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Tsukimura T, Saito K, Shiga T, Ogawa Y, Sakuraba H, Togawa T. Does administration of hydroxychloroquine/amiodarone affect the efficacy of enzyme replacement therapy for Fabry mice? Mol Genet Metab Rep 2024; 39:101079. [PMID: 38601121 PMCID: PMC11004688 DOI: 10.1016/j.ymgmr.2024.101079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Accepted: 03/29/2024] [Indexed: 04/12/2024] Open
Abstract
As a standard therapy for Fabry disease, enzyme replacement therapy (ERT) with recombinant human α-galactosidase A (α-Gal) has been successfully used, and the instructions for this drug state that "it should not be co-administrated with cationic amphiphilic drugs such as hydroxychloroquine (HCQ) and amiodarone (AMI), since these drugs have the potential to inhibit intracellular α-Gal activity". However, there would be cases in which HCQ or AMI is required for patients with Fabry disease, considering their medical efficacy and application. Thus, we examined the impact of HCQ/AMI on recombinant human α-Gal by in vitro, cellular, and animal experiments. The results revealed that HCQ/AMI affected the enzyme activity of α-Gal incorporated into cultured fibroblasts from a Fabry mouse when the cells were cultured in medium containing these drugs and the enzyme, although their direct inhibitory effect on the enzyme is not strong. These lysosomotropic drugs may be trapped and concentrated in lysosomes, followed by inhibition of α-Gal. On the other hand, no reduction of α-Gal activity incorporated into the organs and tissues, or acceleration of glycoshingolipid accumulation was observed in Fabry mice co-administered with HCQ/AMI and the enzyme, compared with in the case of usual ERT. As HCQ/AMI administered are catabolized in the liver, these drugs possibly do not affect ERT for Fabry mice, different from in the case of cultured cells in an environment isolated from the surroundings.
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Affiliation(s)
- Takahiro Tsukimura
- Department of Functional Bioanalysis, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
| | - Koki Saito
- Department of Functional Bioanalysis, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
| | - Tomoko Shiga
- Department of Clinical Genetics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
| | - Yasuhiro Ogawa
- Department of Pharmacodynamics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
| | - Hitoshi Sakuraba
- Department of Clinical Genetics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
| | - Tadayasu Togawa
- Department of Functional Bioanalysis, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
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Menke AF, Heitplatz B, Van Marck V, Pavenstädt H, Jehn U. Hydroxychloroquine-Induced Renal Phospholipidosis: Case Report and Review of Differential Diagnoses. Case Rep Nephrol Dial 2024; 14:20-29. [PMID: 38370571 PMCID: PMC10871737 DOI: 10.1159/000536448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Accepted: 01/20/2024] [Indexed: 02/20/2024] Open
Abstract
Introduction Renal phospholipidosis describes the accumulation of phospholipids in the lysosomes of kidney cells, in particular podocytes. Originally, this was described primarily in the context of the lysosomal storage disorder Fabry disease. It is now known that a variety of drugs can lead to the accumulation of lysosomal phospholipids. Case Presentation We present the case of a 69-year-old female patient suffering chronic kidney disease and systemic lupus erythematosus who underwent a kidney biopsy because of a further increase in serum creatinine levels. There was no evidence of lupus nephritis, but electron microscopy showed zebra bodies as a morphological sign of phospholipidosis. This was most likely drug-induced after 25 years of continuous medication with hydroxychloroquine. A renal biopsy 2 years and 6 months earlier, when the renal function of the patient was distinctively better, showed no signs of renal phospholipidosis. Afterward, medication with hydroxychloroquine was discontinued, and renal function parameters remained stable in the 1-year course. Conclusion This case raises the question of how severely impaired renal function affects the risk of hydroxychloroquine-induced renal phospholipidosis and underlines that hydroxychloroquine should be administered with caution in patients with kidney insufficiency. Moreover, we provide a review of the causes of renal phospholipidosis, which have been described in the literature and give an overview of possible differential diagnoses in cases with histologically proven phospholipidosis in renal biopsies.
