Alport syndrome: its effects on the glomerular filtration barrier and implications for future treatment (original) (raw)
Related papers
Glomerular pathology in Alport syndrome: a molecular perspective
Pediatric Nephrology, 2011
We have known for some time that mutations in the genes encoding 3 of the 6 type IV collagen chains are the underlying defect responsible for both X-linked (where the COL4A5 gene is involved) and autosomal (where either COL4A3 or COL4A4 genes are involved) Alport syndrome. The result of these mutations is the absence of the sub-epithelial network of all three chains in the glomerular basement membrane (GBM) resulting, at maturity, in a type IV collagen GBM network comprised of only α1(IV) and α2(IV) chains. The altered GBM functions adequately in early life. Eventually there is onset of proteinuria associated with the classic and progressive irregular thickening, thinning, and splitting of the GBM, which culminates in end stage renal failure. We have learned much about the molecular events associated with disease onset and progression through the study of animal models for Alport syndrome, and have identified some potential therapeutic approaches that may serve to delay the onset or slow the progression of the disease. This review focuses on where we are in our understanding of the disease, where we need to go to understand the molecular triggers that set the process in motion, and what emergent therapeutic approaches show promise for ameliorating disease progression in the clinic.
Collagen IV diseases: A focus on the glomerular basement membrane in Alport syndrome
Matrix biology : journal of the International Society for Matrix Biology, 2017
Alport syndrome is the result of mutations in any of three type IV collagen genes, COL4A3, COL4A4, or COL4A5. Because the three collagen chains form heterotrimers, there is an absence of all three proteins in the basement membranes where they are expressed. In the glomerulus, the mature glomerular basement membrane type IV collagen network, normally comprised of two separate networks, α3(IV)/α4(IV)/α5(IV) and α1(IV)/α2(IV), is comprised entirely of collagen α1(IV)/α2. This review addresses the current state of our knowledge regarding the consequence of this change in basement membrane composition, including both the direct, via collagen receptor binding, and indirect, regarding influences on glomerular biomechanics. The state of our current understanding regarding mechanisms of glomerular disease initiation and progression will be examined, as will the current state of the art regarding emergent therapeutic approaches to slow or arrest glomerular disease in Alport patients.
Kidney International, 1992
The pathogenesis of Alport syndrome involves type IV collagen molecules containing the a3(IV) chain: Evidence from anti-GBM nephritis after renal transplantation. Mutations in the COL4A5 collagen gene have been implicated as the primary defect in Alport syndrome, a heritable disorder characterized by sensorineural deafness and glomerulonephritis that progresses to end-stage renal failure. In the present study, the molecular nature of the defect in Alport glomerular basement membrane (GBM) was explored using anti-GBM alloantibodies (tissuebound and circulating) produced in three Alport patients subsequent to renal transplantation. The alloantibodies bound to the cs3(IV)NC I domain of type IV collagen and not to any other basement membrane component. In tissue sections, the alloantibodies bound specifically to peripheral GBM in normal kidney and the affected renal transplant but not to that of Alport kidney. These results establish that: the a3 chain in type IV collagen molecules, the Goodpasture autoantigen, is the target alloantigen in post-transplant anti-GBM nephritis in patients with Alport syndrome, and that a molecular commonality exists in the pathogenesis of anti-GBM nephritis causing loss of renal allografts in patients with Alport syndrome and renal failure in patients with Goodpasture syndrome. These findings implicate: (1) defective assembly of type IV collagen molecules containing the a3(IV) chain in Alport GBM; and (2) the existence of a mechanism linking the assembly of molecules containing the a3(IV) chain with those containing the a5(IV) chain. Alport syndrome is an X-linked heritable disorder that results in kidney failure and sensorineural deafness [1-31. Clinically, the nephritis is characterized by hematuria with relentless progression to end-stage renal disease. The renal lesion is characterized by ultrastructural abnormalities (thinning, diffuse splitting and multilaminations of the lamina densa) in the glomerular basement membrane (GBM). Recent studies indicate that the molecular defect in Alport GBM is a structural abnormality in type IV collagen. In normal GBM, type IV collagen is composed of five
Kidney International, 2004
In Alport syndrome (AS) a spectrum of phenotypes ranging from progressive renal disease with extrarenal abnormalities to isolated hematuria with a non-progressive or very slowly progressive course is observed. Approximately two thirds of AS is X-linked (XLAS); approximately 15% is autosomal recessive (ARAS), and approximately 20% is autosomal dominant (ADAS). In the absence of treatment, renal disease progresses from microscopic hematuria (microhematuria) to proteinuria, progressive renal insufficiency, and end-stage renal disease (ESRD) in all males with XLAS, and in all males and females with ARAS. Progressive sensorineural hearing loss (SNHL) is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion. In individuals with ADAS, ESRD is frequently delayed until later adulthood, SNHL is relatively late in onset, and ocular involvement is rare. Diagnosis/testing The diagnosis of Alport syndrome is established in a proband with a pathogenic variant(s) in COL4A3, COL4A4, or COL4A5 identified on molecular genetic testing. Management Treatment of manifestations: Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to delay onset of ESRD; routine treatment of hypertension; renal transplantation for ESRD. Potential living related donors must be evaluated carefully to avoid nephrectomy in an affected individual. Routine treatment of SNHL and cataracts; surgical intervention for symptomatic leiomyomas. Agents/circumstances to avoid: Protection of corneas from minor trauma in those with recurrent corneal erosions. Minimize exposure to loud noise.
