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Acute Rejection Treatment

CASE 34-1, QUESTION 8: A biopsy of G.P.’s transplanted kidney shows grade 1A, moderate acute cellular

rejection. G.P. is started on methylprednisolone 500 mg daily IV for three doses. His maintenance oral

prednisone is discontinued and will increase MPA and TAC dose. He will be placed on a high-dose oral

prednisone tapering regimen after his IV doses. Why is methylprednisolone therapy of G.P.’s first acute

episode of rejection appropriate?

High-dose or “pulse” IV methylprednisolone, IV rabbit antithymocyte globulin, IV

antithymocyte globulin, and oral prednisone are options to treat acute rejection in all

types of solid organ transplants. A high-dose corticosteroid (usually IV

methylprednisolone) is considered first-line therapy because it works very quickly in

decreasing lymphocyte responsiveness, is easy to administer, and reverses at least

75% of acute rejection episodes. Rabbit antithymocyte globulin is usually reserved

for steroid-resistant rejection or more severe grades of rejection. IVIG has also been

used as an alternative for resistant rejection. The ideal corticosteroid dosage, route,

and regimen are unknown. Corticosteroid protocols vary among transplant programs.

IV methylprednisolone and oral prednisone are equally effective in reversing

rejection, but oral corticosteroids are given for a longer period and have been

associated with a higher incidence of adverse effects. Even though 50 mg of IV

methylprednisolone has a similar lymphocyte suppressive effect as a 1-g IV dose,

most programs use methylprednisolone 250 to 1,000 mg (most commonly 500 mg) IV

every day for three doses and adjust the prerejection oral prednisone regimen

accordingly. An example of an oral prednisone regimen is 100 to 200 mg/day tapered

for 1 to 3 weeks to baseline maintenance dose. For G.P., IV methylprednisolone is

appropriate because corticosteroids are considered first-line therapy for acute

rejection of a transplanted kidney, and first rejection episodes (such as G.P.’s) are

very responsive. In addition, G.P. has received a prophylactic course of rabbit

antithymocyte globulin recently and additional doses should be avoided, if possible.

Rabbit antithymocyte globulin is associated with a higher risk of CMV infection and

malignancy; it is more difficult to administer, requires more intensive monitoring, is

more expensive, and usually is held in reserve for corticosteroid-resistant or more

severe forms of rejection.

Nevertheless, high-dose corticosteroids are not without risk. They increase the

risk of infection, and long-term therapy can induce ocular, bone, cardiovascular, and

endocrine abnormalities. Although G.P. will be receiving high-dose IV

methylprednisolone for only 3 days, because he is diabetic, he should be monitored

for hyperglycemia, and a change in his insulin requirements should be anticipated

because corticosteroids can alter glucose metabolism. Short-course

methylprednisolone also can mask signs of infection (e.g., fever, changes in WBC

counts, pain associated with inflammation) and delay the diagnosis. Insomnia,

nervousness, euphoria, mood shifts, acute psychosis, and mania also can occur with

short-term corticosteroid use. If the methylprednisolone regimen is effective in

reversing G.P.’s acute rejection, his serum creatinine concentration should decline

within 2 to 5 days and his urine output increase.

In addition, it would be appropriate to increase G.P.’s tacrolimus dosage to 7 mg

twice a day because the concentration is low (5 ng/mL) and low trough has been

associated with a higher risk of acute rejection. Because small changes in tacrolimus

dose can increase levels disproportionately, a trough whole blood concentration

should be re-evaluated in 2 to 3 days. The mycophenolate dose could be increased to

1 g BID and up to 1.5 g BID, because this dose in combination with a CNI has

reduced acute rejection in African-American patients, particularly if the patient was

on cyclosporine therapy. There are limited data supporting the increase of the

mycophenolate dose beyond 1 g BID with tacrolimus-based regimens.

32,33

If G.P. had

been on cyclosporine, another option would be to change cyclosporine to tacrolimus,

which has been shown to reduce future episodes of acute rejection. Another

important aspect for prevention of future rejection would be to assess G.P.’s

adherence with, and understanding of, his medication regimen. Nonadherence is a

major cause of acute rejection and graft loss.

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CASE 34-1, QUESTION 9: Six months later G.P. is noted to have another elevation in Scr. In addition,

donor-specific antibodies are also detected in blood. Did kidney biopsy indicate it as AMR? How would this

type of acute rejection be treated?

AMR is more difficult to treat and approaches vary. It may not respond to steroids

and thymoglobulin, which is used initially. The most common treatment is

plasmapheresis or immunoadsorption. These modalities are used to remove

circulating antibodies, and low- or high-dose intravenous immunoglobulin for

residual antibody inhibition, given after these procedures. Because of increased

recognition and diagnosis, and resistance to treatment, a number of approaches are

being used and investigated. Along with plasmapheresis and IVIG, rituximab may be

used to treat acute AMR. Other agents, not currently approved for transplantation, are

being utilized and studied as treatment, including bortezomib, which causes plasma

cell apoptosis/depletion and eculizumab which is an anti C5 antibody. Given the

sparsity of large-scale, randomized trials assessing which agents to utilize to treat

AMR, there is no consensus regarding which should be considered first-line therapy

to treat AMR, although most clinicians do utilize plasmapheresis with IVIG as a

starting point, and add on the aforementioned therapies at various stages or severities

of AMR.