Cyclosporine-induced Myopathy in a Liver Transplant Recipient with Acute Kidney Injury

Dear Editor, Cyclosporine A (CsA) is a potent immunosuppressive agent used to prevent rejection after organ transplantation. Its common adverse effects include nephrotoxicity, glucose intolerance, gingival hyperplasia, and hyperuricemia, but painful myopathy is extremely rare. We report the case of a deceased donor liver transplant recipient who developed myopathy due to cyclosporine after 45 days of initiation which improved after switching to tacrolimus. A 56-year-old female deceased donor liver transplant recipient presented with severe pain, swelling, and weakness in lower limbs for 2 weeks. She had undergone liver transplant 6 weeks before presentation with tacrolimus, mycophenolate sodium, and prednisolone as maintenance immunosuppression initially. On postoperative day 5, she had seizures and blood investigations were suggestive of microangiopathic hemolytic anemia with acute kidney injury. Suspecting thrombotic microangiopathy due to tacrolimus, it was switched to cyclosporine following which there was neurological improvement and improved anemia and renal function, and was discharged after 20 days of liver transplant. On examination, she had bilateral lower limb edema with tenderness without skin changes. Power in lower limbs was 2/5 with depressed deep-tendon reflexes. Blood investigations showed platelets count – 84,000/mm3, C-reactive protein – 18 mg/L creatinine – 2 mg/dL, aspartate transferase – 412 U/L, alanine aminotransferase – 36 U/L, creatinine phosphokinase (CPK) – 980 U/L, and 1 + protein with no red blood cells on urinalysis. She was given an injection of cefoperazone + sulbactam 1.5 g twice a day and ongoing immunosuppressants (cyclosporine, mycophenolate sodium, and prednisolone) was continued with bed rest and passive physiotherapy exercises. Muscle biopsy was done after consultation with the neurologist to rule out myopathy and sample was sent for examination. The muscle biopsy showed the variable size of myocyte with foci of moderate periventricular inflammation comprising polymorphs, lymphocytes, and plasma cells [Figure 1] and edema. Evaluation for infective myopathy (muscle fluid Gram and acid-fast bacillus stain, culture, gene Xpert, and blood bio fire) and inflammatory myopathies (antinuclear antibody blot – 18 antigens and myositis profile – 16 antigens) was found to be negative. The cyclosporine levels were C0 – 246 ng/mL and C2 – 1266 ng/mL. Suspecting new-onset myopathy due to cyclosporine, it was switched back to tacrolimus with lower trough levels of 5.6 ng/mL. After 10 days, there was a significant reduction in muscle pain, limb edema, and normalization of CPK levels. The patient was able to walk with minimal support after 1 month of physiotherapy exercises and is on regular follow-up with stable liver and kidney function.Figure 1: Image in ×10 magnification showing altered muscle fiber sizes and moderate perivascular inflammation comprising polymorphs, lymphocytes, and plasma cellsCsA is an inhibitor of calcineurin (CaN) which has three subunits, CaNα, CaNβ, and CaNɣ, of which the former 2 are widely expressed in skeletal muscle responsible for muscle growth and health. CaN activates the expression of peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) that promotes the transformation of type IIb muscle fibers into type I and type IIa muscle fibers. CaN inhibition leads to downstream suppression of CaNα, CaNβ and PGC-1α causing muscle inflammation and myopathy.[1,2] CsA-induced myopathy on histopathology examination is typically manifested as disordered ragged red fibers and intracellular lipid droplet aggregation with inflammatory cell infiltration indicating drug-induced myopathy as noted in our case.[2] Cyclosporine-associated muscle toxicity has been observed in solid organ and bone marrow transplant patients with higher doses and was found to have improved with dose reduction or complete withdrawal of the drug.[3] Although cyclosporine and tacrolimus both can lead to muscle toxicity, in our patient, we changed cyclosporine with tacrolimus maintaining lower trough levels.[4] Switch to lower dose tacrolimus with physiotherapy exercises led to complete resolution of the myopathy evident with reduction of pain, swelling, and improved muscle power. CsA-induced myopathy is an extremely rare adverse effect and prompt and meticulous evaluation leads to diagnosis. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.