A 58-year-old woman comes to clinic for follow-up. She has a history of end-stage renal disease due to polycystic kidney disease and underwent renal transplantation 2 years ago. Two months ago, the patient was diagnosed with paroxysmal atrial fibrillation. She had been feeling well until the past several weeks when she noticed decreased urine output and mild fatigue. Current medications include diltiazem, apixaban, prednisone, tacrolimus, and mycophenolate sodium. Temperature is 37 C (98.6 F), blood pressure is 152/86 mm Hg, pulse is 82/min, and respirations are 12/min. Abdominal examination reveals no tenderness to palpation. Laboratory results reveal a serum creatinine of 2.3 mg/dL, which is increased from her baseline of 1.4 mg/dL that was last checked 2 months ago. Urinalysis with microscopy is as follows: Blood tacrolimus level is moderately elevated. Transplant ultrasound reveals no hydronephrosis. Which of the following is the most likely cause of this patient's worsening renal function?

Question

A 58-year-old woman comes to clinic for follow-up.  She has a history of end-stage renal disease due to polycystic kidney disease and underwent renal transplantation 2 years ago.  Two months ago, the patient was diagnosed with paroxysmal atrial fibrillation.  She had been feeling well until the past several weeks when she noticed decreased urine output and mild fatigue.  Current medications include diltiazem, apixaban, prednisone, tacrolimus, and mycophenolate sodium.  Temperature is 37 C (98.6 F), blood pressure is 152/86 mm Hg, pulse is 82/min, and respirations are 12/min.  Abdominal examination reveals no tenderness to palpation.  Laboratory results reveal a serum creatinine of 2.3 mg/dL, which is increased from her baseline of 1.4 mg/dL that was last checked 2 months ago.  Urinalysis with microscopy is as follows:  Blood tacrolimus level is moderately elevated.  Transplant ultrasound reveals no hydronephrosis.  Which of the following is the most likely cause of this patient's worsening renal function?

Quizplus · Accepted Answer

This patient with acute kidney injury (AKI) and an elevated blood tacrolimus level likely has acute calcineurin inhibitor (CNI) renal toxicity. CNIs (eg, tacrolimus, cyclosporine) revolutionized organ transplant immunosuppression by providing relatively targeted inhibition of lymphocyte-mediated rejection (via inhibition of IL-2 production) with minimal hindrance of antimicrobial immunity. However, these drugs are not without adverse effects; they have vasoconstrictive properties that are responsible for much of their toxicity. CNIs are mainly hepatically cleared, making blood levels susceptible to influence by medications that affect the cytochrome P450 system. In this patient with recently diagnosed atrial fibrillation, the initiation of diltiazem, a cytochrome P450 inhibitor, likely triggered increased CNI blood levels. Patients with acute toxicity typically have hypertension as well as AKI caused by constriction of the afferent and efferent renal arterioles. Urine studies are usually unremarkable (bland), consistent with a prerenal etiology. The AKI is typically reversible with adjustment of CNI dosing and reduction in blood levels. Chronic CNI renal toxicity can also occur. It likely results from both prolonged vasoconstrictive renal ischemia as well as possible direct tubular toxicity of the medication. It leads to a progressive, slow decline in renal function and is typically irreversible. (Choice A) Certain medications (eg, beta-lactam antibiotics, nonsteroidal anti-inflammatory drugs) can trigger AKI due to acute interstitial nephritis (AIN). However, this patient's medications are not commonly associated with AIN, and evidence of inflammation (eg, positive leukocyte esterase, elevated white blood cells with casts) is usually expected on urine studies. (Choice B) Acute tubular necrosis in renal transplant recipients is most common in the first week following transplantation, usually resulting from perioperative graft ischemia. Muddy brown casts are commonly expected on urine microscopy. (Choices C and E) Acute rejection is predominantly antibody-mediated and is common within the first 6 months following renal transplantation, usually presenting with AKI. Reactivation of BK virus (a polyoma virus) is also a potential cause of worsening renal function in renal transplant recipients. However, both acute rejection and BK virus reactivation are often accompanied by evidence of inflammation on urine studies, and this patient's elevated blood tacrolimus level and hypertension make acute CNI toxicity more likely. Educational objective: Calcineurin inhibitors (eg, tacrolimus, cyclosporine) have vasoconstrictive properties that are responsible for much of their toxicity. Acute calcineurin inhibitor toxicity is often triggered by impaired hepatic clearance of the drug and presents with hypertension and prerenal acute kidney injury. References: Pathophysiological mechanisms of calcineurin inhibitor-induced nephrotoxicity and arterial hypertension. (http://www.ncbi.nlm.nih.gov/pubmed/27982677)

A 58-Year-Old Woman Comes to Clinic for Follow-Up