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Affiliation(s)
- Amélie Friederike Menke
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Münster, Münster, Germany
| | - Barbara Heitplatz
- Gerhard-Domagk-Institut of Pathology, University Hospital of Münster, Münster, Germany
| | - Veerle Van Marck
- Gerhard-Domagk-Institut of Pathology, University Hospital of Münster, Münster, Germany
| | - Hermann Pavenstädt
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Münster, Münster, Germany
| | - Ulrich Jehn
- Division of General Internal Medicine, Nephrology and Rheumatology, Department of Medicine D, University Hospital of Münster, Münster, Germany
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3
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Ojha PR, Kumar R. Intraepithelial Inclusions on Urinalysis Screening among COVID-19 Cases: Are they Covicytes?-A Hospital-Based Cohort Study with Narrative Review. J Cytol 2024; 41:34-40. [PMID: 38282809 PMCID: PMC10810077 DOI: 10.4103/joc.joc_102_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 10/20/2023] [Accepted: 11/20/2023] [Indexed: 01/30/2024] Open
Abstract
Title "Intraepithelial inclusions on urinalysis screening among COVID-19 cases: Are they Covicytes?-A hospital-based cohort study with narrative review." Context Coronavirus disease 2019 (COVID-19)-associated delayed acute kidney injury (AKI) is often reported in subsequent waves of the pandemic. Early intervention and regular follow-up influence the outcome and inhibit progression into chronic kidney disease (CKD). This is the first study to identify urinary cytomorphological abnormalities (Covicytes) and predict COVID-19-associated delayed AKI with a narrative review of the possible etiologies for intraepithelial inclusions. Settings and Design A hospital-based cohort study with a narrative review. Material and Methods Screening urinalysis to assess the cytomorphology of epithelial cells (ECs) and inclusions in Leishman and periodic acid-Schiff (PAS)-stained smears by two independent pathologists was performed in reverse transcriptase polymerase chain reaction (RT-PCR)-confirmed COVID-19 cases at a tertiary care center. Statistical Analysis Basic statistical tools were used for descriptive statistical analysis, and data were expressed in mean, proportion, and frequency. Results Cytomorphological abnormalities (48/188) were predominant among adult males. Leukocyturia (39/48) with positive nitrite test (28/39), high ECs (27/48) and squamous cell-to-tubular EC (SC:TEC) ratio, intraepithelial intracytoplasmic inclusions predominantly in TECs (Covicytes), and multiple well-visualized, perinuclear PAS-negative neutrophilic vacuoles (17/39) were found. The association with preexisting diabetes (31/48), hypertension (10/48), and disease severity was noted. Conclusions This study reported COVID-19-associated urinary cytomorphological abnormalities and interesting unique inclusions (Covicytes) that may be a result of underlying inflammatory changes, reactive hyperplasia, degenerative changes, or defective endocytosed vacuoles. The possible etiologies for renal inclusions were reviewed. We recommend compulsory baseline and follow-up urinary cytology screening for all COVID-19-suspected patients to detect and predict delayed AKI before clinical and biochemical manifestation during disease endemicity.
