renal transplantation. The authors concluded that these findings (1) confirmed the higher incidence of tuberculosis in renal transplant recipients, compared to the general population; (2) suggested that pretransplant skin testing probably had little value in identifying patients at risk; (3) showed that disseminated tuberculosis was common after renal transplantation and required invasive procedures for diagnosis; (4) confirmed that the donor kidney might be an important source of infection; and (5) indicated that concomitant infection with other organisms was common. 6. In 1990, Al-Khader et al 213 studied 25 patients who developed diffuse, non-lobar, bilateral lung shadows after renal trans-plantation. 7. In 1990, Aswad et al 214 reported about the role of National Kidney Foundation in cadaveric renal transplantation in Saudi Arabia. The author concluded that more energetic measures were to be formulated to increase the reporting of brain-death cases and improved the rate of harvesting. Such a move would necessitate the establishment of more regional transplantation centers. 8. In 1990, Al-Muhanna et al 215 reported about the prospects of renal transplantation in Saudi Arabia. 9. In 1991, Onmubalili et al 216 reported a 50-year-old lady maintained on prednisolone and cyclosporine, following cadaveric kidney transplantation three-and-a-half years earlier, developed spreading broncho-pneumonic mucormycosis and candidiasis. 10. In 1991, Al-Faqih 217 reported about the influence of Islamic views on public attitudes towards kidney transplant donation in a Saudi Arabian community 11. In 1991, Aswad 218 reported about the role of public education in cadaver organ donation and transplantation in Saudi Arabia. 12. In 1991, Dhar et al 219 reported about the significance and implications of hepatitis B infection in renal transplant recipients. 13. In 1992, Hakim et al 220 reviewed the surgical complications of renal transplantation in the Jeddah Transplant Program. 14. In 1992, Lundgren et al 221 reported about the kidney transplantation program at King Faisal Specialist Hospital and Research Center in Riyadh, Saudi Arabia. 15. 1n 1992, Chaballout et al 222 reported about the living related cadaver and living unrelated kidney transplants: a comparison study at King Fahad Hospital, Riyadh. 16. In 1992, Aswad 223 reported about the cadaveric transplantation in Saudi Arabia. 17. In 1992, Lundgren et al 224 reported about five-year experience of the cadaver kidney transplantation at King Faisal Specialist Hospital and Research Center, Riyadh. 9 18. In 1992, Aswad et al 225 reported about the role of the media in cadaver transplantation in a developing country. 19. In 1992, Aswad et al 226 reported about the public attitudes toward organ donation in Saudi Arabia. 20. In 1992, Shaheen et al 227 reported about the outcome of brain-dead patients in Jeddah Kidney Center. 21. In 1993, Qunibi et al 228 reported about Kaposi's sarcoma in renal transplant recipients: a report on 26 cases from a single institution 22. In 1993, Aswad 229 reported about the cadaver organ donation in Saudi Arabia: a new experience. 23. In 1993, The Living non-Related Renal Transplant Study Group (LNRRT) 230 reported about the physicians attitudes toward living non-related renal transplantation. 24. In 1994, Mansy et al 231 reported about a unique kidney donor in Tabuk. 25. In 1994, Shehab et al 232 reported about Impact of donor source on short-term outcome of renal transplantation in children. 26. In 1994, Bernieh et al 233 studied 11 renal transplant recipients while fasting during the month of Ramadan. 27. In 1995, Sheikh et al 234 reported about the diagnosis of acute renal allograft rejection using T-lymphocyte subsets in the peripheral blood. The authors concluded that their study indicated that T-lymphocyte subset ratio was useful in diagnosing acute rejection with a sensitivity and specificity of 81% and 100% respectively when the cutoff points was taken as 1.7 Studies with larger series of patients were needed to confirm this observation. 28. In 1995, Shaheen et al 235 reported about the Saudi Center for Organ Transplantation: activities and achievements. 29. In 1995, Alfurayh et al 236 reported about the impact of hepatitis C virus infection on kidney transplant outcome. The authors concluded that the HCV infection was a serious health problem among kidney transplant recipients and it significantly affected the graft outcome. 30. In 1995, Abdulla et al 237 presented a patient with hepatitis C virus (HCV) infection who developed chronic active hepatitis (CAH) after renal transplantation. The authors concluded that their case indicated that liver disease in anti-HCV positive patients could follow a serious course following renal transplantation. 31. In 1995, Shaheen 238 reported about transplantation in Saudi Arabia. 32. In 1995, Ebrahim 239 reported about organ transplantation: contemporary Sunni Muslim legal and ethical perspectives. 33. In 1995, Qunibi et al 240 reported about the attitudes of commercial renal transplant recipients toward renal transplantation in India. The results substantiated the impression that CRT in India does not conform to the high standards of renal transplant medicine. 34. In 1995, Chaballout et al 241 reported about living-related, cadaveric, and living unrelated donor kidney transplants at King Fahad Hospital, Riyadh. 35. In 1996, Al-Khudair et al 242 reported about the kidney transplantation in the kingdom of Saudi Arabia that began 16 years ago. 10 36. In 1996, al Shohaib 243 reported about pregnancy and renal transplant in Saudi Arabia. 37. In 1996, Mansy et al 244 reported about two-year follow-up of the outcome of commercial renal transplantation. 38. In 1996, Shaheen et al 245 reported the results of a survey of opinion of secondary school students on organ donation. 39. In 1996, Altraif et al 246 reported the results of the study about the knowledge and attitude towards organ donation among males in Riyadh, Saudi Arabia. 40. In 1996, Al-Khader et al 247 reported some of the lessons learnt from renal transplant recipients cared-for at the Riyadh Armed Forces hospital. 41. In 1996, Mansy 248 reported on patients from the northwestern area of Saudi Arabia had to travel to Riyadh or Jeddah for renal transplantation and post-transplant follow-up. 42. In 1996, Al-Dayel et al 249 reported about their experience with renal transplantation in the Eastern Province of Saudi Arabia. 43. Shaheen et al 250 reported about the renal transplantation at the Jeddah Kidney Center. Renal transplantation was the optimal treatment for patients with end-stage renal failure. 44. In 1996, Huraib et al 251 reported about the renal transplant experience at King Fahad National Guard hospital. Between September 1988 and end of 1995. 45. In 1996, Sidahmed et al 252 reported about the southern region renal transplant program at the Armed Forces Hospital, Khamis Mushayt. 46. In 1996, Hussein et al 253 reported the complications in kidney transplant recipients: a single center experience. 47. In 1996, Al-Khudair et al 254 reported about an unusual cause of recurrent bacteriuria in a kidney transplant recipients. 48. In 1996, Al-Khader et al 255 reported about the reasons for unused retrieved organs in the cadaveric organ donation program in Saudi Arabia. 49. In 1996, Shaheen et al 256 reported about the Saudi Center for Organ Transplantation as an ideal model for Arab countries to improve treatment of end-stage organ failure. 50. In 1996, Shaheen et al 257 reported about multiorgan donation from brain-death cases in the Kingdom of Saudi Arabia. 51. In 1996, Souqiyyeh et al 258 reported about the role of computers in coordination of renal care facilities: experience in the Kingdom of Saudi Arabia. 52. In 1996, Shaheen et al 259 reported about the current status of organ transplantation in Saudi Arabia. 53. In 1996, Hussein et al 260 reported about the commercial living-non-related renal transplantation and their observations on early complications. 54. In 1997, Souqiyyeh et al 261 reported about pediatric renal transplantation in Saudi Arabia. 55. In 1998, Qunibi et al 262 reported about serologic association of human herpesvirus eight with posttransplant Kaposi's sarcoma in Saudi Arabia. The authors concluded that the serologic results provide evidence of a strong association between HHV8 and 11 posttransplant KS in Saudi Arabia. 56. In 1998, Alshaibani et al 263 reported about the kidney transplant program at King Faisal Specialist Hospital and Research Center: results of the last 10 years. 57. In 1998, Shaheen et al 264 reported about the impact of donor/recipient gender, age, HLA matching, and weight on short-term graft survival following living related renal transplantation. 58. In 1998, al Baba et al 265 reported about the experience of Jeddah Kidney Center in pediatric renal transplantation. 59. In 1998, Shaaban 266 reported about the incidence and types of malignant tumors in renal transplant recipients: a single center experience. 60. In 1998, Al Ghamdi et al 267 reported about neurological disorders in renal transplant recipients. 61. In 1999, Said et al 268 reported about the urological complications of cadaveric renal transplantation. 62. In 1999, Souqiyyeh et al 269 reported about the Saudi Arabian experience in hypertension in renal transplantation. The authors concluded that hypertension was highly prevalent in the renal transplant population in Saudi Arabia. Moreover, they emphasized that the risk factors for the development of hypertension or its complications should be more aggressively approached in order to protect the patients and their grafts alike. 64. In 1999, Bernieh et al 270 reported about the short-term post renal transplant followup at Madinah Al Munawarah. 65. In 1999, Al-Khader et al 271 reported about the cadaveric renal transplantation in the Kingdom of Saudi Arabia. 66. In 1999, Al-Khader et al 272 reported about the strategies for increasing transplantation: the Saudi experience. 67. In 2000, Shaheen et al 273 reported about the factors influencing organ donation and transplantation in the Middle East. 68. In 2000, Souqiyyeh et al 274 reported about the Saudi experience of diabetes in renal transplantation patients. 69. In 2001, Shaheen et al 275 reported a study about hypercholesterolemia in renal transplantation. 70. In 2001, Almuneef et al 276 reported a study about the prevalence of antibodies to human herpesvirus 8 (HHV-8) in Saudi Arabian patients with and without renal failure. 71. In 2001, Al-Attar et al 277 reported about brain death and organ donation in Saudi Arabia. 72. In 2001, Shaheen et al 278 reported about solid organ registry: organization and structure. 73. In 2001, Hussein et al 279 reported about regression of post-transplant Kaposi's sarcoma after replacing cyclosporine with mycophenolate mofetil. 74. In 2002, Shaheen et al 280 reported about the use of marginal donors for kidney transplantation. 75. In 2002, Huraib et al 281 presented a case report of post transplant acute tubular 12 necrosis. 76. In 2002, Shaheen et al 282 reported about the use of marginal donors for kidney transplantation. 77. In 2003, Alkhunaizi et al 283 reported about the renal transplantation at Saudi Aramco. 78. In 2004, Al-Ibrahim et al 284 reported a 9-year experience at a tertiary care center of post renal transplantation tubulopathies in children: 79. In 2004, Shaheen et al 285 reported about the current status of renal transplantation in the Kingdom of Saudi Arabia. 80. In 2004, Shaheen et al 286 reported about how to improve organ donation in the MESOT countries. 81. In 2004, Shaheen et al 287 reported about increasing organ donation rates from Muslim donors: lessons from a successful model. 82. In 2004, Jumani et al 288 reported about the causes of acute thrombotic microangiopathy in patients receiving kidney transplantation. 83. In 2005, Souqiyyeh et al 289 reported about the post-renal transplant proteinuria. 84. In 2005, Shaheen et al 290 reported about comparative psychosocial analysis of patients on maintenance hemodialysis and transplanted patients. 85. In 2005, Al Shehri et al 291 reported about the organ donations from deceased persons in the Saudi Arabian population. 87. In 2005, Alzahrani et al 292 reported about increased seroprevalence of human herpes virus-8 in renal transplant recipients in Saudi Arabia. 88. In 2005, Shaheen et al 293 reported about the experience of renal transplantation at the King Fahd Hospital-Jeddah Kidney Center (JKC), Jeddah, Saudi Arabia. 89. In 2005, Al Meshari 294 reported the kidney transplant program at King Faisal Specialist Hospital and Research Center. 13 GUIDELINES STATEMENTS 14 SECTION I: Preparation of the Potential Transplant Recipient and Donor 15 General Rules A. In estimating the number of patients in need of renal transplantation, one should integrate the basic epidemiological data concerning endstage renal failure (ESRF), and in particular the currently linear increase of the point prevalence by 10% each year in Saudi Arabia. B. All patients with end-stage renal disease (ESRD) should be considered for renal transplantation unless they have absolute contraindications, because renal transplantation offers a better life expectancy and quality of life than dialysis. C. Long duration of dialysis, previous incidence of recurrent infections, cancer, cardiovascular disease or gastrointestinal complications should not be considered as absolute contra-indications to renal transplantation, despite the fact that these conditions increase the risk of post-transplant morbidity and mortality. D. Psychological evaluation of transplant candidates may be useful in assessing compliance with future immunosuppressive treatment. Poor compliance significantly worsens the outcome of renal allografts. E. Comprehensive information on renal transplantation should be given to all potential candidates with ESRF, including mortality, morbidity, results compared with dialysis, and also data concerning the different sources of kidneys, including marginal organs. F. The specific transplant evaluation should only be performed after this information is delivered and clear acceptance is given by the patient. Inclusion on the waiting list is the final step of the procedure G. All critical aspects concerning kidney donor selection for transplantation, including the use of marginal organs, need clear informed consent from the prospective candidate at the time of an offer. 16 Contra-indications for Renal Transplantation 1. Absolute contra-indications for transplantation A. There are few absolute contra-indications to renal transplantation. These include uncontrolled cancer, human immuno-deficiency virus (HIV) positivity, active systemic infections and/or any condition with a life expectancy < 2 years. 2. Relative contra-indications 2.1. Work-up for cancer and waiting time for preexisting cancer A. Candidates for renal transplantation, particularly those older than 50 years of age, should be screened for the presence of pre-existing cancer. B. In patients with previous cancer, renal transplantation should only be considered if there is no evidence of persistent cancer. It is recommended that the waiting time between tumor treatment and transplantation be based on the type of cancer. C. After renal transplant, general preventive measures of surveillance for occurrence of de novo cancer are recommended. 2.2. Infectious risk  Hepatitis C virus (HCV) infection in kidney transplant recipients and kidney donors A. All transplant candidates should be tested for anti-HCV antibodies. Anti-HCV-positive patients with negative HCV viremia are at very low risk of liver disease after renal transplantation. The presence of HCV-RNA in serum may be searched for in all prospective recipients with liver disease, even in cases where anti-HCV antibodies are not detectable. B. All HCV-positive patients should be considered for renal transplantation, as this procedure is not associated with increased mortality compared with dialysis, at least not during the first posttransplant decade. C. HCV-infected transplant candidates with elevated (alanine aminotransferase, (ALT) levels should undergo a liver biopsy. It is desirable, but not essential, to perform a liver biopsy in HCV-infected patients who display consistently normal liver enzymes, because HCV liver disease is often undetected. D. Transplant candidates with existing cirrhosis should not be 17 considered for isolated renal transplantation, but should be considered for combined kidney and liver grafts. E. Patients with chronic active hepatitis (CAH) might be offered a treatment with long-acting interferon (IFN-α) prior to transplantation. They may be maintained on the active transplant waiting list during the period of IFN-α administration, the drug being stopped if transplantation occurs before the end of planned therapy. Patients without improvement after IFN-a therapy may still be put on the waiting list for transplantation, but only after careful consideration and information. F. Kidneys from HCV-infected living or cadaveric donors may be offered to HCV RNA-positive recipients with their consent and when permitted by the national regulations. Obtaining the donor and recipient HCV genotypes is desirable for further careful evaluation of the results.  