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Kidney Transplant

November 4th, 2016

Brad West, MD, FACPMedical Director of Transplant Services,

Memorial Medical CenterChairman Department of Nephrology,

Springfield Clinic

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Incident dialysis patients & patients receiving a first transplant in the calendar year. All probabilities are adjusted for

age, gender, & race; overall probabilities are also adjusted for primary diagnosis. All ESRD patients, 1996, used as

reference cohort. Modality determined on first ESRD service date; excludes patients transplanted or dying during the

first 90 days.

Adjusted survival: 1993-1997 incident patients

Transplant has better outcomes than Dialysis

http://www.usrds.org/2007/pdf/06_hosp_morte_07.pdf

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Benefit of transplant versus waiting list?

Age Without Transplant

With Transplant

Difference

0-19 26 y 39 y 13 y

20-39 14y 31y 17y

40-59 11y 22y 11y

60-74 6y 10y 4y

Wolfe et al, NEJM 1999;341:1725

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GFR distribution by year transplant

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Segev et al. JASN 2011

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KI 1.5 Characteristics of adult patients on the kidney

transplant waiting list on December 31, 2002 & December 31,

2012

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Post Transplant Diabetes Risk

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Kuypers et al. Nephrol Dial Transplant 2008

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KI 6.11 Post-transplant diabetes

among kidney transplant recipients by BMI

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BMI at MMC40% Diabetic

0

5

10

15

20

25

30

35

40

45

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0 20 40 60 80 100 120 140 160 180 200

BMI

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Post Transplant Diabetes (PTDM)

Risk factors for PTDM

• BPAR

• Steroid use

• Tacrolimus

• Family history

• Improved Kidneys

• BMI

• Age

• Result of PTDM

– Patient overall survival

– Kidney transplant survival

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KI 4.1 Total kidney transplants Nationwide

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KI 1.10 Three-year outcomes for adult patients waiting

for a kidney transplant among new listings in 2009

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KI 1.1 Adult patients waiting for a kidney transplant

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KI 3.1 living donors, by donor relation

Living donors key to shortening wait times

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KI 3.5 living kidney donor complications

Low complication rates

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KI 6.7 Half-lives for adult kidney transplant recipients

…..Living Kidneys Work better!

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Evaluation for Transplant

• EKG

• CXR

• Blood work

– ABO (blood type)

– Tissue Typing (HLA)

– Viral Serology

• Standard Cancer screening

– Colonoscopy

– Prostate

– Pap / Mammogram

• Other diagnostic testing (as needed)

– Cardiac Tests

– Urological tests

– Pulmonary Tests

– Frailty testing

• Vaccinations

– Pneumonia

– Influenza

– Shingles

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Kidney Transplant Surgery

• The transplanted kidney is attached to the blood supply– Artery

– Vein

• The ureter (urine draining tube) is attached to your bladder

• Surgery lasts about

3 – 4 hours

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Brief Case

• 30 year old man on dialysis for 1 year got a transplant with IL2 induction

• He developed 102.2 F fever on day 2, and urine decreased 6 hours later

• Preoperative immunological studies

– HLA 0/6 match

– PRA 6% (DR9)

– Flow Cross-match negative

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KI 6.9 Incidence of first acute rejection among adult

patients receiving a kidney transplant in 2006–2010

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Transplant History

– 1950 Ruth Tucker • -Little Company of Mary

– 1957 Azathioprine– 1972 MMC, Dr. Birtch– 1980s 50-60% Rejection

• 1983 CYCLOSPORINE• 1986 OKT3

– 1990s 30% Rejection• 1995 Mycophenolate• 1994 Tacrolimus

– 1998 Hand Transplant, Lyon– 2005 Face Transplant, Lyon– 2000s <10-15% Rejection– 2013 VCA Established at MMC

Herrick Brothers

(above)

1954 Dr Joseph

Murray, Boston

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Immunosuppressant Induction

• Thymoglobulin (Polyclonal)– Cytokine release syndrome– Administer through a high-flow

vein. – Pre-medication 1 hour prior

• corticosteroids• Acetaminophen• antihistamine (Benadryl)

– WBC count 2,000 to 3,000 cells/mm3 or platelet count 50,000 to 75,000 cells/mm3: Reduce dose by 50%.

