Cascade plasmapheresis (CP) as a preconditioning regime in ABO-incompatible live related donor liver transplants (ABOi-LDLT)
© Tiwari et al.; licensee BioMed Central Ltd. 2014
Received: 28 February 2014
Accepted: 7 September 2014
Published: 12 September 2014
ABO-incompatible live donor liver transplant (ABOi-LDLT) is being widely done to bridge the gap of demand and supply of organs. Different desensitization regimes are being used to reduce titer of blood group antibodies for successful transplant and accommodation of graft. The authors used cascade plasmapheresis (CP) to bring down titer of naturally occurring blood group antibody to 16 or lower.
Material and methods
Four recipients of ABOi-LDLT were of blood groups O, O, B, and B while donors were of blood groups B, A, AB, and AB, respectively. Desensitization protocol included immunosuppressive drugs and plasmapheresis. CP consisted of separating patient’s plasma as the first step and passing it through pore size based filter column as the second step. The first step was performed using disposable kit (PL1, Fresenius Kabi, Germany) with minor modification on apheresis equipment COM.TEC (Fresenius Kabi, Germany). Pore size based filter column used was 2A column (Evaflux, Kawasumi Laboratories, Japan). Blood group antibody titer (immunoglobulin G (IgG)) was done by column agglutination technology (Ortho-Clinical Diagnostics).
Cases 1, 2, 3, and 4 with pre-CP titer of 1,024, 512, 32, and 64 required four, three, one, and one CP procedures, respectively. No signs of antibody-mediated rejection were exhibited on histopathological evaluation by any of the patients. Successful organ engraftment occurred as documented by post-operative liver function tests and liver biopsy.
Cascade plasmapheresis offers a cost-effective and efficient way to decrease blood group antibody titer and helps in successful transplant.
A large number of liver transplants are being performed in India, and majority is live donor liver transplant (LDLT) . In India, the organ transplants are governed by Organ Donation Act , which allows only first-degree relatives or spouse to be donor(s) for the patient. Sometimes this willing donor is not suitable on the grounds of ABO blood group incompatibility. However, in recent times, people have found their way around this ‘suitability issue’ by doing ABO-incompatible (ABOi) solid organ transplants successfully using various desensitization protocols [3, 4].
Desensitizing protocols play an important role in successful outcome of these transplants by decreasing the chances of acute antibody-mediated organ rejection . These protocols include immunosuppressive drugs and plasmapheresis. Immunosuppressive drugs inhibit the formation of new antibodies, and plasmapheresis lowers the titer of existing blood group antibodies. There is a report from India reiterating pivotal role of plasmapheresis in desensitization protocols leading to successful solid organ transplant and adequate patient follow-up after the transplant, as well . However, this was conventional plasmapheresis with removal of patient’s plasma, and volume replacement was done with normal saline and donor fresh frozen plasma (FFP) units. We would like to present a case series of four consecutive ABOi-LDLT patients where we used cascade plasmapheresis (CP) successfully as a part of preconditioning regime to reduce the titer of naturally occurring antibody in ABO incompatible LDLT.
Materials and methods
Patient and donor selection
Profile of the patients and donors
Age and gender
Comorbid conditions (indication for transplant
Relationship with patient
HCV-related chronic liver disease (CLD)
Jaundice, ascites, PH
Jaundice, ascites, HRS
SBP, HE, Ascites
Cholecystitis, PH , HCC
Desensitization protocol included immunosuppressant drugs and cascade plasmapheresis.
Immunosuppressant drug regime
The drug regime was started with anti-CD20 drug (rituximab) which was administered as a single dose of 100 mg, 19 days prior to planned date of surgery to inhibit formation of new antibodies. Thereafter, plasmapheresis was initiated to remove the existing blood group antibodies till the titer of 16 or lower was achieved. The other three immunosuppressive drugs (mycophenolate mofetil, tacrolimus, and glucocorticoids) were initiated prior to the surgery as per the standard hospital protocol. Oral mycophenolate mofetil (MMF) 500 mg/twice a day was started 7 days prior to LDLT. Tacrolimus was initiated on the day of LDLT, and tacrolimus trough level was maintained between 10–15 ng/ml in the first 2 weeks, 7–10 ng/ml between 2–12 weeks, and 5–7 ng/ml until 6 months. Prednisolone was administered on the day of surgery at a dose of 2 mg/kg for 1 week, then at 1 mg/kg for 2 weeks, then gradually tapered to 0.5 mg/kg by fourth week, and stopped 3 months after surgery. MMF and tacrolimus were continued for life. These three drugs were also used in ABO-compatible (ABOc) liver transplants.