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Affiliation(s)
- Pushpanjali R. Ojha
- Department of Pathology, Rajendra Institute of Medical Sciences (RIMS), Ranchi, Jharkhand, India
| | - Rakesh Kumar
- Assistant Professor, Department of Emergency Medicine, HiTech Medical College and Hospital, Rourkela, Odisha, India
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Esposito P, Caputo C, Repetto M, Somaschini A, Pietro B, Colomba P, Zizzo C, Parodi A, Zanetti V, Canepa M, Eustachi V, Sanguineri F, Mandich P, Viazzi F. Diagnosing Fabry nephropathy: the challenge of multiple kidney disease. BMC Nephrol 2023; 24:344. [PMID: 37990184 PMCID: PMC10664682 DOI: 10.1186/s12882-023-03388-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 11/03/2023] [Indexed: 11/23/2023] Open
Abstract
Fabry disease (FD) is an X-linked inherited lysosomal disorder due to a deficiency of the enzyme alpha-galactosidase A (α-gla) due to mutations in the GLA gene. These mutations result in plasma and lysosome accumulation of glycosphingolipids, leading to progressive organ damage and reduced life expectancy. Due to the availability of specific disease-modifying treatments, proper and timely diagnosis and therapy are essential to prevent irreversible complications. However, diagnosis of FD is often delayed because of the wide clinical heterogeneity of the disease and multiple organ involvement developing in variable temporal sequences. This observation is also valid for renal involvement, which may manifest with non-specific signs, such as proteinuria and chronic kidney disease, which are also common in many other nephropathies. Moreover, an additional confounding factor is the possibility of the coexistence of FD with other kidney disorders. Thus, suspecting and diagnosing FD nephropathy in patients with signs of kidney disease may be challenging for the clinical nephrologist. Herein, also through the presentation of a unique case of co-occurrence of autosomal dominant polycystic kidney disease and FD, we review the available literature on cases of coexistence of FD and other renal diseases and discuss the implications of these conditions. Moreover, we highlight the clinical, laboratory, and histological elements that may suggest clinical suspicion and address a proper diagnosis of Fabry nephropathy.
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Affiliation(s)
- Pasquale Esposito
- Department of Internal Medicine, University of Genoa, Genoa, Italy.
- Unit of Nephrology, Dialysis, and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.
| | - Carmela Caputo
- Unit of Nephrology and Dialysis, Ospedale San Paolo, Savona, Italy
| | - Monica Repetto
- Unit of Nephrology and Dialysis, Ospedale San Paolo, Savona, Italy
| | - Alberto Somaschini
- Division of Cardiology and Cardiac Intensive Care Unit, Ospedale San Paolo, Savona, Italy
| | - Bellone Pietro
- Division of Cardiology and Cardiac Intensive Care Unit, Ospedale San Paolo, Savona, Italy
| | - Paolo Colomba
- Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), Palermo, Italy
| | - Carmela Zizzo
- Institute for Biomedical Research and Innovation (IRIB), National Research Council (CNR), Palermo, Italy
| | - Angelica Parodi
- Unit of Nephrology, Dialysis, and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Valentina Zanetti
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- Unit of Nephrology, Dialysis, and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Marco Canepa
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Virginia Eustachi
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- Cardiovascular Disease Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Francesca Sanguineri
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal and Infantile Sciences, University of Genoa, Genoa, Italy
| | - Paola Mandich
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal and Infantile Sciences, University of Genoa, Genoa, Italy
- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Francesca Viazzi
- Department of Internal Medicine, University of Genoa, Genoa, Italy
- Unit of Nephrology, Dialysis, and Transplantation, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
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5
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Harty T, O'Shaughnessy M, Harney S. Therapeutics in rheumatology and the kidney. Rheumatology (Oxford) 2023; 62:1009-1020. [PMID: 35951751 DOI: 10.1093/rheumatology/keac460] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 07/08/2022] [Accepted: 08/05/2022] [Indexed: 11/13/2022] Open
Abstract
The field of rheumatology has advanced significantly in recent years to provide rheumatologists with an extensive array of medications to combat rheumatic joint conditions. In contrast to an older era, when NSAIDs and other nephrotoxic agents were the mainstay of treatment, modern DMARDs vary considerably in their nephrotoxic potential and their use is not always precluded in populations with pre-existing chronic kidney disease (CKD). This review will explore in detail the safety and efficacy profiles of medications used to treat rheumatologic disease, specifically in the setting of CKD. Specifically, we discuss both traditional agents used, i.e. NSAIDs, CSs and conventional synthetic DMARDs, as well as novel biologic DMARDs and targeted synthetic DMARDs. Anti-gout prescribing in CKD is also reviewed. We aim to provide practical guidance to rheumatologists, nephrologists and general physicians when prescribing these medications in the setting of CKD.
