Search

Alport syndrome is an inherited disorder characterized by the association of a progressive haematuric nephropathy with ultrastructural abnormalities of the glomerular basement membranes, a progressive sensorineural hearing loss and sometimes ocular involvement. Its incidence is less than 1 per 5000 individuals and the disease is the cause of about 2% of end stage renal disease in Europe and the United States. Alport syndrome is clinically and genetically heterogeneous. It is related to mutations in the genes encoding one of three chains, α3, α4 α5 of type IV collagen, the main component of basement membranes, expressed in the glomerular basement membrane. COL4A5 mutations are associated with X-linked Alport syndrome, which represents 80 to 85% of cases and is more severe in boys than in girls. Mutations in COL4A3 or COL4A4 are associated with autosomal Alport syndrome. The expression of collagen chains in skin and kidney basement membranes allows for the diagnosis and characterization of the mode of transmission in most patients. It is necessary to diagnose this syndrome because its family involvement, its severity, and the importance of genetic counseling. Angiotensin blockers are increasingly prescribed in proteinuric patients. Prospective studies are needed to assess the effectiveness of these treatments on proteinuria and progression of kidney failure, and to specify indications. Animal studies have shown the potential value of different molecules (protease inhibitors, chemokine receptor blockers, transforming growth factor-β1 inhibitors, hydroxy-methyl-coenzyme A reductase inhibitors, bone morphogenetic protein-7 inhibitors), hematopoietic stem cells, and of a anti-micro-RNA., (Copyright © 2016. Published by Elsevier SAS.)

Renal tubular dysgenesis is a severe disease characterized by the absence of differentiated proximal tubules, leading to fetal anuria and persistent oligohydramnios. The absence of amniotic fluid results in a series of malformations, including facial dysmorphia, limb deformation and also lung hypoplasia, leading to respiratory distress at birth. The disease is linked to mutations in the AGT, REN ACE andAGTR1 genes that compose the renin-angiotensin system (RAS). The absence of functional RAS leads to fetal and neonatal hypotension, renal hypoperfusion, and tubular dysgenesis. The use of cellular models expressing these mutations has advanced our understanding of the structure-function relationship of RAS proteins, notably by showing that defective misfolded proteins undergo either intracellular accumulation and retention, or rapid degradation. Moreover, these studies confirm that ACE has to be inserted in the plasma membrane to be active.

Autosomal recessive renal tubular dysgenesis (RTD) is a clinical disorder observed in fetuses, characterized by absence or poor development of proximal tubules and early onset and persistent oligohydramnios leading to the Potter sequence, associated with skull ossification defect. The disease is uniformly severe resulting in low blood pressure and perinatal death in most cases or in chronic renal disease in the few surviving patients. Based on the phenotype and the finding of striking changes in renal renin expression (absent or massive), we hypothesized and demonstrated that genetic defects in the renin-angiotensin system (RAS) components are the underlying causes of the disease. At the present time, molecular screening has been performed in 46 families (F) and homozygous or compound heterozygous mutations have been detected in 41. They affect the genes encoding renine (9F), angiotensinogen (3F), AT1 receptor (3F) and angiotensin converting enzyme (26F). These findings highlight the importance of the RAS during human kidney development. Moreover, the identification of the disease based on precise histological and immunohistological analysis, and the research of the genetic defect, now allow genetic counseling and early prenatal diagnosis.

Alport syndrome is an inherited disorder characterized by progressive hematuric nephritis with structural defects of the glomerular basement membrane, and sensorineural deafness. Ocular abnormalities are frequently associated. The incidence is approximatively 1/5000. The renal disease is severe in male patients and should be responsible for 2% of end-stage renal failure. Alport syndrome is heterogeneous at the clinical and genetic levels. It occurs as a consequence of structural abnormalities in type IV collagen, the major constituent of basement membranes. Six genetically distinct chains of type IV collagen have been identified. Mutations in the COL4A5 gene located at Xq22, and encoding the alpha 5(IV) chain are responsible for X-linked Alport syndrome whereas COL4A3 or COL4A4 located "head to head" on chromosome 2 are involved in the rarer autosomal forms of the disease.

The various clinicopathological forms of primary glomerulonephritis (GN) in humans include lipoid nephrosis with its histological variants (minimal change disease, focal segmental glomerular sclerosis, diffuse mesangial proliferation, collapsing glomerulopathy), membranous GN, IgA nephropathy, membranoproliferative GN (type I and type II) and crescentic GN. Each of these entities is characterised by pathological, clinical, and immunological features. Although the precise aetiology of primary GN remains unknown, progress has been recently achieved in the understanding of the mechanisms of the glomerular lesions and of their progression. Early diagnosis may lead to adequate treatment and prevention of progressive glomerular damage.