Hepatitis B virus (HBV) infection in kidney transplant recipients and kidney donors. A. All transplant candidates should be tested for HBV infection. Hepatitis B surface antigen (HBsAg)-positive patients are at increased risk of long-term death over after renal transplantation compared with HBsAg-negative patients, and should therefore be informed. B. Renal transplant candidates infected with HBV and who present with markers of viral replication, such as Hepatitis B envelope antigen (HBeAg)-positive and/or HBV-DNA positivity, should undergo a complete evaluation for liver disease, including a liver biopsy (when ALT is elevated), because they are at increased risk of progressive liver disease after renal transplantation. C. Transplant candidates with existing cirrhosis should not be considered for isolated renal transplantation, but might be considered for a combined kidney/liver graft whenever possible. D. Transplant candidates with active liver disease (including chronic active hepatitis) should be offered treatment with long-acting interferon (IFN-α) and/or lamivudine prior to renal transplantation. Patients without improvement after treatment may be registered for transplantation, but after very careful consideration and information. E. Kidneys from HBV-infected living or cadaveric donors may be offered to already HBsAg-positive recipients or HBV well protected recipients (active and passive immunization) with their consent and 18 when permitted by the national law. 2.3. Recurrence of original renal disease  Recurrence of primary glomerulonephritis A. Focal and segmental glomerulosclerosis (FSGS) is not a contraindication to renal transplantation despite the high risk of recurrence. Patients with recurrence have reduced graft survival. In case of live donation, the possibility of early recurrence leading to graft loss should be clearly explained to the potential donor. Approximately 15-50% of patients develop early recurrence of FSGS in the first allograft. It is almost impossible to predict which patient will have a recurrence after transplantation. Plasmapheresis and increased dosage of calcineurin inhibitors may be of value in severe cases. B. Membranous glomerulonephritis (MN) is not a contra-indication to renal transplantation despite the fact that there is no effective treatment for recurrent MN and around 20-30% of adult patients may develop recurrence after transplantation. C. Membranoproliferative glomerulonephritis (MPGN) is not a contraindication to renal transplantation. Type I MPGN may recur in children where it accounts for around 6% of graft failures, and in adults where the recurrence rate is around 50% and graft survival is poorer at 4 years. Most patients with type II MPGN show histological recurrence. Clinical recurrence is less common, around 10% in adults and 28% in children. D. IgA glomerulonephritis (IgAGN) is not a contra-indication to transplantation. The risk of recurrence is related to the length of posttransplant follow-up, being almost 100% by 10-20 years. Patients with histological signs of recurrence have a lower probability of long- term graft survival than patients without recurrence. E. In antiglomerular basement membrane glomerulonephritis (antiGBM GN), it is recommended to wait until the circulating antiGBM antibodies measured by specific techniques (RIA or ELISA) have disappeared before transplantation. Anti-GBM GN tends to recur only in patients with circulating anti-GBM antibodies. Recurrence does not usually lead to graft loss.  Recurrence of systemic diseases A. Lupus nephritis is not a contra-indication to transplantation because 19 the risk of recurrence after transplantation is low and does not affect prognosis. B. Henoch-Schonlein purpura (HSP) is not a contra-indication to renal transplantation despite the risk of recurrence. Histological recurrence may occur in about half of the cases and is more frequent in children than in adults. Graft survival rates are lower in patients with recurrence. C. At the moment, no recommendation can be proposed for fibrillary/ immunotactoid glomerulopathy (FG) because little information is available on the subject. However, recurrence seems to be frequent, although some cases showed good function in spite of recurrence. D. Renal amyloidosis associated with familial Mediterranean fever (FMF) is not a contra-indication to renal transplantation despite the fact that amyloidosis may recur after kidney allograft, because it can be prevented by early administration of colchicine. No recommendation can be proposed for the other causes of amyloidosis, which overall carry a 10-40% recurrence rate after renal transplantation. E. Light-chain deposition disease (LCDD) should be considered a contra-indication to renal transplantation because recurrence is frequent and associated with poor prognosis. F. Hemolyticuremic syndrome (HUS) is not a contraindication to renal transplantation despite the well-established risk of recurrence although this risk is poorly defined. The effect of cyclosporine and tacrolimus on recurrence is still unclear. G. Anti-neutrophilic cytoplasmic antibody-associated (ANCA) vasculitis is not a contra-indication to transplantation: there is a low but substantial risk of recurrence, which is independent of the presence of circulating ANCA or type of vasculitis. Graft survival is similar in patients with ANCA-associated vasculitis and those with other causes of renal failure. H. Idiopathic mixed cryoglobulinemic nephritis (MCN) is not an absolute contra-indication to renal transplantation when there is no severe liver involvement. However, the risk of recurrence after transplantation is high, but it remains unclear whether recurrence is detrimental to graft survival, as very few cases have been described.  Recurrence of metabolic disease A. Diabetic nephropathy: Renal transplantation should be considered 20 as the treatment of choice for many patients with diabetes mellitus despite almost inevitable histological recurrence a few years after renal transplantation. However, overt clinical nephropathy leading to late graft loss occurs in only a minority of patients. B. Type 1 primary hyperoxaluria: Patients with type I primary hyperoxaluria should generally be considered for combined kidney and liver transplantation because renal transplantation alone is associated with rapid recurrent deposition of oxalate and graft loss and liver grafting corrects the enzyme deficiency. Few patients with pyridoxinesensitive hyperoxaluria may receive preemptive kidney transplantation alone but in association with forced diuresis and early/ prolonged pyridoxine administration. C. Cystinosis: Renal transplantation should be recommended in patients (usually children) with cystinosis, because the disease does not recur. D. Fabry's disease (alpha galactosidase defect): Fabry's disease is not a contra-indication to renal transplantation; limited information is available regarding recurrence. 2.4. Work-up and preventive measures for thrombotic complications A. General measures such as subcutaneous heparin, early mobilization and graduate compression stockings to reduce the risk of deep vein thrombosis and consequences should be recommended for renal transplantation because of an increased risk associated with the surgery and the immunosuppressive treatment. B. Specific measures to reduce the risk of vascular thrombosis of the graft after renal transplant surgery should be recommended because it is an early cause of graft complication in 2-7% of cases, more frequently in children, in patients with delayed graft function and in grafts with multiple arteries. C. A specific work-up to identify increased thrombotic risk should be performed in transplant candidates with a previous history of venous thrombosis, in women taking oral contraceptives, in patients with diabetes mellitus, and in patients with atherosclerosis. 2.5. Co-morbid conditions  Diabetes mellitus A. Kidney transplantation should be considered as the first therapeutic choice for all suitable patients with end-stage renal disease (ESRD) 21 due to diabetes mellitus, because kidney transplantation is able to significantly extend survival as compared with dialysis. B. Diabetic ESRD patients should be considered for an early and preemptive transplantation of either a simultaneous pancreas-kidney transplantation (SPK), a living related donor graft, or an early cadaver graft when residual glomerular filtration rate (GFR) decreases to <20 ml/min. C. Diabetes mellitus should be considered as a serious co-morbid condition affecting transplant success and patient morbidity/ mortality, mainly because of increased cardiovascular and infectious risks. D. A thorough evaluation of diabetic transplant candidates is recommended with particular attention to the cardiovascular risk (e.g. coronary angiography).  Cardiovascular disease A. Cardiovascular disease is the main cause of mortality after transplantation. Careful evaluation of the cardiovascular system is mandatory to detect and treat symptomatic coronary artery disease, congestive heart failure due to valvular failure or cardiomyopathy and pericardial constriction. B. As technical graft failure and impaired patient survival is often due to symptomatic peripheral artery disease, extensive pelvic vessel calcification, aortic and pelvic vessel dissection and symptomatic cerebral vascular disease should be excluded or treated in advance. C. As venous vessel disease such as post-thrombotic occlusion of the pelvic veins, radiation injury and retroperitoneal fibrosis of the pelvic and lower abdominal region carry a high risk of technical graft failure, these conditions should be excluded or treated in advance. 2.6 Individual risk factors  Older recipients A. Advanced age per se is not a contra-indication to renal transplantation. B. In elderly (older) patients, renal transplantation should be offered because it increases the chance of survival compared with dialysis. C. In older recipients, careful assessment of the cardiovascular status and tailored immunosuppression are both recommended after renal transplantation, because cardiovascular disease and infections are frequent causes of death and older recipients usually have less ejection. 22 Immunologic Work-up of Donor and Recipient 1. ABO blood grouping and HLA typing A. The ABO blood group should be determined for all candidates awaiting transplantation. B. The HLA-A, -B and -DR phenotypes should be determined for all candidates awaiting transplantation. C. Cells for HLA typing should be obtained from 20 ml of recipient's peripheral blood using an appropriate anticoagulant (e.g. ACD, EDTA or PFH). D. Comprehensive sets of reagents capable of detecting all commonly occurring HLA antigens within the relevant ethnic groups should be used and results should be accepted only if HLA antigens are unequivocally defined. If only one allele is identified at an HLA-locus, additional techniques should be employed to confirm true homo- or hetero-zygosity due to an undetected allele. E. If the patient has been heavily transfused especially with nonleukodepleted blood within the previous 7 days, care should be taken in interpreting the level of mismatch since there is a risk of a 'mixed field' result giving more than two alleles per HLA locus. F. When a relative is being evaluated for live donation and there is ambiguity with regard to the level of HLA matching, the immediate family members may be typed to obtain accurate HLA haplotype assignments and to identify any recombination between HLA genes. 2. Antibody screening to evaluate sensitization status A. Overtime, anti-HLA antibodies may appear in a patient's blood and react against a potential donor. These antibodies may cause hyperacute rejection of the transplant. Accordingly, sequential serum samples should be routinely collected from the transplant candidate immediately before dialysis and at intervals no greater than 3 months. B. Sequential serum samples should be analysed for antibody and freeze-stored ready for cross-matching against a potential donor. Samples should be screened against a reference panel of cells selected to cover the majority of the HLA alleles in the donor population. The results should be expressed both as percentage panel reactive antibody (% PRA) and as the HLA specificity (s) that they react against. 23 C. In serum samples with a high %PRA, careful analysis of the reaction patterns against the panel can often reveal allelic products against which the patient failed to make antibodies. These 'windows of non-reactivity' may be used to predict and select cross-match negative donors. D. The most reactive sera available (highest % PRA) either after rejection and/or nephrectomy of a previously rejected graft, or after blood transfusion, should be identified by testing sera at frequent intervals in the 4 subsequent weeks after the event. The highest % PRA sera should be used in any subsequent cross-match test with a potential donor. E. A system should exist whereby the laboratory is notified every time a patient receives either a transfusion or treatment with anti-thymocyte or -lymphocyte globulin or monoclonal antibodies such as OKT3. Antibodies may linger in the serum and interfere with the antibody screening and cross-match tests. 24 Special Situations and Specific Groups 1. Pre-emptive transplantation A. Pre-emptive transplantation from either live or cadaveric donors results in equivalent or even better patient and graft survivals than transplantation performed after the start of dialysis. Pre-emptive renal transplantation should be encouraged for all patients whenever a living donor is available. Pre-emptive cadaveric transplantation may ideally be offered to all transplant candidates but is of particular importance for children and patients with diabetes mellitus; however cadaveric organ shortage makes this unlikely. B. Patients should have progressive deterioration in renal function and a creatinine clearance <15ml/min/l.73 m2 to be eligible for pre-emptive transplantation. 2. Waiting list 2.1. Assignment to the transplant waiting list A. Assignment to the transplant waiting list is the first crucial step for the patient, and this process should be seen to be transparent and to follow objective scientific principles after careful evaluation of the patient's medical history. B. The process of assignment should balance the possible success of a graft with the personal needs of the patient. C. Discrimination by age, gender, social and ethnic background is not acceptable. 2.2. Regular check-up while on waiting list A. Due to the possible rapid change in the waiting recipient's medical condition, an update at regular intervals is recommended to avoid unexpected risks at the time of an offer of transplantation. B. The updated record available to the transplant centre should contain information on the cardiovascular condition, on new infectious and viral diseases and on the lower urinary tract. C. Assessment may be performed every 6-12 months depending on the age and condition of the recipient. 2.3. Principles of organ sharing A. Centers undertaking cadaveric kidney transplantation should participate in the national organ sharing program in order to fulfill the principal of 25 equity of distribution to all of the participating centers. B. The Saudi Center for Organ Transplantation (SCOT) should maintain accurate, confidential and up-to-date central records containing the HLA-A, -B and -DR types, % PRA, gender, parity, previous transplants and other basic information on patients from the participating centers. C. The degree of resolution and the accuracy of HLA typing should be at a uniform level throughout all participating centers and should be regularly monitored. 3. Pre-operative transfusion A. Administration of random blood transfusions to first cadaveric kidney transplant candidates improved graft survival is still observed in the early calcineurin inhibitors era. However, graft survival and rejection rates in non-transfused recipients are better today with the new immunosuppressive drugs than in previously transfused patients. Since transfusion still carries a small risk of alloimmunization and transmission of infectious diseases, there is no indication for pretransplant transfusion. B. Administration of donor-specific transfusion (DST) from living donor to non-HLA-identical recipient improved graft survival in the azathioprine era. This beneficial effect continued in the early calcinuerin inhibitors era, but there are no data about the possible impact of DST with the present immunosuppressive regimens. However, DST carries a risk of anti-donor sensitization precluding transplantation in up to 10% of patients. The decision to perform a DST should be made on a case-per-case basis. C. In patients with previous exposure to allo-antigens, such as multiparous women, previously transplanted patients and those already HLA-sensitized, both random and donor-specific transfusions carry an increased risk of anti-HLA sensitization. The risks and benefits of transfusing these patients should be carefully evaluated. D. The blood transfusions, whether random or HLA semi-identical or donor-specific, should meet the following requirements: (i) they should not be leukocyte free; (ii) the number of units administered should be ≤3; (iii) fresh rather than frozen blood should be given; and (iv) the blood should be transfused at least several weeks before 26 transplantation, as perioperative blood transfusions have no consistent effects. 4. Specific groups 4.1. Simultaneous transplantation of kidney and pancreas A. Simultaneous transplantation of kidney and pancreas should be offered to young recipients with juvenile onset diabetes mellitus as a first therapeutic option to prolong their survival. B. Simultaneous transplantation of kidney and pancreas may be carried out preemptively or early after the start of renal replacement therapy to avoid or retard serious diabetic sequelae. 4.2. Combined transplants with liver, heart and lung A. Combined kidney and liver transplants should be offered to carefully selected recipients suffering from simultaneous renal and hepatic failure secondary to viral hepatitis, extensive polycystic liver disease and primary hyperoxaluria. B. Combined kidney and heart (lung) transplants should be offered to carefully selected groups of recipients suffering from both chronic renal failure and severe heart failure irrespective of the cause (valvular, myocardial or coronary artery disease). 4.3. Retransplants A. Retransplants after early loss of a previous graft from rejection should be considered to be at increased risk of graft failure. Preventive measures such as improved HLA compatibility and adequate immunosuppression should be undertaken. B. Retransplants after early loss of a previous graft for technical reasons or late graft loss for any reason give similar results to first grafts and do not require special precautions. For retransplantation, nephrectomy of asymptomatic grafts is not necessary. 