The Impact of COVID-19 on Patients With ADPKD.

PURPOSE OF REVIEW: Patients with autosomal dominant polycystic kidney disease (ADPKD) have kidney cysts and kidney enlargement decades before progressing to advanced chronic kidney disease (CKD), meaning patients live most of their adult life with a chronic medical condition. The coronavirus disease 2019 (COVID-19) pandemic has created common questions among patients with ADPKD. In this review, we discuss COVID-19 concerns centered around a patient with a common clinical vignette. SOURCES OF INFORMATION: We performed PubMed and Google scholar searches for English, peer-reviewed studies related to "COVID-19," "ADPKD," "CKD," "tolvaptan," "angiotensin-converting enzyme inhibitors" (ACEi), "angiotensin receptor blockers" (ARB), and "vaccination." We also evaluated transplant data provided by the Ontario Trillium Gift of Life Network. METHODS: Following an assessment of available literature, this narrative review addresses common questions of patients with ADPKD in the context of the COVID-19 pandemic. KEY FINDINGS: Data regarding the risk of developing COVID-19 and the risk of adverse COVID-19 outcomes in patients with ADPKD remain limited, but patients with ADPKD with impaired estimated glomerular filtration rate (eGFR), kidney transplants, or on dialysis are likely at similar increased risk as those with generally defined CKD. We provide strategies to improve virtual care, which is likely to persist after the pandemic. Current evidence suggests ACEi, ARB, and tolvaptan treatment should be continued unless contraindicated due to severe illness. When available, and in the absence of a severe allergy, vaccination is recommended for all patients with ADPKD. LIMITATIONS: This narrative review is limited by a paucity of high-quality data on COVID-19 outcomes in patients specifically with ADPKD. IMPLICATIONS: Patients with ADPKD who have developed advanced CKD, require dialysis, or who have received a kidney transplant are at elevated risk of COVID-19 complications.

Late-Onset Systemic Lupus Erythematosus With Lupus Nephritis in a 74-Year-Old Male: A Brief Case and Review.

RATIONALE: Late-onset systemic lupus erythematosus (SLE) represents a specific subgroup of SLE, and although there is no strict age cut-off, 50 years is commonly used as the minimum age for disease onset. In this report, we present a case of a 74-year-old male with late-onset SLE and biopsy-proven lupus nephritis (LN). PRESENTING CONCERNS OF THE PATIENT: A 74-year-old male was referred to the nephrology clinic with a rapidly rising creatinine from a baseline of 60 µmol/L to 176 µmol/L. His labs showed pancytopenia, a positive antinuclear antibodies (ANA), and hypocomplementemia. DIAGNOSES: Renal biopsy showed focal proliferative glomerulonephritis that was immune-mediated and immunofluorescence showed C3, IgM, IgA, IgG, lambda, and C1q diffuse mesangial and glomerular basement membrane staining. Together these findings were in keeping with a diagnosis of stage III LN. INTERVENTIONS: Treatment included hemodialysis and induction with pulse methylprednisone and cyclophosphamide. He was then placed on the Euro-Lupus Protocol. OUTCOMES: One year after the diagnosis, he was off dialysis, had no signs of fluid retention or uremia, and his creatinine had stabilized at ~ 330 µmol/L. LESSONS LEARNED: To the best of our knowledge, this case represents the oldest known biopsy-confirmed case of late-onset SLE and LN. Late-onset SLE is uncommon and often overlooked as classical symptoms such as malar rash or photosensitivity may not be present. The American College of Rheumatology (ACR) guidelines for treatment of LN can be applied to these patients but physicians should be cognizant of the fact that these patients may not tolerate immunosuppressive therapy as well as younger patients.

CONTEXTE: La forme tardive du lupus érythémateux disséminé (LED) constitue un sous-groupe particulier de la maladie. Bien qu'il n'existe pas de limite d'âge précise pour établir la manifestation tardive du LED, cette limite est généralement fixée à 50 ans. Dans ce rapport, nous présentons le cas d'un patient âgé de 74 ans atteint de la forme tardive du LED et d'une néphropathie lupique (NL) avérée par biopsie. PRÉSENTATION DU CAS: Il s'agit d'un patient âgé de 74 ans orienté en clinique de néphrologie en raison d'une augmentation rapide de son taux de créatinine, lequel était passé de 60 µmol/L (valeur initiale) à 176 µmol/L. Les analyses de laboratoire ont confirmé la présence d'une pancytopénie, d'une hypocomplémentémie et d'un résultat positif pour la détection des anticorps antinucléaires (AAN). DIAGNOSTIC: La biopsie rénale a révélé la présence d'une néphrite de Löhlein à médiation immunologique et l'immunofluorescence a mis en évidence une coloration diffuse des membranes basales mésangiales et glomérulaires pour les fragments de C3 et de C1q, pour les IgM, les IgA, les IgG, de même que pour les chaînes Lambda. Ces constatations mises ensemble concordaient avec un diagnostic de NL de stade 3. INTERVENTION: Le patient a été traité par hémodialyse et par l'administration intermittente de méthylprednisone et de cyclophosphamide. Il a par la suite suivi le protocole « Euro-Lupus ¼. RÉSULTATS: Un an après le diagnostic, le patient n'était plus sous dialyse, ne montrait aucun signe d'urémie ou de rétention hydrique, et son taux de créatinine était stable autour de 330 µmol/L. ENSEIGNEMENTS TIRÉS: À notre connaissance, ce patient représente le cas connu le plus tardif de manifestation d'un LED et d'une NL confirmée par biopsie. La forme tardive du LED est plutôt rare et souvent négligée en raison de l'absence d'érythème malaire ou de réaction de photosensibilité; des symptômes normalement associés à la maladie. Les recommandations de l'ACR pour le traitement de la NL peuvent être appliquées chez ces patients, mais les médecins doivent garder à l'esprit que ces patients pourraient ne pas tolérer les traitements immunosuppresseurs aussi bien que les patients plus jeunes.

