images in clinical medicineT h e n e w e ng l a n d j o u r na l o f m e dic i n e n engl j med 358;13 www.nejm.org march 27, 2008 e14 A 60-year-old man infected with the human immunodeficiency virus (HIV) (CD4 count of 450 per cubic millimeter and HIV viral load of <50 copies per milliliter) who had HIV-associated dementia was admitted to our hospital because of an altered mental status, a temperature of 101°F (38.3°C), and seizure-like activity. His medications included efavirenz, emtricitabine, tenofovir, and pravastatin sodium. Empirical treatment with intravenous acyclovir (10 mg per kilogram of body weight) and antibiotics was initiated before the patient underwent a lumbar puncture. Two hours after the administration of acyclovir, his urine became cloudy and white in the proximal portion of the Foley catheter, with clear yellow urine distally. A urinalysis was remarkable for a specific gravity of 1.025 with a urinary pH of 5.0. Ketones, albumin, and blood were detected. Microscopical analysis revealed birefringent needle-shaped crystals (Panel A; visualized under polarizing light in Panel B), a finding consistent with the precipitation of acyclovir. His serum creatinine level increased from 0.7 to 1.1 mg per deciliter (62 to 97 µmol per liter) and returned to the baseline level after the discontinuation of acyclovir and administration of 2 liters of normal saline. Additional treatment with intravenous acyclovir did not result in urinary crystallization of the drug. A lumbar puncture was unremarkable, and an infectious pathogen was not detected. It was concluded that the signs and symptoms on presentation were due to HIV-associated dementia and that the seizure-like activity was myoclonus. The patient was discharged to hospice care.
Plasma ultrafiltration in the kidney occurs across glomerular capillaries, which are surrounded by epithelial cells called podocytes. Podocytes have a unique shape maintained by a complex cytoskeleton, which becomes disrupted in glomerular disease resulting in defective filtration and albuminuria. Lack of endogenous thymosin β4 (TB4), an actin sequestering peptide, exacerbates glomerular injury and disrupts the organisation of the podocyte actin cytoskeleton, however, the potential of exogenous TB4 therapy to improve podocyte injury is unknown. Here, we have used Adriamycin (ADR), a toxin which injures podocytes and damages the glomerular filtration barrier leading to albuminuria in mice. Through interrogating single-cell RNA-sequencing data of isolated glomeruli we demonstrate that ADR injury results in reduced levels of podocyte TB4. Administration of an adeno-associated viral vector encoding TB4 increased the circulating level of TB4 and prevented ADR-induced podocyte loss and albuminuria. ADR injury was associated with disorganisation of the podocyte actin cytoskeleton in vitro, which was ameliorated by treatment with exogenous TB4. Collectively, we propose that systemic gene therapy with TB4 prevents podocyte injury and maintains glomerular filtration via protection of the podocyte cytoskeleton thus presenting a novel treatment strategy for glomerular disease.
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