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1.
Pediatr Transplant ; 28(2): e14724, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38450793

ABSTRACT

BACKGROUND: BK viremia after kidney transplantation (KT) poses significant risk for BK virus-associated nephropathy and impacts graft survival. Conventional treatment involves reduction of immunosuppression, which in turn may increase risk for rejection. To address this dilemma, use of anti-viral therapy with immunosuppressive properties such as leflunomide is an attractive option. METHODS: We performed a multi-center, retrospective chart review to report tolerability and effectiveness of leflunomide use for the eradication of BK viremia and prevention of BK virus-associated nephropathy in pediatric KT recipients. RESULTS: Seventy patients prescribed leflunomide were included and were followed up from initiation until 1 year following leflunomide completion. BK viremia was eradicated in 64 (91.4%) patients including 8 of 11 with nephropathy (BKVN) on initial biopsy. Reduced anti-proliferative medication (AP) dosing was not associated with increase in biopsy proven rejection (BPAR). However, complete discontinuation of AP during leflunomide therapy was associated with increase in BPAR in uni- and multivariate logistic regression, as was targeted reduction in calcineurin inhibitor (CNI) trough goals. One graft was lost to BKVN. There was no significant association found between time to BK eradication and leflunomide trough concentration, mycophenolate dose reduction, or steroid use (univariate logistic regression). Few leflunomide adverse drug reactions (ADR) were reported (most commonly: gastrointestinal, hematologic). CONCLUSION: Leflunomide is a promising adjunctive treatment to immunosuppression reduction for BK virus eradication with minimal ADR. AP reduction, not discontinuation, and judicious reduction in CNI trough goals with close monitoring, is a promising strategy for treatment of BK viremia with concomitant use of leflunomide therapy.


Subject(s)
Kidney Transplantation , Nephritis, Interstitial , Humans , Child , Leflunomide/therapeutic use , Retrospective Studies , Viremia/drug therapy , Immunosuppressive Agents/therapeutic use , Calcineurin Inhibitors
2.
Sci Transl Med ; 13(601)2021 07 07.
Article in English | MEDLINE | ID: mdl-34233951

ABSTRACT

Triggers of innate immune signaling in the CNS of patients with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD) remain elusive. We report the presence of cytoplasmic double-stranded RNA (cdsRNA), an established trigger of innate immunity, in ALS-FTD brains carrying C9ORF72 intronic hexanucleotide expansions that included genomically encoded expansions of the G4C2 repeat sequences. The presence of cdsRNA in human brains was coincident with cytoplasmic TAR DNA binding protein 43 (TDP-43) inclusions, a pathologic hallmark of ALS/FTD. Introducing cdsRNA into cultured human neural cells induced type I interferon (IFN-I) signaling and death that was rescued by FDA-approved JAK inhibitors. In mice, genomically encoded dsRNAs expressed exclusively in a neuronal class induced IFN-I and death in connected neurons non-cell-autonomously. Our findings establish that genomically encoded cdsRNAs trigger sterile, viral-mimetic IFN-I induction and propagated death within neural circuits and may drive neuroinflammation and neurodegeneration in patients with ALS/FTD.


Subject(s)
Amyotrophic Lateral Sclerosis , C9orf72 Protein , Frontotemporal Dementia , Amyotrophic Lateral Sclerosis/genetics , Animals , Brain/metabolism , C9orf72 Protein/genetics , DNA Repeat Expansion , Frontotemporal Dementia/genetics , Humans , Mice , RNA, Double-Stranded
4.
Pediatr Nephrol ; 36(9): 2639-2658, 2021 09.
Article in English | MEDLINE | ID: mdl-33474686

ABSTRACT

Autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD) are characterized by bilateral cystic kidney disease leading to progressive kidney function decline. These diseases also have distinct liver manifestations. The range of clinical presentation and severity of both ADPKD and ARPKD is much wider than was once recognized. Pediatric and adult nephrologists are likely to care for individuals with both diseases in their lifetimes. This article will review genetic, clinical, and imaging predictors of kidney and liver disease progression in ADPKD and ARPKD and will briefly summarize pharmacologic therapies to prevent progression.


