Medical Management After Organ Transplantation

Phil Gauthier MD Medical Director, Kidney and Pancreas

Transplant Program February 8th, 2013

Disclosures

• Speaker’s bureau Novartis Pharmaceuticals (Myfortic) • I will NOT discuss off-label use of medications • I am receiving a free hotel room (1 night) to give this talk.

– ? And lunch

Objectives: at the conclusion of this talk, the recipient should be able to:

• Describe current standard immunosuppression • Discuss approach to acute kidney allograft dysfunction • Be familiar with the common causes of late kidney graft

loss • Know the indication and contraindications to vaccinations

in solid organ transplant (SOT) recipients • Be aware of risks of and guidelines for the screening of

malignancies in SOT recipients • Be able to manage an uncomplicated URI in a SOT

recipient

The most common cause of late (> 1 year) loss of a kidney transplant is:

1. Death of the patient 2. Chronic allograft

dysfunction 3. Acute rejection 4. Other 5. Both 1 and 2 are equally as

common

8%

41%

6%9%

36%

1 2 3 4 5

25

Flu vaccine should be given to solid-organ transplant recipients:

1. At start of season 2. At start of season if at least

1 month post-transplant 3. At start of season if at least

6 months post-transplant 4. Never

59%

20% 20%

1%

1 2 3 4

11

The risk of which of the following cancers is increased the most after SOT?

1. Skin 2. Kaposi’s 3. Mouth 4. Lymphoma 5. All of the above

44%

1% 0%

30%

25%

1 2 3 4 5

6

Which is the following is the biggest risk for chronic rejection in kidney transplant

recipients (KTRs)? 1. Poorly matched kidney 2. Delayed graft function 3. Non-adherence 4. Donor/recipient size

mismatch

7%14%

78%

1%

1 2 3 4

9

Adults With a Functioning Kidney Transplant

SRTR 2010 Annual Report www.srtr.org

Total Kidney Transplants

SRTR 2010 Annual Report www.srtr.org

Waitlist

SRTR 2010 Annual Report www.srtr.org

Living Donors

SRTR 2010 Annual Report www.srtr.org

Deceased Donors

SRTR 2010 Annual Report www.srtr.org

Transplant Rates

SRTR 2010 Annual Report www.srtr.org

Centers

SRTR 2010 Annual Report www.srtr.org

Transplant is Cost-Effective

Loubeau P et al Prog in Trans 2001(11)

8 transplant centers in NYC 1998 data

Savings after 34 months = $3800 per month Average graft survival = 10 years Total savings = $326,800

Immunosuppression: Current State

• At discharge: – 94% on a calcineurin inhibitor 79% tacrolimus 15% cyclosporin

– 87% on mycophenolate (CellCept or Myfortic) – 26% steroid-free

• Maintenance (1 year and beyond) – 99% on calcineurin inhibitor – 87% mycophenolate – 20% steroid-free

OPTN/SRTR annual report

Immunosuppression: Steroid free

• Suggest that in low-risk patients who receive induction, steroids can be withdrawn during the first week post-transplant (2B)*

– Should not be routine – May lead to more rejection – Minimal improvement in adverse effects compared to 5mg

daily (usual baseline dose) • Steroids should NOT be withdrawn more than 6-months post

transplant

*AJT 2009 (9 suppl 3): KDIGO

Steroid Free

• Woodle et al Ann Surg 2008(4) • Placebo controlled, double blind, compared prednisone

5mg daily to placebo, 5 year f/u • Significant benefits:

– Less diabetes, osteoporosis, avascular necrosis, weight gain

• Significant risks: – More rejection, more fibrosis on biopsies (although no

difference in graft function at 5 years.)

