MODERN PROBLEMS OF АLPORT SYNDROME DIAGNOSIS

Introduction. In the practice of adult nephrologists there are cases of rare genetically caused kidney damage, in particular, Alport syndrome. This is due to the availability and improvement of instrumental diagnostic methods, timely approaches to treatment in pediatric practice, and prolongation of the pre-dialysis period. Goal. Analysis and synthesis of new data from domestic and foreign sources on the etiology, pathogenesis, clinical manifestations, types of inheritance, differential diagnosis of Alport syndrome in order to improve the success of students, interns and teachers in the study of nephrological subjects. Material and methods. Review of contemporary and foreign literary sources; techniques – description, analysis, abstracting. Results. Alport syndrome (AS, synonym: hereditary nephritis) is non-immune genetically determined glomerulopathy caused by a mutation of genes that encode collagen type IV of basement membranes, manifested by hematuria and / or proteinuria, a progressive decreased renal function, combined with pathology of hearing and abnormalities affecting the eyes. Alport syndrome inherited type: X-linked dominant (XLAS): 85%, autosomal recessive (ARAS): 15%, autosomal dominant (ADAS): 1%. Conclusions. Family history, electron microscopy, immunochemical analysis of type IV collagen expression are informative for verifying the diagnosis of Alport syndrome. Due to the rarity of this disease, in addition, the fact that patients often refuse kidney biopsy, it is necessary to cooperate more closely with genetic laboratories, to take measures to improve the availability of molecular analysis of mutations of collagen IV genes. In addition, it is a fact that sometimes the family history of the disease is ambiguous, unavailable for genetic analysis, and patients refuse to have a kidney biopsy. It is a motive to encourage doctors to improve their educational work with patients about safety of this analysis and its value.

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Expression of collagen type IV in human kidney during prenatal development

Vojnosanitetski pregled ◽

10.2298/vsp200927111p ◽

2020 ◽

pp. 111-111

Author(s):

Vladimir Petrovic ◽

Ivan Nikolic ◽

Marko Jovic ◽

Vladimir Zivkovic ◽

Miodrag Jocic ◽

...

Keyword(s):

Type Iv Collagen ◽

Collagen Type ◽

Kidney Tissue ◽

Volume Density ◽

Collagen Iv ◽

Basement Membranes ◽

Collagen Type Iv ◽

Type Iv ◽

Metanephric Kidney ◽

Collecting System

Background / Aim. Type IV collagen belongs to the group of non-fibrillar collagens and is an important component of the basement membranes where it accounts for approximately 50% of its structural elements. The aim of the paper was to describe the expression and distribution of collagen type IV in embryonic and fetal metanephric kidney, and to determine the volume density of collagen type IV in kidney tissue in each trimester of development. Methods. The material consisted of 19 human embryos/fetuses, in the gestational age from 8th to 37th week. Kidney tissue specimens were routinely processed to paraffin molds and stained with hematoxylin and eosin and immunohistochemically using polyclonal anti-collagen IV antibody. Stained slides were examined using light microscope and images of the selected areas, under different lens magnification were captured with digital camera. Volume density of collagen type IV was determined by using ImageJ 1.48v and a plugin of the software which inserted a grid system with 336 points. For the data comparison One-Way Analysis of Variance was used. Results. Strong collagen IV immunopositivity was seen in all specimens, with a distribution in the basement membranes of urinary bud, parietal leaf of Bowman?s capsule, glomerular basement membrane, basement membrane of interstitial blood vessels, and basement membranes of nephron tubules and collecting ducts. No statistically significant difference in the volume density of type IV collagen was found between the different trimesters of development. Conclusion. The synthesis and secretion of collagen type IV simultaneously follows the development of nephron structures, collecting system and blood vessels. The volume density of collagen type IV remains constant throughout all the trimesters of metanephric kidney development, indicating that it plays a crucial role in normal development of nephron and collecting system structures, as well as in maintaining the normal kidney function.

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Regulation of collagen type IV genes is organ-specific: Evidence from a canine model of Alport syndrome

Kidney International ◽

10.1111/j.1523-1755.2005.00668.x ◽

2005 ◽

Vol 68 (5) ◽

pp. 2121-2130 ◽

Cited By ~ 4

Author(s):

Keqin Zheng ◽

Julie Perry ◽

Scott J. Harvey ◽

Yoshikazu Sado ◽

Yoshifumi Ninomiya ◽

...

Keyword(s):

Alport Syndrome ◽

Collagen Type ◽

Canine Model ◽

Collagen Type Iv ◽

Type Iv ◽

Organ Specific

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Diffuse Leiomyomatosis of the Esophagus: Disorder of Cell-Matrix Interaction?

