Coexisting presentation of two rare genetic variants of autosomal dominant polycystic kidney disease and Alport syndrome.

Alport syndrome and autosomal dominant polycystic kidney disease are monogenic causes of chronic kidney disease and end-stage kidney failure. We present a case of a man in his 60s with progressive chronic kidney disease, bilateral sensorineural hearing loss and multiple renal cysts. Genetic analysis revealed a heterozygous variant in COL4A3 (linked to Alport syndrome) and in the GANAB gene (associated with a milder form of autosomal dominant polycystic kidney disease). Although each variant confers a mild risk of developing end-stage kidney disease, the patient presented a pronounced and accelerated progression of chronic kidney disease, which goes beyond what would be predicted by adding up their individual effects. This suggests a potential synergic effect of both variants, which warrants further investigation.

A case of crescentic glomerulonephritis with exacerbation of pre-existing IgA nephropathy after COVID-19.

BACKGROUND: Relapses or new-onset IgA nephropathy (IgAN) have been documented in patients after vaccination against SARS-CoV-2; however, only one adult patient has been reported in whom pre-existing IgAN worsened during coronavirus disease 2019 (COVID-19). CASE: We present the first pediatric case with biopsy-proven IgAN and genetically confirmed Alport syndrome, who developed end-stage kidney disease after an exacerbation of IgAN associated with COVID-19. The patient`s basal serum creatinine was 0.7-0.9 mg/dL before infection. He had not been vaccinated against COVID-19. He was admitted to the hospital with edema, hypertension, an elevated serum creatinine of 4.7 mg/ dL, and massive proteinuria. Three months before admission, he had been admitted to another hospital with COVID -19 and an elevated serum creatinine (1.9 mg/dL), but no biopsy had been performed at that time. The kidney biopsy revealed IgAN with 50% fibrocellular crescents with sclerosed glomeruli, tubular atrophy, and interstitial fibrosis. His serum creatinine did not decrease even after five administrations of pulse steroids, and hemodialysis was initiated. CONCLUSION: In conclusion, COVID -19 may pose a high risk for exacerbation of pre-existing glomerular disease. It is therefore necessary to closely monitor the kidney function of patients with underlying glomerulonephritis during and after COVID-19 and consider an early biopsy if serum creatinine does not return to baseline levels. In addition, this case report highlights the clinical importance of the co-occurence of IgAN and Alport syndrome.

Human umbilical cord mesenchymal stem cell therapy for renal dysfunction in Alport syndrome: protocol for an open-label, single-arm trial in China.

INTRODUCTION: Alport syndrome (AS) is one of the most common fatal hereditary renal diseases in human, with a high risk of progressing to end-stage renal disease without effective treatments. Mesenchymal stem cells (MSCs) have recently emerged as a promising therapeutic strategy for chronic kidney disease. However, the safety and therapeutic potential of MSC transfusion for patients with AS are still need to be confirmed. Therefore, we have designed a clinical trial to evaluate the hypothesis that intravenous infusion of human umbilical cord-derived MSC (hUC-MSC) is safe, feasible, and well-tolerated in children with AS. METHODS AND ANALYSIS: We report the protocol of the first prospective, open-label, single-arm clinical trial to evaluate the safety and preliminary efficacy of hUC-MSC transfusion in children with early-stage AS. Paediatric patients diagnosed with AS who have persistent albuminuria will be candidates for screening. Twelve eligible patients are planned to recruit and will receive hUC-MSC infusions under close safety monitoring, and complete the efficacy assessments at scheduled follow-up visits. The primary endpoints include the occurrence of adverse events to assess safety and the albuminuria level for efficacy evaluation. Secondary endpoint assessments are based on haematuria and glomerular filtration measurements. Each patient's efficacy endpoints will be evaluated against their baseline levels. Additionally, the underlying mechanism of hUC-MSC therapy will be explored through transcriptomic and proteomic analysis of blood and urine samples. ETHICS AND DISSEMINATION: The protocol (V.1.0, date 17 January 2015) was approved by the institutional review board of the Affiliated Taihe Hospital of Hubei University of Medicine (ethical approval 03 March 2015). Written informed consent will be obtained from the patient and/or guardians before study specific process. In addition to publication in a peer-reviewed scientific journal, a lay summary of study will be available for participants and the public on the Chinese Organization for Rare Disorders website (http://www.cord.org.cn/). TRIAL REGISTRATION NUMBER: ISRCTN62094626.