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Affiliation(s)
| | | | - Sinead Harney
- School of Medicine, University College Cork.,Department of Rheumatology, Cork University Hospital, Cork, Ireland
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Gagnon LR, Sadasivan C, Yogasundaram H, Oudit GY. Review of Hydroxychloroquine Cardiotoxicity: Lessons From the COVID-19 Pandemic. Curr Heart Fail Rep 2022; 19:458-466. [PMID: 36167917 PMCID: PMC9514702 DOI: 10.1007/s11897-022-00581-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/15/2022] [Indexed: 11/30/2022]
Abstract
Purpose of Review The coronavirus disease 2019 (COVID-19) pandemic has popularized the usage of hydroxychloroquine and chloroquine (HCQ/CQ) as treatments for COVID-19. Previously used as anti-malarial and now commonly used in rheumatologic conditions, preliminary in vitro studies have demonstrated these medications also have anti-viral properties. Retinopathy and neuromyopathy are well recognized complications of using these treatments; however, cardiotoxicity is under-recognized. This review will discuss the implications and cardiotoxicity of HCQ/CQ, their mechanisms of action, and their utility in COVID-19. Recent Findings Early clinical trials demonstrated a modest benefit of HCQ in COVID-19, causing a push for the usage of it. However, further large multi-center randomized control centers, demonstrated no benefit, and even a trend towards worse outcomes. The predominant cardiac complication observed with HCQ in COVID-19 was cardiac arrhythmias and prolonging of the QT interval. However, with chronic usage of HCQ/CQ, the development of heart failure (HF) and cardiomyopathy (CM) can occur. Summary Although, most adverse cardiac events related to HCQ/CQ usage in COVID-19 were secondary to conduction disorders given the short duration of treatment, HCQ/CQ can cause CM and HF, with chronic usage. Given the insufficient evidence, HCQ/CQ usage in COVID-19 is not routinely recommended, especially with novel therapies now being developed and used. Additionally, usage of HCQ/CQ should prompt initial cardiac evaluation with ECG, and yearly monitoring, with consideration for advanced imaging if clinically warranted. The diagnosis of HCQ/CQ cardiomyopathy is important, as prompt cessation can allow for recovery when these changes are still reversible.
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Affiliation(s)
- Luke R Gagnon
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.,Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Chandu Sadasivan
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.,Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Haran Yogasundaram
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.,Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Gavin Y Oudit
- Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. .,Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada. .,Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
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7
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Dima A, Jurcut C, Chasset F, Felten R, Arnaud L. Hydroxychloroquine in systemic lupus erythematosus: overview of current knowledge. Ther Adv Musculoskelet Dis 2022; 14:1759720X211073001. [PMID: 35186126 PMCID: PMC8848057 DOI: 10.1177/1759720x211073001] [Citation(s) in RCA: 91] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 12/17/2021] [Indexed: 12/22/2022] Open
Abstract
The antimalarial hydroxychloroquine (HCQ) has demonstrated several crucial properties for the treatment of systemic lupus erythematosus (SLE). Herein, we reviewed the main HCQ pharmacologic features, detailed its mechanism of action, and summarized the existing guidelines and recommendations for HCQ use in rheumatology with a systematic literature search for the randomized controlled trials focused on lupus. HCQ has been shown to decrease SLE activity, especially in mild and moderate disease, to prevent disease flare and to lower the long-term glucocorticoid need. The numerous benefits of HCQ are extended to pregnancy and breastfeeding period. Based on cohort studies, antithrombotic and metabolic HCQ’s effects were shown, including lipid-lowering properties, which might contribute to an improved cardiovascular risk. Moreover, early HCQ use in antinuclear antibodies positive individuals might delay the progression to SLE. Finally, HCQ has a significant favorable impact on long-term outcomes such as damage accrual and mortality in SLE. Based on these multiple benefits, HCQ is now the mainstay long-term treatment in SLE, recommended by current guidelines in all patients unless contraindications or side effects. The daily dose associated with the best compromise between efficacy and safety is matter of debate. The concern regarding retinal toxicity rather than proper efficacy data is the one that dictated the daily dosage of ⩽5 mg/kg/day actual body weight currently agreed upon.