– WBC count <2,000 cells/mm3

or platelet count <50,000 cells/mm3: Consider discontinuing treatment

• Basiliximab (IL2)– 20 mg within 2 hours prior to

transplant surgery, followed by a second 20 mg dose 4 days after transplantation

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Maintenance Immunosuppression

1. Primary Immunosuppressant

Tacrolimus

Cyclosporine

Sirolimus

Belatacept (IV)

2. Anti-metabolite

Mycophenolate

Azathioprine

3. Prednisone22

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Calcineurin Inhibitor interactions

• Calcium channel blockers• Proton Pump Inhibitors (less with Pantoprazole)• Statins (less with Pravastatin)• Antifungal therapies• St. Johns Wort• Conivaptan• Protease inhibitors• Decreased with cinacalcet, Dilantin• QT prolonging drugs: Quinolones, Thioridazine

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Side effects

• Cyclosporine– Hirsutism, gingival hyperplasia, lipid abnormalities

• Tacrolimus side effects– Diarrhea, Headache, Tremors, Hyperkalemia, ARF,

Thrombotic microangiopathy (rare)

• Mycophenolate side effects– Diarrhea, Leukopenia, Pancytopenia

• CMV Disease– Diarrhea, Leukopenia, Pancytopenia

• Ebstein Barr Virus and BK Virus

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Acute kidney failure- (Native Kidneys)

Pre-renal Renal

Glomerular (<5%) Interstitial (<5%) Tubular (90%)

ToxicObstructive

Ischemic

Vasculitis (<5%)

Post-renal

Aminoglycosides

Myoglobin

Cast Nephropathy

Acyclovir

Oxalate

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Acute kidney failure- (Transplant)

Pre-renal

-RENAL VEIN/ARTERYRenal

Glomerular (<5%)Interstitial

Rejection vs BK Virus

Tubular

Calcineurin

Oxalate

Ivig

ATN

Vasculitis

Post-renal

URETER ANASTOMOSIS

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Back to our patient…..

• 30 year old man developed 102.2 F fever and kidney failure 2 days after transplantation.

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BIOPSY RESULTS

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Our patient had a bad case ofREJECTION!

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Repeat Immunological studies

• New Donor Specific Antibody (DSA) detected

– DR7

• B and T cell cross-match now positive as well

• Biopsy shows both

– BANFF 2 A Cellular Rejection

– Humoral rejection

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Purpose of Banff Staging-Prognosis and Treatment

• Mueller et al Transplantation 2000 Mar 27;69(6):1123-7

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Update On Patient

• Treated with

– Cellular Rejection; Thymoglobulin & steroids

– Humeral Rejection; IVIG & Rituximab

• Result: Home off and off dialysis

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Patient home and doing well….

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THE TRANSPLANT TEAM

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Questions?

• Transplant office: 217-788-3441

• National Kidney Foundation (NKF)– http://www.kidney.org/

• United Network for Organ Sharing (UNOS)– http://www.unos.org/

• American Society of Transplantation (AST)– http://www.a-s-t.org/

• SRTR– http://www.ustransplant.org/

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3737

3838

3939

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Humoral rejection(Antibody-mediated)• Positive antibodies

• Histological Findings

• C4d

• Graft dysfunction

• Staging– Type I - An acute tubular necrosis-like histology, with minimal inflammation

– Type II - A capillary-glomerulitis, with margination and/or thromboses

– Type III - Arterial-transmural inflammation/fibrinoid changes.

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What is C4d?

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C4d Physiology and Prognosis

• C4->C4a, C4b-> C4b is converted into C4d, • C4d binds covalently to the endothelial and collagen

basement membranes • Why in the Peritubular capillary (PTC)?

