incompatible kidney transplantation: strategies for ... · incompatible kidney transplantation:...

Apheresis Medicine in ABO Incompatible Kidney Transplantation:

Strategies for Successful Outcomes

Lance Williams, MD

Assistant Professor

Transfusion Medicine, Apheresis, and Coagulation

• No conflicts of interest to disclose relevant to this presentation

Kidney Transplant Benefits

• Life expectancy1

– In diabetics (Wolfe et al.), transplant increased life expectancy by a mean of 17 years compared with 8 years for treatment with dialysis alone

• Cost2

– 1972 Social Security Amendment guaranteed access to care for those with ESRD• Cost estimated at $75,000,000/year

– Cost of kidney transplant ~$110,000 the first year, then $19,000/year thereafter

Supply and Demand

• January 2016– 100,791 patients on the kidney transplant list

• Up from 77,684 in 2008!• ~7,000/year die or become too sick for transplant

– Median wait time on the list: 3.6 years

• In 2014, only 17,107 kidney transplants took place– 11,570 from deceased donors– 5,537 from living donors3

• Sensitization makes matching donors and recipients much more difficult– ~30% of those on the wait list are sensitized….may

increase wait time to 7 years!4,5

How to Overcome Kidney Shortage

• Redefine criteria for brainstem death

• Use dual kidney transplants for older, deceased donors

• Surgical techniques to decrease donor morbidity

– Laparoscopic

– Transumbilical

– Robot-assisted

• Matched donor programs or kidney chains

• ABO-incompatible transplants

First Attempts at Kidney Transplant

• 1933 – Yurii Voronoy, MD6

– Deceased donor

– Patient Type O, Donor Type B

– Patient died after 2 days

• 1954 – Joseph Murray, MD7

– Living Donor, monozygotic twins

– Richard (recipient) and Ronald (donor) Herrick

– Richard lived 8 more years; Ronald lived 56 more years

– Dr. Murray received the Nobel Prize in 1990

Concepts of Successful Kidney Transplantation in Sensitized or

Incompatible Patients

• Remove antibodies with apheresis

– Number of procedures often based on titer

• Suppress further antibody production with immunosuppressive agents

• Monitor patient for continued graft function while accommodation takes place8

Immunosuppression Strategies – Past and Present

• Immunosuppression10

– Irradiation– Splenectomy– 6-mercaptopurine (azathioprine)

• 1960 – Prolonged graft life in dogs from 7.5 to 23.7 days

– High-dose steroids– Cyclosporine– Tacrolimus– IVIG with low titer anti-A and anti-B9

• Plasma-based therapies10

• Standard therapeutic plasma exchange (TPE)• Double-Filtration TPE• Immunoadsorption (IA)

But…What About ABOi Kidney Transplant (ABOi-KT)?

• 1955

– Another failed transplant by Hume et al. between a type B donor and a type O recipient11

• Chung et al., performed 10 ABOi transplants• 8 failed within days12

• 1982-1987• Alexandre finally has success

• 23 transplants with 75% graft survival at 1 year

ABO Basics13

ABO type

Antigens on RBC

Antibodies in serum/plasma

Prevalence in United States

Caucasian African-American

O Noneanti-A and

anti-B45% 49%

A A anti-B 40% 27%

B B anti-A 11% 20%

AB A and B none 4% 4%

ABOi-KT: A Paradigm Ready for Broad Implementation18

• 60 consecutive ABOi-KT

• 1999 to 2007

• TPE before and after transplant– Number of procedures based on starting titer

– Titer must be <16 prior to surgery

– Titers monitored daily, then at 2, 3, 6, and 12 months

– Titer rise ≥32 triggers biopsy and possible TPE

• 100 mg/kg IVIG (Cytogam) after each TPE

• Tacrolimus and mycophenolate mofetil (MMF) from day 1

• Dexamethosone 100 mg pre-op, then taper until tacrolimus in therapeutic range


Transplantation. 2009 Apr 27;87(8):1246-55. doi: 10.1097/TP.0b013e31819f2024


• Rejection treatment

– Cellular

• 3-day course of dexamethosone (100 mg/day), followed by taper

– Antibody-mediated (AMR)

• TPE and IVIG until histologic resolution of rejection


• Graft Survival

– 1 year 98.3%

– 3 years 92.9%

– 5 years 88.7%

• No hyperacute rejection or graft loss from AMR

– Splenectomy not necessary to prevent antibody mediated rejection in ABOi-KT

– Tight control of ABO titers in peri-transplant period allowed for elimination of rituximab (anti-CD20) from protocol

– High starting titer not predictive of graft failure due to AMR (controversial statement)18

Roles of Apheresis in ABOi-KT

• Pre-transplant

– “Desensitization” along with IVIG

• Post-transplant

–Continued “desensitization”

–And / or treatment of AMR

Apheresis in ABOi-KT

• Remove anti-A or anti-B antibodies20

75%

63%

ASFA Guidelines for Kidney Transplant21

J Clin Apher 2013; 28:145–284.