27 Donors Selection and Preparation 1. Cadaveric heart-beating donors 1.1. Selection of donors A. Any comatose patient with irreversible cerebral damage who appears likely to progress to brain death prior to terminal circulatory failure must be considered as a potential donor, regardless of age. B. Physicians caring for the potential donors should be encouraged to make early contact with the organ procurement team for assistance in the further management of the donor and the donor's family. C. Absolute contra-indications against organ donation are based on risk of disease transmission and include a history of cancer other than non-invasive tumors, HIV- positive serology, acute hepatitis, tuberculosis, severe untreated systemic sepsis and viral infection. Persons who have been engaged in activities with a high risk of HIV infection should not be considered as organ donors. D. Relative contra-indications to organ donation are based on the quality of the potential graft and include suboptimal to non-acceptable renal function or presence of risk factors. It is recommended that each organ donating hospital follow the Saudi procurement standards and follow up on the effects of their implementation. E. The aim of the procurement team in the donating hospitals should be to increase the acceptance rate of potential donors without risking unacceptably poor graft function and survival. F. Donors may be evaluated on the basis of renal function (calculated creatinine clearance, CrCl), age and vascular disease. Limits may be set as CrCl > 60ml/min as acceptable, 50-60 ml/min as marginal and < 50 ml/min as non-acceptable for single kidney transplantation. Nonacceptable kidneys may be considered for dual transplantation. High donor age (70 +) and vascular risk factors such as long-term history of hypertension, severe vascular disease, long-term diabetes or proteinuria, or findings of vascular changes or extensive glomerular sclerosis on procurement biopsy may add negatively to the evaluation. G. Recipients of sub-optimal kidneys or dual kidneys should give their informed consent prior to transplantation. 28 1.2. Determination of brain death A. It is recommended that the organ donating hospitals encourage standardization of the management of the brain-dead donor including easy-to-use forms to assist the responsible physician in the emergency situation, and in line with national regulations, which determine the criteria and methods for diagnosing terminal and irreversible loss of brain functions, i.e. brain death. 1.3. Support of the potential donor and optimization of organ function A. Any comatose patient with irreversible cerebral disease should be identified as a potential donor and monitored carefully awaiting determination of brain death, evaluation and consent of organ donation and the final event of retrieval. B. The management of a potential donor should be basically similar to normal intensive care but with important variations, i.e. the objectives are to support future function of renal, cardiac and/or pulmonary grafts. C. A simplified goal for management of the donor may be to maintain a central venous pressure of 10 cm H2O, a systemic blood pressure of 100 mmHg and a urine output of 100 ml/h. 2. Cadaveric non-heart beating donors (NHBD) A. Non-heart beating donors should be considered as a valuable source of kidneys for transplantation, despite shorter graft survival and higher serum creatinine in recipients compared with those transplanted from classical cadaveric donors. B. Young donors who die from trauma can be safely considered as non-heart beating donors. C. To optimize this promising alternative, it is recommended that centers start and accumulate experience. 3. Living kidney donors A. Use of kidneys from 'living donors' is recommended for renal transplantation whenever possible and is supported by the especially favorable results obtained after transplantation. 29 Table 1. Evaluation of the potential live kidney donor ABO blood typing HLA-A, -B and -DR tissue typing Cross-match Initial medical evaluation: History and physical examination Blood pressure Psychosocial evaluation (optional) Cardiovascular evaluation chest radiograph, optional pulmonary function tests Electrocardiogram, (including echocardiography and/or scintigraphy) for donors older than 50 years or with a history of heavy smoking or with mild hypertension Laboratory investigations complete blood count, platelet count, prothrombin time, partial thromboplastin time, blood urea nitrogen, s-creatinine, sodium, potassium, bicarbonate, fasting blood glucose, calcium, phosphorus, albumin, total protein, uric acid, liver enzymes, bilirubin, fasting cholesterol, triglycerides. Further renal assessment: Urine culture Evaluation of glomerular filtration rate 24-hour urine for creatinine clearance or a direct evaluation of the GFR by CrEDTA or iohexol or inulin clearance (renograpgy) 24-hour urine for total protein Urine for microalbuminuria (optional) Ultrasound examination of the kidneys Intravenous pyelogram (optional) Renal arteriogram Additional screening tests CMV antibodies (Ab) titres, HBsAg, HCV antibody, HIV antibody, EBV Ab titres, herpes simplex virus (HSV) Ab, varicella zoster virus (VZV) Ab, Toxoplasma Ab and syphilis test. In females: pregnancy test, if relevant, gynecological examination when older than 40 years In males: PSA when older than 50 years 30 Table 2. Exclusion criteria for a potential living kidney donor Kidney disease:  Reduced GFR, in comparison to normal range for age  Proteinuria of > 300 mg/day  Microhematuria, except when an urologic evaluation and a possible kidney biopsy are normal  Multiple kidney stones  Multiple cysts  Three or more arteries  Family history of autosomal dominant polycyslic kidney disease (ADPKD), unless ultrasound or CT scan is normal and donor age is >30 years  Bilateral fibromuscular arterial dysplasia Other exclusion criteria  ABO incompatible  Cross-match positive  Hypertension without good control  Diabetes mellitus  Cardiovascular disease  Pulmonary insufficiency  Abuse of morphine, heroin or cocaine  HIV positive  Hepatitis B antigen-positive to a negative recipient (or unprotected)  Hepatitis C-positive to a negative recipient  Other severe infections  Malignancy  Long-term use of nephrotoxic drugs  Age <18 years  Previous severe abdominal surgery B. Before being selected as a 'living donor', careful information should be provided to the potential donor who should undergo a careful medical and physical evaluation, as listed in Table 1. C. After complete evaluation of the donor, formal written consent (often legal) must be obtained from the donor. D. Special care must be taken to ensure that a potential 'living related 31 donor' does not fulfill any of the exclusion criteria listed in Table 2. E. The use of 'living non-related donors' may be justified if the donor is a spouse, milk-fed relative, a step parent or in some occasions a close friend, and if it is ensured that the donation is purely altruistic, and if commercial transactions are excluded. F. Commercially motivated kidney transplantation is not acceptable and all procedures must comply with the existing Saudi regulations. G. It is desirable that the 'living donor' should be offered long term follow-up at regular intervals. Steps should be taken to ensure against the rare development of late complications. H. The 'living donor' should always be left with the best kidney. 32 Section II. Operation and Early Follow-up of Transplant Recipients 33 Cross-Matching Donor/Recipient 1. ABO blood group matching A. The first priority is to avoid mismatch for the ABO blood group antigens between donor and recipient. B. In cadaveric kidney transplantation, the donor should be ABO identical to the recipient, and ABO blood group compatibility should be discouraged. This preserves the balance between demand and supply for different ABO phenotypes and counteracts the tendency for O patients to accumulate on waiting lists. It also reduces the risk of hemolytic disease. C. In live donor kidney transplantation, ABO identity or compatibility are equally acceptable. D. In a highly selected minority of patients where the most suitable kidney is ABO mismatched and incompatible, transplantation is justified, provided special protocols designed to minimize the risk of hyperacute rejection are followed. 2. HLA matching and mismatching A. Top priority should be given to allocating donor organs to patients with no HLA-A, -B and -DR mismatches. Kidneys from cadaveric donors should be allocated to recipients with the least number of mismatches at HLA-A, -B and -DR loci, and thereafter according to other major risk factors, including age and waiting time. B. When a living donor transplant is being considered, HLA matching is important, but of lower priority than with cadaveric donor transplants. Theoretically, if a choice exists between several live donors considered to be equally eligible by all other clinical criteria, priority should be given to the donor with the least number of HLA mismatches. C. Due to extensive polymorphism of HLA, only partial matching is achievable when allocating cadaveric organs to most patients. Therefore, consideration should be given to the relative 'importance' of mismatches at the different HLA loci. Priority should be given to minimizing mismatches for HLA-DR. Once the level of DR mismatch has been agreed, the next priority is to minimize mismatches for HLAB and finally HLA-A. D. In repeat transplants, especially where the previous graft was lost 34 rapidly within the first year, there is an increased risk of graft loss. Great care should be taken to establish the HLA specificities to which the recipient has developed antibodies. Repeat HLA-DR mismatches in retransplants should be avoided in all cases. However HLA-A and -B mismatches may be repeated, provided the recipient failed to develop an antibody response to them and the cross-match test is negative with all available sera. 3. Pre-transplant antibody cross-matching A. A cross-match test must be performed in all cases immediately prior to transplantation using at least one technique that detects complementdependent lymphocytotoxic antibodies. Selected stored sera from the patient should be tested against donor's mononuclear cells prepared from blood, spleen or lymph node. Sera selected for testing should include all samples from the transplant candidate that have been shown to contain antibodies to mononuclear cells. B. Other techniques such as flow cytometry cross-match may be used to confirm the complement-dependent lymphocytotoxicity cross-match result, but the clinical relevance of a positive flow cytometry crossmatch result in the absence of a positive lymphocytotoxicity crossmatch result is still under evaluation. C. A positive lymphocytotoxicity cross-match test with the current serum taken from the prospective recipient is a contra-indication to transplantation. But if a positive cross-match is attributable solely to IgM antibody directed to non-HLA antigens or to auto-antigens, the result may be ignored and the transplant performed. D. A complement dependent lymphocytotoxicity cross-match test result that reacts positively with the transplant candidate's non-current or historical sera, but negatively with current sera should be considered as a contra-indication to transplantation in patients receiving retransplants and in all those with high panel reactive antibody (> 40% PR A) unless it is attributable solely to IgM antibody to non-HLA antigens or to auto-antigens. 4. Post-transplant antibody monitoring A. Post-transplant serum analysis for changes in anti-donor antibodies may give information of prognostic and therapeutic value. 35 Pre-Transplant Dialysis/Volume Correction A. Pre-operative dialysis should not be performed routinely, except for patients with heart failure and/or hyperkalemia. B. Pre-operative hypovolemia should be avoided to prevent delayed graft function. C. In patients who will be treated with OKT3, it is mandatory to correct overhydration, if present, to avoid pulmonary edema. In this situation, calcium channel blockers may be useful to decrease the incidence of delayed graft function. Prophylactic Induction Immunosuppression with Biological Agents A. Prophylactic immunosuppression with antibodies may be administered to renal transplant recipients as an optional initial therapy to reduce the number and severity of acute rejections during the first 36 months after renal transplantation. However, these benefits must be balanced against the risks of over-immunosuppression with increased susceptibility to opportunistic viral infections and post-transplant lymphoproliferative disease (PTLD). B. Classical 'induction therapy' with polyclonal (ALG, ATG) or monoclonal (muromonab-CD3) antibodies administered during the perioperative period for a limited time (1-3 weeks) does not consistently improve graft survival at 3 years post-transplant in unselected recipients. C. Recipients with delayed graft function, recipients with low and high panel reactive antibodies directed to HLA may benefit from classical induction therapy with polyclonal ALG, ATG or monoclonal antibodies (OKT3 or muromonab-CD3). D. The biological agents antilymphocyte globulin (ALG), antithymocyte globulin (ATG) and murine monoclonal antibody to the human Tlymphocyte surface marker CD3 (OKT3 or muromonab-CD3) used for classical induction therapy show equivalent efficacy. E. Recently, safe and effective prophylactic therapy has been achieved with high affinity humanized or chimeric monoclonal antibodies 36 (daclizumab and basiliximab, interleukin-2 (IL2) receptor. respectively) which target the Initial and Treatment Maintenance Immunosuppressive A. The use of daily maintenance immunosuppression (IS) is mandatory in renal transplantation in order to reduce the incidence of acute rejection episodes during the first 6 months after transplantation and to improve graft survival in the short- (1 year), medium- (5 years) and long term (> 10 years). B. Maintenance immunosuppression could lead to overimmunosuppression characterized by an increased incidence of infectious complications (mainly viral diseases) and of de novo malignancies, which both carry a greater risk of morbidity and mortality for the recipients. Therefore the choice of the initial maintenance IS should be at a balance between efficacy and tolerance of the IS drugs used in association and targeted to the need of the recipient (immunized vs. non-immunized). C. Initial maintenance IS should be administered before transplantation (for living-related graft), or at time of transplantation but before vascular anastomosis (for cadaver graft). IS must be continued daily forever. However, the need for IS decreases overtime and it should be tailored accordingly: greater IS during the first weeks or months in order to improve acceptance to the graft and lower IS after months or a few years. D. Non-compliance with immunosuppressive drugs and its consequences (deterioration and loss of kidney function) have been clearly overlooked and its frequency is currently estimated at -25% of the recipients. It could be one the major causes of late graft failure. Therefore, every measure should be implemented and then carefully evaluated in order to reduce non-compliance. E. Over the past five years, the tacrolimus mycophenolate combination has been having growing popularity in Europe and USA as the primary maintenance IS regimens as they have demonstrated a significant reduction in the incidence and severity of acute rejection episodes 37 during the first year besides a better side effects profile, compared with previous regimens, used as initial and maintenance IS treatment, which traditionally includes the combination cyclosporine, azathioprine and prednisolone/ prednisone. 38 Evaluation of Renal Transplant Patients and Their Grafts in the First Post-Transplant Year A. Renal transplant patients and their grafts should be monitored frequently to diagnose complications and deterioration of function. Monitoring should start immediately after surgery and be repeated at least once daily during the initial hospital stay. After discharge, graft function should be assessed at least twice-weekly for 1 month and once-weekly for another month, and then at regular intervals. B Minimal routine evaluation should consist of: • Brief medical history • Blood pressure, pulse rate, body weight • General medical examination as indicated • Plasma Na, K, Cl, bicarbonate, creatinine concentration, blood count • Urinalysis for glycosuria, proteinuria, hematuria, leukocyturia; sodium concentration; urine culture • Blood levels of calcineurin inhibitors and other relevant immunosuppressive drugs. C. Additional evaluations performed in case of graft dysfunction should include: • Detailed medical history • Complete physical examination • Complete hematology and chemistry work-up, including liver function tests and calcium concentrations • Transplant ultrasound with doppler flow measurements and/or scintigraphy • Twenty-four-hour urine collection for protein, creatinine and Na determinations • Creatinine clearance when the graft function is stable • Virological surveillance D. A more extensive evaluation is recommended before discharge, at 6 and 12 months after transplantation, and in patients with deterioration in graft function. 39 Evaluation Function of Patients with Delayed Graft A. Hypovolemia, urinary catheter obstruction or other urological complications, vascular complications, acute pyelonephritis, immunosuppressive drug toxicity and acute rejection should be excluded as the cause of delayed graft function. If present, these conditions should be treated promptly. B. Conditions that result in an increased risk of delayed graft function due to acute tubular necrosis should be avoided both in donor and recipient. C. Graft function should be monitored closely in patients with delayed graft function, and surveillance biopsies should be considered. Evaluation of the Patient with Fever A. Fever in a renal transplant patient should be evaluated promptly and treatment should be instituted as soon as possible. B. The minimal evaluation prior to treatment should include blood count, blood and urine cultures. The optimal work-up should be designed to detect bacterial, viral, parasitic and fungal infections. 