1. Kidney Transplantation– Medical, Surgical, and Immunologic Considerations Anil Kapoor, MD, FRCS(C) Associate Professor of Surgery McMaster University

2. OBJECTIVES Transplant immunology Acute and Chronic Rejection How does a transplant program work ? Indications for renal transplant Patient selection Technical/ Surgical considerations in renal transplant

3. Background DEMOGRAPHICS OF THE TRANSPLANT WAITING LIST TRANSPLANT DONOR & RECIPIENT WORK UP TRANSPLANT SURGERY TRANSPLANT IMMUNOLOGY ( REJECTION ) POST TRANSPLANT ISSUES HLA/ CROSS MATCH

4. Single kidney transplants by organ source, Canada, 1990-1999 (Number) Source: CORR/CIHI 2001

5. Comparison of cadaveric organ donation rates, Canada and Provinces, 1998 -2000 (Rate per million population 1 ) 1 Crude rate Source: CORR/CIHI 2001

6. International comparison of cadaveric organ donation rates, 1999 (Rate per million population 1 ) 1 Crude rate. Sources: CORR/CIHI 2000; United Network for Organ Sharing (UNOS); Organizacion Nacional de Trasplantes in Spain; Australia & New Zealand Organ Donation Registry.

7. Cadaveric donor cause of death, Canada, 1999 1 Includes cerebrovascular accident, ruptured cerebral aneurysm and spontaneous cerebral haemorrhage. 2 Motor vehicle collision Source: CIHI/CORR 2001

8. Cadaveric donors by gender and average age, Canada, 1992-1999 Source: CIHI/CORR 2001

9. Actual cadaveric, potential cadaveric and living organ donors, Provinces, 2000 (Rate per million population 1 ) 1 Crude rate. Source: CIHI/CORR 2001

10. Bertram L. Kasiske

39. John M. Barry

46. Angelo M. de Mattos

47. Laurence Chan

53. Medical Issues following Renal Transplantation Cardiovascular Disease Hypertension Bone Disease Infection and malignancy

54. Ischemic Heart Disease After Kidney Transplantation Nature of the Problem Registry and retrospective studies consistently show  ~ 4 fold  in major coronary events vs general population  ~ 2 fold coronary fatality rate vs general population  reported annual major cardiac event rates vary widely (0.4- 3.0%) By 15 yrs post transplant 23% rate of IHD, 15% cerebrovascular disease and 15% PVD.

55. Meier-Kriesche KI April 2001 Cardiovascular Mortality Wait listed vs Transplanted

56. Event Rates Lindholm 1995: -11% of grafts were lost 2-5 yrs post transplant -death with function accounts for 49% of graft loss -53% of deaths were due to IHD Kasiske 1996: -23% of pts have an ischemic event within 15 yrs of transplant.

57. Relative Risk Incident IHD FHS Variables Men and Women Surviving > 1 year (n=1124) Variable (%) RR(95% CI) Age (yr)1.06(1.04-1.08) Diabetes* (0.18)2.78(1.73-4.49) Smoking (0.25)1.95(1.20-3.19) Cholesterol >5.2 (0.77)2.18(1.01- 4.72) BP 140-1591.68(0.56-2.55) BP >1601.86(0.61 -3.55) *female diabetic RR 5.40 (2.73-10.66)

58. Cardiovascular Disease After Renal Transplantation Summary- Kasiske 2000 1.Most comprehensive analysis of CV risk after transplantation. 2.Unusually low event rate and single centre analysis limits the generalizability of the findings. 3.Older diabetics, especially women, are at highest risk. 4.Hyperlipidemia and smoking emerge clearly as important risk factors. 5. Hypertension was not a significant factor contributing to IHD in this population. 6.Dihydropyridine calcium antagonists and higher CV risk requires further study, particularly with new antihypertensive agents.

59. Treatment of Hyperlipidemia General Population Meta analysis of statin trials (JAMA 1999;282:2340) 1.5 RCT’s of 30,817 patients followed for 5.4 years 2.Treatment  TC 20%,  LDL-C 28%,  TG 13%,  HDL- C 5% 3.Reduced relative risk for major coronary events (31%) and all cause mortality (21%) 4.Benefit seen in those with and without a history of heart disease, men and women and both young and older patient

60. Hypertension After Renal Transplantation Causes Calcineurin Inhibitors Steroids Renal Dysfunction RAS Native Kidneys Essential Hypertension etc

61. Post Transplant Hypertension 1.Graded independent relationship between degree of systolic and diastolic hypertension and graft loss. 2.Relationship persists when patient death is either considered graft loss, or is censored. 3.Independent association between blood pressure control at 1 year and all cause mortality. 4. Kasiske’s data fails to demonstrate an association between HTN and atherosclerotic disease.

62. Treatment of Post Transplant Hypertension Calcium channel blockers Reduce calcineurin inhibitor induced afferent arteriolar vasoconstriction and may reduce nephrotoxicity. JASN 1999 : nifedipine resulted in improved renal function compared to lisinopril with equivalent BP control. Ace inhibitors Reduce proteinuria (compared to betablocker Hypertension 1999). Reduce post transplant erythrocytosis.

63. Prevention of Cardiovascular Disease After Renal Transplantation Prevention and treatment of diabetes Smoking cessation Aggressive lipid control - our current target for >1 risk factor is LDL<2.5 Treatment of hypertension (LVH / CHF / graft dysfunction) ASA and other anti-platelet agents Further information on risk factor modification is required for the renal transplant population.

64. Natural History of Bone Loss Following Transplantation Corticosteroid-induced osteoporosis Prednisone dose > 7.5mg / day In non-transplant populations the rate of bone loss due to corticosteroids is 3 - 4% over one year ( NEJM 1997 ). Renal transplant recipients lose 7 - 10% of BMD in the first year, and 1 -2% per year thereafter.

65. 20 adult LRD renal transplants 11 pre-emptive transplants, 9 transplants 11±22 months on dialysis BMD decreased 6.8% first 6 months, then 2.6% in the subsequent 12 months Biopsies showed resolution of secondary hyperparathyroidism, and a reduction in the amount of bone replaced during each remodelling cycle. We now recognize this bone loss to be predominanty due to the effects of corticosteroids on bone. Bone Loss - Julian et al, NEJM 1991

66. Treatment of Osteoporosis Post Transplant Post menopausal women, patients with osteoporosis or osteopenia should be considered for bisphosphonate therapy (treatment and prophylaxis) when starting prednisone. Patients who will receive very high dose steroids should be considered for prophylaxis. Patients with normal baseline bone density should be considered for therapy with calcitriol.

67. Meier-Kriesche Transplantation 2000 Relative Risk of Infectious Death and Acute Rejection

68. Connie L. Davis

71. Medical Management of the Renal Transplant Recipient 2002 -Summary- Cardiovascular Disease remains the major cause of morbidity and mortality following transplantation. The traditional risk factors for CVD do not apply to this population in the same way that they do for the general population. We have reasonable strategies for bone disease following transplantation. Over immunosuppression in the elderly leads to increased morbidity due to infection and perhaps malignancy.

72. Medical Management of the Renal Transplant Recipient 2002 -Comments- Care of the renal transplant recipient is becoming less an issue of adequate immunosuppression and more an issue of CKD in the face of drugs which worsen many medical conditions. We recognize the efforts of primary nephrologists and the multidisciplinary teams that they work with, in preparing patients for renal transplant and following their medical course following transplantation.