Retinal Detachment After Macular Hole Repair in Alport Syndrome.

Alport syndrome is characterized by type IV collagen network disruptions leading to renal, auditory, and ocular manifestations. This case report details a 24-year-old man with Alport syndrome who developed a rhegmatogenous retinal detachment following macular hole repair. The patient underwent a successful vitrectomy and internal limiting membrane peel for macular hole repair but returned with vision loss due to retinal detachment five weeks later, which necessitated a combined scleral buckle and vitrectomy. This is the first case describing rhegmatogenous retinal detachment post-macular hole repair in Alport syndrome. [Ophthalmic Surg Lasers Imaging Retina 2024;55:289-292.].

Follow-Up of Bilateral Iridoschisis in a Patient With Alport Syndrome.

This case report discusses the long-term follow-up of a patient with bilateral iridoschisis and Alport syndrome.

Alport syndrome: A puzzling case of thrombocytopenia and giant unusual platelets in blood smear.

A puzzling case of thrombocytopenia and giant unusual platelets in blood smear reveals a past diagnosis of Alport syndrome in 44-year-old woman with end-stage renal disease and abnormal CBC values.

[Macrohematuria in children and adolescents]. / Makrohämaturie im Kindes- und Jugendalter.

Hematuria is usually only noticed early in the case of macrohematuria. In around half of affected children, macrohematuria is caused by a urinary tract infection. In all other cases, a careful diagnosis is required. In addition to a detailed medical history, this builds upon a precise examination of the urine (microscopy, quantitative determination of proteinuria [mg albumin/g creatinine in spontaneously voided urine]) and measurement of blood pressure. The work-up usually includes sonography as the primary imaging modality. Invasive diagnostic tests using cystoscopy are only necessary in exceptional cases. If there is evidence of glomerulonephritis, a kidney biopsy may be indicated. Careful attention should be given to persisting microhematuria (> 6 months) and Alport syndrome should be confirmed or ruled out. Heterozygotic Alport syndrome can also be a possible cause of chronic renal failure.

Ascending aortic aneurysm and histopathology in Alport syndrome: a case report.

BACKGROUND: Alport syndrome (AS) is caused by mutations in type IV collagen genes that typically target and compromise the integrity of basement membranes in kidney, ocular, and sensorineural cochlear tissues. Type IV and V collagens are also integral components of arterial walls, and whereas collagenopathies including AS are implicated in aortic disease, the incidence of aortic aneurysm in AS is unknown probably because of underreporting. Consequently, AS is not presently considered an independent risk factor for aortic aneurysm and more detailed case studies including histological evidence of basement membrane abnormalities are needed to determine such a possible linkage. CASE PRESENTATION: Here, we present unique histopathological findings of an ascending aortic aneurysm collected at the time of surgery from an AS patient wherein hypertension was the only other known risk factor. CONCLUSIONS: The studies reveal classical histological features of aortic aneurysm, including atheroma, lymphocytic infiltration, elastin disruption, and myxoid degeneration with probable AS association.

A comparison of the ocular features in Pierson and Alport syndrome: a case report and literature review.