– Glomerulus has 4 cell surface complement inhibitors» Decay accelerating factor (CD55)» membrane co-factor protein (CD46)» CR1 (complement receptor 1)-CD35» protectin (CD59 )

– PTC has only one- Protectin (CD59)

• C4d relative risk (RR) of graft loss in 126 biopsies for Acute rejection– RR 8.72 (CI 95% 2.24 to 19.03),

» Herzenberg AM; Gill JS; Djurdjev O; Magil AB; C4d deposition in acute rejection: an independent long-term prognostic factor. J Am Soc Nephrol 2002 Jan;13(1):234-41.

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Humoral Rejection Treatment

Alemtuzumab and thymoglobulin

Cellular rejection treatments

Rituximab (CD20)

Bortezomib (Tyrosine Kinase)

IVIG & Plasmapheresis

Eculizumab (C5)

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Maintenance Immunosuppression

• Solumedrol

– 500 mg POD0

– 200 mg POD1

– 160 mg POD2

– 120 mg POD3

– 80 mg POD 4

– 40 mg POD 5

– 20 mg POD 6

– Wean 5 mg q 2 weeks until at 5 mg daily.

• Mycophenolate Mofetil1000 mg po BID, first dose pre-op

• Tacrolimus goal

– 8-11 first 3 months

– 5-8 thereafter

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Infectious prophylaxis

• High risk Valgancyclovir 900 mg daily• Moderate risk Valgancyclovir 450 mg daily• Low risk Acyclovir 400 mg po BID

• Trimethoprim DS MWF• Fungal prophylaxis

– Nystatin– Fluconazole

• GI Prophylaxis• Vitamin D supplementation

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CHRONIC REJECTION

• Grade I —– Mild interstitial fibrosis 6-25%

– mild atrophy of the tubules (<25%)

• Grade II —– Moderate interstitial fibrosis 25-50%

– And moderate tubular atrophy 25-50%)

• Grade III —– Severe interstitial fibrosis >50%

– And tubular atrophy >50%

• Severity of glomerular, mesangial matrix, and vascular change is also quantified

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CHRONIC ALLOGRAFT FAILURE FROM NEPHROPATHY

• Accounts for <4% of failures.– DM -

– Primary focal segmental glomerulosclerosis – relative contraindication to living donor transplant- >65% recur

– IgA 20% to 75% recur, but <10% graft loss.

– MPGN type 1- 20-30% recurrence, 30-40% loss

– MPGN type 2 –50-100% recurrence, 10-20% loss

– Anti GBM disease – titers should be negative for 6 months before transplant.

– SLE/ANCA vasculitis – avoid if active disease

– Fabry disease/Hyperoxaluria –Disease always recurs

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Campath (Anti CD-52)Basu. Transplant Proc. 2005 (Pittsburg)

– Alemtuzumab (anti-CD52)

• CD-52 on B and T-cells, monocytes, macrophages, and NK cells.

– Has ½ life of 15-21 days

• 40 pt series in Steroid resistant rejection and Banff grade 1B or higher rejection on FK mono.– 62.5% graft survival

– 4 patients had an infection

» 2 died (PTLD, and infected hematoma)

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CHRONIC REJECTION

• Grade I —– Mild interstitial fibrosis 6-25%

– mild atrophy of the tubules (<25%)

• Grade II —– Moderate interstitial fibrosis 25-50%

– And moderate tubular atrophy 25-50%)

• Grade III —– Severe interstitial fibrosis >50%

– And tubular atrophy >50%

• Severity of glomerular, mesangial matrix, and vascular change is also quantified

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CHRONIC ALLOGRAFT NEPHROPATHY

• Accounts for <4% of failures.– DM -

– Primary focal segmental glomerulosclerosis – relative contraindication to living donor transplant- >65% recur

– IgA 20% to 75% recur, but <10% graft loss.

