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Posaconazole-induced Pseudohyperaldosteronism Manifesting with Nephrotic-range Proteinuria

Year: 2020

Type: article

Abstract: To the Editor—In a recent Clinical Infectious Diseases article, Nguyen et al [1] reported posaconazole-induced pseudohyperaldosteronism (PIPH) featuring hypertension, hypokalemia, and elevated 11-deoxycortisol. PIPH was frequent (23.2%) and correlated with higher posaconazole levels, preexisting hypertension, and older age. We describe a child with PIPH with predominant clinical features of edema and nephrotic-range proteinuria: a presentation that, to our knowledge, has not been previously associated with PIPH. A 12-year-old Caspase Recruiting Domain Family Member 9-deficient girl with invasive nasofacial phaeohyphomycosis [2] was found to have a contiguous infection that spread into the frontal lobes during evaluation under a National Institute of Allergy and Infectious Diseases Institutional Review Board–approved protocol. Antifungal therapy comprised liposomal amphotericin B (AMB), isavuconazole, micafungin, and terbinafine. She had AMB-induced chronic kidney disease (creatinine, 0.5–0.7 mg/dL; glomerular filtration rate 55–65 ml/min/1.773m2) with associated hypertension (controlled on 2.5 mg amlodipine twice daily) and non–nephrotic range proteinuria without edema. Despite antifungals and surgical removal of the frontal lobe disease, the brain infection recurred, prompting a transition from isavuconazole to posaconazole, which had a low minimum inhibitory concentration (0.06 μg/mL). At Day 8 following posaconazole loading, she developed bilateral hand and foot swelling while on 300 mg of oral posaconazole daily (9.7 mg/Kg), which spontaneously resolved within 24 hours. On Day 13 of posaconazole, the dose was increased to 400 mg daily (12.7 mg/Kg) in response to a level of 1660 ng/mL, with a goal of >2000 ng/mL given the brain fungal invasion. At 24 hours after the dose escalation, she developed progressively worsening periorbital and bilateral lower extremity edema with an associated 4 Kg of weight gain, while her renal function remained stable. A repeat posaconazole level was 2490 ng/mL. An adrenal steroidogenesis evaluation revealed elevated 11-deoxycortisol (206.5 ng/dL; normal: 12–158 ng/dL), increased 11-deoxycorticosterone (18 ng/dL) relative to the pre-posaconazole measurement (<5.0 ng/dl; normal: <30 ng/dL), undetectable renin (<0.6 ng/ml/h) and aldosterone (<3.0 ng/dL), and normal cortisol (13.4 mcg/dL; normal: 5–25 mcg/dL), in a pattern consistent with PIPH via 11β-hydroxylase inhibition [1, 3–5]. Notably, of the 2 predominant clinical features of PIPH, neither a worsening of the baseline hypertension nor clinically meaningful hypokalemia developed, despite a >0.5 mmol/L potassium decline (nadir, 3.6 mmol/L) [1]. Strikingly, urine studies revealed dramatically increased nephrotic-range proteinuria (from 1733.1 to 6123.0 mg/24 hours) and albuminuria (from 669.2 to 2042.5 μg/min; Figure 1). We switched posaconazole to isavuconazole. Within 23 days of posaconazole discontinuation, proteinuria and albuminuria returned to pre-posaconazole levels (1764.0 mg/24 hours and 728 μg/min, respectively; Figure 1), 11-deoxycortisol (26.6 ng/dL) and 11-deoxycorticosterone (<5.0 ng/dL) normalized, and the edema and weight gain resolved, indicating that PIPH is reversible and azole-specific, as previously reported [3, 6, 7]. Posaconazole-induced pseudohyperaldosteronism featuring nephrotic-range proteinuria, with 24-hour protein and albumin excretion over time before, during, and after posaconazole administration. The black bar represents the days that the patient was receiving 300 mg of oral posaconazole daily, and the dashed bar represents the days that the patient was receiving 400 mg of oral posaconazole daily. Although PIPH has not been previously linked to overt proteinuria, Conn’s initial report of primary hyperaldosteronism/Conn’s syndrome [8] described proteinuria in 85% of patients; proteinuria and albuminuria were also reported in subsequent Conn’s syndrome cohorts [9, 10]. Our report extends the scope of PIPH presentation to include severe proteinuria and suggests that PIPH-associated edema may be caused in some patients by hyperaldosteronism-associated proteinuria, which may reach the nephrotic range in patients with a preexisting kidney injury and might be more common in children, an understudied population. Protein and albumin urine excretion assessments in future studies of PIPH will be needed to accurately define the frequency, extent, and reversibility of PIPH-associated proteinuria. Financial support. This work was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the National Institutes of Health Clinical Center. Potential conflicts of interest. B. C. owns stock in Merck & Co. Inc and Pfizer Inc. D. P. M. has received research funding through a National Institutes of Health Cooperative Research and Development Agreement from Diurnal Limited and Spruce Biosciences, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Source: Clinical Infectious Diseases

DOI: 10.1093/cid/ciaa119