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Journal of Nephrology Nov 2023Hydroxychloroquine is one of the oldest disease-modifying anti-rheumatic drugs in clinical use. The drug interferes with lysosomal activity and antigen presentation,... (Review)
Review
Hydroxychloroquine is one of the oldest disease-modifying anti-rheumatic drugs in clinical use. The drug interferes with lysosomal activity and antigen presentation, inhibits autophagy, and decreases transcription of pro-inflammatory cytokines. Owing to its immunomodulatory, anti-inflammatory, anti-thrombotic effect, hydroxychloroquine has been an integral part of therapy for systemic lupus erythematosus and lupus nephritis for several decades. The therapeutic versatility of hydroxychloroquine has led to repurposing it for other clinical conditions, with recent studies showing reduction in proteinuria in IgA nephropathy. Research is also underway to investigate the efficacy of hydroxychloroquine in primary membranous nephropathy, Alport's syndrome, systemic vasculitis, anti-GBM disease, acute kidney injury and for cardiovascular risk reduction in chronic kidney disease. Hydroxychloroquine is well-tolerated, inexpensive, and widely available and therefore, should its indications expand in the future, it would certainly be welcomed. However, clinicians should be aware of the risk of irreversible and progressive retinal toxicity and rarely, cardiomyopathy. Monitoring hydroxychloroquine levels in blood appears to be a promising tool to evaluate compliance, individualize the dose and reduce the risk of retinal toxicity, although this is not yet standard clinical practice. In this review, we discuss the existing knowledge regarding the mechanism of action of hydroxychloroquine, its utility in lupus nephritis and other kidney diseases, the main adverse effects and the evidence gaps that need to be addressed in future research. Created with Biorender.com. HCQ, hydroxychloroquine; GBM, glomerular basement membrane; mDC, myeloid dendritic cell; MHC, major histocompatibility complex; TLR, toll-like receptor.
Topics: Humans; Hydroxychloroquine; Lupus Nephritis; Nephrology; Antirheumatic Agents; Lupus Erythematosus, Systemic
PubMed: 37530940
DOI: 10.1007/s40620-023-01733-6 -
Zhongguo Dang Dai Er Ke Za Zhi =... Jul 2023To investigate the genotypes of the pathogenic gene and the characteristics of clinical phenotypes in children with Alport syndrome (AS).
OBJECTIVES
To investigate the genotypes of the pathogenic gene and the characteristics of clinical phenotypes in children with Alport syndrome (AS).
METHODS
A retrospective analysis was performed for the genetic testing results and clinical data of 19 AS children with gene mutations.
RESULTS
Among the 19 children with AS caused by gene mutations, 1 (5%) carried a new mutation of the gene, i.e., c.3372A>G(p.P1124=) and presented with AS coexisting with IgA vasculitis nephritis; 3 children (16%) had large fragment deletion of the gene, among whom 2 children (case 7 had a new mutation site of loss51-53) had gross hematuria and albuminuria at the onset, and 1 child (case 13 had a new mutation site of loss3-53) only had microscopic hematuria, while the other 15 children (79%) had common clinical phenotypes of AS, among whom 7 carried new mutations of the gene. Among all 19 children, 3 children (16%) who carried gene mutations also had gene mutations, and 1 child (5%) had gene mutations. Among these children with double gene mutations, 2 had gross hematuria and proteinuria at the onset.
CONCLUSIONS
This study expands the genotype and phenotype spectrums of the pathogenic gene for AS. Children with large fragment deletion of the gene or double gene mutations of with or tend to have more serious clinical manifestations.
Topics: Humans; Nephritis, Hereditary; Hematuria; Retrospective Studies; Collagen Type IV; Genotype; Mutation
PubMed: 37529956
DOI: 10.7499/j.issn.1008-8830.2303069 -
Frontiers in Genetics 2023Alport syndrome (#308940) is an X-linked genetic disease with clinical manifestations, such as hematuria, proteinuria, renal insufficiency, and end-stage renal disease....
