Immunosuppression After Liver Transplant: Tacrolimus Levels

Immunosuppression after liver transplant is front-loaded and then tapered. Dr. Dheeraj Manchanda, Associate Consultant - HPB Surgery and Liver Transplantation, BLK-Max Super Speciality Hospital, New Delhi, India, and his team target tacrolimus trough levels of 8 to 10 in the first month, 5 to 8 through six months, and about 5 or lower after a year, by which point steroids and mycophenolate have usually been stopped.

The taper exists to limit infection, kidney damage and metabolic harm without inviting rejection. The liver makes this possible. It has a natural immunomodulatory property: it tempers the recipient's immune response against it. Dr. Manchanda is explicit that this is a property of the organ, not something the team does. What the team controls is how quickly it takes advantage of it. For the wider picture of indications and outcomes, see the pillar guide, recent advances in liver transplant.

Immunosuppression after liver transplant, step by step

Induction in theatre

In his team's regimen, induction begins during the operation with a higher dose of steroid: methylprednisolone at 1 mg per kg, given during implantation of the graft. The steroid is then tapered after surgery.

Tacrolimus on the night of surgery

About six months to a year before the masterclass, his team changed one step. Patients whose transplant finishes early in the day, by the afternoon or evening, now receive low-dose tacrolimus on the night of the operation itself, post-operative day zero. Mycophenolate starts the next day.

Tapering, steroids first

The first drug to go is the steroid, because of its metabolic complications. The broader rationale for tapering early is sepsis: infection is the first problem immunosuppression causes in the immediate post-operative period. The balance shifts in patients who develop rejection, because their immunosuppression has to be increased at once to counter it.

Tacrolimus levels after liver transplant

A trough level is the concentration of the drug in the blood just before the next dose, its lowest point between doses. His team's tacrolimus trough targets are:

• First month: 8 to 10.
• Up to six months: 5 to 8.
• After the first year: about 5, or lower.

With these levels, his team maintains stable liver function tests. Mycophenolate is tapered after the first six months and stopped about a year after surgery, leaving most patients on tacrolimus alone.

Why stopping mycophenolate matters for women

Stopping mycophenolate at around one year is what allows women to conceive after transplant. Mycophenolate causes birth defects and must be stopped before conception under specialist supervision. Women who come to Dr. Manchanda's clinic often ask whether they will be able to become mothers; his answer is yes, and his centre has had successful pregnancies in women after liver transplant.

Protecting the kidneys after liver transplant

The kidneys are vulnerable at two points after transplant, and his team handles them differently.

Early: surgical stress

Dr. Manchanda tells his patients that undergoing a liver transplant is equivalent to running a marathon. That stress shows up in the kidneys as a rise in creatinine and a fall in urine output in about 5% of patients immediately after surgery.

For these patients the protocol changes:

1. Albumin. They receive albumin infusions after surgery.
2. No immediate tacrolimus. Tacrolimus is withheld in the first days.
3. Basiliximab induction. Instead, they receive basiliximab, an antibody against the interleukin-2 receptor, as part of induction: two doses, four days apart.
4. Tacrolimus once creatinine settles. Tacrolimus starts only when the creatinine begins to fall.

Late: tacrolimus nephrotoxicity

The later threat comes from tacrolimus itself, which is toxic to the kidneys. The first defence is staying within the therapeutic window, the stepped targets above. If creatinine still rises, his team switches the patient to an extended-release preparation of tacrolimus, taken once a day. His rationale is that nephrotoxicity relates mostly to the peak tacrolimus level, which the once-daily preparation lowers while keeping the immunosuppressive effect the same.

Infection: the price of immunosuppression

Because of immunosuppression, a transplant recipient is always predisposed to infection. The risk is highest during the first six months, when the induction doses and the early, higher-dose regimen are in place. As steroids are tapered and mycophenolate follows, the risk falls; once a patient is maintained on tacrolimus alone after about a year, it is lower still. It never disappears, which is why lifelong immunosuppression is, in Dr. Manchanda's words, the Achilles heel of all organ transplantation.