Woodle et al Ann Surg 2008(4)

Acute Allograft Dysfunction

• Divided into: – Immediate: initial hospitalization – Early: 1-12 weeks post transplant – Late: more than 12 weeks post transplant

• Helpful to think in terms of pre-renal, post-renal, and intrinsic renal

• Any increase of creatinine ≥ 20% should prompt investigation

• Creatinine should be checked AT LEAST every month in first year, AT LEAST every 3 months thereafter

• Be aware that creatinine may vary between labs

Acute Allograft Dysfunction

• Labs use “IDMS (isotope dilution mass spectrometry)” or not.

• IDMS normal= 0.66- 1.25 mg/dl

• Non-IDMS normal = 0.8-1.5

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

1.8

Cre

atin

ine

Serum creatinine over time

Acute Allograft Dysfunction: pre-renal

• Kidney adapts to hypovolemia via afferent arteriolar dilation and efferent arteriolar constriction

• To some extent mediated via the sympathetic nervous system (in addition to renin/angiotensin/aldosterone axis)

• Transplanted kidney is denervated.

• Less able to auto-regulate • Patients have often been fluid

restricted for years.

Acute Allograft Dysfunction: pre-renal

Acute Allograft Dysfunction: pre-renal

• Tacrolimus causes decreased glomerular perfusion • Dose- and level- dependent • Particularly holds in non-kidney transplant recipients

– Denervated kidney LESS susceptible to effect • Tacrolimus level should always be obtained with creatinine

Gaston R S CJASN 2009;4:2029-2034

Acute Allograft Dysfunction: post-renal

• Similar to general population, EXCEPT: – High rate of neurogenic bladder in diabetics – Unmasked prostate disease – Transplant ureteral stenosis Perfusion Infections (polyoma)

Acute Allograft Dysfunction: Intrinsic

• Rejection – Late acute rejection usually associated with non-

adherence • Recurrent native disease

– May recur: FSGS, diabetic nephropathy, IgA, MPGN, unknown

• Infection – Polyoma – CMV

Acute Rejection: Adherence

146 patients, adherence measured at 1 year, then group followed prospectively. 22.6% were non-adherent at 1 year. Nearly 3-fold risk of late acute rejection in non-adherent group, 21.2% vs. 8%

Valminck et al AJT 2004 (4)

Adherence

Note that “good” adherence is not good enough. Non-adherent groups cost $33,000 more over 3 years

Pinsky et al AJT 2009 (9) 2597-2606 N=15525

Acute Allograft Dysfunction: Approach

Biopsy

Ultrasound

Hydrate and repeat in 72 hours

Check tacrolimus or cyclosporin level

Tacro: 4-8 Cyclo: 100-150

Level too high: adjust dose, repeat labs in 1 week

Improved, remind patient to drink 3-4 liters water/day

Treat findings, biopsy for elevated resistive indices

Treat findings in consultation with transplant program

50% Death With a Functioning Graft

Pascual M, et al. N Engl J Med 2002;346:580-9 Lindholm A, et al. Transplantation 1995;60:451-7

37% Infection Malignancy Other

62.9% Cardiovascular Disease

16.1% Vascular Event

83.9% Ischemic Heart Disease

50% Chronic Kidney Allograft Dysfunction

Causes of Late Graft Loss

Chronic Allograft Dysfunction

“Input” Donor age

Living vs. deceased Cold ischemia/DGF

Donor quality

Early insults Rejection

ATN Obstruction

HTN Diabetes Medication toxicity Infection Recurrent disease Hyperfiltration Donor/recipient size mismatch Initial function

Non-immunologic Immunologic

Acute rejection Chronic rejection Donor-specific antibodies

Initial Function

Chronic Allograft Dysfunction/injury

Chronic Rejection

Consecutive transplants 1/99-12/08

n=392

dnDSA (n=47)

Acute dysfunction dnDSA (n=14)

Indolent dysfunction dnDSA (n=15)

Stable function dnDSA (n=18)

No dnDSA (n=268)

Dysfunction No dnDSA

(n=55)

Stable function No dnDSA

(n=213)