40 Infectious Complications 1. Cytomegalovirus (CMV) infection A. CMV antibody status (seronegative vs. seropositive) must be systematically evaluated in both the donor and the recipient before or at the time of renal transplantation. It should be determined using a sensitive ELISA technique for specific IgG antibody. This distinction allows the recipient a better evaluation of the risk of CMV infection/disease and more adequate use of prophylactic treatment if appropriate. B. Because of the high prevalence of CMV infection early after renal transplantation, systematic surveillance for CMV infection is justified in all recipients during the first 3 months. This survey must be repeated if any febrile episode or evocative sign of CMV disease, for example thrombocytopenia or elevated liver enzymes, occurs during the first 6 months or later. C. The screening procedure for CMV infection should include virus detection in blood leukocytes using the PP65 anti-genemia technique or a more sensitive technique. For urine, the use of the rapid culture technique is an option. Serial CMV serology tests should be performed to detect seroconversion from negative to positive and from IgM to IgG production. D. To decrease the risk of CMV infection in CMV seronegative recipients, they may receive CMV-secured blood products when appro-priate. This can be achieved either by selection of blood products from CMV seronegative blood donors or after adequate filtration of CMV non-typed leukodepleted or leukofiltered blood. E. All CMV seronegative recipients receiving a kidney from a CMV seropositive donor (D + /R-) or from a CMV non-typed donor, should receive a prophylactic treatment for CMV infection initiated at the time of surgery. F. During the first year post-transplant, all CMV seropositive recipients, treated with polyclonal (ALG, ATG) or monoclonal (OKT3) antibodies either as induction therapy or for an acute steroidresistant rejection, should receive CMV prophylaxis. G. Prophylaxis can be selected from the following five different 41 validated modalities of preventive treatment for CMV infection/ disease: (i) Weekly intravenous infusions of hyperimmune globulins for 6 weeks (high dose) or for 16 weeks (lower dose). (ii) Oral acyclovir administered for 12 weeks at a daily dose of 3200 mg (800 mg x 4) adjusted regularly to GFR. (iii) Oral valgancyclovir given for 100 days at a daily dose of 900 mg (450 mg x 2) adjusted regularly to GFR. (iv) Ganciclovir administered IV for at least 14 days at a daily dose of 10 mg/kg (5 mg/kg x 2) adjusted regularly to GFR. (v) Oral ganciclovir given for a longer period (2-12 weeks) at a daily dose of 3000 mg (1000 mg x 3) adjusted regularly to GFR. H. All recipients with documented CMV disease (symptomatic CMV infection) must receive a curative treatment. Currently, the only validated treatment is IV ganciclovir at a daily dose of 10 mg/kg (5 mg/kg x 2) adjusted to GFR for at least 14 days. Alternatively, they may receive IV ganciclovir for at least 5 days followed by oral ganciclovir at a daily dose of 3000 mg (1000 mg x3) for a longer period (2-12 weeks). I. All recipients with asymptomatic CMV infection early after renal transplantation, documented by routine screening should receive a preemptive treatment in order to limit spread of the virus and avoid CMV disease. This can be achieved by early use of the validated curative treatment described above. J. Acute rejection episodes are clearly associated with CMV infection or disease. In this situation, CMV infection or disease should be treated first using IV ganciclovir as recommended and, only when necessary, acute rejection may be treated by methylprednisolone pulses. ALG/ATG/OKT3 should be avoided whenever possible. 2. Hepatitis B virus infection A. Transplant recipients positive for hepatitis B surface antigen (HBsAg) should be carefully followed after transplantation with monitoring of liver function and viral replication (HBV-DNA). This follow-up should also detect early infectious complications. B. Tailored immunosuppression and possibly specific antiviral therapy may be recommended in these patients. 42 3. Hepatitis C virus infection A. HCV antibody positive patients should be carefully followed after transplantation with monitoring of liver disease, viral replication (HCV-RNA) and renal disease. B. Tailored immunosuppression is recommended in these HCV antibody-positive patients to reduce the risk of death from infectious diseases. C. Interferon therapy should not be used during transplantation in HCV antibody positive patients with chronic active hepatitis. Currently no effective therapy is available. 43 Rejection: Diagnosis and Treatment 1. Clinical and pathological diagnosis of acute rejection A. Acute rejection should be suspected in patients with established graft function who experience a rapid increase within 1-2 days in their plasma creatinine concentration of > 10-25% over baseline with or without decreased urine output, graft tenderness or fever in the absence of other obvious causes of acute graft dysfunction. The baseline plasma creatinine is the most recent creatinine concentration prior to the diagnosis of rejection. B. It is recommended to exclude other causes of graft dysfunction and to take a biopsy to confirm the clinical diagnosis of acute rejection. The biopsy result can be used to guide the intensity of anti-rejection therapy or to assess the long-term prognosis. C. Reporting of biopsies should be standardized according to an internationally agreed scheme to reflect the histopathological pattern and severity of the rejection episode. D. In patients with prolonged delayed graft function, surveillance biopsies should be considered to detect or exclude acute rejection episodes. 2. Treatment of acute rejection episodes A. for the treatment of the first acute cellular rejection episode, high doses of intravenous methylprednisolone are recommended. This treatment is expected to reverse most acute rejection episodes. Although the use of poly-clonal (ATG/ ALG) or monoclonal (OKT3) antibodies as first-line therapy is effective, their adverse event profile and cost mean that the use of corticosteroids as first-line therapy is preferred. B. ATG/ALG or OKT3 are recommended for the treatment of severe acute rejection episodes (Banff grade III), recurrent acute rejection episodes, corticosteroid-resistant rejection episodes or in patients with contra-indications to corticosteroids. C. In patients with recurrent rejection after anti-T lymphocyte antibody treatment, it is recommended to modify baseline immunosuppression. 44 D. ALG/ATG is preferable to OKT3 for the treatment of acute rejection episodes. Although both preparations are effective in reversing such episodes, OKT3 has a slightly poorer adverse event profile because of the first dose effect. E. Rabbit anti-T lymphocyte antisera (such as ATG Thymoglobulin ®) are preferable to horse anti-T lymphocyte antisera. Standards of Graft and Patient Survival A. A center's actuarial probability of graft survival at 1 year in unselected primary renal transplants should exceed 80%. B. A center's actuarial patient survival at 1 year in an unselected renal transplant population should exceed 90%. 45 Section III: Long Term Management of the Transplant Recipient 46 Organization of Follow-up of Transplant Recipients after the First Year A. All renal transplant recipients should undergo regular laboratory check-ups (at least every 2 or 3 months) and regular medical visits as out-patients (at least every 4-6 months) after the first year posttransplant. B. All renal transplant recipients should be seen at least once a year in the transplant center where the transplantation has been performed or referred to a closer transplant center for a complete annual evaluation. 47 Graft Dysfunction 1. Differential diagnosis of chronic graft dysfunction A. Any significant deterioration in graft function should be investigated using the appropriate diagnostic tools and, if possible, therapeutic interventions should be initiated. The usual causes of a decline in glomerular filtration rate after the first year include transplant- specific causes such as chronic allograft nephropathy, acute rejection episodes, chronic calcineurin inhibitor nephrotoxicity, transplant renal artery stenosis and ureteric obstruction, as well as immunodeficiency- related causes and non-transplant-related causes, such as recurrent or de novo renal diseases and bacterial infections. B. Any new onset and persistent proteinuria of> 0.5g/24 hr should be investigated and therapeutic interventions should be initiated. The usual causes include chronic allograft nephropathy and transplant glomerulopathy, and recurrent or de novo glomerulonephritis. 2. Immunological factors (allo-immunity) A. All recipients of an allogeneic kidney graft should take life-long maintenance immunosuppressive medication. Whereas there is no immunological test to diagnose chronic allograft dysfunction, circumstantial evidence suggests that immunological factors play an important role in its pathogenesis. This evidence is based on experimental data, the beneficial effect of sharing HLA antigens between donor and recipient and post-transplantation immunological monitoring studies. 3. Non- alloimmunal factors A. Whereas immunological mechanisms dominate in the initiation and propagation of the injury that leads to chronic allograft dysfunction and nephropathy, there is circumstantial evidence that non-immunological factors, such as advanced donor age, hyperfiltration, overweight, delayed graft function, heavy proteinuria, smoking, arterial hypertension, hypercholesterolemia and hypertriglyceridemia, play a role as aggravating or progression factors. It is recommended to prevent or, if possible, treat all these factors. B. As arterial hypertension is very frequent among renal transplant patients and associated with increased graft (and patient) loss, it is 48 recommended to aim at a blood pressure less than 130/85 mmHg in renal transplant patients and <125/75 mmHg in recipients with proteinuria >1 g/day. 4. De novo renal disease after transplantation A. Acute pyelonephritis is relatively frequent in the transplanted kidney and carries a risk of septicemia. The condition should be recognized and the patient should be treated promptly. B. After initiation of any drugs known to induce the development of interstitial nephritis in the transplant patient, it is recommended to monitor renal function and abnormalities in order to detect any side effects rapidly. If interstitial nephritis is observed, it is recommended to stop the offending drug, and to initiate appropriate treatment. C. De novo membranous nephropathy should be considered in cases of proteinuria and nephrotic syndrome after transplantation. Viral infection, such as HCV, should be excluded. D. In the case of the development of graft dysfunction in a transplant patient with Alport's syndrome, one should consider additionally the possibility of de novo anti-glomerular basement membrane (antiGBM) glomerulonephritis. 5. Late recurrence of primary glomerulonephritides A. In the case of recurrent focal and segmental glomerulosclerosis (FSGS), aggressive treatment with high-dose cyclosporine in children, ACE inhibitors and/or Angiotensin II antagonists, plasma exchange or immunoadsorption may result in remission in some patients. B. In case of recurrent membranous nephropathy (MN), there is no specific treatment. However, control of risk factors, such as hypertension, heavy proteinuria and hyperlipidemia, and prevention of thrombotic complications are recommended. C. In case of recurrent membranoproliferative glomerulonephritis (MPGN), there is no specific treatment However, control of risk factors, such as hypertension, heavy proteinuria and hyperlipidemia, and prevention of thrombotic complications are recommended. D. In case of recurrent IgA glomerulonephritis, use of additional steroids is not yet a validated treatment. The control of risk factors, such as hypertension, heavy proteinuria and hyperlipidemia, and prevention of thrombotic complications are recommended. 49 E. In the rare case of recurrent anti-glomerular basement membrane (anti-GBM) glomerulonephritis with reappearance of anti-GBM antibodies, it is recommended to initiate plasma exchange and to treat with appropriate immunosuppressive agents (e.g. cyclophosphamide). 6. Late recurrence of other diseases A. In the rare case of recurrent lupus nephritis, no particular treatment is recommended. Only in the few patients with clinically evident flare up is a reinforcement of immunosuppression recommended. B. Recurrence of Henoch-Schonlein purpura may occur even in the absence of clinical signs and symptoms. The prognosis for the graft may be severe, particularly in adults. C. In the case of recurrent ANCA-associated renal or systemic vasculitis, it is recommended to reinforce the immunosuppression with appropriate agents. D. Since diabetic nephropathy recurs almost invariably after transplantation, strict control of diabetes and hypertension, and the use of ACE inhibitors and/or angiotensin II receptor antagonists are recommended in order to prevent or slow the risk of recurrence. 50 Immunosuppressives Modulation 1. Late steroid or calcinuerin inhibitors withdrawal A. In order to reduce or avoid long-term serious adverse effects of corticosteroids, such as bone fractures diabetes mellitus, arterial hypertension, osteoporosis and eye complications, steroid withdrawal should be considered. B. Steroid withdrawal is safe only in a proportion of graft recipients and is recommended only in low-risk patients. The efficacy of the remaining immunosuppression should be considered. C. After steroid withdrawal, graft function has to be monitored very carefully because of the risk of a delayed but continuous loss of function due to chronic graft dysfunction. In the case of functional deterioration or dysfunction, steroids should be readministered. D. Cyclosporine withdrawal might be considered in order to ameliorate nephrotoxicity, arterial hypertension, lipid disorders and hypertrichosis. This can be carried out with no significant long-term risk of progressive graft loss. The efficacy of the remaining immunosuppression should be considered. After cyclosporine withdrawal, careful monitoring for acute rejection is recommended. Switch to tacrolimus based regimen is a viable alternative according to the new trend of using tacrolimus mycophenolate combination. 2. Toxicity of immunosuppression A. Careful long-term monitoring of graft recipients is mandatory to discover signs of immunosuppressive drug toxicity, in particular nephrotoxicity. B. In the case of a discrepancy between the drug dose and signs of toxicity, then a thorough pharmacokinetic analysis should be performed. C. Cardiovascular, renal and metabolic risks and the risk of de novo malignancy must be considered in a long-term monitoring program. 3. Non compliance A. The detection of non-compliers should be a permanent concern of the transplant team (doctors, nurses and others). B. Because non-compliance is associated with late graft dysfunction and graft loss, it is important to reduce the proportion of non-compliers 51 by implementing specific educational programs addressing this problem and the importance of immunosuppressive medications. C. Non-compliance starts during the first year and may increase thereafter. Therefore, the specific educational program should be repeated and adapted to the need of the transplant recipient, with delivery of few but clear messages. 52 Cardiovascular Disease after Renal Transplantation 1. Importance and evaluation A. Post-transplant cardiovascular disease is very common and important cause of morbidity and the first cause of mortality in renal transplant recipients. Therefore, detection and early treatment of posttransplant cardiovascular disease are mandatory. B. Specific risk factors for developing post-transplant cardiovascular disease arterial hypertension, uremia (graft dysfunction), hyperlipidemia, diabetes mellitus, smoking and immunosuppressive treatment. These factors should be targeted for intervention. C. Pre-transplant cardiovascular disease is a major risk factor for posttransplant cardiovascular disease. Therefore, prior to transplantation, it is mandatory to detect and treat symptomatic coronary artery disease, heart failure due to valvular failure or cardiomyopathy, and pericardial constriction. This policy should also be followed in asymptomatic diabetic patients. 2. Arterial hypertension A. Arterial hypertension is often present after renal transplantation and is of multifactorial origin. Pre-transplant arterial hypertension, chronic allograft nephropathy and immunosuppressive therapy are the most frequent causes of post-transplant arterial hypertension. Careful monitoring and treatment of high blood pressure are recommended following transplantation. B. Post-transplant arterial hypertension is associated with an increased incidence of cardiovascular disease in renal transplant patients and is an independent risk factor for graft failure. Therefore, blood pressure control (< 130/85 mmHg for renal transplant recipients without proteinuria and < 125/75 mmHg for proteinuric patients) is mandatory in these patients. General measures and pharmacological intervention are necessary in many cases. In proteinuric patients, anti-hypertensive and anti-proteinuric agents could be used, and stricter blood pressure control is recommended. C. In patients with uncontrolled arterial hypertension and/or renal function deterioration, underlying causes should be excluded, especially transplant renal artery stenosis. 53 3. Hyperlipidemia A. Hyperlipidemia risk profiles should be identified by regular screening (at least once a year) for cholesterol, HDL-cholesterol, LDLcholesterol and triglyceride blood levels in renal transplant patients B. In renal transplant patients, hyperlipidemia must be treated in order to keep the cholesterol /lipid levels within the recommended limits according to the number of risk factors. C. Management of hyperlipidemia after renal transplantation should be the same as for the dialysis population, with modification of the immunosuppressive protocol when appropriate. D. Patients should be carefully monitored for adverse effects of lipidlowering agents or interactions with immunosuppressive drugs. 