Pediatric and Developmental Pathology ◽

10.1007/s100249900075 ◽

1998 ◽

Vol 1 (6) ◽

pp. 543-549 ◽

Cited By ~ 20

Author(s):

Paul Thorner ◽

Laurence Heidet ◽

Fernando Moreno Merlo ◽

Vern Edwards ◽

Corinne Antignac ◽

...

Keyword(s):

Collagen Type ◽

Rare Condition ◽

Basement Membranes ◽

Collagen Type Iv ◽

Cell Periphery ◽

Matrix Interaction ◽

Type Iv ◽

Cell Matrix ◽

Reverse Pattern ◽

Genes Encoding

Diffuse leiomyomatosis (DL) is rare condition characterized by proliferation of smooth muscle in the upper gastrointestinal tract. Most cases are associated with X-linked Alport syndrome and have partial deletions in the genes encoding both the α5 and α6 chains of collagen type IV. We studied aspects of cell-matrix interaction of myocytes in an esophagogastrectomy specimen from a 12-year-old patient with DL. Myocytes had central areas of cytoplasmic rarefaction, which were actin positive and desmin poor, with the reverse pattern of staining at the cell periphery. Electron microscopy (EM) showed that the areas of rarefaction consisted of disorganized aggregates of filaments. The basement membranes ranged from thickened to thinned or absent. Immunohistochemical staining for the α1–α4 chains of collagen type IV, the α1, α2, β2, and γ1 chains of laminin, nidogen, type VI collagen, and fibronectin was normal. There was loss of the α5 and α6 chains of collagen type IV and the β1 chain of laminin. Normal staining for α1, α2, α3, α4, α6, α8, and β1 integrins was noted. Staining for α5 integrin varied from normal to reduced or negative in different cells. In DL, a primary abnormality of basement membrane may be associated with disorganization of the contractile apparatus and alterations of certain integrins. This may reflect a disturbance of cell-matrix interactions that play a role in cell differentiation and internal organization.

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An attempt at quantitation of procollagens I and III and of collagen IV in tooth sections by exposure to the corresponding antibodies followed by 125I-protein A and radioautography.

Journal of Histochemistry & Cytochemistry ◽

10.1177/28.12.7229339 ◽

1980 ◽

Vol 28 (12) ◽

pp. 1355-1358 ◽

Cited By ~ 6

Author(s):

G M Wright ◽

C P Leblond

Keyword(s):

Collagen Type ◽

Protein A ◽

Collagen Iv ◽

Basement Membranes ◽

Collagen Type Iv ◽

Periodontal Tissue ◽

Rat Incisor ◽

Type Iv ◽

Silver Grains ◽

Procollagen Iii

The immunoreactivity of procollagen types I and III and of collagen type IV was detected in frozen sections of the growing apical end of rat incisor teeth by an indirect method making use of protein A. The sections were exposed to affinity-purified antibodies against these substances. The bound antibodies were then detected by incubation with radioiodinated protein A, followed by radioautography. This immunoradioautographic approach yielded preparations with low background, in which the reactions could be quantitated by counts of silver grains. The distribution of the radioautographic reactions was essentially the same as that previously observed with direct and indirect peroxidase methods, that is, procollagen I antigenicity predominated in odontoblasts and predentin, with minor amounts in periodontal tissue and pulp; procollagen III antigenicity was present in periodontal tissue and, to a lesser extent, in the pulp; and collagen IV antigenicity was restricted to basement membranes. Moreover, grain counts provided quantitative support for the conclusions on the distribution of procollagen I and III antigenicity.

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An Absence of the Collagen Type IV α5 Chain in Alport Syndrome

Journal of Nippon Medical School ◽

10.1272/jnms.69.86 ◽

2002 ◽

Vol 69 (2) ◽

pp. 86-87 ◽

Cited By ~ 1

Author(s):

Masamichi Ishizaki

Keyword(s):

Alport Syndrome ◽

Collagen Type ◽

Collagen Type Iv ◽

Type Iv

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

Case Reports in Nephrology ◽

10.1155/2022/5243137 ◽

2022 ◽

Vol 2022 ◽

pp. 1-5

Author(s):

Ulrich Jehn ◽

Cornelie Müller-Hofstede ◽

Barbara Heitplatz ◽

Veerle Van Marck ◽

Stefan Reuter ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Case Report ◽

Alport Syndrome ◽

Kidney Biopsy ◽

Novel Mutation ◽

Basement Membranes ◽

Homozygous Mutation ◽

Lamina Densa ◽

Case Presentation ◽

Hereditary Defect

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.

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Adverse effects of Alport syndrome-related Gly missense mutations on collagen type IV: Insights from molecular simulations and experiments

Biomaterials ◽

10.1016/j.biomaterials.2020.119857 ◽

2020 ◽

Vol 240 ◽

pp. 119857 ◽

Cited By ~ 2

Author(s):

Jingjie Yeo ◽

Yimin Qiu ◽

Gang Seob Jung ◽

Yong-Wei Zhang ◽

Markus J. Buehler ◽

...