Excluded (n=77) DSA pre-transplant (n=30) Primary non-function (n=11) Moved (n=14) Death with function (n=22)

Wiebe et al. AJT 2012 (12)

dnDSA= De novo donor-specific antibodies

Acute dysfunction = >25% rise in creatinine in < 2 months Indolent dysfunction = >25% rise in creatinine in > 2 months OR proteinuria > 0.5 g /24 hours

Chronic Rejection

Adapted from Wiebe et al. AJT 2012 (12)

Chronic Allograft Dysfunction: Approach

• Assess and optimize adherence • Consider biopsy

– Acute rejection can occur – Infection can occur, particularly polyoma

• Consider DSA, although seems more useful as a prognostic factor

Vaccination

• Kidney transplant recipients should receive all approved, inactivated vaccines according to the schedule for the general population (1D)

• No live vaccines (2C) • Avoid vaccines, except for influenza, for the first 6 months

after transplant (2C) • Influenza vaccine is recommended at start of season for all

KTR’s at least 1 month post-transplant (1C) • Main issue is not harm, but lack of benefit

AJT 2009 (9 suppl 3)

Vaccination

Adapted from Crespo et al CJASN 2011 (6) Seroconversion in controls = 9/11 (81.8%)

Seroconversion to H1N1 vaccine

Vaccination

• Recommended: – DPT – HiB – Hep A (for travel to endemic regions) – Hep B – Pneumovax – Inactivated polio – Influenza – Meningococcus, if high risk

AJT 2009 (9 suppl 3)

Vaccination

• NOT recommended: – Varicella (give pre-transplant if non-immune) – Zostavax (give pre-transplant) – BCG – Intranasal influenza – Live oral typhoid – MMR – Oral polio – Yellow fever

AJT 2009 (9 suppl 3)

Cancer

• In general, data on transplant patients is mixed

• Higher rates of skin cancer, lymphoma • Slightly higher rates of solid tumors • Despite that, death rates from cancer are

lower than in the general population, although higher than in dialysis.

Cancers With Increased RR in KTR’s*

Adapted from Kasiske BL et al AJT 2004 *Compared to wait-listed patients. N=42,201

Cancer: Recommendations

• KTRs should minimize life-long sun exposure (1D) • KTRs should perform skin and lip self-exams and report

changes to HCP (2D) • KTRs should have an annual exam by a HCP experienced

in diagnosing skin cancers, except possibly those with dark skin (2D)

• Screen for other cancers as per local guidelines for the general population (not graded)

AJT 2009 (9 suppl 3)

Upper Respiratory Infections

• Seasonality is similar to general population • Atypical presentations of pneumonia may be seen • Viral shedding may be prolonged • High risk of infectious complications

– In some studies there was a >50% rate of progression to lower tract involvement1,2

1. Ison MG et al Curr Opin Organ Transplant 2005 (10)

2. Ison MG et al Curr Opin Infect Dis 2002(15)

Upper Respiratory Infections

• Based on limited data anti-virals for influenza are safe and effective

• Therapy should be extended beyond 5 days, although no good data on duration

• Low threshold for anti-bacterials – No macrolides. Can raise prograf levels, azithro/tacro

combo can cause QT prolongation – Floroquinolones drug of choice Usually reduce dose Higher risk for tendon rupture in patients on steroids

Transplant Options for Type 1 Diabetics • Dialysis • Kidney transplant

– Living donor – Deceased donor

• Simultaneous kidney-pancreas transplant – Deceased donor

• Living donor kidney, pancreas after kidney – Deceased donor pancreas 6-12 months after living

donor kidney

Pancreas Transplant: Technique

Improvement in Life Expectancy for Type 1 Diabetics After Transplant

Morath C et al Clin J Am Soc Nephrol 2010 95)

Pancreas Alone

Gruessner et al Transplantation 2008 (85)

Thank You!