Alport syndrome (#308940) is an X-linked genetic disease with clinical manifestations, such as hematuria, proteinuria, renal insufficiency, and end-stage renal disease. The disease is characterized by the thinning of the glomerular basement membrane in the early stages and the thickening of the glomerular basement membrane in the late stages and may be associated with ocular lesions and varying degrees of sensorineural deafness. Herein, we report a case of Alport syndrome caused by a mutation in . The patient was a young male with clinical manifestations of hematuria and massive proteinuria who was diagnosed with Alport syndrome based on renal pathology and genetic testing.
PubMed: 37529776
DOI: 10.3389/fgene.2023.1216809 -
The Tohoku Journal of Experimental... Sep 2023X-linked Alport syndrome is a hereditary progressive renal disease resulting from the disruption of collagen α3α4α5 (IV) heterotrimerization caused by pathogenic...
X-linked Alport Syndrome with Type IV Collagen α5 Chain Staining Revealing Normal Expression in the Glomerular Basement Membrane and Negative on Bowman's Capsule and Distal Tubular Basement Membrane: A Case Report.
X-linked Alport syndrome is a hereditary progressive renal disease resulting from the disruption of collagen α3α4α5 (IV) heterotrimerization caused by pathogenic variants in the COL4A5 gene. This study aimed to report a male case of X-linked Alport syndrome with a mild phenotype accompanied by an atypical expression pattern of type IV collagen α5 [α5 (IV)] chain in glomerulus. A 38-year-old male presented with proteinuria (2.3 g/day) and hematuria. He has been detected urinary protein and occult blood since childhood. A renal biopsy was performed at the age of 29 years; however, a diagnosis of Alport syndrome was not considered. A renal biopsy 9 years later revealed diffuse thinning and lamellation of the glomerular basement membrane. Α staining for α5 (IV) revealed a normal expression pattern in the glomerular basement membrane and a complete negative expression in Bowman's capsule and distal tubular basement membrane. Using next-generation sequencing, we detected a COL4A5 missense variant within exon 35 (NM_000495.5: c.3088G>A, p. G1030S). The possibility of X-linked Alport syndrome should be considered when negative expression of α5 (IV) staining on Bowman's capsule was observed.
Topics: Male; Humans; Child; Adult; Nephritis, Hereditary; Collagen Type IV; Bowman Capsule; Glomerular Basement Membrane; Exons
PubMed: 37495524
DOI: 10.1620/tjem.2023.J060 -
Clinical and Experimental Nephrology Sep 2023Alport syndrome is one of the most common inherited kidney diseases worldwide. A genetic test or kidney biopsy is necessary for a definite diagnosis of this disease, and...
Investigation of the current situation regarding diagnosis and treatment of Alport syndrome in Asian countries: results of survey of the Asian Paediatric Nephrology association (AsPNA) tubular and inherited working group.
BACKGROUND
Alport syndrome is one of the most common inherited kidney diseases worldwide. A genetic test or kidney biopsy is necessary for a definite diagnosis of this disease, and an accurate diagnosis system for this disease is highly desired in each country. However, the current situation in Asian countries is not clear. Therefore, the tubular and inherited disease working group of the Asian Pediatric Nephrology Association (AsPNA) aimed to assess the current situation of diagnosis and treatment for Alport syndrome in Asia.
METHODS
The group conducted an online survey among the members of AsPNA in 2021-2022. Collected data included the number of patients for each inheritance mode, availability of gene tests or kidney biopsy, and treatment strategies for Alport syndrome.
RESULTS
A total of 165 pediatric nephrologists from 22 countries in Asia participated. Gene test was available in 129 institutes (78%), but the cost was still expensive in most countries. Kidney biopsy was available in 87 institutes (53%); however, only 70 can access electron microscopy, and 42 can conduct type IV collagen α5 chain staining. Regarding treatment, 140 centers use renin-angiotensin system (RAS) inhibitors (85%) for Alport syndrome patients.
