Re-understand Glomerular Filtration Barrier And Related Diseases
Jan 12, 2023
The nephron is the basic unit of the kidney to perform its functions, and the glomerular filtration barrier is an important line of defense for its normal physiological functions. The glomerular filtration barrier is composed of endothelial cells, podocytes, and glomerular basement membrane (GBM), which are mutually dependent and cooperate to complete the function of the glomerular filtration barrier. Given this, diseases caused by damage to its structural components have become one of the important areas of kidney disease research, such as podocyte disease, GBM-related diseases, type IV collagen-related diseases, etc.
Click to cistanche deserticola extract for kidney diseae
With the rapid development of genomic medicine and the continuous deepening of related research, especially the successive discoveries of genes related to the glomerular filtration barrier, our understanding of the regulatory mechanism of the glomerular filtration barrier and related diseases are also constantly being updated.
On August 4, 2022, at the 2021 Academic Annual Meeting (CSN 2021) of the Nephrology Branch of the Chinese Medical Association, academician Liu Zhihong, director of the Eastern Theater General Hospital and the National Clinical Research Center for Kidney Diseases, made a presentation on "re-understanding glomerular Filtration Barriers and Related Diseases". Academician Liu Zhihong pointed out that studying such diseases represented by Alport syndrome should start with the analysis of disease gene variation, which will provide us with a new way to systematically understand the abnormal structure and interaction of the glomerular filtration barrier. The complexity of disease gene variation, the diversity of clinical phenotypes, and the importance of genetic diagnosis have brought new understanding, thereby improving the level of diagnosis and treatment of such diseases.
Gene variation and pathogenesis of kidney disease
Gene variation plays a very important role in the occurrence and development of diseases, including the regulation of gene functions/key pathways and functional cell subsets, and ultimately leads to the differentiation and activation of pathogenic cell subsets. In clinical practice, kidney diseases associated with gene mutations are not uncommon. Taking the detection rate of type IV collagen gene mutations in patients with chronic kidney disease (CKD) as an example: Whole exome sequencing was performed on 3315 CKD patients, and 307 (9.3%) patients had pathogenic gene mutations, including 66 different pathogenic genes, including 27 cases (9%) of COL4A3, 21 cases (7%) of COL4A4, and 44 cases (14%) of COL4A5. Hematuria patients were also significantly associated with type IV collagen gene mutations. UK Biobank data analysis showed that COL4A4 p.Ser969 X was most significantly associated, followed by COL4A3 p.Gly695Arg and COL4A4 intron 25 Variant.
Type IV collagen and laminin (laminin) are important components of GBM, which are secreted by endothelial cells and podocytes during glomerular development, and their gene mutations will cause the protein products to fail to form normal trimers, resulting in GBM mesh The structure loss and easily hydrolyzed by proteolytic enzymes, which not only loses its supporting function but also directly affects its adjacent podocytes and endothelial cells. Podocytes are the main secretory cells of type IV collagen and laminin, and their functional defects will affect the normal formation and function of GBM. For example, podocyte WT1 mutations cause GBM diffuse thinning, accompanied by tearing and layering changes. INF2 mutations cause GBM thinning and segmental delamination, a fusion of foot process segments, etc. Alport syndrome is one of the representative diseases in which the above-mentioned abnormalities lead to diseases.
Alport syndrome
Our research on Alport syndrome has a long history, which can be traced back to 1875. However, no corresponding guidelines for diagnosis and treatment came out until 2013.
01Genetic Features and Diagnosis
In the early stage of kidney development, α1α1α2(IV) and laminin-111 are the main components of GBM. As they mature, they are gradually replaced by α3α4α5(IV) and laminin-521, eventually forming a stable GBM structure.