Evidence for Apheresis in Kidney Transplant8

J Clin Apher. 2011;26(5):252-60. doi: 10.1002/jca.20297. Epub 2011 Sep 5. Review.

Apheresis Methodologies in ABOi-KT

• Standard therapeutic plasma exchange (TPE)

• Immunoadsorption

–Mainly used in Europe

• Double filtration plasma exchange

–Mainly used in Japan

Therapeutic Plasma Exchange

TPE Advantages and Disadvantages

• Advantages

– Removes both IgG, IgM, and complement

– Allows for isovolemic plasma replacement pre-op

– May remove other antibodies that play a role in rejection

• Disadvantages

– Is non-selective in removal of immunoglobulins

– Depletes coagulation factors

– Some studies demonstrate increased bleeding and increased infections with TPE9

Immunoadsorption of ABO Antibodies

Double Filtration Plasmapheresis (DFPP)

Procedure Details for TPE

• Pre-op

– TPE typically performed every other day 3-5 times

• Post-op

– Up to the discretion of the transplant team

• Replacement fluid

– 5% Albumin for most procedures

– For the day before and day after surgery, some centers use half albumin and half plasma to prevent coagulation factor depletion perioperatively

Procedure Details for TPE • Labs

– Basic metabolic panel, mainly for electrolytes

– CBC

• Evaluate hematocrit to see if ECV will exceed 15%

• Avoid RBC transfusion, if possible

– Fibrinogen

• If low, either skip procedure or replace with blood products

– Donor-specific antibodies (DSAs) levels

– Anti-A or anti-B titers before and after procedure

Procedure Details for TPE

• Calcium supplementation

–Used to prevent citrate toxicity / hypocalcemia

– Either added to albumin bottles and / or given as IV drip

– ½ Plasma typically used the day before and the day after surgery

• Higher citrate load

Compatible Blood Products13

Recipient type

RBCsAVOID foreign

antigen

PlasmaAVOID antibody against

recipient RBCA A or O A or ABB B or O B or AB

AB AB, A, B, or O ABO O O, A, B, or AB

Blood Product Considerations for ABOi-KT13

Recipient Donor Plasma and platelets1st 2nd 3rd 4th*

O A A AB B OO B B AB A OO AB AB A B OA O A AB B OB O B AB A O

AB O AB A B OA B AB A B OB A AB B A OA AB AB A B OB AB AB B A O

AB A AB A B OAB B AB B A O

*Issue low titer (< 50) if other than 1st choice is provided (UAB)

Plasma or Platelet Transfusion Options for ABOi-KT Patients

Case Study• January 2014

• 59 year old male, O negative

– Donor Type A negative

• Received 5 pre-transplant TPEs

• Day before surgery, TPE with 50% O plasma and 50% albumin as the replacement fluids = BIG PROBLEM

– Anti-A titer rose from 16 to 32 (pre- to post-TPE)

– Procedure repeated overnight with the correct plasma (type A)

• Post-TPE and pre-op, titers decreased to 8

• Transplant proceeded without problems

• Graft remains functional 2 years later

Titer Measurement• IgG (anti-A or anti-B) functionally significant in

ABOi9

• High variability in tube titers among centers

– Interinstitutional variability

• 8 to 32 for IgM

• 16 to 256 for IgG

– Gel and flow cytometry more reproducible26,27

Tube Testing Gel Testing Flow Cytometry

Case Study28

• 52 year old type O male

• ESRD secondary to IgA nephropathy

• Donor is type A

• Pre-transplant anti-A titer 4 after 5 TPEs

• Post-transplant titers rising

– TPE is re-initiated along with post-TPE IVIG

• However, titers continue to rise even with daily TPE???

– Could the IVIG have high titer anti-A or anti-B???