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Affiliation(s)
- Alina Dima
- Department of Rheumatology, Colentina Clinical Hospital, Bucharest, Romania
| | - Ciprian Jurcut
- Department of Internal Medicine, Dr. Carol Davila Central Military Emergency University Hospital, Bucharest, Romania
| | - François Chasset
- Department of Dermatology and Allergology, Hôpital Tenon, Paris, France; Faculté de Médecine, Sorbonne Université, Paris, France
| | - Renaud Felten
- National Reference Center for Rare Auto-immune and Systemic Diseases Est Sud-Est (RESO), Strasbourg, France
- Department of Rheumatology, Les Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Laurent Arnaud
- National Reference Center for Rare Auto-immune and Systemic Diseases Est Sud-Est (RESO), Strasbourg, France
- Department of Rheumatology, Les Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- Université de Strasbourg, Inserm UMR-S 1109, Strasbourg, France
- Service de Rhumatologie, Hôpital de Hautepierre, 1, avenue Molière BP 83049, 67098 Strasbourg Cedex, France
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Jonny, Violetta L, Kartasasmita AS, Amirullah Roesli RM, Rita C. Pharmacological Treatment Options for Coronavirus Disease-19 in Renal Patients. Int J Nephrol 2021; 2021:4078713. [PMID: 34858665 PMCID: PMC8632427 DOI: 10.1155/2021/4078713] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Revised: 10/11/2021] [Accepted: 11/10/2021] [Indexed: 12/15/2022] Open
Abstract
Patients with chronic kidney disease (CKD), including dialysis and transplant patients, are at greater risk of contracting SARS-CoV-2 due to kidney dysfunction and preexisting comorbidities. To date, a specific guideline on managing these high-risk patients infected with COVID-19 has not been established. As the current management of COVID-19 comprises mainly experimental drugs, the authors aim to provide information on dosing adjustments at different stages of kidney dysfunction and notable renal side effects. We performed a nonsystematical review of currently available COVID-19 drugs exploring several different clinical trial databases and search browsers. Several antivirals and monoclonal antibodies used in COVID-19 treatment require dosage adjustments in kidney dysfunction. In a global pandemic setting, nephrologists need to consider the appropriate dosage according to the renal function and closely monitor the side effects of different drug combinations to obtain the optimum therapeutic effect while avoiding further renal damage. Further studies are required to determine the safety and efficacy of these drugs in renal patients.
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Affiliation(s)
- Jonny
- Nephrology Division, Department of Internal Medicine, Gatot Soebroto Indonesia Army Central Hospital, Jakarta, Indonesia
| | - Laurencia Violetta
- Nephrology Division, Department of Internal Medicine, Gatot Soebroto Indonesia Army Central Hospital, Jakarta, Indonesia
| | | | | | - Coriejati Rita
- Faculty of Medicine, Universitas Padjajaran, Bandung, West Java, Indonesia
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Davis J, Umeh U, Saba R. Treatment of SARS-CoV-2 (COVID-19): A safety perspective. World J Pharmacol 2021; 10:1-32. [DOI: 10.5497/wjp.v10.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/22/2021] [Accepted: 09/17/2021] [Indexed: 02/06/2023] Open
Abstract
The goal of this review is to report a balanced perspective of current evidence for efficacy of treatments for coronavirus disease 2019 (COVID-19) against the historical safety of these treatments as of May 2021. We preselected therapies of interest for COVID-19 based on national guidelines and modified over time. We searched PubMed and Medline for these specific COVID-19 treatments and data related to their efficacy. We also searched for prior randomized controlled trials of each therapy to assess adverse effects, and we obtained the Food and Drug Administration Approval label for this information. Several drugs have been approved for the treatment of COVID-19, and many more are under study. This includes dexamethasone, remdesivir, hydroxychloroquine/chloroquine, lopinvir/ritonavir, interferon or interleukin inhibitors, convalescent plasma and several vitamins and minerals. The strongest evidence for benefit is mortality benefit with dexamethasone in patients with COVID-19 and hypoxemia, although there is a signal of harm if this is started too early. There are several other promising therapies, like interleukin inhibitors and ivermectin. Hydroxychloroquine/chloroquine, lopinvir/ritonavir, and convalescent plasma do not have enough evidence of benefit to outweigh the known risks of these drugs.