Metabolic complications and their timeline

The commonest metabolic complications after transplant are:

• diabetes
• hypertension
• obesity
• dyslipidaemia
• osteoporosis
• renal impairment

Much of this burden comes from the steroids used in the initial regimen; tacrolimus also contributes, notably to diabetes, hypertension and kidney impairment. That is why his team tapers steroids and does not use them long term. Once the steroids are stopped, diabetes, hypertension and obesity begin to settle, typically over about six months after surgery.

Cancer after transplant and the surveillance protocol

Immunosuppressed patients carry a higher risk of cancer, and not only of the liver. Squamous cell carcinoma, chiefly of the skin, is one of the most common cancers in immunosuppressed patients across all organ transplants. Over-immunosuppression also raises the risk of post-transplant lymphoproliferative disorders (PTLD), an uncontrolled growth of immune cells called lymphocytes.

Follow-up is designed to detect both recurrent and new (de novo) cancer. His centre's protocol is:

• Patients transplanted for hepatocellular carcinoma: alpha-fetoprotein and other tumour markers every six months, with a triphasic CT scan every six months.
• Patients transplanted for other causes: surveillance yearly.

What kills transplant recipients in the long term

In the long run, coronary artery disease and chronic kidney disease are among the leading causes of death. Both are linked to the immunosuppressive drugs, and both tend to creep in when patients are lost to follow-up and stop monitoring themselves. That is the core of Dr. Manchanda's argument for regular review: the long-term risks are largely the risks of unmonitored medication.

Rejection and what follows non-adherence

At his centre, acute cellular rejection is the most common complication after transplant. It is managed by increasing the immunosuppression. Chronic rejection is a late complication, and it typically occurs in patients who fail to comply with their immunosuppressive regimen. Adherence to the regimen is therefore central to keeping the graft for the long term.

The regimen is a balance with an error on each side. Too little immunosuppression invites rejection; too much invites sepsis in the early weeks and, over the years, post-transplant lymphoproliferative disorders and other cancers. The level is adjusted to the patient rather than fixed. Two examples from the session show the range. In ABO-incompatible transplants, tacrolimus and mycophenolate start about a week before surgery rather than after it. In HIV-positive recipients, whose own immunity is already reduced, his team deliberately keeps the overall dose of immunosuppression lower.

Can immunosuppression ever be stopped?

For most recipients, immunosuppression is lifelong. The liver's immunomodulatory property does, however, allow withdrawal in some patients. Dr. Manchanda can recall at least three patients who were free of immunosuppression about five years after transplant. Current research aims to make this predictable, and he hopes for a breakthrough in time. Until then, withdrawal is an exception and is undertaken only under the transplant team's supervision; patients should never stop their medication on their own.

Life on long-term follow-up

Long-term care rests on the recipient's own habits as much as on the drugs. Dr. Manchanda's expectations are direct:

• No return to alcohol.
• No return to a sedentary life. Regular exercise is part of treatment.
• A healthy diet.
• Regular blood tests and clinic reviews, indefinitely.
• Medication taken regularly.

In exchange, the symptoms of cirrhosis go away. Recipients return to a healthy life and enjoy everyday activities like people who never had cirrhosis: gym training, exercise and demanding pursuits such as trekking. The drugs and the follow-up are the price of that. In Dr. Manchanda's view, most late problems appear when monitoring stops, which makes staying on follow-up the recipient's most important task.

For how surgeons expand the donor pool before any of this begins, see ABO-incompatible liver transplant and complex cases. Dr. Ashish George's masterclass looks at long-term results from another angle in liver transplant survival rates and life after surgery. Dr. Manchanda's detailed answers on immunosuppression and kidney protection, given to attending doctors from Nigeria and Tanzania, are on the Live Discussion page.