Expression of an RNA glycosidase inhibits HIV-1 transactivation of transcription.

HIV-1 (human immunodeficiency virus) transcription is primarily controlled by the virally encoded Tat (transactivator of transcription) protein and its interaction with the viral TAR (transcription response element) RNA element. Specifically, binding of a Tat-containing complex to TAR recruits cellular factors that promote elongation of the host RNA polymerase engaging the viral DNA template. Disruption of this interaction halts viral RNA transcription. In the present study, we investigated the effect of pokeweed antiviral protein (PAP), an RNA glycosidase (EC#: 3.2.2.22) synthesized by the pokeweed plant (Phytolacca americana), on transcription of HIV-1 mRNA. We show that co-expression of PAP with a proviral clone in culture cells resulted in a Tat-dependent decrease in viral mRNA levels. PAP reduced HIV-1 transcriptional activity by inhibiting Tat protein synthesis. The effects of PAP expression on host factors AP-1 (activator protein 1), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B-cells) and specificity protein 1, which modulate HIV-1 transcription by binding to the viral LTR (5'-long terminal repeat), were also investigated. Only AP-1 showed a modest JNK pathway-dependent increase in activity in the presence of PAP; however, this activation was not sufficient to significantly enhance transcription from a partial viral LTR containing AP-1 binding sites. Therefore, the primary effect of PAP on HIV-1 transcription is to reduce viral RNA synthesis by decreasing the abundance of Tat. These findings provide a mechanistic explanation for the observed decrease in viral RNAs in cells expressing PAP and contribute to our understanding of the antiviral effects of this plant protein.

Pokeweed antiviral protein increases HIV-1 particle infectivity by activating the cellular mitogen activated protein kinase pathway.

Pokeweed antiviral protein (PAP) is a plant-derived N-glycosidase that exhibits antiviral activity against several viruses. The enzyme removes purine bases from the messenger RNAs of the retroviruses Human immunodeficiency virus-1 and Human T-cell leukemia virus-1. This depurination reduces viral protein synthesis by stalling elongating ribosomes at nucleotides with a missing base. Here, we transiently expressed PAP in cells with a proviral clone of HIV-1 to examine the effect of the protein on virus production and quality. PAP reduced virus production by approximately 450-fold, as measured by p24 ELISA of media containing virions, which correlated with a substantial decline in virus protein synthesis in cells. However, particles released from PAP-expressing cells were approximately 7-fold more infectious, as determined by single-cycle infection of 1G5 cells and productive infection of MT2 cells. This increase in infectivity was not likely due to changes in the processing of HIV-1 polyproteins, RNA packaging efficiency or maturation of virus. Rather, expression of PAP activated the ERK1/2 MAPK pathway to a limited extent, resulting in increased phosphorylation of viral p17 matrix protein. The increase in infectivity of HIV-1 particles produced from PAP-expressing cells was compensated by the reduction in virus number; that is, virus production decreased upon de novo infection of cells over time. However, our findings emphasize the importance of investigating the influence of heterologous protein expression upon host cells when assessing their potential for antiviral applications.

RNA toxins: mediators of stress adaptation and pathogen defense.

RNA toxins are a group of enzymes primarily synthesized by bacteria, fungi, and plants that either cleave or depurinate RNA molecules. These proteins may be divided according to their RNA substrates: ribotoxins are nucleases that cleave ribosomal RNA (rRNA), ribosome inactivating proteins are glycosidases that remove a base from rRNA, messenger RNA (mRNA) interferases are nucleases that cleave mRNAs, and anticodon nucleases cleave transfer RNAs (tRNAs). These modifications to the RNAs may substantially alter gene expression and translation rates. Given that some of these enzymes cause cell death, it has been suggested that they function mainly in defense, either to kill competing cells or to elicit suicide and thereby limit pathogen spread from infected cells. Although good correlations have been drawn between their enzymatic functions and toxicity, recent work has shown that some RNA toxins cause apoptosis in the absence of damage to RNA and that defense against pathogens can be achieved without host cell death. Moreover, a decrease in cellular translation rate, insufficient to cause cell death, allows some organisms to adapt to stress and environmental change. Although ascribing effects observed in vitro to the roles of these toxins in nature has been challenging, recent results have expanded our understanding of their modes of action, and emphasized the importance of these toxins in development, adaptation to stress and defense against pathogens.