Alport syndrome--insights from basic and clinical research
Nature reviews. Nephrology, 2013
In 1927, Arthur C. Alport first published his description of a triad of symptoms in a family with hereditary congenital haemorrhagic nephritis, deafness and ocular changes. A few years after his death, this group of symptoms was renamed Alport syndrome. To this day, Alport syndrome still inevitably leads to end-stage renal disease and the need for renal replacement therapy, starting in young adulthood. During the past two decades, research into this rare disease has focused on the effects of mutations in collagen type IV and the role of changes in podocytes and the glomerular basement membrane that lead to early kidney fibrosis. Animal models of Alport syndrome also demonstrate the pathogenetic importance of interactions between podocytes and the extracellular matrix. Such models might also help researchers to answer basic questions about podocyte function and the development of fibrosis, and to develop new therapeutic approaches that might be of use in other kidney diseases. In thi...
Journal of The American Society of Nephrology, 2007
Alport disease is caused by mutations in genes encoding the ␣3, ␣4, or ␣5 chains of type IV collagen, which form the collagenous network of mature glomerular basement membrane (GBM). In the absence of ␣3, ␣4, ␣5 (IV) collagen, ␣1, ␣2 (IV) collagen persists, which ordinarily is found only in GBM of developing kidney. In addition to dysregulation of collagen IV, Alport GBM contains aberrant laminins, which may contribute to the progressive GBM thickening and splitting, proteinuria, and renal failure seen in this disorder. This study sought to characterize further the laminin dysregulation in collagen ␣3(IV) knockout mice, a model of Alport disease. With the use of confocal microscopy, laminin ␣1 and ␣5 abundance was quantified, and it was found that they co-distributed in significantly large amounts in areas of GBM thickening. In addition, labeling of entire glomeruli for laminin ␣5 was significantly greater in Alport mice than in wild-type siblings. Reverse transcriptase-PCR from isolated glomeruli demonstrated significantly more laminin ␣5 mRNA in Alport mice than in wild-type controls, indicating upregulated transcription of Lama5. For testing glomerular barrier function, ferritin was injected into 2-wk-old Alport and control mice, and GBM was examined by electron microscopy. Highest ferritin levels were seen in Alport GBM thickenings beneath effaced podocyte foot processes, but morphologically normal GBM was significantly permeable as well. We concluded that (1) ultrastructurally normal Alport GBM residing beneath differentiated podocyte foot processes is inherently and abnormally permeable, and (2) upregulation of Lama5 transcription and concentration of laminin ␣1 and ␣5 within Alport GBM thickenings contribute to abnormal permeabilities.
Alport syndrome and Pierson syndrome: Diseases of the glomerular basement membrane
Matrix Biology, 2018
The glomerular basement membrane (GBM) is an important component of the kidney's glomerular filtration barrier. Like all basement membranes, the GBM contains type IV collagen, laminin, nidogen, and heparan sulfate proteoglycan. It is flanked by the podocytes and glomerular endothelial cells that both synthesize it and adhere to it. Mutations that affect the GBM's collagen α3α4α5(IV) components cause Alport syndrome (kidney disease with variable ear and eye defects) and its variants, including thin basement membrane nephropathy. Mutations in LAMB2 that impact the synthesis or function of laminin α5β2γ1 (LM-521) cause Pierson syndrome (congenital nephrotic syndrome with eye and neurological defects) and its less severe variants, including isolated congenital nephrotic syndrome. The very different types of kidney diseases that result from mutations in collagen IV vs. laminin are likely due to very different pathogenic mechanisms. A better understanding of these mechanisms should lead to targeted therapeutic approaches that can help people with these rare but important diseases.