Subject(s)
Polycystic Kidney, Autosomal Dominant , Polycystic Kidney, Autosomal Recessive , Adult , Child , Disease Progression , Humans , Polycystic Kidney, Autosomal Dominant/diagnostic imaging , Polycystic Kidney, Autosomal Dominant/drug therapy , Polycystic Kidney, Autosomal Dominant/genetics , Polycystic Kidney, Autosomal Dominant/pathology , Polycystic Kidney, Autosomal Recessive/diagnostic imaging , Polycystic Kidney, Autosomal Recessive/drug therapy , Polycystic Kidney, Autosomal Recessive/genetics , Polycystic Kidney, Autosomal Recessive/pathology
5.
medRxiv ; 2020 Jun 16.
Article in English | MEDLINE | ID: mdl-32587994

ABSTRACT

Post-infectious anosmias typically follow death of olfactory sensory neurons (OSNs) with a months-long recovery phase associated with parosmias. While profound anosmia is the leading symptom associated with COVID-19 infection, many patients regain olfactory function within days to weeks without distortions. Here, we demonstrate that sterile induction of anti-viral type I interferon signaling in the mouse olfactory epithelium is associated with diminished odor discrimination and reduced odor-evoked local field potentials. RNA levels of all class I, class II, and TAAR odorant receptors are markedly reduced in OSNs in a non-cell autonomous manner. We find that people infected with COVID-19 rate odors with lower intensities and have odor discrimination deficits relative to people that tested negative for COVID-19. Taken together, we propose that inflammatory-mediated loss of odorant receptor expression with preserved circuit integrity accounts for the profound anosmia and rapid recovery of olfactory function without parosmias caused by COVID-19.

6.
PLoS One ; 7(9): e45395, 2012.
Article in English | MEDLINE | ID: mdl-23028982

ABSTRACT

The vacuolar proton-pumping ATPase (V-ATPase) is the main mediator of intracellular organelle acidification and also regulates transmembrane proton (H(+)) secretion, which is necessary for an array of physiological functions fulfilled by organs such as the kidney, male reproductive tract, lung, bone, and ear. In this study we characterize expression of the V-ATPase in the main olfactory epithelium of the mouse, as well as a functional role for the V-ATPase in odor detection. We report that the V-ATPase localizes to the apical membrane microvilli of olfactory sustentacular cells and to the basolateral membrane of microvillar cells. Plasma membrane V-ATPases containing the B1 subunit isoform are not detected in olfactory sensory neurons or in the olfactory bulb. This precise localization of expression affords the opportunity to ascertain the functional relevance of V-ATPase expression upon innate, odor-evoked behaviors in B1-deficient mice. This animal model exhibits diminished innate avoidance behavior (revealed as a decrease in freezing time and an increase in the number of sniffs in the presence of trimethyl-thiazoline) and diminished innate appetitive behavior (a decrease in time spent investigating the urine of the opposite sex). We conclude that V-ATPase-mediated H(+) secretion in the olfactory epithelium is required for optimal olfactory function.


Subject(s)
Olfactory Bulb/cytology , Olfactory Mucosa/metabolism , Protein Isoforms/metabolism , Sensory Receptor Cells/metabolism , Vacuolar Proton-Translocating ATPases/metabolism , Animals , Cell Membrane/metabolism , Immunohistochemistry , Male , Mice , Microscopy, Electron , Microvilli/metabolism , Odorants
7.
Nat Commun ; 3: 1009, 2012.
Article in English | MEDLINE | ID: mdl-22910355

ABSTRACT

The amyloid beta peptide aggregates into amyloid plaques at presymptomatic stages of Alzheimer's disease, but the temporal relationship between plaque formation and neuronal dysfunction is poorly understood. Here we demonstrate that the connectivity of the peripheral olfactory neural circuit is perturbed in mice overexpressing human APPsw (Swedish mutation) before the onset of plaques. Expression of human APPsw exclusively in olfactory sensory neurons also perturbs connectivity with associated reductions in odour-evoked gene expression and olfactory acuity. By contrast, olfactory sensory neuron axons project correctly in mice overexpressing wild-type human amyloid precursor protein throughout the brain and in mice overexpressing M671V human APP, a missense mutation that reduces amyloid beta production, exclusively in olfactory sensory neurons. Furthermore, expression of Aß40 or Aß42 solely in the olfactory epithelium disrupts the olfactory sensory neuron axon targeting. Our data indicate that altering the structural connectivity and function of highly plastic neural circuits is one of the pleiotropic actions of soluble human amyloid beta.


Subject(s)
Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Neural Conduction , Olfactory Perception , Sensory Receptor Cells/physiology , Alzheimer Disease/genetics , Alzheimer Disease/pathology , Amyloid beta-Peptides/genetics , Animals , Axons/metabolism , Disease Models, Animal , Female , Humans , Male , Mice , Mice, Transgenic , Plaque, Amyloid/metabolism
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