BACKGROUND: Pierson syndrome and X-linked Alport syndrome result from pathogenic variants in LAMB2 and COL4A5, respectively, and both affect basement membranes in the kidney and the eye. This study describes the ocular features in an individual with a homozygous LAMB2 pathogenic variant and compares the reported abnormalities in Pierson syndrome with those in Alport syndrome. METHODS: A 28-year-old man who developed kidney failure 10 years previously and subsequently had an atrial septal defect repair was suspected of having genetic kidney disease on the basis of his likely diagnosis of Focal and Segmental Glomerulosclerosis (FSGS), his young age at presentation, and his cardiac anomaly. He then underwent Whole Exome Sequencing and a formal ophthalmological examination. RESULTS: The patient was found to have a homozygous Likely Pathogenic missense variant (p.(Arg1719Cys)) in LAMB2 consistent with the diagnosis of Pierson syndrome. He had normal visual acuity, normal optic globe and cornea size, and normal lens appearance on direct examination. Upon further testing, his cornea demonstrated central thinning. There was also increased corneal endothelial pleomorphism, a reduced foveal reflex, and a blunted foveal curvature, similar to the features seen in X-linked Alport syndrome. CONCLUSION: Our patient had a later onset form of Pierson syndrome or "FSGS type 5, with or without ocular abnormalities," consistent with his "milder" LAMB2 missense variant. The resemblance of the ocular features in Pierson syndrome and X-linked Alport syndrome suggests that mutations in LAMB2 and COL4A5 have similar effects on basement membranes and the pathogenesis of ocular damage.

[COL4A5 genotypes and clinical characteristics of children with Alport syndrome]. / 儿童Alport综合征COL4A5åŸºå› åž‹åŠä¸´åºŠç‰¹ç‚¹åˆ†æž.

OBJECTIVES: To investigate the genotypes of the pathogenic gene COL4A5 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 COL4A5 gene mutations. RESULTS: Among the 19 children with AS caused by COL4A5 gene mutations, 1 (5%) carried a new mutation of the COL4A5 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 COL4A5 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 COL4A5 gene. Among all 19 children, 3 children (16%) who carried COL4A5 gene mutations also had COL4A4 gene mutations, and 1 child (5%) had COL4A3 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 COL4A5 for AS. Children with large fragment deletion of the COL4A5 gene or double gene mutations of COL4A5 with COL4A3 or COL4A4 tend to have more serious clinical manifestations.

Electroretinographic abnormalities in Alport syndrome with a novel COL4A5 truncated variant (p.Try20GlyfsTer19).

PURPOSE: Alport syndrome comprises a heterogeneous group of inherited kidney diseases that are associated with ocular complications. In this study, we aimed to detail the clinical characteristics of a patient with X-linked Alport syndrome. METHODS: We performed next-generation sequencing (NGS) with hybridization capture to identify the disease-causing variant of Alport syndrome and a comprehensive ophthalmic examination, including full-field electroretinography (FF-ERG). RESULTS: Genetic testing using NGS with hybridization capture revealed a novel hemizygous variant [c.51_52delGA (p.Trp20GlyfsTer19)] in exon 1 of COL4A5. The patient underwent cataract surgery in both eyes because of decreased visual acuity and photophobia. The best-corrected visual acuity improved from 0.9 and 0.7 in the right and left eyes, respectively, to 1.5 in both eyes. Anterior-segment optical coherence tomography (OCT) revealed anterior and posterior lenticonus. Fundus photographs showed central and peripheral fleck retinopathy. Wide-field fundus autofluorescence (AF) imaging showed mottled hyper- and hypo-AF in the peripheral retina, which was consistent with peripheral fleck retinopathy. Furthermore, OCT revealed thinning of the inner retinal layers, especially at the temporal macular, but the outer retinal layers were preserved. Ganglion cell analysis showed no progression for 5 years. FF-ERG was performed at 41 (phakia) and 46 (pseudophakia) years of age. The amplitudes of dark-adapted (DA) and light-adapted (LA) responses showed selective b-wave abnormalities. The b/a-wave ratios of DA 3.0 were 1.22 and 1.16 in the right and left eyes, respectively. The amplitudes of DA 3.0 oscillatory potentials (OP) were reduced. Five years later, the amplitudes of DA and LA responses revealed no remarkable changes, except for an OP wave of DA 3.0, which was substantially reduced. CONCLUSIONS: Our findings revealed electroretinographic abnormalities in a patient with Alport syndrome, which predominantly indicated impairment of the inner retina. Notably, little short-term progression was observed.

COL4A gene variants are common in children with hematuria and a family history of kidney disease.