Accommodation

• Even with optimal protocols, titer may return to baseline within 1 week of transplant15

• Intense monitoring of titers 2 weeks after transplant is advisable

• Accommodation

– Allows for survival of graft, even with increasing titers

– Thought to be a change of antibody specificity, avidity, and affinity

– Possible alteration of antigen structure9

Procedure-Related Adverse Events

• Mild allergic (urticaria, hives) - 4.3%

• Citrate toxicity (lack of renal function) - 6.8%

• Anaphylactic reactions (IgA deficiency) - rare

• Hypotension - 2.9%

– Procedure-related (ECV)

– Associated with ACE-inhibitor use

• Nausea and vomiting – 1.2%

• TRALI (plasma use pre- and post-op)29

• Infectious disease transmission from blood products (e.g. WNV)30

Apheresis in the Treatment of AMR

• AMR occurs in 30-60% of ABOi-KT

• Donor-directed antibodies: graft destruction/dysfunction

• Importantly, C4d staining cannot be used as the only sign of AMR in ABOi transplants!!!33-36

– C4d staining positive in 94% of ABOi-KT at 3 months post-KT WITHOUT any signs of AMR…compared with only 11% of ABOc-KTs with C4d staining

Apheresis in the Treatment of AMR

• Other recommended findings37

• Neutrophils in peritubular capillaries; acute tubular necrosis; arterial fibrinoid necrosis / transmural arteritis; intracapillary fibrin thrombi in glomeruli; RBC stasis

• Advanced stages => Tubular dilatation and epithelial flattening

• Laboratory and / or clinical signs of graft dysfunction

Apheresis in the Treatment of AMR - continued

• Lefaucher and colleagues39

– IVIG Group = 12 patients

• IVIG (2g/kg) given over 2 days, every 3 weeks, 4 times

• Graft survival at 36 months: only 50%

– IVIG, rituximab, and TPE Group = 12 patients

• Daily TPE for 4 days with low dose IVIG (100 mg/kg)

• High-dose IVIG as above

• Rituximab (375mg/m2) x 2 for 2 weeks

• Graft survival at 36 months: 91%!

KEYS to a Successful ABOi Program

• Communication!– Calendars

– Computer alerts

• Education– Nurses, residents/fellows, Attendings, blood bank

staff, patients, family members

• Being OCD

CommunicationHLAi Desensitization Planner: John Doe (MR# 123456)- Transplant Scheduled for December 11, 2014 final REVISED 10/30/14

Sunday Monday Tuesday Wednesday Thursday Friday Saturday

30 1 DECEMBER Valcyte 450mg Bactrim SS

2 0800 Heart/Vascular □ Permcath placement as

an outpatient 1200 OUTPATIENT PHERESIS □ DSA- blood should be

sent before PP □ PP/IVIG (100 mg/kg) □ Pre-PP: coags,

fibrinogen levels, ionized calcium

□ FK and MPA levels □ Keep active T&S

3 1200 OUTPATIENT PHERESIS

□ DSA- blood should be sent before PP

□ Pre-PP: coags, fibrinogen levels, ionized calcium

□ PP/IVIG (100 mg/kg) □ FK and MPA levels □ Keep active T&S

4 Valcyte 450mg Bactrim SS





6

7





9 Final Crossmatch; HLA lab to arrange with donor. Donor lives locally.

10 0800 ADMIT TO HOSPITAL/PHERESIS □ Pre-PP Labs: DSA, coags,

fibrinogen levels, ionized calcium FK and MPA levels, and T&S

□ PP (50% FFP) □ IVIG (100 mg/kg)with

premeds- infuse immediately after PP

**IVIG will need to be ordered on days of PP by inpatient service; it will be infused by Txp floor nurses.**

11 DAY OF SURGERY

□ Thymo 1.5mg/kg induction (1 of 4)

□ Hold FK morning of surgery

□ Restart FK night of surgery

□ Cellcept should be increased to 1000mg bid following surgery

□ Patient should be on IV SoluMedrol

12 PHERESIS *ALL SPECIMENS W/ AM LABS

□ DSA - blood should be sent before PP


□ FK and MPA levels □ Keep active T&S □ Urine Protein/Creatinine □ PP (50% FFP) □ IVIG (100 mg/kg) with

premeds-infuse immediately after PP

Thymo 1.5mg/kg Infuse after PP/IVIG (2 of 4)

13 *ALL SPECIMENS W/ AM

LABS

□ FK and MPA levels □ Keep active T&S

Once

Today

Once

Today

The Future of Kidney Transplantation

• Organs grown in laboratory using stem cell technology

• Xenotransplants (transgenic pigs)

• Apheresis has allowed us to break the ABO barrier in kidney transplantation

• Apheresis is an effective part of the treatment regimen for AMR in ABOitransplants

Comments or Questions?

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