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Affiliation(s)
- Joshua Davis
- Department of Emergency Medicine, Vituity, Wichita, KS 67214, United States
| | - Ugochukwu Umeh
- College of Medicine, Medical University of Lublin, Lublin 20-093, Poland
| | - Rand Saba
- Department of Surgery, Ascension Providence Hospital, Southfield, MI 48075, United States
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Tsukimura T, Shiga T, Saito K, Ogawa Y, Sakuraba H, Togawa T. Does administration of hydroxychloroquine/amiodarone accelerate accumulation of globotriaosylceramide and globotriaosylsphingosine in Fabry mice? Mol Genet Metab Rep 2021; 28:100773. [PMID: 34136356 PMCID: PMC8178118 DOI: 10.1016/j.ymgmr.2021.100773] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 11/19/2022] Open
Abstract
Drug-induced lysosomal storage disease (DILSD) caused by cationic amphiphilic drugs (CADs), which exhibits toxic manifestations and pathological findings mimicking Fabry disease (α-galactosidase A deficiency), has attracted the interests of clinicians and pathologists. Although the affected region is lysosomes in both the diseases, DILSD is characterized by intralysosomal accumulation of phospholipids and Fabry disease that of globotriaosylceramide (Gb3) and globotriaosylsphingosine (Lyso-Gb3). However, it is unknown whether administration of CADs affects the catabolism of Gb3 and Lyso-Gb3 in Fabry disease. In this study, we independently administered hydroxychloroquine/amiodarone to wild-type and Fabry mice and examined the effects of the drugs on the enzyme activity and substrates accumulated in organs and tissues. The results revealed that the administration of the drugs induced accumulation of phosphatidylcholine in both the wild-type and Fabry mice. However, reduction of α-galactosidase A activity in the organs and tissues of the wild-type mice was not found, and the storage of Gb3 and Lyso-Gb3 was not accelerated by these drugs in the Fabry mice. This suggests that hydroxychloroquine/amiodarone do not have any significant impact on the catabolism of Gb3 and Lyso-Gb3 in organs and tissues of both wild-type and Fabry mice.
Effects of cationic amphiphilic drugs on the catabolism of Gb3/Lyso-Gb3 were examined. The drugs induced phospholipidosis in the wild-type and Fabry mice. The drugs did not induce reduction of α-galactosidase A activity in the wild-type mice. The drugs did not accelerate accumulation of Gb3/Lyso-gb3 in the Fabry mice.
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Key Words
- Amiodarone
- CAD, cationic amphiphilic drug
- DILSD, drug-induced lysosomal storage disease
- Drug-induced lysosomal storage disease
- Fabry disease
- Gb3, globotriaosylceramide
- Globotriaosylceramide
- Globotriaosylsphingosine
- Hydroxychloroquine
- ILV, intralysosomal luminal vesicle
- LC, liquid chromatography
- Lyso-Gb3, globotriaosylsphingosine
- MRM, multiple reaction monitoring
- MS/MS, tandem mass spectrometry
- PhC, phosphatidylcholine
- Phospholipid
- α-Gal, α-galactosidase A
- α-Galactosidase A
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Affiliation(s)
- Takahiro Tsukimura
- Department of Functional Bioanalysis, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
| | - Tomoko Shiga
- Department of Clinical Genetics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
| | - Koki Saito
- Department of Functional Bioanalysis, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
| | - Yasuhiro Ogawa
- Department of Pharmacology, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
| | - Hitoshi Sakuraba
- Department of Clinical Genetics, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
| | - Tadayasu Togawa
- Department of Functional Bioanalysis, Meiji Pharmaceutical University, 2-522-1 Noshio, Kiyose, Tokyo 204-8588, Japan
- Corresponding author.