BACKGROUND: Inherited kidney diseases are a common cause of chronic kidney disease (CKD) in children. Identification of a monogenic cause of CKD is more common in children than in adults. This study evaluated the diagnostic yield and phenotypic spectrum of children who received genetic testing through the KIDNEYCODE sponsored genetic testing program. METHODS: Unrelated children < 18 years of age who received panel testing through the KIDNEYCODE sponsored genetic testing program from September 2019 through August 2021 were included (N = 832). Eligible children met at least one of the following clinician-reported criteria: estimated GFR ≤ 90 ml/min/1.73 m2, hematuria, a family history of kidney disease, or suspected or biopsy confirmed Alport syndrome or focal segmental glomerulosclerosis (FSGS) in the tested individual or family member. RESULTS: A positive genetic diagnosis was observed in 234 children (28.1%, 95% CI [25.2-31.4%]) in genes associated with Alport syndrome (N = 213), FSGS (N = 9), or other disorders (N = 12). Among children with a family history of kidney disease, 30.8% had a positive genetic diagnosis. Among those with hematuria and a family history of CKD, the genetic diagnostic rate increased to 40.4%. CONCLUSIONS: Children with hematuria and a family history of CKD have a high likelihood of being diagnosed with a monogenic cause of kidney disease, identified through KIDNEYCODE panel testing, particularly COL4A variants. Early genetic diagnosis can be valuable in targeting appropriate therapy and identification of other at-risk family members. A higher resolution version of the Graphical abstract is available as Supplementary information.

Alport syndrome misdiagnosed with IgA nephropathy from familial history: a case report and brief review.

BACKGROUND: Alport syndrome is a rare inherited disease resulting from a primary disorder of the glomerular basement membrane. This disease results from mutations in genes encoding alpha chains of type IV collagen. In the differential diagnosis of this disease, IgA nephropathy is the most common primary glomerular disease with gross or microscopic hematuria. CASE PRESENTATION: A 50-year-old woman was presented with microscopic hematuria and proteinuria of under one gram. Due to the diagnosis of IgA nephropathy in family members, she was treated and followed up for 4 years as a possible case of IgA nephropathy. Eye examination and audiometry were normal. She underwent renal biopsy with an exacerbation of proteinuria. There was no finding in favor of IgA nephropathy in the histological examination, but the findings of electron microscopy and family history favored Alport syndrome. CONCLUSIONS: This case demonstrates the importance of accurate history and electron microscopy in the complete histological evaluation and diagnosis of glomerular disease. Although in most cases the two can be differentiated based on clinical manifestations, laboratory findings, and histopathological examination, sometimes the association of these two diseases in the families involved or the lack of accurate history and complete histological examinations can complicate the diagnosis.

Thin Basement Membrane: An Underrated Cause of End-Stage Renal Disease.

The term "thin basement membrane" (TBM) refers to a glomerular disorder characterized by diffuse uniform thinning of the glomerular basement membrane (GBM) on electron microscopy. Patients with TBM usually show an isolated hematuria with excellent renal prognosis. However, some patients can develop proteinuria and progressive kidney dysfunction in the long term. Most patients with TBM are heterozygous for pathogenic variants in genes encoding for both the α3 and α4 chains of collagen IV, a major constituent of GBM. Such variants are responsible for a wide range of clinical and histological phenotypes. The differential diagnosis between TBM and autosomal-dominant Alport syndrome and IgA nephritis (IGAN) may be difficult in some cases. Patients who progress to chronic kidney disease may show clinicopathologic features similar to those of primary focal and segmental glomerular sclerosis (FSGS). Without a shared classification of these patients, the risk of misdiagnosis and/or underestimation of the risk of progressive kidney disease is real. New efforts are needed to understand the determinants of renal prognosis and recognize the early signs of renal deterioration, allowing a custom-made diagnosis and therapeutic approach. For this purpose, a practical and simple clinical approach is supplied.

Combined Alport syndrome, Klinefelter syndrome and Fanconi syndrome in a Chinese boy.

