Kidney Transplantation– Kidney Transplantation– Medical, Surgical, and Immunologic Medical, Surgical, and Immunologic

ConsiderationsConsiderations

Anil Kapoor, MD, FRCS(C)Anil Kapoor, MD, FRCS(C)

Associate Professor of SurgeryAssociate Professor of Surgery

McMaster UniversityMcMaster University

OBJECTIVESOBJECTIVES

Transplant immunologyTransplant immunology

Acute and Chronic RejectionAcute and Chronic Rejection

How does a transplant program work ?How does a transplant program work ?

Indications for renal transplantIndications for renal transplant

Patient selectionPatient selection

Technical/ Surgical considerations in renal transplantTechnical/ Surgical considerations in renal transplant

BackgroundBackground

DEMOGRAPHICS OF THE TRANSPLANT WAITING LISTDEMOGRAPHICS OF THE TRANSPLANT WAITING LIST

TRANSPLANT DONOR & RECIPIENT WORK UPTRANSPLANT DONOR & RECIPIENT WORK UP

TRANSPLANT SURGERYTRANSPLANT SURGERYTRANSPLANT IMMUNOLOGY ( REJECTION )TRANSPLANT IMMUNOLOGY ( REJECTION )

POST TRANSPLANT ISSUESPOST TRANSPLANT ISSUES

HLA/ CROSS MATCHHLA/ CROSS MATCH

Single kidney transplants by organ source, Canada, 1990-1999

(Number)

0

100

200

300

400

500

600

700

800

Nu

mb

er

ofo

rga

ns

Cadaveric Organs 699 708 598 713 702 717 676 684 629 631

Live Organs 118 132 149 178 209 223 261 285 364 379

1990 1991 1992 1993 1994 1995 1996 1997 1998 1999

Source: CORR/CIHI 2001

Comparison of cadaveric organ donation rates, Canada and Provinces, 1998 -2000 (Rate per million population1)

0

5

10

15

20

25

CAN AB ATL BC MB ON QC SK

Ra

te p

er

mill

ion

po

pu

latio

n

1998 1999 2000

1Crude rate

Source: CORR/CIHI 2001

International comparison of cadaveric organ donation rates, 1999 (Rate per million population1)

1Crude rate.

Sources: CORR/CIHI 2000; United Network for Organ Sharing (UNOS); Organizacion Nacional de Trasplantes in Spain; Australia & New Zealand Organ Donation Registry.

13.8

8.6

14.415.9 16.5 16.2

12.7 13.7

33.6

13.015.5

12.1

21.4

0.0

5.0

10.0

15.0

20.0

25.0

30.0

35.0

40.0

CAN AUS CHE CZE FIN FRA DEU ITA ESP GB/IE NOR SWE USA

Rat

e pe

r m

illio

n po

pula

tion

Cadaveric donor cause of death, Canada, 1999

MVC (2)22%

Other/Unknown10%

Head Trauma not MVC8%

Anoxia6% Intracranial event

(1)54%

1 Includes cerebrovascular accident, ruptured cerebral aneurysm and spontaneous cerebral haemorrhage.

2 Motor vehicle collision

Source: CIHI/CORR 2001

Cadaveric donors by gender and average age, Canada, 1992-1999

0

10

20

30

40

50

60

% m

ale

0

5

10

15

20

25

30

35

40

45

Avera

ge a

ge (y

ears

)

% male 60 53 57 54 54 54 59 52

Average age 34 35 37 37 38 37 42 40

1992 1993 1994 995 1996 1997 1998 1999

Source: CIHI/CORR 2001

Actual cadaveric, potential cadaveric and living organ donors, Provinces, 2000 (Rate per million population1)

0.0

10.0

20.0

30.0

40.0

50.0R

PM

P

Actual Cadaveric 9.4 18.7 12.7 17.4 14.1 18.3 20.2

Potential Cadaveric 9.8 23.0 12.7 20.0 19.6 21.4 24.8

Living Donor 19.9 15.3 7.8 12.2 15.7 4.1 18.5

Actual+Living 29.3 34.0 20.5 29.6 29.8 22.4 38.7

Potential + Living 29.8 38.4 20.5 32.2 35.3 25.5 43.4

BC AB SK MB ON QC ATL

1Crude rate.

Source: CIHI/CORR 2001

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

Bertram L. Kasiske

John M. Barry

John M. Barry

John M. Barry

John M. Barry

John M. Barry

Angelo M. de Mattos

Laurence Chan

Laurence Chan

Laurence Chan

Laurence Chan

Laurence Chan

Medical Issues following Renal Transplantation

• Cardiovascular Disease

• Hypertension

• Bone Disease

• Infection and malignancy

Ischemic Heart DiseaseAfter 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.

•

Meier-Kriesche KI April 2001

Cardiovascular Mortality Wait listed vs Transplanted

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.

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 140-159 1.68 (0.56-2.55)• BP >160 1.86 (0.61 -3.55)• *female diabetic RR 5.40 (2.73-10.66)

Cardiovascular DiseaseAfter 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.

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

Hypertension After RenalTransplantation

• Causes

• Calcineurin Inhibitors• Steroids• Renal Dysfunction• RAS• Native Kidneys• Essential Hypertension etc

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.

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.

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.

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.

• 20 adult LRD renal transplants11 pre-emptive transplants, 9 transplants 11±22 months on dialysis

BMD decreased 6.8% first 6 months, then 2.6% in the subsequent 12 monthsBiopsies 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

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.

Meier-Kriesche Transplantation 2000

Relative Risk of Infectious Death and Acute Rejection

Connie L. Davis

Connie L. Davis

Connie L. Davis

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.

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.