4. Post-transplant diabetes mellitus A. Post-transplant diabetes mellitus (PTDM) should be identified by regular (every 3 months) fasting blood glucose and/or glycated hemoglobin (HbAlc) measurements. PTDM should be treated as appropriate to achieve normoglycemia. B. Immunosuppressive therapy should be adjusted to reverse or ameliorate PTDM. 5. Hyperhomocysteinemia A. Based on the present data, it is not recommended to measure homocysteine levels. 6. Smoking A. Cigarette smoking is associated with a high frequency of posttransplant cardiovascular disease and may adversely influence patient and graft survival. Active measures against tobacco smoking are recommended. 7. Obesity and weight gain A. Obesity (BMI > 30 kg/m2) and weight gain are associated with increased prevalence of cardiovascular disease after transplantation. Appropriate dietary and lifestyle measures should be recommended to these patients. 8. Immunosuppressive therapy A. Immunosuppressive therapies, especially corticosteroids and calcineurin inhibitors contribute to the prevalence of cardiovascular risk factors, such as arterial hypertension, hyperlipidemia and 54 hyperglycemia, and this effect is dose dependent. Reduction of the dose, withdrawal and/or switching to another drug could be useful to control these risk factors. 55 Post-Transplant Malignancy 1. Post-transplant lymphoproliferative disease (PTLD): prevention and treatment A. In the first year after organ transplantation, recipients are at the greatest risk of developing lymphoproliferative diseases (PTLDs), which are induced most often by Epstein-Barr virus (EBV) infection, and patients should therefore be screened prior to or at the time of transplantation for EBV antibodies. B. In the rare cases (< 5%) where the recipient is EBV seronegative, he or she has a 95% likelihood of receiving an organ from an EBVseropositive donor, which translates into a high risk of primary EBV infection with seroconversion soon after transplantation. In such cases, the recipient should receive a prophylactic antiviral treatment with acyclovir, valgancyclovir or ganciclovir, starting at the time of transplant and lasting for at least 3 months. The specific recommendations given for CMV prophylaxis could be applicable in this situation. C. The treatment of PTLD should be based on accurate pathology with extensive cell markers and phenotyping. The treatment modalities are as follows. 1. Reduction of basal immunosuppression in all cases (either maintain only steroids, or decrease by at least 50% the anti-calcineurin drugs and stop other immunosuppressive drugs). 2. In the case of EBV-positive B-cell lymphoma, antiviral treatment with acyclovir, valgancyclovir or ganciclovir may be initiated for at least 1 month or according to the blood level of EBV replication when available. 3. In the case of rare lymphomas from the mucosal-associated lymphoid tissue (MALT) with positive Helicobacter pylori, full eradication of H. pylori should be carried out with a validated protocol. Subsequent H. pylori prophylaxis should be implemented to avoid relapse. 4. In the case of CD20-positive lymphomas, treatment with rituximab, a chimeric monoclonal antibody directed against CD20, should be carried out with one IV injection per week for 4 weeks. 5. In the case of diffuse lymphomas or improper response to previous 56 treatment, CHOP chemotherapy should be used alone or in combination with rituximab. The CHOP regimen is cyclophosphamide, doxorubicine, vincristine and prednisone. Complete cessation of immunosuppression with or without graft nephrectomy should also be considered. 2. Skin cancers prevention and treatment A. Due to the high prevalence of skin cancers after organ transplantation, it is highly recommended to inform patients about selfawareness. In Saudi Arabia, Kaposi Sarcoma due to Herpes type 8 infection is the most common skin tumor. B. Squamous-cell carcinoma is also encountered in the Saudi renal transplant population. Primary prevention should include the avoidance of sun exposure, use of protective clothing and use of an effective sunscreen (protection factor >15) for unclothed body parts (head, neck, hands and arms) in order to prevent the occurrence of this type of carcinoma. C. Recipients with pre-malignant skin lesions (warts, epidermodysplasia verruciformis or actinic keratoses) should be referred early to a dermatologist for active treatment and close follow-up D. All skin cancers (except Kaposi sarcoma, which may respond to reduction of immunosuppression alone) should be completely removed by a dermatologist with appropriate techniques, such as electrodesiccation with curettage, cryotherapy or surgical excision. E. Secondary prevention for recipients should include close follow-up by a dermatologist (at least every 6 months), the use of topical retinoids to control actinic keratoses and to diminish squamous-cell carcinoma recurrence, and reduction of immunosuppression whenever possible. F. Reduction in immunosuppression whenever possible. 3. Solid Organ cancers prevention and treatment A. All renal transplant recipients should have regular ultrasonography of their native kidneys (when applicable) for screening of renal cell carcinomas, which are observed at much higher incidence in both dialyzed and transplant patients. B. Guidelines published for screening and prevention of solid organ cancers in the general population should be strictly applied to transplant recipients, who are in general at higher cancer risk, but 57 would benefit equally or even greater. C. All male renal transplant recipients aged 50 and over should have a yearly prostate specific antigen (PSA) test prior to a regular digital rectal examination. D. All female renal transplant recipients should have a yearly cervical (PAP) smear together with regular pelvic examination and regular mammography, according to recommendations where available. E. All renal transplant recipients should undergo a faecal occult-blood testing as a screening for colorectal cancer and other (pre-malignant) lesions, according to recommendations where available. F. In all these conditions, it is recommended to reduce immunosuppression whenever possible. 58 Late Infections 1. Pneumocystis carinii pneumonia A. Approximately 5% of patients develop Pneumocystis carinii pneumonia (PCP) after renal transplantation if they do not receive prophylaxis. PCP is a severe disease, with a very high fatality rate. Therefore, all renal transplant recipients should receive PCP prophylaxis. The treatment of choice is trimethoprim- sulfamethoxazole (TMPSMX), at a dose of 80/400 mg/day or 160/800 mg every other day, for at least 4 months. Patients who are treated for rejection should receive TMP-SMX prophylaxis for 3-4 months. B. In the case of TMP-SMX intolerance, aerosolized pentamidine (300 mg once or twice per month) is an alternative for prophylaxis. C. The first-line treatment of PCP is high-dose TMP-SMX. Patients with a PaO2 of <70mmHg initially should be treated parenterally, and the administration of additional steroids should be considered. 2. Tuberculosis A. Tuberculosis (TB) is not rare after renal transplantation, and can be life-threatening. Treatment of active TB in renal transplant recipients should be the same as in the general population, i.e. 2 months of quadruple therapy combining rifampicin, isoniazid, ethambutol and pyrazinamide, followed by a 4-months double therapy with isoniazid and rifampicin. The drug ethambutol should not be used initially if the rate of resistance to isoniazid is less than 4% in the community B. As rifampicin will reduce the plasma concentration of calcineurin inhibitors and rapamycin, the blood levels of these agents must be monitored closely. Rifabutin may be used as an alternative to rifampicin, as this drug is a less potent inducer of the microsomal P4S0 enzymes C. Renal transplant candidates and renal transplant recipients should be screened for latent TB infection. Patients considered to have latent TB infection are defined as: (i) Those who display a 5 mm (renal transplant recipients) or a 10 mm (dialysis patients) induration after tuberculin skin testing; (ii) Those with chest X-ray images suggestive of past TB infection; 59 (iii) Those with a history of past TB infection that was not treated adequately. (iv) Those who have been in close contact with infectious patients. D. The preferred treatment of latent TB infection is isoniazid 300 mg/day for 9 months. 60 Bone Disease A. All kidney-transplanted patients should undergo a systematic evaluation of their skeletal status, including pre-transplant history of renal osteodystrophy, history of fractures and plasma concentrations of calciotropic hormones and other parameters, and if possible measurement of bone mineral density (BMD). B. Glucocorticoid therapy should be given at the lowest possible dosage. As long as patients are receiving steroids, vitamin D treatment (ergocalciferol or 1, 25-dihydroxyvitamin D) is highly recommended C. Optimal prevention of bone disease by vitamin D treatment, sufficient calcium intake, sex hormone substitution and appropriate use of thiazide diuretics should be considered in all transplant patients. D. In established osteopenia, bisphosphonate treatment should be considered despite limited information in transplant recipients. E. Persistent tertiary hyperparathyroidism should be observed for 1 year after transplantation whenever possible to allow for a spontaneous involution. F. In patients with GFR<50 ml/min after transplantation, uremic osteodystrophy should be prevented. 61 Hematological Complications 1. Anemia A. Because anemia is relatively common after kidney transplantation, regular screening and careful evaluation of its causes are recommended. In many cases, post-transplant anemia is caused by allograft dysfunction. The use of purine synthesis inhibitors (azathioprine and MMF), ACE inhibitors and angiotensin II receptor antagonists may frequently cause post-transplant anemia. Anemia is reversible after withdrawing the offending agent. Hemolytic anemia may develop in transplant recipients. B. Treatment of anemia should follow the Saudi guidelines for treatment of anemia in chronic renal failure. 2. Leukopenia A. Because leukopenia is relatively common after kidney transplantation, regular screening and careful evaluation of its causes are recommended. Azathioprine and mycophenolate may lead to leukopenia. The combination of allopurinol and azathioprine should be avoided. Leukopenia is often associated with viral infections. 3 Erythrocytosis A. In the case of erythrocytosis, the first-line treatment should be administration of ACE inhibitors or angiotensin II receptor antagonists. 62 Pregnancy in Renal Transplant Recipients A. Renal transplantation restores fertility and successful pregnancies have been reported in renal transplant women. In women with normal graft function, pregnancy usually has no adverse effect on graft function and survival. Therefore, women of childbearing age who consider pregnancy should receive complete information and support from the transplant team. B. Pregnancy could be considered safe about 2 years after transplantation in women with good renal function, without proteinuria, without arterial hypertension, with no evidence of ongoing rejection and with normal allograft ultrasound. C. Pregnancy after transplantation should be considered a high-risk pregnancy and should be monitored by both an obstetrician and the transplant physician. Pregnancy should be diagnosed as early as possible. The principal risks are infection, proteinuria, anemia, arterial hypertension and acute rejection for the mother, and prematurity and low birth weight for the fetus. D. Pregnant women and transplanted patients are at increased risk of infections, especially bacterial urinary tract infections and acute pyelonephritis of the graft. Urine cultures should be performed monthly and all asymptomatic infections should be treated. Monitoring of viral infections is also recommended. E. Acute rejection episodes are uncommon but may occur after delivery. Therefore, immunosuppression should be re-adjusted immediately after delivery. F. Because pre-eclampsia develops in 30% of pregnant transplant patients, especially those with prior arterial hypertension, blood pressure, renal function, proteinuria and weight should be monitored every 2-4 weeks, with more attention during the third trimester. Antihypertensive agents should be changed to those tolerated during pregnancy. ACE inhibitors and angiotensin II receptor antagonists are absolutely contra-indicated. G. Immunosuppressive therapy based on cyclosporine or tacrolimus with or without steroids and azathioprine may be continued in renal transplant women during pregnancy. Other drugs, such as 63 mycophenolate and sirolimus, are not recommended based on current information available. Because of drug transfer into maternal milk, breastfeeding is not recommended. H. Vaginal delivery is recommended, but caesarean section is required in at least 50% of cases. Delivery should occur in a specialized center. In the puerperium, renal function, proteinuria, blood pressure, cyclosporine/ tacrolimus blood levels and fluid balance should be closely monitored. 64 Pediatrics (Specific Problems) A. Kidney transplantation should be the treatment of choice for endstage renal disease (ESRD) in children (up to 16 years of age). Because the incidence rate of ESRD is very low, ~l-2 children per million general population or 4-6 children per million childhood population, kidney transplantation in children should be performed in specialized pediatric centers with multidisciplinary experts, i.e. transplant surgeons, anesthetists and pediatric nephrologists, and optimally should be supported by psychologists, pediatric nurses and social workers. B. Due to the urgent need for transplantation, children should have priority in the allocation systems. In addition, preemptive transplantation from either live or cadaveric donors should be offered to all pediatric transplant candidates whenever possible. These protocols will reduce the time on dialysis, thus limiting the retardation of growth and development. C. Absolute contra-indications to renal transplantation in children are extremely rare but should be respected: uncontrollable malignancy, ABO incompatibility, the presence of a current positive cross-match or multi-organ failure. There are few relative or transient contraindications: history of cancer (Wilms tumor), viral infection (HIV, HBV, EBV), very young age (<6 months), severe mental retardation and/or additional disabilities. D. In contrast to adult patients, primary renal diseases responsible for ESRD in children are mostly congenital and hereditary disorders (60%). Children with massive vesicoureteric reflux or permanent urinary infection should undergo nephroureterectomy to avoid the development of sepsis. In children with ESRD not due to any urinary tract malformation, pre-transplant bilateral nephrectomy of the native kidney should be considered in the case of severe arterial hypertension, heavy proteinuria or risk of renal cancer. E. Psychosocial evaluation of future transplant recipients and their parents is necessary in assessing compliance with management of dialysis and after transplantation. Poor compliance worsens the outcome of pediatric renal transplantation. F. Routine childhood vaccination should be completed whenever 65 possible prior to transplantation, in addition to vaccination against hepatitis B and varicella. G. The pharmacokinetics of immunosuppressive drugs often differ between adult and pediatric recipients. Therefore, drug monitoring is mandatory in order to find the correct drug dosage. H. Today the actuarial probability of graft survival at 1 year should exceed 90% in unselected renal transplant children and the acute rejection rate should be lower than 30%. I. Special attention should be paid to specific risk factors in pediatric transplantation, such as thrombotic complications, EBV and CMV infections, post-transplant lymphoproliferative disease (PTLD) and recurrence of original renal disease, mainly in patients with focal segmental glomerulosclerosis (FSGS) or atypical hemolyticuremic syndrome (HUS). 66 Elderly (Specific Problems) A. Because renal transplantation can extend the duration and quality of life in elderly patients (age 60-70 years) with end-stage renal disease, transplantation should be considered in all patients, particularly if special programs and preparations are applied. B. In elderly kidney transplant recipients, immunosuppression has to be adapted to avoid both rejections and adverse effects. C. Accurate diagnosis and aggressive treatment of cardiovascular disease in elderly recipients are recommended because of the high number of deaths with functioning grafts. D. The high risk of concomitant diseases, such as diabetes mellitus, bone disease and malignancies, needs special consideration E. Early detection and close monitoring and prompt treatment of infections and complications, especially bronchopneumonia. 