The pore size based column was a semi-selective column and manufactured in different pore sizes (2A, 3A, 4A, 5A). The 2A column performs well with separation of globulins and albumin. The sieving coefficient of the column for IgM is 0.0, immunoglobulin G (IgG) is 0.2, and albumin is 0.62. The sieving coefficient is defined as the ratio of a solute in the filtrate to the simultaneous concentration of the same solute in the plasma. In other words, sieving coefficient is the ratio of solute returned to the patient. The manufacturer markets the 2A column for various applications including nephrologic (rapidly progressive glomerulonephritis, Goodpasture’s syndrome, ABOi renal transplant), dermatologic (pemphigus vulgaris, bullous pemphigoid), systemic lupus erythematosus, neurologic (myasthenia gravis, Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy), etc. With the understanding of the principle, the authors used 2A column for decreasing the antibody titers in ABOi-LT.
The blood group antibody titer was done by column agglutination technology (Ortho-Clinical Diagnostics). The cassettes used were anti-IgG, anti-C3d, and polyspecific (Ortho BioVue System, Ortho-Clinical Diagnostics, High Wycombe, UK), and the technique was low ionic salt solution-indirect antiglobulin test (LISS-IAT). The procedure was the same as published previously , and only IgG was considered to decide upon patient management. The titer was done before and after each CP procedure before surgery, daily for 7 days after surgery, and at least twice weekly till 6 weeks post-surgery.
The protocols used for desensitization were ‘standard of care’. The study was purely an observational one, and therefore, no ethical approval was needed.
Post-operative hospital course was largely uneventful. No histopathological evidence of antibody-mediated rejection was exhibited by any of the four patients in the biopsy performed at 1 month (protocol biopsy) post-LDLT. Successful organ engraftment occurred as documented by post-operative liver function tests, ultrasonography, and liver biopsy. Two out of four patients (case no. 3 and 4) had sinus ventricular tachycardia, two and 17 days post-LDLT, respectively, which was managed by intravenous diltiazem. Antibiotics administered prophylactically to all four patients were pipracillin-tazobactum and teicoplanin. Case no. 3 required additional antibiotics (linezolid, polymixin E, and meropenem) on post-operation day 3 based on culture and sensitivity of blood and endotracheal tube secretions. All the four patients were discharged after an average of 21 days (range 20–23 days) with dietary and medical advice.
Follow-up regime after discharge was once a week until 3 months, once a fortnight till sixth month, once a month till 2.5 years, and once every 2 months till life. Case 1 was readmitted on post-operation day 56 with acute pancreatitis. She succumbed despite 5 days of active medical management. All other three patients continue to do well with mean follow-up of 9 months.
Rituximab was given to all four patients to inhibit the formation of new antibodies and thus, decrease the titer of naturally occurring blood group antibodies. Plasmapheresis was subsequent to antibody titer decrease obtained by rituximab alone as evidenced by antibody titer monitoring. However, either there was no decrease in titers or at best decrease by one dilution. Plasmapheresis sessions achieved the desired levels of 16 or less thereafter. Plasmapheresis, therefore, remains an integral part of any desensitization regime.
Plasmapheresis can be conventional, cascade, or adsorption. While the conventional plasmapheresis is completely nonspecific with removal of entire plasma and its substitution with replacement fluid like FFP, albumin, normal saline alone, or more commonly in combination; cascade plasmapheresis is semi-selective with removal of high molecular weight substances mainly immunoglobulins; and some amount of albumin and adsorption column plasmapheresis is the most specific with removal of only ABO-specific immunoglobulins.
Comparison between numbers of plasmapheresis procedure required as per guidelines and number of procedures in the present series and their costing
Case (pre-CP titer IgG)
Number of conventional plasmapheresis as per guidelines
Costs of conventional procedures in US dollars
Number of CP procedures in this series
Costs of CP in US dollars
Cost savings in US dollars
Case 1 (2,048)
Case 2 (1,024)
Case 3 (32)
Case 4 (64)
Immediate post-operative follow-up of patients revealed ventricular tachycardia in two out of the four patients, which could be managed easily by antiarrhythmic agent. One patient had to be put on higher antibiotics based on culture reports to which the patient responded well. One patient (case 1) was readmitted because of acute pancreatitis and died after successful discharge. Larger series of patients would establish long-term safety of such patients.
ABO blood group hurdle has now been crossed, and ABO-incompatible solid organ transplants are being successfully performed in India and other countries. ABO-incompatible liver transplant can and should be an option for seriously ill patients, who are awaiting transplantation and should be offered to all patients in cases of immediate need of allograft and are without any blood group compatible organ donor. Cascade plasmapheresis using modified PL1 offers a cost-effective and efficient way to decrease the blood group antibody titer and helps in successful transplant.
The authors wish to acknowledge the conceptual inputs from Dr. Padam Singh and Dr. Pooja Sharma.
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