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11
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Schneider J, Jaenigen B, Wagner D, Rieg S, Hornuss D, Biever PM, Kern WV, Walz G. Therapy with lopinavir/ritonavir and hydroxychloroquine is associated with acute kidney injury in COVID-19 patients. PLoS One 2021; 16:e0249760. [PMID: 33974624 PMCID: PMC8112697 DOI: 10.1371/journal.pone.0249760] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Accepted: 03/25/2021] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Acute kidney injury (AKI) is an independent risk factor for mortality, which affects about 5% of hospitalized coronavirus disease-2019 (COVID-19) patients and up to 25-29% of severely ill COVID-19 patients. Lopinavir/ritonavir and hydroxychloroquine show in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and have been used for the treatment of COVID-19. Both, lopinavir and hydroxychloroquine are metabolized by cytochrome P450 (CYP) 3A4. The impact of a triple therapy with lopinavir/ritonavir and hydroxychloroquine (triple therapy) on kidney function in COVID-19 is currently not known. METHODS We retrospectively analyzed both non-ICU and ICU patients with COVID-19 receiving triple therapy for the incidence of AKI. Patients receiving standard therapy served as a control group. All patients were hospitalized at the University Hospital of Freiburg, Germany, between March and April 2020. A matched-pair analysis for the National Early Warning Score (NEWS) 2 was performed to control for the severity of illness among non-intensive care unit (ICU) patients. RESULTS In non-ICU patients, the incidence of AKI was markedly increased following triple therapy (78.6% vs. 21.4% in controls, p = 0.002), while a high incidence of AKI was observed in both groups of ICU patients (triple therapy: 80.0%, control group: 90.5%). ICU patients treated with triple therapy showed a trend towards more oliguric or anuric kidney injury. We also observed a linear correlation between the duration of the triple therapy and the maximum serum creatinine level (p = 0.004, R2 = 0.276, R = 0.597). CONCLUSION Triple therapy is associated with an increase in the incidence of AKI in non-ICU COVID-19 patients. The underlying mechanisms may comprise a CYP3A4 enzyme interaction, and may be relevant for any future therapy combining hydroxychloroquine with antiviral agents.
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Affiliation(s)
- Johanna Schneider
- Department of Medicine IV, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Bernd Jaenigen
- Department of General and Digestive Surgery, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Dirk Wagner
- Department of Medicine II, Division of Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Siegbert Rieg
- Department of Medicine II, Division of Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Daniel Hornuss
- Department of Medicine II, Division of Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Paul M. Biever
- Department of Medicine II, Division of Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
- Department of Medicine III (Interdisciplinary Medical Intensive Care), Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Cardiology and Angiology I, Heart Center Freiburg University, Medical Center–University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Winfried V. Kern
- Department of Medicine II, Division of Infectious Diseases, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
| | - Gerd Walz
- Department of Medicine IV, Faculty of Medicine, Medical Center, University of Freiburg, Freiburg, Germany
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Systemic toxicity of chloroquine and hydroxychloroquine: prevalence, mechanisms, risk factors, prognostic and screening possibilities. Rheumatol Int 2021; 41:1189-1202. [PMID: 33893862 PMCID: PMC8064887 DOI: 10.1007/s00296-021-04868-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 04/13/2021] [Indexed: 02/07/2023]
Abstract
Chloroquine (CQ) and its hydroxylated analog, hydroxychloroquine (HCQ), are 4-aminoquinoline initially used as an antimalarial treatment. CQ and HCQ (4-aminoquinoline, 4-AQ) are today used in rheumatology, especially to treat rheumatoid arthritis and systemic lupus erythematosus. Their mechanism of action revolves around a singular triptych: 4-AQ acts as alkalizing agents, ionized amphiphilic molecules, and by binding to numerous targets. 4-AQ have so pleiotropic and original mechanisms of action, providing them an effect at the heart of the regulation of several physiological functions. However, this broad spectrum of action is also at the origin of various and original side effects, notably a remarkable chronic systemic toxicity. We describe here the 4-AQ-induced lesions on the eye, the heart, muscle, the nerves, the inner ear, and the kidney. We also describe their prevalence, their pathophysiological mechanisms, their risk factors, their potential severity, and the means to detect them early. Most of these side effects are reversible if treatment is stopped promptly. This 4-AQ-induced toxicity must be known to prescribing physicians, to closely monitor its appearance and stop treatment in time if necessary.
