A 45-year-old woman comes to the office for follow-up. The patient has a history of type 2 diabetes mellitus complicated by nephropathy and end-stage renal disease and underwent kidney transplant from an unrelated donor 6 months ago. She is adherent with immunosuppressive therapy and regularly follows up with the transplant nephrologist. The patient reports good urine output and no pain at the transplant site but has had tremors in both upper limbs since the surgery. She has had no headaches, dizziness, or falls. The patient takes insulin and lately has been requiring a higher dosage despite no significant dietary changes. Temperature is 36.1 C (97 F), blood pressure is 152/90 mm Hg, pulse is 78/min, and respirations are 16/min. Physical examination shows bilateral hand tremor, which is most prominent during action. There is no rigidity; muscle strength, deep tendon reflexes, finger-nose testing, and gait are normal. Laboratory results are as follows: Which of the following immunosuppression medications is most likely responsible for this patient's current findings?

Question

A 45-year-old woman comes to the office for follow-up.  The patient has a history of type 2 diabetes mellitus complicated by nephropathy and end-stage renal disease and underwent kidney transplant from an unrelated donor 6 months ago.  She is adherent with immunosuppressive therapy and regularly follows up with the transplant nephrologist.  The patient reports good urine output and no pain at the transplant site but has had tremors in both upper limbs since the surgery.  She has had no headaches, dizziness, or falls.  The patient takes insulin and lately has been requiring a higher dosage despite no significant dietary changes.  Temperature is 36.1 C (97 F), blood pressure is 152/90 mm Hg, pulse is 78/min, and respirations are 16/min.  Physical examination shows bilateral hand tremor, which is most prominent during action.  There is no rigidity; muscle strength, deep tendon reflexes, finger-nose testing, and gait are normal.  Laboratory results are as follows:  Which of the following immunosuppression medications is most likely responsible for this patient's current findings?

Quizplus · Accepted Answer

Explanation: Calcineurin inhibitors (eg, tacrolimus, cyclosporine) inhibit the transcription of IL-2 to reduce T-lymphocyte activity and are an important component of chronic immunosuppression following solid-organ transplantation. Although these drugs are generally well tolerated, they have numerous adverse effects that must be monitored. These include: Nephrotoxicity: Calcineurin inhibitors have vasoconstrictive properties that can lead to reversible acute kidney injury (usually in the setting of elevated blood levels of the drug) or slowly progressive, chronic kidney injury that is typically irreversible. Associated electrolyte abnormalities are also common and include hyperkalemia and hyperuricemia with increased rates of gout. Hypertension: The vasoconstrictive properties can also cause hypertension, both by triggering increased sodium retention by the kidneys and through increased arteriolar peripheral resistance. Neurotoxicity: These effects may be due to low levels of vasoconstrictive cerebellar or cerebral ischemia. Tremor is a common manifestation; it can be either resting or with intention and often improves over time. Other less common and more serious effects include visual disturbance and seizures. Glucose intolerance (eg, increased insulin requirements): Calcineurin inhibitors impair the secretion of insulin from pancreatic islet cells, contributing to hyperglycemia. Tacrolimus appears to have a stronger hyperglycemic effect than cyclosporine. Cosmetic effects: Gingival hypertrophy (mostly with cyclosporine), hirsutism, and alopecia can occur. Gastrointestinal disturbance: These effects are usually mild and can include anorexia, nausea, vomiting, and diarrhea. As with most immunosuppression drugs, calcineurin inhibitors also increase the risk of infection and malignancy (eg, squamous cell skin cancer, lymphoma). (Choice A) Antithymocyte globulin is an immune globulin that is derived from rabbit serum and targets human T-lymphocytes. It is commonly used for induction of potent immunosuppression at the time of renal transplantation. Adverse effects include serum sickness (eg, fever, joint pains, skin rash), leukopenia, and thrombocytopenia. (Choice B) Azathioprine inhibits purine synthesis to impair the replication of lymphocytes and is sometimes used for chronic transplant immunosuppression. Common adverse effects include bone marrow suppression and hepatotoxicity. (Choice C) Mycophenolate formulations (eg, mycophenolate mofetil, mycophenolate sodium) are commonly used for chronic transplant immunosuppression. These drugs are known for causing gastrointestinal disturbances (eg, nausea, diarrhea) and bone marrow suppression. (Choice D) Low-dose prednisone is commonly used for chronic transplant immunosuppression. Adverse effects are many and include glucose intolerance and hypertension; however, tremor, renal insufficiency, and hyperkalemia are not typical. Educational objective: Calcineurin inhibitors (eg, tacrolimus, cyclosporine) have a wide range of adverse effects, including nephrotoxicity, hypertension, neurotoxicity (eg, tremor), and impaired glucose control. References: Tremor induced by calcineurin inhibitor immunosuppression: a single centre observational study in kidney transplanted patients. (http://www.ncbi.nlm.nih.gov/pubmed/29777361) Islet cell damage associated with tacrolimus and cyclosporine: morphological features in pancreas allograft biopsies and clinical correlation. (http://www.ncbi.nlm.nih.gov/pubmed/10459544)

A 45-Year-Old Woman Comes to the Office for Follow-Up