– MPGN type 1- 20-30% recurrence, 30-40% loss

– MPGN type 2 –50-100% recurrence, 10-20% loss

– Anti GBM disease – titers should be negative for 6 months before transplant.

– SLE/ANCA vasculitis – avoid if active disease

– Fabry disease/Hyperoxaluria –Disease always recurs

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Early Allograft Algorithm

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BK virus

• Onset 8 weeks to 5 years

• Median is about 10-12 months.» Randhawa PS; Human polyoma virus-associated interstitial

nephritis in the allograft kidney. Transplantation 1999 Jan 15;67(1):103-9.

» Ramos E; Clinical course of polyoma virus nephropathy in 67 renal transplant patients. J Am Soc Nephrol 2002 Aug;13(8):2145-51.

» Vasudev B; BK virus nephritis: risk factors, timing, and outcome in renal transplant recipients. Kidney Int 2005 Oct;68(4):1834-9.

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C4D prognosis

• C4d relative risk (RR) of graft loss in 126 biopsies for Acute rejection– RR 8.72 (CI 95% 2.24 to 19.03),

» Herzenberg AM; Gill JS; Djurdjev O; Magil AB; C4d deposition in acute rejection: an independent long-term prognostic factor. J Am Soc Nephrol 2002 Jan;13(1):234-41.

• 218 renal biopsies done within 6 months – 35% vs 67% graft survival 1 year post diagnosis.

» Lederer SR; Kluth-Pepper B; Schneeberger H; Albert E; Land W; Feucht HE; Impact of humoral alloreactivity early after transplantation on the long-term survival of renal allografts. Kidney Int 2001 Jan;59(1):334-41.

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BIOPSY RESULTS

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BIOPSY RESULTS

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Organ Allocation - History

• 1954- First successful Kidney transplant• 1968- Southeast Organ Procurement Foundation (SEOPF) is formed• 1977 SEOPF implements first computerized Organ matching system,

United Network for Organ Sharing• 1982- SEOPF establishes kidney center for round the clock donor organ

placement• 1984- United Network for Organ Sharing separates from SEOPF• 1984- National Organ Transplant Act (NOTA) Enacted• 1986- UNOS receives initial federal contract to operate to Organ

Procurement and Transplantation Network (OPTN)• 2000- US Department of Health and Human Services (HHS) publishes

Final Rule for the operation of the OPTN

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ImmunosuppressantsNEJM 351;26, 2004

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NOTA- national Organ Transplant Act

• Prohibits Buying and Selling Organs• Establishes two department of Health and Human Services

(DHHS) Contracts:

• Organ Procurement and Transplantation Network (OPTN)– Responsible for Organ Allocation policy development– Responsible for Organ allocation

• Scientific Registry of Transplant Recipients (SRTR)– Provides Ongoing Evaluation of the Scientific and Clinical

Status of Organ Transplantation– Data Collection

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Public Health Service High Risk

• Behaviors indicating high risk donors– Men who have had sex with another man within 5 years

– IV drug use within 5 years

– Men and women who have engaged in sex in exchange for money or drugs within 5 years

– Inmates of correctional systems

• If screening for infection is negative organs are offered.

• Voluntary, Change your mind at any time

• Expands the pool of donors available to you

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Acute Cellular RejectionDetailed BANFF staging

Borderline changes no intimal arteritis, mild tubulitis (1-4 mononuclear cells/tubular cross

section) 10 to 25 % involvement of the interstitium.

Type I — Significant interstitial inflammation (>25 percent of parenchyma affected) and Type 1A - moderate tubulitis (>4 mononuclear cells/tubular section). Type IB- severe tubulitis (>10 mononuclear cells/tubular section)

Type II — Arteritis found in at least one arterial cross section. Type IIA-Mild to moderate arteritis Type IIB- Severe arteritis, which is associated with greater than 25 percent

loss of the luminal area Type III — Transmural arteritis, and/or arterial fibrinoid alterations, and

necrosis of medial smooth muscle cells occurring in association with lymphocytic inflammation of the vessel.