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13
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Celia AI, Priori R, Cerbelli B, Diomedi-Camassei F, Leuzzi V, Scrivo R, Alessandri C, d'Amati G, Conti F. "Protenuria in SLE: Is it always lupus?". Lupus 2021; 30:664-668. [PMID: 33413001 DOI: 10.1177/0961203320983458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Proteinuria is one of the most typical manifestations of kidney involvement in Systemic Lupus Erythematosus (SLE). We report the case of a 23-year-old woman with a 6-year-long history of SLE presenting with proteinuria after a three-year remission on hydroxychloroquine. Kidney histological examination showed alterations inconsistent with lupus nephritis and suggestive of hydroxychloroquine toxicity or Fabry disease. The latter was confirmed by genetic assay.
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Affiliation(s)
- Alessandra Ida Celia
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Roberta Priori
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Bruna Cerbelli
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | | | - Vincenzo Leuzzi
- Department of Human Neuroscience, Sapienza University of Rome, Rome, Italy
| | - Rossana Scrivo
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Cristiano Alessandri
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Giulia d'Amati
- Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
| | - Fabrizio Conti
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
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Obeidat M, Isaacson AL, Chen SJ, Ivanovic M, Holanda D. Zebra-like bodies in COVID-19: is phospholipidosis evidence of hydroxychloroquine induced acute kidney injury? Ultrastruct Pathol 2020; 44:519-523. [PMID: 33274661 DOI: 10.1080/01913123.2020.1850966] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
COVID-19 (from SARS-CoV-2) is the cause of an ongoing pandemic, with an increasing number of cases and significant mortality worldwide. Clinical trials and extensive studies are being conducted on a large scale for a better understanding of the pathophysiology of this disease and its effect on different organs. Several experimental treatment protocols have been introduced, in which hydroxychloroquine (HCQ) was one of the first drugs used. While patients can develop many side effects of HCQ, studies have documented a rare association of long-term HCQ treatment with zebra-like bodies in the ultrastructural examination of kidney biopsies, a finding typically seen in Fabry's disease, as well as in association with chronic HCQ use, among other drugs. We present a similar finding in the postmortem examination of a male in his early seventies with COVID-19 infection, who received five days of HCQ treatment before stopping the medication due to cardiac and renal toxicity.
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Affiliation(s)
- Mohammad Obeidat
- Department of Pathology, University of Iowa Hospitals and Clinics , Iowa City, IA, USA
| | - Alexandra L Isaacson
- Department of Pathology, University of Iowa Hospitals and Clinics , Iowa City, IA, USA
| | - Stephanie J Chen
- Department of Pathology, University of Iowa Hospitals and Clinics , Iowa City, IA, USA
| | - Marina Ivanovic
- Department of Pathology, University of Iowa Hospitals and Clinics , Iowa City, IA, USA
| | - Danniele Holanda
- Department of Pathology, University of Iowa Hospitals and Clinics , Iowa City, IA, USA
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