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!