CONCLUSIONS
This study result might suggest that the system is underdeveloped enough to diagnose all Alport syndrome patients in most Asian countries. However, once diagnosed with Alport syndrome, most of them were treated with RAS inhibitors. These survey results can be used to address knowledge, diagnostic system, and treatment strategy gaps and improve the Alport patients' outcomes in Asian countries.
Topics: Child; Humans; Nephritis, Hereditary; Nephrology; Collagen Type IV; Genetic Testing; Asia
PubMed: 37289334
DOI: 10.1007/s10157-023-02358-6 -
Kidney International Aug 2023X-linked Alport syndrome (XLAS) is an inherited kidney disease caused exclusively by pathogenic variants in the COL4A5 gene. In 10-20% of cases, DNA sequencing of COL4A5...
X-linked Alport syndrome (XLAS) is an inherited kidney disease caused exclusively by pathogenic variants in the COL4A5 gene. In 10-20% of cases, DNA sequencing of COL4A5 exons or flanking regions cannot identify molecular causes. Here, our objective was to use a transcriptomic approach to identify causative events in a group of 19 patients with XLAS without identified mutation by Alport gene panel sequencing. Bulk RNAseq and/or targeted RNAseq using a capture panel of kidney genes was performed. Alternative splicing events were compared to those of 15 controls by a developed bioinformatic score. When using targeted RNAseq, COL4A5 coverage was found to be 23-fold higher than with bulk RNASeq and revealed 30 significant alternative splicing events in 17 of the 19 patients. After computational scoring, a pathogenic transcript was found in all patients. A causative variant affecting COL4A5 splicing and absent in the general population was identified in all cases. Altogether, we developed a simple and robust method for identification of aberrant transcripts due to pathogenic deep-intronic COL4A5 variants. Thus, these variants, potentially targetable by specific antisense oligonucleotide therapies, were found in a high percentage of patients with XLAS in whom pathogenic variants were missed by conventional DNA sequencing.
Topics: Humans; Nephritis, Hereditary; Collagen Type IV; Mutation; Exons; RNA Splicing
PubMed: 37230224
DOI: 10.1016/j.kint.2023.05.006 -
Kidney International Aug 2023Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical...
Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.
Topics: Adult; Humans; Kidney Failure, Chronic; Polycystic Kidney Diseases; Kidney Diseases, Cystic; Mutation; Ciliopathies
PubMed: 37230223
DOI: 10.1016/j.kint.2023.05.007 -
Medical Molecular Morphology Sep 2023To improve the resolution of low-vacuum scanning electron microscopy (LVSEM), the epoxy resin block for the transmission electron microscopy (TEM) was observed directly...
To improve the resolution of low-vacuum scanning electron microscopy (LVSEM), the epoxy resin block for the transmission electron microscopy (TEM) was observed directly with LVSEM. After observing ultrathin sections from renal biopsies of IgA nephropathy, membranous nephropathy, lupus nephritis, diabetic nephropathy (DM), thin basement membrane disease (TBMD), Alport's syndrome, Fabry's disease, and renal amyloidosis, the epoxy resin blocks of the same sites were observed by LVSEM and compared. The LVSEM image of the epoxy resin block corresponds to the negative of the TEM image, and when the gradation is reversed, the LVSEM image was comparable to the TEM image. At a low magnification of 100 ×, the entire specimen, including the glomerulus, was obtained. LVSEM at 5000 × magnification was sufficient to identify paramesangial deposits in IgA nephropathy and subepithelial electron-dense deposits (EDD) and spikes in membranous nephropathy. Glomerular basement membrane thickening in DM and thinning in TBMD could be sufficiently diagnosed with LVSEM at 6000 ×. Accumulation of ceramide in Fabry's disease was easily identified, but amyloid fibril could not be identified by LVSEM. LVSEM of renal biopsy epoxy resin blocks can replace TEM up to moderate magnification.
Topics: Humans; Microscopy, Electron, Scanning; Epoxy Resins; Fabry Disease; Vacuum; Glomerulonephritis, IGA; Biopsy
PubMed: 37165248
DOI: 10.1007/s00795-023-00356-x