67 Analysis of Patient and Graft Survival A. It is important for a transplant unit to follow-up on the results of their transplant activities. In order to achieve correct reports on graft and patient outcome in all patients, it is necessary to have sufficient resources, such as a computerized database, and continuous updates of patient information. All data collected should be subjected to validation procedures to ensure completeness and accuracy B. Improved outcomes following implementation of new protocols, based on evaluation of clinical multi-centre trials, should be verified at local transplant centers since centers often include a range of patients different from those selected for the trial. C. The most widely accepted descriptor of outcome is the KaplanMeier probability estimate of patient and graft survival. Survival estimates should be calculated at intervals of time after transplantation and should always be expressed with their 95% confidence intervals. D. Kaplan-Meier survival estimates may be calculated in three ways: (i) 'Patient survival' should be calculated from the date of transplantation to the date of death or the date of the last follow-up. (ii) 'Graft survival' (non-censored for death) should be calculated from the date of transplantation to the date of irreversible graft failure signified by return to long-term dialysis (or retransplantation) or the date of the last follow-up during the period when the transplant was still functioning or to the date of death. Here, death with graft function is treated as graft failure. (iii) 'Graft survival censored for death with a functioning graft' (death-censored graft survival) should be calculated from the date of transplantation to the date of irreversible graft failure signified by return to long-term dialysis (or retransplantation) or the date of last follow-up during the period when the transplant was still functioning. In the event of death with a functioning graft, the follow-up period is censored at the date of death. E. The outcome of transplants carried out at a center should be compared with those achieved across a range of data from centers collated by national and international multi-centre registries. 68 Interpretation of a center's performance should take into account the number of transplants performed and the prevalence of major risk factors. F. Major risk factors that influence transplant outcome are identifiable by applying multivariate analytical methods to large multi-center follow-up databases. Although these major risk factors may not be identifiable in individual center data, they should nonetheless be taken into account in patient management. G. When designing a clinical trial or evaluating data from a recent trial, the expected improvement in graft survival resulting from a reduction in acute rejection may be estimated from a knowledge of the rejection and graft survival rates that existed prior to the introduction of the new therapeutic regimen. H. When designing or evaluating a clinical trial, it is important to analyze the power of the study to verify statistically the difference (in graft survival) that might be expected and its statistical significance. A study resulting in absence of statistically significant differences between two treatment groups with insufficient statistical power to verify a difference at the expected level should not be taken as evidence of absence of a true difference. 69 References 1. Edwards EB, Bennett LE, Cccka JM. Effect of HLA matching on the relative risk of mortality for kidney recipients: a comparison of the mortality risk after transplant to the mortality risk of remaining on the waiting list. Transplantation 1997; 64: 1274-1277. 2. Schnuelie P, Lorenz D, Trede M, Van Der Woude FJ. Impact of renal cadaveric transplantation on survival in end-stage renal failure: evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. J Am Soc Nephrol 1998; 9: 21352141 3. Montagnino G, Tarantino A, Cesana B et al. Prognostic factors of long-term allograft survival in 632 CyA-treated recipients of a primary renal transplant Transpl Int 1997; 10: 268 275 4. Cosio FG, Alamir A, Yim S et al. Patient survival after renal transplantation: I. The impact of dialysis pre-transplant. Kidney Int 1998; 53: 767-772 5. De Geest S, Borgermans L, Gemoets H et al. Incidence, determinants, and consequences of sub clinical non-compliance with immunosuppressive therapy in renal transplant recipients. Transplantation 1995; 59: 340-347 6. Panico M, Solomon M, Burrows L. Issues of informed consent and access to extended donor pool kidneys. Transplant Proc 1997; 29: 3667-3668 7. Penn I. The effect of immunosuppression on pre-existing cancers. Transplantation 1993; 55: 742-747 8. Kliem V, Kolditz M, Behrend M et al. Risk of renal cell carcinoma after kidney transplantation. Clin Transplant 1997; 11:255-258 9. Gulanikar AC, Daily PP, Kilambi NK, Ham rick-Turner JE, Butkus DE. Prospective pretransplant ultrasound screening in 206 patients for acquired renal cysts and renal cell carcinoma. Transplantation 1998; 66: 1669-1672 10. Penn I. De novo malignancies in pediatric organ transplant recipients. Pediatr Transplant 1998; 2: 56-63 11. Duramcr JS, Erb S, Braining MK el al. Infection with human immunodeficiency virus in the Pittsburgh transplant population. A study of 583 donors and 1043 recipients. 1981-1986. Transplantation 1989; 47: 134-140 12. Mathurin P, Mouquet C, Poynard T et al. Impact of hepatitis B and C virus on kidney transplantation outcome. Hepatology 1999; 29: 257-263 13. Morales JM, Campistol JM. Transplantation in the patient with Hepatitis C. J Am Soc Nephrol 2000; 11: 1343-1353 14. Ponticelli C, Banfi G. Focal and segmental glomerulosclerosis In: Ponticelli C, Glassock RJ, eds. Treatment of primary glomerutonephritis. Oxford Medical Publication, Oxford: 1997; 108-145 15. Hariharan S, Adams MB, Brennan DC et al Recurrent and de novo glomerular diseases after renal transplantation. Transplantation 1999; 68: 635-641 16. Dantal J, Godfrin Y, Koll R et al. Antihuman immunoglobulin affinity immmunoadsorption strongly decreases proteinuria in patients with relapsing nephrotic syndrome. J Am Soc Nephrol 1998; 9: 1709-1715 17. Cosyns JP, Couchoud C, Pouteil-Noble C, Squifflet JP, Pirson Y. Recurrence of membranous nephropathy after renal transplantation: probability, outcome and risk factors. Clin Nephrol 1998; 50: 144-153 18. Andresdottir MB, Assmann KJ, Koene RA, Wetzels JF. Immunohistological and ultrastructural differences between recurrent type I membranoproliferative glomerulonephritis and chronic transplant glomerulopathy. Am J Kidney Dis 1998; 32: 582-588 19. Briggs JD, Jones E. Recurrence of glomerulonephritis following renal transplantation. Nephrol Dial Transplant 1999; 14: 564 565 70 20. Bumgardner GL, Amend WC, Ascher NL, Vincenti EG. Single- center long-term results of renal transplantation for IgA nephro pathy. Transplantation 1998; 65: 1053-1060 21. Hartung R, Livingston B. Excell L, Disney A, Woodstraffe AJ. Recurrence of IgA deposits/disease in grafts. Contrib Nephrol 1995; 111: 13-17 22. Stone JH. End-stage renal disease in lupus: Disease activity, dialysis, and the outcome of transplantation. Lupus 1998; 7: 654-659 23. Meulders Q, Pirson Y, Cosyns JP, Squifflet JP, Van Ypersele de Strihou Ch. Course of Henoch-Schonlein nephritis after renal transplantation. Transplantation 1994; 58: 1172-1186 24. Pronovost PH, Brady HR, Gunning ME, Espinoza O, Rcnnkc HG. Clinical features, predictors of disease progression and results of renal transplantation in fibrillary/immunotactoid glomerulopathy. Nephrol Dial Transplant 1996; 11: 837-842 25. Livnech A, Zemer D, Siegal B et al. Colchicine prevents kidney transplant amyloidosis in familial mediterranean fever. Nephron 1992; 60: 418-422 26. Trimarchi HM, Troung LD, Brennans S, Gonzales JM, Suki WN. FK 560-associated thrombotic microangiopathy: report of two cases and review of the literature. Transplantation 1999; 67: 539-543 27. Nachman PH, Segelmark M, Westman K el al. Recurrent ANCA-associated small vessel vasculitis after transplantation: A pooled analysis. Kidney Int 1999; 56: 1544-1550 28. Tarantino A, Moroni G, Banfi G et al. Renal replacement therapy in cryoglobulinemic nephritis. Nephrol Dial Transplant 1994; 9: 1426-1430. 29. Gerlag PGG, Koene RAP, Berden JHM. Renal transplantation in light chain nephro-pathy: case report and review of the literature. Clin Nephrol 1986; 25: 101-104 30. Hariharan S, Smith RD, Viero R et al. Diabetic nephropathy after renal transplantation. Transplantation 1996; 62: 632-635 31. RischeivVos J, Van der Woude FJ, Tcgzess AM el al. Increased morbidity and mortality in patients with diabetes mellitus after kidney transplantation as compared with non-diabetic patients. Nephrol Dial Transplant 1992; 7: 433-437 32. Saborio P, Scheinman JI. Transplantation for primary hyperoxaluria in the United States. Kidney int 1999; 56: 1094-1100 33. Ehrich JHH, Brodehl J, Byrd DJ el al. Renal transplantation in 22 children with nephropathic cystinosis. Pediatr Nephrol 1991; 5:708-714 34. Mosnier JF, Degott C, Bedrossian J el al. Recurrence of Fabry's disease in a renal allograft eleven years after successful renal transplantation. Transplantation 1991; 51: 759-762 35. Humar A, Johnson EM, Gillingham KJ et al. Venous thromboembolic complications after kidney and kidney-pancreas transplantation. Transplantation !998; 65: 229-234 36. Alkhunaizi AM, Olyaei AJ, Barry JM et al. Efficacy and safety of low molecular weight heparin in renal transplantation. Transplantation 1998; 66: 533-534 37. Irish A. Renal allograft thrombosis: can thrombophilia explain the inexplicable? Nephrol Dial Transplant 1999; 14: 2297-2303 38. Wolfe RA, Ashby VB, Milford EL et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting trans plantation, and recipients of a first cadaveric transplant. N Engl J Med 1999; 341: 1725 1730 39. Kasisko BL. Ramos EL, Gaston RS et al. The evaluation of renal transplant candidates: clinical practice guidelines. Patient Care and Education Committee of the American Society of Transplant Physicians. J Am Soc Nephrol 1995; 6: 1-34 40. Holiey JL, Monaghan J, Bycr B, Bronsthcr O. An examination of the renal transplant evaluation process focusing on cost and the reasons for patient exclusion. Am J Kidney Dis 1998; 32: 567-574 41. Ferguson ER, Hudson SL, Diethelm AG, Pacifico AD, Dean LS, Holman WL. Outcome after myocardial revascularization and renal transplantation: a 25-year single-institution experience Ann Surg 1999; 230: 232-241 71 42. Basar H, Soran A, Shapiro R et al. Renal transplantation in recipients over the age of 60. Transplantation 1999; 67: 1191-1193 43. Roodnat JI, Zietse R, Mulder PGH et al. The vanishing importance of age in renal transplantation. Transplantation 1999; 67: 576-580 44. Bodmer J, Marsh S, Albert E et al. Nomenclature for factors of the HLA system, 1998. Eur J Immunogen 1999; 26: 81-116 45. Mytilineos J, Lempert M, Scherer S, Schwarz V, Opelz G. Comparison of serological and DNA PCR-SSP typing results for HLA-A and HLA-B in 421 Black individuals: a Collaborative Transplant Study report. Hum Immunol 1998;59:512-7. 46. Worthington JE, Thomas AA, Dyer PA, Martin S. Detection of HLA-specific antibodies by PRA-STAT and their association with transplant outcome. Transplantation 1998; 65: 121-125 47. Sumitran-Karuppan S. The clinical importance of choosing the right assay for detection of HLA-specific donor-reactive antibodies. Transplantation 1999; 68: 502-509 48. Asderakis A, Augustine T, Dyer P et al. Pre-emptive kidney transplantation: the attractive alternative. Nephrol Dial Transplant 1998; 13: 1799-1803 49. John AG. Rao M. Jacob CK. Pre-emptive live-related renal transplantation. Transplantation 1998; 66: 204 209 50. Petronc H, Marlinoia A, Ferreiro E et al. Renal transplant waiting list exclusion causes: hepatitis C virus infection and liver disease prevalence. Transplant Proc 1999; 31: 3038-3040 51. Curtoni ES, Magistroni P, Fasano ME, Pratico L, Roggero S. Waiting list for kidney transplant. Some patients wait too long. J Biol Regul Homeost Agents 1999; 13: 37-41 52. Leffell MS, Zachary AA. The national impact of the 1995 changes to the UNOS renal allocation system. United Network for Organ Sharing. Clin Transplant 1999; 13: 287-295 53. Goodnough LT, Brecher ME, Kanter MH, AuBuchon JP. Transfusion medicine: blood transfusion. N Engl J Med 1999; 340: 438 447 54. Christiaans ML, Van Hoof JP, Nieman F, Van Den Bcrg- Loonen EM. HLA-DR matched transfusions: development of donor-specific T- and B-cell antibodies and renal allograft outcome. Transplantation 1999; 67: 1029-1035 55. Alexander JW, Light JA, Donaldson LA el al. Evaluation of pre-and post transplant donorspecific transfusion/cyclosporine A in non-HLA identical living donor kidney transplant recipients. Transplantation 1999; 68: 1117-1124 56. Tyden G, Bolindcr J, Solders G, Brattslrom C, Tibell A, Groth CG. Improved survival in patients with insulin-dependent diabetes mellitus and end-stage diabetic nephropathy 10 years after combined pancreas and kidney transplantation. Transplantation 1999; 67: 645-648 57. Smets YF, Westendorp RG, van der Pijl JW et al. Effect of simultaneous pancreas-kidney transplantation on mortality of patients with type-1 diabetes mellitus and end-stage renal failure. Lancet 1999; 353: 1915 1919 58. Burke GW, Ciancio G, Cirocco R et al. Microangiopathy in kidney and simultaneous pancreas/kidney recipients treated with tacrolimus: evidence of endothelin and cytokinc involvement. Transplantation 1999; 68: 1336-1342 59. Jcyarajah DR, Gonwa TA, Testa G et al. Liver and kidney transplantation for polycystic disease. Transplantation 1998; 66: 529-532 60. Lang M, Kahl A, Bechstein WO et al. Combined liver-kidney transplantation: long-term follow-up in 18 patients. Transplant Proc 1998; 30: 1865-1867 61. Bernard TMJ, Piraino B, Kormos RL. Patient survival with renal replacement therapy in heart transplantation patients. ASAIO J 1998; 44: M546-M548 62. Cecka JM. The UNOS Scientific Renal Transplant Registry. Clin Transplant 1998: 1-16 63. Abouljoud MS, Deierhoi MH, Hudson SL, Diethelm AG. Risk factors affecting second renal transplant outcome, with special reference to primary allograft nephrectomy. Transplantation 1995; 60: 138-144 64. Sola R, Guirado LL, Lopez Navidad A et al. Renal transplantation with limit donors. To what 72 extent should the good results obtained be attributed? Transplantation 1998; 66: 1159-1163 65. Hariharan S, McBride MA, Bennett LE, Cohen EP. Risk factors for renal allograft survival from older cadaver donors. Transplantation 1997; 64: 1748-1754 66. Scheinkestel CD, Tuxen DV, Cooper DJ, Butt W. Medical management of the (potential) organ donor. Anaesth Intens Care 1995; 23: 51-59 67. Eastlund T. Infectious disease transmission through cell, tissue, and organ transplantation: Reducing the risk through donor selection. Cell Transpl 1995; 4: 455-477 68. Freeman RB, Giatras I, Falagas ME et al. Outcome of transplantation of organs procured from bacteremic donors. Transplantation 1999; 68: 1107-1111 69. Sanchez-Fructuoso AI, Prats D, Torrcntc J el al. Renal trans plantation from non-heart beating donors: a promising alternative to enlarge the donor pool. / Am Soc Nephrol 2000; 11: 350 358 70. Kasiske BL, Bia MJ. The evaluation and selection of living kidney donors. Am J Kidney Dis 1995; 26: 387-398 71. Lumsdaine JA, Wigmorc SJ, Forsythc JLR. Live kidney donor assessment in the UK and Ireland. Brit J Surg 1999; 86: 877-881 72. Daar AS, Land W, Yahya TM, Schncewind K, Gutmann T, Jakobsen A. Lining-donor renal transplantation: evidence-based justification for an ethical option. Transplant Rev 1997; 11: 95- 109 73. Cecka JM. Kidney donation from unrelated living donors. Saudi J Kidney Dis Transplant 1999; 10: 464-469 74. Karakayali H, Moray G, Demirag A, Turan M, Bilgin N, Haberal M. Long-term follow-up of ABO-incompatible renal transplant recipients. Transplant Proc 1999; 31: 256-257 75. Haberal M, Demirag A, Moray G et al. Graft survival rates in kidney transplant recipients of different blood groups. Transplant Proc 1998; 30: 741-743 76. Opelz G, Wujciak T, Dohler B. Is HLA matching worth the effort? Collaborative Transplant Study. Transplant Proc 1999; 31: 717-720 77. Fuller A, Profaizer T, Roberts L, Fuller TC. Repeal donor HLA-DR mismatches in renal transplantation: is the increased failure rate caused by noncytotoxic HLA-DR alloantibodies? Transplantation 1999; 68: 589-591 78. McKenna RM, Lee KR, Gough JC et al. Matching for private or public HLA epitopes reduces acute rejection episodes and improves two-year renal allograft function. Transplantation 1998; 66: 38-43 79. Schonemann C, Groth J, Leverenz S, May G. HLA class I and class II antibodies: monitoring before and after kidney transplantation and their clinical relevance. Transplantation 1998; 65: 1519-1523 80. McKenna R, Takemoto S, Terasaki P. Anti-HLA antibodies after solid organ transplantation. Transplantation 2000; 69: 319-326 81. Shoskes DA, Halloran P. Delayed graft function in renal transplantation: etiology, management and long-term significance. / Urol 1996; 155: 1831-1840 82. Valeri A, Radhakishnan J, Ryan R, Powell D. Biocompatible dialysis membranes and acute renal failure: a study in post operative acute tubular necrosis in cadaveric renal transplant recipients. Clin Nephrol 1996; 46: 402-409 83. Thibaudin D, Alamartine E, de Filippis JP, Diab N, Laurent B, Berthoux F. Advantage of antithymocyte globulin induction in sensitized kidney recipients : a randomised prospective study comparing induction with and without antithymocyte globulin. Nephrol Dial Transplant 1998; 13: 711-715 84. Lange H, Muller TF, Ebel H et al. Immediate and long-term results of ATG induction therapy for delayed graft function compared to conventional therapy for immediate graft function. Transplant Int 1999; 12: 2-9 85. Kalian BD, Rajagopalan PR, Hall M, for the United States Simulect Renal Study Group. 73 Reduction of the occurrence of acute cellular rejection among renal allograft recipients treated with basiliximab, a chimeric anti-interleukin-2-receptor monoclonal antibody. Transplantation 1999; 67: 276-284 86. Ekberg H, Backman L, Tufveson G, Tyden G, Nashan B. Vincenti F. Daclizumab prevents acute rejection and improves patient survival post transplantation: 1 year pooled analysis. Transplant Int 2000; 13: 151-159 87. Denton MD, Magee CC, Sayegh MH. Immunosuppressive strategies in transplantation. Lancet 1999; 353: 1083-1091 88. Newstead CG, Johnston PA, Will EJ, Davison AM. The case for withdrawal of cyclosporine after renal transplantation. Nephrol Dial Transplant 1998; 13: 28-31 89. European Mycophenolate Mofetil Cooperative Study Group. Mycophenolate mofetil in renal transplantation: 3-year results from the placebo-controlled trial. Transplantation 1999; 68: 391-396 90. Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation FK506 Kidney Transplant Study Group. Transplantation 1997; 63: 977-983 91. Shapiro R, Jordan ML, Scantlebury VP el al. A prospective, randomized trial of tacrolimus/prednisone versus tacrolimus/ prednisone/mycophenolatc mofetil in renal transplant recipients. Transplantation 1999; 67: 411-415 92. Kreis H, Cisterne JM, Land W et al. Sirolimus in association with mycophenolate mofetil induction for the prevention of acute graft rejection in renal allograft recipients. Transplantation 2000; 69: 1252-1260 93. Vincenti F, Kirkman R, Light S et al. Interleukin-2 receptor blockade with daclizumab to prevent acute rejection in renal transplantation. N EnglJ Med 1998; 338: 161-165 94. Mayer AD, Dmitrewski J, Squifflet JP et al. Multicenter randomized trial comparing tacrolimus (FK506) and cyclosporine in the prevention of renal allograft rejection. A report of the European Tacrolimus Multicenter Renal Study Group. Transplantation 1997; 64: 436-443 95. Lcichtman AB. Pathogenesis and pathology of early kidney allograft dysfunction. In: Norman DJ and Thorofare SW, eds. Primer on transplantation. The American Society of- Transplant Physicians: 1998; 217-222 96. Boom H, Mallat MJ, De Fijter JW, Zwinderman AH, Paul LC. Delayed graft function influences renal function but not survival. Kidney Int 2000; 58: 859-866 97. Cohen DJ, Weir MR. Post-transplant in-hospital care. In: Norman DJ and Thorofare SW, eds. Primer on transplantation. The American Society of Transplant Physicians: 1998; 223-228 98. Rubin RH. Infectious diseases in transplantation/pre-and post- transplantation. In: Norman DJ, Thorofare SW, eds. Primer on transplantation. The American Society of Transplant Physicians: 1998; 141-152 99. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med 1998; 338: 1741 -1751 100.Jassal SV, Roscoe JM, Zaltzman JS el al. Clinical practice guidelines: prevention of cytomegalovirus disease after renal transplantation. ./ Am Soc Nephrol 1998; 9: 1697-1708 101.Blok MJ, Christiaans MH, Goossens VJ et al. Evaluation of a new method for early detection of active cytomegalovirus infec tions. A study in kidney transplant recipients. Transpl Inl 1998; II [Suppl 1]: S107-S109 102.Couchoud C, Cucherat M, Haugh M, Pouteil-Noblc C. Cytomegalovirus prophylaxis with antiviral agents in solid organ transplantation: a meta-analysis. Transplantation 1998; 65: 641-647 103.Lowance D, Ncumayer HH, Lcgcndre CM et al Valacyclovir for the prevention of cytomegalovirus disease after renal transplantation. International Valacyclovir Cytomcgalovirus Prophylaxis Transplantation Study Group. N Engl J Med 1999; 340: 14621470 74 104. Morales JM. Renal transplantation in patients positive for Hepatitis B or C (Pro). Transplant Proc 1998; 30: 2064-2069 105.Morales JM, Campistol JM, Andres A, Rodicio JL. Hepatitis C virus and renal transplantation. Curr Opin Nephrol Hypertens 1998; 7: 177-183 106.Mufloz de Bustillo E, Ibarrola C, Colina F et al. Fibrosing cholestatic hepatitis in hepatitis C virus-infected renal transplant patients. / Am Soc Nephrol 1998; 9: 1109- 1113 107.Baid S, Pascual M, Williams WW et al. Renal thrombotic microangiopathy associated with anticardiolipin antibodies in hepatitis C-positive renal allograft recipients. J Am Soc Nephrul 1999; 10: 146-153 108.Racusen LC, Solez K, Colvin RB et al. The Banff 97 working classification of renal allograft pathology. Kidney Int 1999; 55:713-723 109.Pascual M, Vallhonrat H, Cosimi AB et al. The clinical usefulness of the renal allograft biopsy in the cyclosporine era. A prospective study. Transplantation 1999; 67: 737-741 110.Collins AB, Schneeberger EE, Pascual MA el al. Complement activation in acute humoral renal allograft rejection: diagnostic significance of C4d deposits in peritubular capillaries. J Am Soc Nephrol 1999; 10: 2208-2214 111.Mauiyyedi S, Delia Pelle P, Saidman S et al. Identifying anti body mediated chronic renal allograft rejection by C4d in peritubular capillaries. J Am Soc Nephrol 2001; 12: 574-582 112.Suri DL, Tomlanovich SJ, Olson JL, Meyer TW. Transplant glomerulopathy as a cause of late graft loss. Am J Kidney Dis 2000; 35: 674-68 113.Moreso F, Lopez M, Vallejos A et al. Serial protocol biopsies to quantify the progression of chronic transplant nephropathy to stable renal allografts. Am J Transplant 2001; 1: 82-88 114.Ojo AO, Hanson JA, Wolfe RA, Leichtman AB, Agodoa LY, Port FK. Long-term survival in renal transplant recipients with graft function. Kidney Int 2000; 57: 307-13. 115.Paul LC, Sijpkens YW. Risk factors that influence the intercept or the slope of graft function over time. Transplant Proc 2001; 33: 3359-60 116.Sijpkens YWJ, Zwinderman AH, Mallat MJK, Boom H, De Fijter JW, Paul LC. Intercept and slope analysis of risk factors in chronic renal allograft nephropathy. Graft 2002; 5, 108-113 117.Prommool S, Jhangri GS, Cockfield SM, Halloran PF. Time dependency of factors affecting renal allograft survival. J AmSoc Nephrol 2000; 11: 565-573 118.Gray DWR. Vascular and lymphatic complications after renal transplantation. In: Morris PJ, ed. Kidney Transplantation. Principles and Practice. WB Saunders Company, Philadelphia, 2001; 419-434 119.De Fijter JW, Mallat MJ, Doxiadis II et al. Increased immunogenicity and cause of graft loss of old donor kidneys. J Am Soc Nephrol 2001; 12: 1538-1546 120.Ruggenenti P, Perna A, Zocalli C et al. Chronic proteinuric nephropathies. II. Outcomes and response to treatment in a prospective cohort of 352 patients: differences between women and men in relation to the ACE gene polymorphism. J Am Soc Nephrol 2000; 11: 88-96 121. Jafar TH, Stark PC, Schmid CH et al. Proteinuria as a modifiable risk factor for the progression of non-diabetic renal disease. Kidney Int 2001; 60: 1131-1140. 122.Holgado R, Anaya F, Del Castillo D. Angiotensin II type (ATI) receptor antagonist in the treatment of hypertension after renal transplantation. Nephrol Dial Transplant 2001; 16 [Suppl 1]: 117-120 123.Orth SR, Ogata H, Ritz E. Smoking and the kidney. Nephrol Dial Transplant 2000; 15: 15091511 124.Kasiske BL, Klinger D. Cigarette smoking in renal transplant recipients. J Am Soc Nephrol 2000; 11: 753-759 125.Nankivell BJ, Lau S-G, Chapman JR, O'Connell PJ, Fletcher JP Allen RDM. Progression of macrovascular disease after transplantation. Transplantation 2000; 69: 574-581 126.Inigo P, Campistol JM, Lario S et al. Effects of losartan and amlodipine on intrarenal 75 hemodynamics and TFG-/J1 plasma levels in a crossover trial in renal transplant recipients. J Am Soc Nephrol 2001; 12: 822-827 127.Wissing KM, Abramowicz D, Broeders N, Vereerstraeten P. Hypercholesterolemia is associated with increased kidney graft loss caused by chronic rejection in male patients with previous acute rejection. Transplantation 2000; 70: 464-472 128.Roodnat JI, Mulder PGH, Zietse R et al. Cholesterol as an independent predictor of outcome after renal transplantation. Transplantation 2000; 69: 1704-1710 129.Seron D, Moreso F, Ramon JM et al. Protocol renal allograft biopsies and the design of clinical trials aimed to prevent or treat chronic allograft nephropathy. Transplantation 2000; 69: 1849-1855 130.Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6: 1399-1402 131.DalPAmico R, Ghiggeri G, Carraro M, Artero M, Ghio L. Prediction and treatment of recurrent focal segmental glomerulosclerosis after renal transplantation in children. Am J Kidney Dis 1999; 34: 1048-1055 132.Andresdottir MB, Ajubi N, Croockewit S, Assmann K.J. Recurrent focal glomerulosclerosis: natural course and treatment with plasma exchange. Nephrol Dial Transplant 1999; 14: 26502656 133.Greenstein SM, Delrio M, Ong E et al. Plasmapheresis treatment for recurrent focal sclerosis in pediatric renal allografts. Pediatr Nephrol 2000; 14: 1061-1065 134.Montagnino G, Tarantino A, Banfi G et al. Double recurrence of FSGS after two renal transplants with complete regression after plasmapheresis and ACE inhibitors. Transplant Int 2000; 13: 166-168 135.Lien YH, Scott K.. Long term cyclophosphamide treatment for recurrent type I membranoproliferative glomerulonephritis after transplantation. Am J Kidney Dis 2000; 35: 539-543 136.Andresdottir MB, Assmann K.J, Hilbrands LB et al. Type I membranoproliferative glomerulonephritis in a renal allograft: a recurrence induced by a cytomegalovirus infection? Am J Kidney Dis 2000; 35: E6 137.Oka K, Imai E, Moryama T et al. A clinicopathological study of IgA nephropathy in renal transplant recipients. Beneficial effect of ACE-inhibitor. Nephrol Dial Transplant 2000; 15: 689-695 138.Donadio JV, Grande JP, Bergstralh EJ, Dart RA, Larson TS. The long-term outcome of patients with IgA nephropathy treated with fish oil in a controlled trial. J Am Soc Nephrol 1999; 10: 1772-1777 139.Kasiske BL, Chakkera HA, Louis TA, Ma JZ. A meta-analysis of immunosuppression withdrawal trials in renal transplantation. J Am Soc Nephrol 2000; 11: 1910-1917 140.Ahsan N, Hricik D, Matas A et al. Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil—a prospective randomized study. Steroid Withdrawal Study Group. Transplantation 1999; 68: 1865-1874 141.Montagnino G, Tarantino A, Segoloni GP et al. Long-term results of a randomized study comparing three immunosuppressive schedules with cyclosporine in cadaveric kidney transplantation. J Am Soc Nephrol 2001; 12: 2163-2169 142.Keunecke C, Rothenpieler U, Zanker B et al. Mycophenolate mofetil monotherapy: an example of a safe nephrotoxicity/ atherogenicity-free immunosuppressive maintenance regimen in a selected group of kidney-transplanted patients. Transplant Proc 2000; 32: 6S-8S 143.Land W, Schneeberger H, Weiss M, Ege T, Stumpfig L. Mycophenolate mofetil monotherapy: an optimal, safe, and efficacious immunosuppressive maintenance regimen in kidney transplant patients. Transplant Proc 2001; 33: 29S-35S 144. Womer KL, Vella JP, Sayegh MH. Chronic allograft dysfunction: mechanisms and new approaches to therapy. Semin Nephrol 2000; 20: 126-147 76 145.De Mattos AM, Olyaei AJ, Bennett WA. Nephrotoxicity of immunosuppressive drugs: longterm consequences and challenges for the future. Am J Kidney Dis 2000; 35: 333-346 146.Kasiske BL. Cardiovascular disease after renal transplantation. Semin Nephrol 2000; 20: 170-187 147.Perez Fontan M, Rodriguez-Carmona A, Garcia Falcon T, Fernandez Rivera C, Valdes F. Early immunologic and non-immunologic predictors of arterial hypertension after renal transplantation. Am J Kidney Dis 1999; 51: 290-295 148.Mange KC, Cizman B, Joffe M, Feldman HI. Arterial hypertension and renal allograft survival. J Am Med Assoc 2000; 283: 633-638 149.Olyaei AJ, Demattos AM, Bennett WM. A practical guide to the management of hypertension in renal transplant recipients. Drugs 1999; 58: 1011-1027 150.Kasiske BL, Chakkera HA, Roel J. Explained and unexplained ischemic heart disease risk after renal transplantation. J Am Soc Nephrol 2000; 11: 1735-1743 151.MsCune TR, Thacker LR, Peters TG el al. Effects of tacrolimus on hyperlipidemia after successful renal transplantation. Transplantation 1998; 30: 1292-1294 152.Kohnle M, Zimmermann U, Lutkes P. Albrecht K-H, Philip T, Heeman U. Conversion from cyclosporine A to tacrolimus after kidney transplantation due to hyperlipidemia. Transplant Int 2000; 13 [Suppl 1]: S345-S348 153. Miles AM, Sumrani N, Horowitz R et al. Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes? Transplantation 1998; 65: 380-384 154.Birkeland SA, Lokkegaard H, Storm HH. Cancer risk in patients on dialysis and after renal transplantation. Lancet 2000; 355: 1886-1887 155.Rowe DT, Webber S, Schauer EM, Reyes J, Green M. Epstein-Barr virus load monitoring: its role in the prevention and management of post-transplant lymphoproliferative disease. Transplant Infect Dis 2001; 3: 79-87 156.Green M, Reyes J, Webber S, Rowe P. The role of antiviral and immunoglobulin therapy in the prevention of Epstein-Barr virus infection and post-transplant lymphoproliferative disease following solid organ transplantation. Transplant Infect Dis 2001; 3: 97-103 157.Colleoni GW, Oliveira JS, Borducchi DM et al. Post-transplant lymphoproliferative disorders (PTLD) after renal transplanta tion: management and evolution of seven cases among 1002 renal transplants in Sao Paulo, Brazil. Leuk Lymphoma 2000; 39: 145-150 158.Mamzer-Bruneel MF, Lome C, Morelon E et al. Durable remission after aggressive chemotherapy for very late post- kidney transplant lymphoproliferation: a report of 16 cases observed in a single center. J Clin Oncol 2000; 18: 3622-3632 159.Ramsay HM, Fryer AA, Reece S, Smith AG, Harden PN. Clinical risk factors associated with nonmelanoma skin cancer in renal transplant recipients. Am J Kidney Dis 2000; 36: 167-176 160.Mork J, Lie AK, Glattre E, Hallmans G et al. Human papillomavirus infection as a risk factor for squamous- cell carcinoma of the head and neck. TV Engl J Med 2001; 344: 11251131 161.Alam M, Ratner D. Cutaneous squamous-cell carcinoma. TV Engl J Med 2001; 344: 975983 162.Malavaud B, Hoff M, Miedouge M, Rostaing L. PSA-based screening for prostate cancer after renal transplantation. Transplantation 2000; 69: 2461-2462 163.Barry MJ. Prostate-specific-antigen testing for early diagnosis of prostate cancer. TV Engl J Med 2001; 344: 1373-1377 164.Mandel JS, Church TR, Bond JH et al. The effect of fecal occult- blood screening on the incidence of colorectal cancer. TV Engl J Med 2000; 343: 1603-160 165.Beard CB, Carter JL, Keely SP et al. Genetic variation in Pneumocystis carinii isolates from different geographic regions: implications for transmission. Emerg Infect Dis 2000; 6: 265-272 166.Touzet S, Pariset C, Rabodonirina M, Pouteil-Noble C. Nosocomial transmission of Pneumocystis carinii in renal transplantation. Transplant Proc 2000; 32: 445 77 167.Rose DN. Benefits of screening for latent Mycobaterium tuberculosis infection. Arch Intern Med 2000; 160: 1513-1521 168.John GT, Shankar V, Abraham AM, Mukundan U, Thomas PP, Jacob CK. Risk factors for post-transplant tuberculosis. Kidney Int 2000; 60: 1148-1145 169.Koselj M, Kandus A, Ales A, Bren AF. Mycobacterial infection in renal transplant recipients. Transplant Proc 2000; 32: 152-154 170.Small PM, Fujiwara PI. Management of tuberculosis in the United States. N Engl J Med 2001; 345: 189-200 171.Espinal MA, Laszlo A, Simonsen L el al. Global trends in resistance to antituberculosis drugs. World Health Organization-International Union against Tuberculosis and Lung Disease working Group on Anti-Tuberculosis Drug Resistance surveillance. JV Engl J Med 2001; 344: 1294-1303 172.Burman WJ, Gallicano K, Peloquin C. Comparative pharmacokinetics and pharmacodynamics of the rifamycin anti-bacterials. Clin Pharmacokinet 2001; 40: 327-324 173. Cayco AV, Wysolmerski J, Simpson C et al. Posttransplant bone disease: evidence for a high bone resorption state. Transplantation 2000; 70: 1722-1728 174.Carlini RG, Rojas E, Weisinger JR et al. Bone disease in patients with long-term renal transplantation and normal renal function. Am J Kidney Dis 2000; 36: 160-166 175.Monier-Faugere M-C, Mawad H, Qi Q, Friedler RM, Malluche HH. High prevalence of low bone turnover and occurrence of osteomalacia after kidney transplantation. J Am Soc Nephrol 2000; 11: 1093-1099 176.Silkensen JR. Long-term complications in renal transplantation. J Am Soc Nephrol 2000; 11: 582-588 177.Westeel FP, Mazouz H, Ezaitouni F et al. Cyclosporine bone remodeling effect prevents steroid osteopenia after kidney transplantation. Kidney Int 2000; 58: 1788-1796 178.Goodman GR, Dissanayake IR, Sodam BR et al. Immunosuppressant use without bone loss—implications for bone loss after transplantation. / Bone Miner Res 2001; 16: 72-78 179.Levi M. Post-transplant hypophosphatemia. Kidney Int 2001; 59: 2377-2387 180.Arlen DJ, Lambert K, Ioannidis G, Adachi JD. Treatment of established bone loss after renal transplantation with etidronate. Transplantation 2001; 71: 669-673 181.Weber TJ, Quarles LD. Preventing bone loss after renal transplantation with bisphosphonates: We can .but should we? Kidney Int 2000; 57: 735-737 182.Lezaic V, Biljanovic-Paunovic L Pavlovic-Kentera V, Djukanovic L. Erythropoiesis after kidney transplantation: the role of erythropoietin, burst promoting activity and early erythroid progenitor cells. Eur J Med Res 2001; 6: 27-32 183.Arbeiter K, Greenbaum L, Balzar E et al. Reproducible erythroid aplasia caused by mycophenolate mofetil. Pediatr Nephrol 2000; 14: 195-197 184.Asaka M, Ishikawa I, Nakazawa T et al. Hemolytic uremic syndrome associated with influenza A virus infection in allograft recipient: case report and review of the literature. Nephron 2000; 84: 258-266 185.Elhence P, Sharma RK, Chaudhary RK, Gupta RK. Acquired hemolytic anemia after minor ABO incompatible renal transplantation. J Nephrol 1998; 11: 40-43 186.Armenti VT, Radomski JS, Moritz MJ, Philips LZ, McGrory CH, Coscia LA. Report from the National Transplantation Pregnancy Registry (NTPR): outcomes of pregnancy after transplantation. Clin Transplant 2000; 123-134 187.Bar J, Ben-Rafael Z, Pados A, Orvieto R, Boner G, Hod M. Prediction of pregnancy outcome in subgroups of women with renal disease. Clin Nephrol 2000; 53: 437-444 188.Di Paolo S, Schena A, Morrone LF et al. Immunologic evaluation during the first year of life of infants born to cyclosporine-treated female kidney transplant recipients: analysis of lymphocyte subpopulation and immunoglobulin serum levels. Transplantation 2000; 69: 20492054 78 189.Kainz A, Harabacz I, Cowlrick IS, Gadgil SD, Hagiwara D. Review of the course and outcome of 100 pregnancies in 84 women treated with tacrolimus. Transplantation 2000; 70: 1718-1721 190.Armenti VT, Herrine SK, Radowski JS, Morotz MJ. Pregnancy after liver transplantation. Liver Transplant 2000; 6: 671-685 191.Kainz A, Harabacz L, Cowlrick IS, Gadgil S, Hagiwara D. Analysis of 100 pregnancy outcomes in women treated systemically with tacrolimus. Transplant Int 2000; 13: S299-S300 192.Vats AN, Donaldson L, Fine RN, Chavers B. Pretransplant dialysis status and outcome of renal transplantation in North American children: a NAPRTCS study. Transplantation 2000; 69: 1414-1419 193.Salvatierra O. Pretransplantation voiding cystography is not necessary for all potential pediatric kidney recipients. PediatrTransplant 2001; 5: 73-4 194.Cochat P, Ranchin B. Is there a need for a multicenter study to determine the optimal approach to recurrent nephritic syndrome following renal transplantation? Pediatr Transplant 2001; 5: 394-397 195.Benfleld MR, Stablein D, Tejani A. Trends in immunosuppressive therapy: a report of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS). Pediatr Transplant 1999; 3: 27-32 196. Morales JM, Campistol JM, Andres A, Herrero JC. Immunosuppression in older renal transplant patients. Drugs Aging 2000; 16: 279-287 197.Meier-Kriesche HU, Ojo A, Hanson J et al. Increased immunosuppressive vulnerability in elderly renal transplant recipients. Transplantation 2000; 69: 885-889 198.Gallucci S, Matzinger P. Danger signals: SOS to the immune system. Curr Opin Immunol 2001; 13: 114-119 199.de Fijter JW, Mallat MJ, Doxiadis II et al. Increased immunogenicity and cause of graft loss of old donor kidneys. JAm Soc Nephrol 2001; 12: 1538-1546 200.Lufft V, Kliem V, Tusch G, Dannenberg B, Brunkhorst R. Renal transplantation in older adults: is graft survival affected by age? A case control study. Transplantation 2000; 69: 790794 201.Meier-Kriesche H, Ojo AO, Arndorfer JA et al. Need for individualized immunosuppression in elderly renal transplant recipients. Transplant Proc 2001; 33: 1190-1191 202.Ojo AO, Hanson JA, Meier-Kriesche H et al. Survival in recipients of marginal cadaveric donor kidneys compared with other recipients and wait-listed transplant candidates. J Am Soc Nephrol 2001; 12: 589-597 203.Meier-Kriesche HU, Ojo AO, Cibrik DM et al. Relationship of recipient age and development of chronic allograft failure. Transplantation 2000; 70: 306-310 204.Opelz G. Factors influencing long-term graft loss. The Collaborative Transplant Study. Transplant Proc 2000; 32: 647-649 205.Roodnat JI, Mulder PG, Rischen Vos J et al. Proteinuria after renal transplantation affects not only graft survival but also patient survival. Transplantation 2001; 72: 438-444 206.Gjertson DW, Cecka JM. Determinants of long-term survival of pediatric kidney grafts reported to the United Network for Organ Sharing kidney transplant registry. Pediatr Transplant 2001; 5: 5-15 207.Vincenti F, Nashan B, Bumgardner G, Hardie I, Pescovitz M, Johnson RWG. Three year outcome of the phase III clinical trials with daclizumab. Transplantation 2001; 69: S261 208. Hefty TR, Barry JM.Renal transplantation in Saudi Arabia. Transplant Proc. 1986 Jun; 18(3 Suppl 2):10-2. 