Alport syndrome (AS) is a progressive renal disease characterized by hematuria and progressive renal failure. X-linked dominant (XLAS) is the major inheritance form, accounting for almost 80% of the cases, caused by mutations in COL4A5 genes. Klinefelter syndrome (KS) is the most common genetic cause of human male gonadal dysgenesis. AS and KS are both rare disease, there are only three cases of combined AS and KS in the literatures. Fanconi syndrome (FS) caused by AS is also very rare. We report here the first case combined AS, KS and FS in a Chinese boy. We suggest that the severe renal phenotype and FS might be due to the two homozygous COL4A5 variants in our boy, and cases of AS combined KS will be good research objects for X chromosome inactivation.

The CARDINAL Trial of Bardoxolone Methyl in Alport Syndrome: When Marketing Interests Prevail over Patients Clinical Needs.

CONTEXT: Alport syndrome (AS) is a hereditary chronic kidney disease (CKD) with X-linked, autosomal, and digenic patterns of transmission. Sieving dysfunction of the glomerular basement membrane caused by congenitally defective type IV collagen results in persistent proteinuria, hematuria, and progressive renal dysfunction. There are no disease-specific medications and treatment is based on conservative interventions in particular with renin-angiotensin-aldosterone-system (RAAS) inhibitors. Subject of Review: Evidence that AS is accompanied by glomerular and tubular inflammatory changes and that bardoxolone methyl exerts anti-inflammatory effects through suppression of NF-kB and activation of transcription of antioxidant and anti-inflammatory genes, provided a justification for the CARDINAL study, a prospective, randomized controlled trial testing the potential renoprotective effect of bardoxolone methyl in 157 adolescent or adult patients with AS. The authors concluded that bardoxolone methyl preserved estimated glomerular filtration rate (eGFR) relative to placebo at 48 and 100 weeks after randomization. However, exactly the same number of patients (n = 3) in each group developed kidney failure. Second Opinion: Despite alarming safety signals from previous trials in type 2 diabetics with CKD (increased hospitalizations for heart failure, fatal and nonfatal cardiovascular events, liver toxicity, and increased blood pressure and albuminuria), major marketing interests encouraged the drug manufacturer to pursue this line of research. Finding that type IV collagen gene mutations account for nearly one-third of cases of hereditary glomerulopathies implies that the population of potential target-patients could probably be much larger than estimated. Moreover, any new medication approved for AS might receive orphan drug designation which might be associated with shortened time to approval, monetary benefits, and a period of market exclusivity. In actual facts, CARDINAL failed to demonstrate any nephro-protective effect of bardoxolone methyl and found an increase in liver enzymes in 70 of the 77 (90.9%) bardoxolone-treated patients consistent with chronic liver toxicity. Indeed, in Zucker diabetic fatty rats treated with an analog of bardoxolone methyl, elevations of liver aminotransferases were associated with enhanced liver weight, severe and diffuse hepatocyte vacuolization, swelling, and degeneration. Moreover, bardoxolone-induced increase in eGFR was associated with a concomitant increase in geometric mean urinary albumin/creatinine ratio, a finding consistent with worsening glomerular hyperfiltration. Considering also the consequent increase in the biomechanical strain on the fragile Alport glomerular basement membrane, this hemodynamic effect is expected to translate into accelerated renal disease progression (consistently with evidence that a bardoxolone methyl analog worsened proteinuria, glomerulosclerosis, and tubular damage in Zucker diabetic fatty rats). These concerns induced the Food and Drug Administration to reject the new drug application for bardoxolone methyl submitted by Reata Pharmaceuticals, Inc. with the proposed indication to slow CKD progression in AS patients 12 years of age and older. Thus, bardoxolone methyl is devoid of any nephro-protective effect and is associated with significant heart, liver, and renal toxicity in patients with CKD, including those with AS. Because of these safety signals, it should not be used in this clinical context. Research programs could explore the potential clinical applications, even outside the kidney field, of novel NF erythroid 2-like 2 modulators devoid of bardoxolone methyl toxicity.