Keyword(s):

Adverse Effects ◽

Alport Syndrome ◽

Collagen Type ◽

Molecular Simulations ◽

Collagen Type Iv ◽

Missense Mutations ◽

Type Iv

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Fcγ Receptor Iib–Deficient Mice Develop Goodpasture's Syndrome upon Immunization with Type IV Collagen

Journal of Experimental Medicine ◽

10.1084/jem.191.5.899 ◽

2000 ◽

Vol 191 (5) ◽

pp. 899-906 ◽

Cited By ~ 158

Author(s):

Akira Nakamura ◽

Takae Yuasa ◽

Azusa Ujike ◽

Masao Ono ◽

Toshihiro Nukiwa ◽

...

Keyword(s):

Rapidly Progressive Glomerulonephritis ◽

Pulmonary Hemorrhage ◽

Basement Membranes ◽

Collagen Type Iv ◽

Goodpasture's Syndrome ◽

Goodpasture’S Syndrome ◽

Type Iv ◽

Suitable Animal Model ◽

And Function

The combination of hemorrhagic pneumonitis and rapidly progressive glomerulonephritis is a characteristic feature of Goodpasture's syndrome (GPS), an autoimmune disease resulting from the interaction of pathogenic anti–collagen type IV (C-IV) antibodies with alveolar and glomerular basement membranes. Lack of a suitable animal model for this fatal disease has hampered both a basic understanding of its etiology and the development of therapeutic strategies. We now report a novel model for GPS using mice deficient in a central regulatory receptor for immunoglobulin (Ig)G antibody expression and function, the type IIB Fc receptor for IgG (FcγRIIB). Mutant mice immunized with bovine C-IV reproducibly develop massive pulmonary hemorrhage with neutrophil and macrophage infiltration and crescentic glomerulonephritis. The distinctive linear, ribbon-like deposition of IgG immune complex seen in GPS was observed along the glomerular and tubulointerstitial membranes of diseased animals. These results highlight the role of FcγRIIB in maintaining tolerance and suggest that it may play a role in the pathogenesis of human GPS.

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Alport Syndrome: a comprehensive review on genetics, pathophysiology, histology, clinical, and therapeutic perspectives

Current Medicinal Chemistry ◽

10.2174/0929867328666210108113500 ◽

2021 ◽

Vol 28 ◽

Author(s):

Ana Luisa Pedrosa ◽

Letícia Bitencourt ◽

Rafaela Moreira Paranhos ◽

Cristiana Afonso Leitão ◽

Guilherme Costa Ferreira ◽

...

Keyword(s):

Alport Syndrome ◽

De Novo ◽

Lysyl Oxidase ◽

Clinical Investigation ◽

Clinical Manifestations ◽

Basement Membranes ◽

De Novo Mutations ◽

Vascular Abnormalities ◽

Wide Range ◽

Novel Therapeutic

Background: Alport syndrome (AS) is a disease caused by mutations in COL4A3, COL4A4 or COL4A5, the genes that encode distinct chains of type IV collagen. The vast majority of cases presents as an inherited disorder, although de novo mutations are present in around 10% of the cases. Methods: This non-systematic review summarizes recent evidence on AS. We discuss the genetic and pathophysiology of AS, clinical manifestations, histopathology, diagnostic protocols, conventional treatment and prognostic markers of the disease. In addition, we summarize experimental findings with novel therapeutic perspectives for AS. Results: The deficient synthesis of collagen heterotrimers throughout the organism leads to impaired basement membranes (BM) in several organs. As a result, the disease manifests in a wide range of conditions, particularly renal, ocular and auricular alterations. Moreover, leiomyomatosis and vascular abnormalities may also be present as atypical presentations. In this framework, diagnosis can be performed based on clinical evaluation, skin or renal biopsy and genetic screening, the latter being the gold standard. There are no formally approved treatments for AS, even though therapeutic options have been described to delay disease progression and increase life expectancy. Novel therapeutic targets under pre-clinical investigation included paricalcitol, sodium-glucose co-transporter-2 inhibitors, bardoxolone methyl, anti-microRNA-21 oligonucleotides, recombinant human pentraxin-2, lysyl oxidase-like-2 blockers, hydroxypropyl-b-cyclodextrin, sodium 4- phenylbutyrate and stem cell therapy. Conclusion: AS is still a greatly under and misdiagnosed disorder. The pathophysiology is still not fully unnderstand and genetics of the disease have also some gaps. Up to know, there is no specific and effective treatment for AS. Further studies are necessary to establish novel and effective therapeutic protocols.

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