209. Boubenider S, Aswad S. The "National Kidney Foundation": a new experience in Saudi Arabia. Nephrologie. 1988;9(5):223-5. 210. Qunibi W, Akhtar M, Sheth K, Ginn HE, Al-Furayh O, DeVol EB, Taher S. Kaposi's sarcoma: the most common tumor after renal transplantation in Saudi Arabia. Am J Med. 1988 79 Feb;84(2):225-32 . 211. Nezamuddin NM, et al En-bloc anencephalic cadaver donor renal transplantation. Transplant Proc. 1989 Feb;21(1):1934-5. 212. Qunibi WY, al-Sibai MB, Taher S, Harder EJ, de Vol E, al-Furayh O, Ginn HE. Mycobacterial infection after renal transplantation--report of 14 cases and review of the literature. Q J Med. 1990 Oct;77(282):1039-60 . 213. Al-Khader A.A., Dhar J.M., Al-Sulaiman M.H. Diffuse Lung Shadowing in Renal Transplant Recipients Saudi Kidney Dis Transplant Bull 1990;1(2):69-72. 214. Aswad S, Timothy Paul T, Edrees A Abdul Rahman Babiker M, Mohammed Saleh AQ, Aldein Taha S, Al-Swailem A R. The Role of National Kidney Foundation in Cadaveric Renal Transplantation in Saudi Arabia. Saudi Kidney Dis Transplant Bull 1990;1(3):145-154 215. Al-Muhanna F A, Saeed I, Malhotra KK. Prospects of Renal Transplantation in Saudi Arabia. Saudi Kidney Dis Transplant Bull 1990;1(3):164-167 216. Onmubalili J, Okereke O, Boye E, Obineche E, Abu-Aisha H. Combined pulmonary mucormycosis and candidiasis after renal transplantation . A case report and review of the literature. Saudi Kidney Dis Transplant Bull 1991;2(2):85-88 217. al-Faqih SR. The influence of Islamic views on public attitudes towards kidney transplant donation in a Saudi Arabian community. Public Health. 1991 Mar;105(2):161-5. 218. Aswad S.The role of public education in cadaveric transplantation in Saudi Arabia. Transplant Proc. 1991 Oct; 23(5):2694-6. 219. Dhar JM, al-Khader AA, al-Sulaiman MH, al-Hasani MK. The significance and implications of hepatitis B infection in renal transplant recipients Transplant Proc 1991 Apr;23(2):1785-6. 220. Hakim H, Iskandarani S, Basri N, Fallata A, Edrees A, Siddiki O, Nezamuddin N. Review of surgical complications of renal transplantation in the Jeddah. Transplant Program. Transplant Proc. 1992 Oct; 24(5):1834-5 . 221. Lundgren G, Alfurayh O, Collste C, Duffy BB, Nicholls P, al-Sabban E, Sanjad S,Taher S, Qunibi W. The kidney transplantation program at King Faisal Specialist Hospital and Research Centre, Riyadh. Transplant Proc. 1992 Feb; 24(1):336-8 . 222.Chaballout A, Said R, Duarte R, Nezamuddin N. Living related-cadaveric-living unrelated kidney transplants: a comparison study at King Fahad Hospital, Riyadh. Transplant Proc. 1992 Oct;24(5):1836 . 223. Aswad S .Transplant Proc. 1992 Oct; 24(5):1837-9. 224. Lundgren G, Alfurayh O, Duffy BB, Nicholls P, Qunibi W, al-Sabban E, Sanjad S, Taher S. Five-years' experience with cadaveric kidney transplantation at King Faisal Specialist Hospital and Research Center, Riyadh. Transplant Proc. 1992 Oct;24(5):1840 225. Aswad S, Souqiyyeh MZ, Huraib S. The role of the media in cadaver transplantation in a developing country. Transplant Proc. Oct; 24(5):2049-50 226. Aswad S, Souqiyyeh MZ, Huraib S, el-Shihabi R. Public attitudes toward organ donation in Saudi Arabia. Transplant Proc. 1992 Oct;24(5):2056-8 . 227. Shaheen F, Nezamuddin N, Adiku W, Badawi L, al Aqeil N, Sheikh I, al-Shumrani A, Maarof HM. Outcome of brain-dead patients in Jeddah Kidney Center. Transplant Proc. 1992 Oct;24(5):2067-8 . 228. Qunibi WY, Barri Y, Alfurayh O, Almeshari K, Khan B, Taher S, Sheth K. Kaposi's sarcoma in renal transplant recipients: a report on 26 cases from a single institution. Transplant Proc. Feb; 25(1 Pt 2):1402-5 . 229. Aswad S. Cadaver organ donation in Saudi Arabia: a new experience. Transplant Proc. 1993 Jun; 25(3):2264 . 230.The Living non-Related Renal Transplant Study Group (LNRRT). Physicians' attitudes toward living non-related renal transplantation. Clin Transplant. 1993 Jun;7(3):289-95 . 231. Mansy H, al-Dusari S, al-Shareef Z, al-Shlash S, Eze C, el-Sherif M. A unique kidney donor in Tabuk. Nephrol Dial Transplant. 1994;9(2):220. 80 232. Shehab AB, Fallatah A, Sheikh IA, Al-Koussi MMH, Gabal MS, Shaheen F A.M. Impact of Donor Source on Short-term Outcome of Renal Transplantation in Children. Saudi J Kidney Dis Transplant 1994; 5(3):347-353 233. Bernieh B O, Mohamed A O, Wafa A M. Ramadan Fasting and Renal Transplant Recipients: Clinical and Biochemical Effects Saudi J Kidney Dis Transplant 1994;5(4):470473 234. Sheikh I A, Al-Menawy L, Shaheen FA.M., Al-Koussi M, Shehab A B. The diagnosis of acute renal allograft rejection using T-lymphocyte subsets in the peripheral blood: A better test now? Saudi J Kidney Dis Transplant; 1995 6(1):15-21 235. Shaheen FA.M , Souqiyyeh M Z , Al-Swailem A R. Saudi Center for Organ Transplantation: activities and achievements. Saudi J Kidney Dis Transplant 1995;6(1):41-52. 236.Alfurayh OI, Sobh MAE, Chaudry T S, Qunibi WY, Al Meshari K, Ellis M, Ali MA., Taher S. Impact of hepatitis C virus infection on kidney transplant outcome. Saudi J Kidney Dis Transplant 1995;6(2):183-189 237. Abdulla A H.,. Mousa D H, Rassoul Z, Al Hawas F, Al Sulaiman M H., Al-Khader A A.Progression of hepatitis C infection in a renal transplant recipient: a case report. Saudi J Kidney Dis Transplant 1995;6(2):206-210 238..Shaheen FA. Transplantation in Saudi Arabia. Transplant Proc. 1995 Feb;27(1):1470-1. 239. Ebrahim AF. Organ transplantation: contemporary Sunni Muslim legal and ethical perspectives. Bioethics. 1995 Jul; 9(3-4):291-302 . 240. Qunibi W, Abulrub D, Shaheen F, el-Din AB, Alfurayh O, Almeshari K. Attitudes of commercial renal transplant recipients toward renal transplantation in India. Clin Transplant. 1995 Aug;9(4):317-21. 241. Chaballout A, Said R, Alboghdadly S, Huraib S, Selim H. Living-related, cadaveric, and living unrelated donor kidney transplants: a comparison study at King Fahad Hospital, Riyadh. Transplant Proc. 1995 Oct;27(5):2775. 242. Al-Khudair WK, Huraib SO. Kidney transplantation in Saudi Arabia: a unique experience. World J Urol. 1996;14(4):268-71 243. al Shohaib S. Pregnancy and renal transplant. Nephron. 1996;74(2):485 244. Mansy H, Khalil A, Aly TF, Filobbos P, al-Dusari S, al-Shareef Z, Shlash S. Outcome of commercial renal transplantation: two years follow-up. Nephron. 1996;74(3):613-6 . 245. Shaheen FA.M, Souqiyyeh M Z, Al-Attar B, Jaralla A, Al-Swailem. Survey of opinion of secondary school students on organ donation. Saudi J Kidney Dis Transplant 1996;7(2):131134 246. Altraif IH., Al Sebayel MI., Nondo H. Knowledge and attitude towards organ donation among males in Riyadh, Saudi Arabia. Saudi J Kidney Dis Transplant 1996;7(2):135-138 247. Al-Khader AA,. Al-Sulaiman M H, Mousa D H., Al-Hawas F. Some of the lessons learnt from renal transplant recipients cared-for at the Riyadh Armed Forces hospital. Saudi J Kidney Dis Transplant 1996; 7(2):139-144 248. Mansy H, Al-Shareef Z, Shlash S, P. Filobbos, Al-Dusari S, Ghsib S. Initiating a new renal transplant program: problems and results. Saudi J Kidney Dis Transplant 1996;7(2):145-148 249. Al-Dayel A, Ezzibdeh M, Daoud M, Egail S, Guella A, Al-Oraifi I, El-Sayed E, Abu Z A. Experience with renal transplantation in the Eastern Province of Saudi Arabia. Saudi J Kidney Dis Transplant 1996;7(2):149-152 250. Shaheen FAM, Sheikh IA, Fallatah A, Shehab AB, Al-Menawy L, Awad A, Nezamuddin N. Renal transplantation at the Jeddah Kidney Center. Saudi J Kidney Dis Transplant 1996;7(2):153-156 251. Huraib S, Al-Khudair W, Saleem H, Quadri K, Abu Romeh S, Chaballout A, Nezamuddin N, Saed R, Duarte R. Renal transplant experience at King Fahad National Guard hospital. Saudi J Kidney Dis Transplant 1996;7(2):157-163 252. Sidahmed Mohammed A, Al-Hjashemy A, Addous A J, Ismail G. The southern region renal 81 transplant program at Armed Forces Hospital, Khamis Mushayt. Saudi J Kidney Dis Transplant 1996;7(2):164-167 253. Hussein M, Mooij J, Roujoulh H. Complications in kidney transplant recipients: a single center experience. Saudi J Kidney Dis Transplant 1996;7(2):168-172 254. Al-Khudair W, Abu-Romeh S, Mansi M.K., Huraib S. An unusual cause of recurrent bacteriuria in a kidney transplant recipients. Saudi J Kidney Dis Transplant 1996; 7(4):398400 255.Al-Khader A, Shaheen FA, Souqiyyeh MZ, Attar MB, Babiker AQ, Ibrahim SM, Babiker MA, al-Swailem AR. Reasons for unused retrieved organs in the cadaveric organ donation program in Saudi Arabia. Transplant Proc. 1996 Feb;28(1):186-7 . 256. Shaheen FA, Souqiyyeh MZ, Attar MB, al-Swailem AR. The Saudi Center for Organ Transplantation: an ideal model for Arabic countries to improve treatment of end-stage organ failure.Transplant Proc. 1996 Feb; 28(1):247-9 . 257. Shaheen FA, Souqiyyeh MZ, Attar MB, Ibrahim SM, al-Khader A, Babiker AQ, al-Swailem AR. Multiorgan donation from brain-death cases in the Kingdom of Saudi Arabia. Transplant Proc. 1996 Feb;28(1):250. 258. Souqiyyeh MZ, Paul TT, Ramprasad KS, Attar MB, Asim G, Ibrahim SA, Babiker MA, Qayum A, Tayeb A, Ikram M, al-Khanani H, Shaheen FA. Role of computers in coordination of renal care facilities: experience in the Kingdom of Saudi Arabia. Transplant Proc. 1996 Feb; 28(1):252-3 . 259. Shaheen FA, Ramprasad KS. Current status of organ transplantation in Saudi Arabia. Transplant Proc. 1996 Jun; 28(3):1200-1. 260. Hussein MM, Mooij JM, Roujouleh H, el-Sayed H. Commercial living-non-related renal transplantation: observations on early complications.Transplant Proc. 1996 Jun; 28(3):1941-4 . 261. Souqiyyeh M Z , Al-Khader AA., A.M. S F, Huraib SO, Al-Harbi M. Pediatric renal transplantation in Saudi Arabia. Saudi J Kidney Dis Transplant 1997;8(3):302-309 262. Qunibi W, Al-Furayh O, Almeshari K, Lin SF, Sun R, Heston L, Ross D, Rigsby M, Miller G.. Transplantation. 1998 Feb 27;65(4):583-5. 263. Alshaibani K, Raza S, Alfurayh O, Almeshari K, Qunibi W, Alahmadi I, Alsabban E, Sanjad S. The kidney transplant program at King Faisal Specialist Hospital and Research Center: results of the last 10 years. Transplant Proc. 1998 Nov; 30(7):3103-5. 264.Shaheen FA, al Sulaiman M, Mousa D, el Din AB, Hawas F, Fallatah A, Bill P, Sheikh IA, al Menawy L, Ramprasad KS, al-Khader AA. Impact of donor/recipient gender, age, HLA matching, and weight on short-term graft survival following living related renal transplantation. Transplant Proc. 1998; 30(7):3655-8. 265. al Baba MA, Shaheen FA, Sheikh IA, Nivien K, Alkhader A, Fallatah A. Experience of Jeddah Kidney Center in pediatric renal transplantation. Transplant Proc. 1998 Nov;30(7):3679-80 . 266. Shaaban AA. Incidence and types of malignant tumors in renal transplant recipients: a single center experience. Saudi J Kidney Dis Transplant 1998; 9(2):116-122 267. Al Ghamdi G, Awada A,. Tanimu DZ,. Huraib SO, Abu Romeh S, Quadri K, Al Khudair W, Iqbal A. Neurological Disorders in Renal Transplant Recipients. Saudi J Kidney Dis Transplant 1998;9(4):435-439 268. Said M T, Abomelha M S, Al Otaibi KE, Orkubi SA, Kourah M A, Shaaban AA. Urological complications of cadaveric renal transplantation. Saudi J Kidney Dis Transplant 1999;10(1):36-40 269. Souqiyyeh M Z , Shaheen F A.M., Sheikh IA, Al-Khader AA, Fedhail H , Al-Sulaiman M , Mousa D, Al-Hawas F. Hypertension in renal transplantation: Saudi Arabian experience. Saudi J Kidney Dis Transplant 1999;10(4):470-480 270. Bernieh B, Nezamuddin N Sirwal IA, Wafa A, Abbade MA, Nasser B, Al Razzaz Z Shortterm post renal transplant follow-up at Madinah Al Munawarah . Saudi J Kidney Dis 82 Transplant 1999; 10(4):493-497. 271. Al-Khader AA. Cadaveric renal transplantation in the Kingdom of Saudi Arabia . Nephrol Dial Transplant. 1999 Apr; 14(4):846-50 . 272. al-Khader AA, Shaheen F. Strategies for increasing transplantation: the Saudi experience. Transplant Proc. 1999 Dec; 31(8):3278 . 273. Shaheen FA, Souqiyyeh MZ. Factors influencing organ donation and transplantation in the Middle East.Transplant Proc. 2000 May; 32(3):645-6. 274. Souqiyyeh M Z , Shaheen F A.M., Sheikh IA, Al-Khader AA, Fedhail H , Al-Sulaiman M , Mousa D, Al-Hawas F. Diabetes and Renal Transplantation: Saudi Experience. Saudi J Kidney Dis Transplant 2000; 11(1):25-30 275. Shaheen FA, Souqiyyeh MZ, Shiek IA, Fedhail H, al-Sulaiman M, Mousa D, al-Hawas F, alKhader AA. Hypercholesterolemia in renal transplantation. Ann Transplant. 2001;6(4):9-13 . 276. Almuneef M, Nimjee S, Khoshnood K, Miller G, Rigsby MO. Prevalence of antibodies to human herpesvirus 8 (HHV-8) in Saudi Arabian patients with and without renal failure. Transplantation. 2001 Apr 27;71(8):1120-4 . 277. Al-Attar B, Shaheen FA, Souqiyyeh MZ, Babiker AQ, Ahmed H. Brain death and organ donation in Saudi Arabia. Transplant Proc. 2001 Aug;33(5):2629-31. 278. Shaheen FA, Souqiyyeh MZ, Ramprassad K, Attar MB. Transplant Proc.2001 Aug; 33(5):2641. 279. Hussein M M, Mooij J M., Roujouleh H M. Regression of post-transplant Kaposi's sarcoma after replacing cyclosporine with mycophenolate mofetil Saudi J Kidney Dis Transplant 2001;12(1):42-44 280.Shaheen FA, Sheikh IA, Awad A, Fallatah AB, Gendoo MZ, Samaha H, Shahat O, Rizvi RH, Ramprasad KS. Transplant Proc. 2002 Sep; 34(6):2454-5. 281.Huraib S, Al Khudair W., Al Ghamdi G., Iqbal A. Post transplant acute tubular necrosis how long you can wait?: a case report. Saudi J Kidney Dis Transplant 2002;13(1):50-54 282. Shaheen FA, Sheikh IA, Awad A, Fallatah AB, Gendoo MZ, Samaha H, Shahat O, Rizvi RH, Ramprasad KS. Use of marginal donors for kidney transplantation. Transplant Proc. 2002 Sep; 34(6):2454-5 . 283. Alkhunaizi AM, Amir A, Yousif B. Renal transplantation at Saudi Aramco. Transplant Proc. 2003; 35(7):2596-7 . 284. Al-Ibrahim A, Sanjed S, Al-Abbad A, Al-Sabban E, Al-Shaibani K. Post renal transplantation tubulopathies in children: a 9-year experience at a tertiary care center. Saudi J Kidney Dis Transplant 2004; 15(1):27-33 285. Shaheen FA, Souqiyyeh MZ. Current status of renal transplantation in the Kingdom of Saudi Arabia. Transplant Proc. 2004; 36(1):125-7 . 286. Shaheen FA, Souqiyyeh MZ. How to improve organ donation in the MESOT countries. Ann Transplant. 2004; 9(1):19-21 . 287. Shaheen FA, Souqiyyeh MZ. Increasing organ donation rates from Muslim donors: lessons from a successful model. Transplant Proc. 2004; 36(7):1878-80 . 288. Jumani A, Hala K, Tahir S, Al-Ghamdi G, Al-Flaiw A, Hejaili F, Qureshi J, Raza H, Ghalib M, Khader AA. Causes of acute thrombotic microangiopathy in patients receiving kidney transplantation. Exp Clin Transplant. 2004; 2(2):268-72 . 289.Souqiyyeh M Z , Shaheen F A.M., Sheikh IA, Al-Khader AA, Fedhail H , Al-Sulaiman M , Mousa D, Al-Hawas F. Post-renal transplant proteinuria: The Saudi Experience. Saudi J Kidney Dis Transplant 2005; 16(4):556-561 290. Shaheen FA, Kurpad R, Al-Attar BA, Muna B, Al-Khader AA. Comparative psychosocial analysis of patients on maintenance hemodialysis and transplanted patients. Ann Transplant. 2005;10(1):17-21. 291. Al Shehri S, Shaheen FA, Al-Khader AA. Organ donations from deceased persons in the Saudi Arabian population. Exp Clin Transplant. 2005; 3(1):301-5. 83 292. Alzahrani AJ, El-Harith el-HA, Milzer J, Obeid OE, Stuhrmann M, Al-Dayel A Mohamed EA, Al-Egail S, Daoud M, Chowdhury A, Guella A, Aloraifi I, Schulz TF..Nephrol Dial Transplant. 2005 Nov;20(11):2532-6. 293. Shaheen FAM, Basri N, Mohammed Z, Abdullah K, Haider R, Awad A, Nasser A, El Gabarty A. Experience of Renal Transplantation at the King Fahd Hospital, Jeddah, Saudi Arabia. Saudi J Kidney Dis Transplant 2005; 16(4):562-572 294. Al Meshari K. The kidney transplant program at King Faisal Specialist Hospital and Research Center. Saudi J Kidney Dis Transplant 2005; 16(4):586-597 Disclaimer These Guidelines are based upon the best information available at the time of publication. They are designed to provide information and assist decision-making. They are not intended to define a standard of care, and should not be construed as one. Neither should they be interpreted as prescribing an exclusive course of management. Variations in practice will inevitably and appropriately occur when clinicians take into account the needs of individual patients, available resources, and limitations unique to an institution or type of practice. Every healthcare professional making use of these Guidelines is responsible for evaluating the appropriateness of applying them in the setting of any particular clinical situation. 84