A Novel Homozygous Mutation in the COL4A4 Gene (Gly1436del) Causing Alport Syndrome Exposed by Pregnancy: A Case Report and Review of the Literature

Background. Alport syndrome results from a hereditary defect of collagen IV synthesis. This causes progressive glomerular disease, ocular abnormalities, and inner ear impairment. Case Presentation. Herein, we present a case of Alport syndrome in a 28-year-old woman caused by a novel mutation (Gly1436del) in the COL4A4 gene that was not unveiled until her first pregnancy. Within the 29th pregnancy week, our patient presented with massive proteinuria and nephrotic syndrome. Light microscopic examination of a kidney biopsy showed typical histological features of segmental sclerosis, and electron microscopy revealed extensive podocyte alterations as well as thickness of glomerular basement membranes with splitting of the lamina densa. One and a half years after childbirth, renal function deteriorated to a preterminal stage, whereas nephrotic syndrome subsided quickly after delivery. Conclusion. This case report highlights the awareness of atypical AS courses and emphasizes the importance of genetic testing in such cases.

Morning Glory Syndrome associated with Autosomal Dominant Alport Syndrome with a Heterozygous COL4A4 Mutation

Morning glory syndrome (MGS) is a rare congenital optic disc anomaly with a characteristic fundal finding with severe visual impairment. It may occur in association with various systemic manifestations, even though most of the reported cases were isolated. A 6-year-old male visited the nephrology clinic with a history of microscopic hematuria and at the age of 12 years, he was diagnosed thin glomerular basement membrane nephropathy by kidney biopsy. After the following years, the patient had progressive deterioration of visual acuity, and diagnosed as MGS. Whole Exome Sequencing of this patient and his mother revealed heterozygous COL4A4 mutations [c.81_86del (p.Ile29_Leu30del)]. It is more reasonable to consider MGS seen in this patient as a coincidental finding of autosomal dominant Alport syndrome. To our knowledge, this case represents the first case report of autosomal dominant Alport syndrome associated with MGS.

The Spectrum of Children's Kidney Diseases—2403 Renal Biopsy-Proven Cases from a Single Centre in China Between 1999 and 2019

Background: This study aimed to investigate the clinical and pathological characteristics and the changes in glomerular diseases in 2403 pediatric renal biopsies from 1999 to 2019.Methods: Renal biopsies performed on children aged ≤18 years between 1999 and 2019 were analysed at our center. We analysed the clinical and histological characteristics, distribution of pediatric glomerular diseases with various clinical presentations, and changes in the glomerular disease patterns during the study period.Results: The most common primary glomerular disease was IgA nephropathy (IgAN) (24.3%), followed by minimal change disease (MCD) (15.3%) and membranous glomerulonephritis (MN) (13.1%). Henoch-Schonlein purpura nephritis (HSPN) (18.1%) and lupus nephritis (LN) (7.2%) were the most frequently recorded secondary glomerular diseases. Alport syndrome and thin basement membrane nephropathy (TBMN) were the most common inherited glomerular diseases, accounting for 1.2% and 0.6% of the total glomerular diseases in children, respectively. The number of boys with IgAN, MCD and IgM nephropathy (IgMN) was higher than that of girls, while the number of girls with MN and LN was higher than that of boys. The frequencies of MCD, MN, IgMN and endocapillary proliferative glomerulonephritis (EnPGN) in the 13-18-year-old group were higher than those in the 0-12-year-old group, while the frequencies of IgAN, mesangial proliferative glomerulonephritis (MsPGN) and focal proliferative glomerulonephritis (FPGN) were lower than those in the 0-12-year-old group. The ratio of Alport syndrome and TBMN in the 0-12-year-old group was higher than that in the 13-18-year-old group. The proportion of patients with MCD and MN in 2010-2019 was higher than that in 1999-2009, while the ratio of IgAN, MsPGN, IgMN, EnPGN, membranoproliferative glomerulonephritis (MPGN), HSPN and HBV-associated glomerulonephritis (HBV-GN) decreased. MCD (28.5%) was the most common cause of nephrotic syndrome (NS). In children with haematuria and proteinuria, HSPN (38.8%) and IgAN (36.9%) were more common than other glomerular diseases. IgAN (39.4%) was the most common cause of AKI. Sclerosing glomerulonephritis (SGN) (21.1%) was the main cause of progressive chronic kidney disease (CKD).Conclusions: Glomerular diseases in children were related to sex and age. From 1999 to 2019, the spectrum of children's kidney disease in our center changed significantly.

Guidelines for Genetic Testing and Management of Alport Syndrome

Genetic testing for pathogenic COL4A3–5 variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic COL4A3 or COL4A4 is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that COL4A3 or COL4A4 heterozygotes do not act as kidney donors. Testing for variants in the COL4A3–COL4A5 genes should also be performed for persistent proteinuria and steroid-resistant nephrotic syndrome due to suspected inherited FSGS and for familial IgA glomerulonephritis and kidney failure of unknown cause.

Novel Keap1-Nrf2 Protein-protein interaction inhibitor UBE-1099 Ameliorates Progressive Phenotype in Alport Syndrome mouse model

Background Bardoxolone methyl activates nuclear factor erythroid 2 related factor 2 (Nrf2) via covalent binding and irreversible inhibition of Kelch-like ECH-associated protein-1 (Keap1), the negative regulator of Nrf2. Ongoing clinical trials of Bardoxolone methyl show promising effects for patients with chronic kidney disease (CKD). But the direct inhibition of Keap1-Nrf2 protein-protein interaction (PPI) as an approach to activate Nrf2 is less explored. Methods We developed a non-covalent Nrf2 activator UBE-1099, which highly selectively inhibits Keap1-Nrf2 PPI, and evaluated its efficacy on progressive phenotype in Alport syndrome mouse model (Col4a5-G5X). Results Similar to Bardoxolone methyl, UBE-1099 transiently increased proteinuria and reduced plasma creatinine in Alport mice. Importantly, UBE-1099 improved the glomerulosclerosis, renal inflammation and fibrosis, and prolonged the lifespan of Alport mice. UBE-1099 ameliorated the dysfunction of Nrf2 signaling in renal tissue of Alport mice. Moreover, transcriptome analysis in glomerulus showed that UBE-1099 induced the expression of genes associated with cell cycle and cytoskeleton, which may explain its unique mechanism of improvement such as glomerular morphological change. Conclusions UBE-1099 significantly ameliorates the progressive phenotype in Alport mice. Our results firstly revealed the efficacy of Keap1-Nrf2 PPI inhibitor for glomerulosclerosis and presents a potential therapeutic drug for CKD.