Alport syndrome (AS) is a hereditary kidney disease caused by pathogenic variants in COL4A3 and COL4A4 genes with autosomal recessive or autosomal dominant transmission or in the COL4A5 gene with X-linked inheritance. Digenic inheritance was also described. Clinically it is associated with microscopic hematuria, followed by proteinuria and chronic renal insufficiency with end-stage renal disease in young adults. Nowadays, there is no curative treatment available. The inhibitors of RAS (renin-angiotensin system) since childhood slow the progression of the disease. Sodium-glucose cotransporter-2 inhibitors seem to be promising drugs from DAPA-CKD (dapagliflozin-chronic kidney disease) study, but only a limited number of patients with Alport syndrome was included. Endothelin type A receptor and angiotensin II type 1 receptor combined inhibitors, and lipid-lowering agents are used in ongoing studies in patients with AS and focal segmental glomerulosclerosis (FSGS). Hydroxychloroquine in AS is studied in a clinical trial in China. Molecular genetic diagnosis of AS is crucial not only for prognosis prediction but also for future therapeutic options. Different types of mutations will require various types of gene, RNA, or protein therapy to improve the function, the of final protein product.

• Keywords
• Alport syndrome, gene, therapy,
• MeSH
• Autoantigens genetics   MeSH
• Renal Insufficiency, Chronic * complications   MeSH
• Nephritis, Hereditary * drug therapy   genetics   MeSH
• Child MeSH
• Sodium-Glucose Transporter 2 Inhibitors * MeSH
• Hematuria MeSH
• Collagen Type IV genetics   MeSH
• Humans MeSH
• Young Adult MeSH
• Mutation MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Young Adult MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Autoantigens MeSH
• Sodium-Glucose Transporter 2 Inhibitors * MeSH
• Collagen Type IV MeSH

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.

• Keywords
• Alport syndrome, COL4A3, COL4A4, COL4A5, FSGS, collagen IV, digenic Alport syndrome, genetic testing, kidney cysts, thin basement membrane nephropathy,
• MeSH
• Autoantigens genetics   MeSH
• Nephritis, Hereditary diagnosis   genetics   therapy   MeSH
• Genetic Testing standards   MeSH
• Collagen Type IV genetics   MeSH
• Humans MeSH
• Practice Guidelines as Topic MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Autoantigens MeSH
• COL4A5 protein, human MeSH Browser
• Collagen Type IV MeSH
• type IV collagen alpha3 chain MeSH Browser

The recent Chandos House meeting of the Alport Variant Collaborative extended the indications for screening for pathogenic variants in the COL4A5, COL4A3 and COL4A4 genes beyond the classical Alport phenotype (haematuria, renal failure; family history of haematuria or renal failure) to include persistent proteinuria, steroid-resistant nephrotic syndrome, focal and segmental glomerulosclerosis (FSGS), familial IgA glomerulonephritis and end-stage kidney failure without an obvious cause. The meeting refined the ACMG criteria for variant assessment for the Alport genes (COL4A3-5). It identified 'mutational hotspots' (PM1) in the collagen IV α5, α3 and α4 chains including position 1 Glycine residues in the Gly-X-Y repeats in the intermediate collagenous domains; and Cysteine residues in the carboxy non-collagenous domain (PP3). It considered that 'well-established' functional assays (PS3, BS3) were still mainly research tools but sequencing and minigene assays were commonly used to confirm splicing variants. It was not possible to define the Minor Allele Frequency (MAF) threshold above which variants were considered Benign (BA1, BS1), because of the different modes of inheritances of Alport syndrome, and the occurrence of hypomorphic variants (often Glycine adjacent to a non-collagenous interruption) and local founder effects. Heterozygous COL4A3 and COL4A4 variants were common 'incidental' findings also present in normal reference databases. The recognition and interpretation of hypomorphic variants in the COL4A3-COL4A5 genes remains a challenge.

• MeSH
• Autoantigens genetics   MeSH
• Nephritis, Hereditary diagnosis   genetics   MeSH
• Phenotype MeSH
• Genetic Testing methods   standards   MeSH
• Collagen Type IV genetics   MeSH
• Consensus * MeSH
• Humans MeSH
• Practice Guidelines as Topic * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Autoantigens MeSH
• COL4A4 protein, human MeSH Browser
• COL4A5 protein, human MeSH Browser
• Collagen Type IV MeSH
• type IV collagen alpha3 chain MeSH Browser

BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by mutations in the UMOD gene (ADTKD-UMOD) is considered rare and often remains unrecognised. We aimed to establish the prevalence of genetic kidney diseases, ADTKD and ADTKD-UMOD in adult chronic kidney disease (CKD) patients, and to investigate characteristic features. METHODS: We sent questionnaires on family history to all patients with CKD stages 3-5 in our tertiary renal centre to identify patients with inherited renal disease. Details on clinical and family history were obtained from patient interviews and clinical records. Sanger sequencing of the UMOD gene was performed from blood or saliva samples. RESULTS: 2027 of 3770 sent questionnaires were returned. 459 patients reported a family history, which was consistent with inherited kidney disease in 217 patients. 182 non-responders with inherited kidney diseases were identified through a database search. Of these 399 individuals, 252 had autosomal dominant polycystic kidney disease (ADPKD), 28 had ADTKD, 25 had Alports, and 44 were unknown, resulting in 11% of CKD 3-5 patients and 19% of end-stage renal disease patients with genetic kidney diseases. Of the unknown, 40 were genotyped, of whom 31 had findings consistent with ADTKD. 30% of unknowns and 39% of unknowns with ADTKD had UMOD mutations. Altogether, 35 individuals from 18 families were found to have ten distinct UMOD mutations (three novel), making up 1% of patients with CKD 3-5, 2% of patients with end-stage renal disease, 9% of inherited kidney diseases and 56% with ADTKD. ADTKD-UMOD was the most common genetic kidney disease after ADPKD with a population prevalence of 9 per million. Less proteinuria and haematuria, but not hyperuricaemia or gout were predictive of ADTKD-UMOD. The main limitations of the study are the single-centre design and a predominantly Caucasian population. CONCLUSIONS: The prevalence of genetic kidney diseases and ADTKD-UMOD is significantly higher than previously described. Clinical features poorly predicted ADTKD-UMOD, highlighting the need for genetic testing guided by family history alone.

• Keywords
• Autosomal dominant tubulointerstitial kidney disease, Genetic kidney disease, Prevalence, UMOD,
• MeSH
• Renal Insufficiency, Chronic diagnosis   epidemiology   genetics   MeSH
• Genetic Testing methods   MeSH
• Nephritis, Interstitial diagnosis   epidemiology   genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Polycystic Kidney, Autosomal Dominant diagnosis   epidemiology   genetics   MeSH
• Surveys and Questionnaires * MeSH
• Aged MeSH
• Uromodulin genetics   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• UMOD protein, human MeSH Browser
• Uromodulin MeSH

ER stress has emerged as a signaling platform underlying the pathogenesis of various kidney diseases. Thus, there is an urgent need to develop ER stress biomarkers in the incipient stages of ER stress-mediated kidney disease, when a kidney biopsy is not yet clinically indicated, for early therapeutic intervention. Cysteine-rich with EGF-like domains 2 (CRELD2) is a newly identified protein that is induced and secreted under ER stress. For the first time to our knowledge, we demonstrate that CRELD2 can serve as a sensitive urinary biomarker for detecting ER stress in podocytes or renal tubular cells in murine models of podocyte ER stress-induced nephrotic syndrome and tunicamycin- or ischemia-reperfusion-induced acute kidney injury (AKI), respectively. Most importantly, urinary CRELD2 elevation occurs in patients with autosomal dominant tubulointerstitial kidney disease caused by UMOD mutations, a prototypical tubular ER stress disease. In addition, in pediatric patients undergoing cardiac surgery, detectable urine levels of CRELD2 within postoperative 6 hours strongly associate with severe AKI after surgery. In conclusion, our study has identified CRELD2 as a potentially novel urinary ER stress biomarker with potential utility in early diagnosis, risk stratification, treatment response monitoring, and directing of ER-targeted therapies in selected patient subgroups in the emerging era of precision nephrology.

• Keywords
• Cell stress, Nephrology,
• MeSH
• Acute Kidney Injury diagnosis   etiology   physiopathology   urine   MeSH
• Biomarkers urine   MeSH
• Child MeSH
• Extracellular Matrix Proteins physiology   urine   MeSH
• Nephritis, Interstitial genetics   physiopathology   urine   MeSH
• Cardiac Surgical Procedures MeSH
• Humans MeSH
• Cell Adhesion Molecules physiology   urine   MeSH
• Mutation MeSH
• Mice, Inbred C57BL MeSH
• Nephrotic Syndrome diagnosis   physiopathology   urine   MeSH
• Podocytes metabolism   MeSH
• Postoperative Complications urine   MeSH
• Endoplasmic Reticulum Stress physiology   MeSH
• Uromodulin genetics   MeSH
• Animals MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Biomarkers MeSH
• CRELD2 protein, human MeSH Browser
• Extracellular Matrix Proteins MeSH
• Cell Adhesion Molecules MeSH
• Umod protein, mouse MeSH Browser
• Uromodulin MeSH