Because the above mechanisms are encoded by different genes, it also leads to the diversity of inheritance patterns, such as X-linked Alport syndrome, autosomal recessive Alport syndrome, and autosomal dominant Alport syndrome. Among them, males with X-linked Alport syndrome are severely ill and are prone to develop end-stage kidney disease (ESKD), while females are relatively mild. The genotype of autosomal recessive Alport syndrome is a homozygous or compound heterozygous mutation, and the severity of the mutation caused by the mutation type is consistent with that of X-linked Alport syndrome. Autosomal dominant Alport syndrome has relatively mild clinical manifestations.
Since gene variation is closely related to the final clinical prognosis, the complexity of the causative gene mutation of Alport syndrome must be recognized in clinical work. For example, whether the patient belongs to type IV collagen gene mutation (inheritance mode, mutation type), double gene mutation, chimeric mutation, or polygenic mutation. With the improvement of the accessibility of genetic testing technology, the genetic testing of Alport syndrome and suspected patients has begun to receive the attention of clinicians. However, due to the lack of professional training and relevant standards and norms, there are some problems in sample submission, interpretation of results, provision of genetic counseling, and long-term management. Further research is needed to formulate norms and guidelines for clinical work.
02 Pathogenic mechanism
In the early stage of kidney development, α1α1α2(IV) and laminin-111 are the main components of GBM. As they mature, they are gradually replaced by α3α4α5(IV) and laminin-521, eventually forming a stable GBM structure. In the pathological state of Alport syndrome, COL4A3-COL4A5 gene mutations will hinder the normal progress of this developmental transition process, α1α1α2(IV) and abnormal laminin subtypes alter the expression of matrix receptors and the distribution of cytoskeletal proteins, resulting in podocyte Foot process fusion disappears and stimulates the secretion of matrix metalloproteinases (MMPs) in podocytes; on the other hand, high filtration pressure stimulates endothelial cells to secrete endothelin-1, which in turn activates mesangial cells and ultimately leads to glomerular filtration barrier function abnormal. Compensatory α1α1α2(IV) expression not only leads to a decrease in GBM stability and is easily hydrolyzed by MMPs, but also binds to DDR1 and DDR2 receptors on podocytes activates integrin-mediated inflammatory signaling pathways, and participates in the triggering and amplification of local inflammation, to induce activation of the RAAS system. Therefore, inhibiting RAAS activation, reducing the local inflammatory response, and anti-fibrosis is considered to be possible treatment to delay the progression of Alport syndrome.
03 Treatment of Alport syndrome
At present, the treatment of Alport syndrome can be divided into four aspects: ① RAAS inhibitors, such as angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers (ACEI/ARB) or aldosterone receptor antagonists; ② inhibition of inflammation response, such as Nrf2 agonist, endothelin A receptor inhibitor; ③ anti-fibrosis, such as Anti-miRNA-21; ④ gene therapy.
Retrospective cohort studies and RCT studies of animal models and clinical patients have confirmed that ACEI/ARB can significantly delay the occurrence of proteinuria in patients with Alport syndrome and prolong the efficacy of renal function, and can extend the time of ESKD in patients with Alport syndrome for more than ten years. And the curative effect of early treatment is more significant. The results of our analysis showed that the response to ACEI/ARB therapy in male patients with X-linked Alport syndrome was significantly related to genotype, and ACEI/ARB therapy delayed the progression to ESKD in patients with non-truncating mutations by 16 years (from 24 years to 40 years). years), delaying the progression to ESKD in patients with truncating mutations by 3 years (from 20 to 23 years).
Based on the significant renal protective effect of ACEI/ARB, the consensus of relevant experts at home and abroad recommends ACEI/ARB as the standard treatment for Alport syndrome. It is recommended that males with X-linked Alport syndrome and patients with autosomal recessive Alport syndrome start ACEI/ARB therapy from the time of diagnosis, and females with X-linked Alport syndrome and patients with autosomal dominant syndrome start ACEI/ARB therapy when microalbuminuria occurs. It should be pointed out that there is still a lack of such clinical research and observation in China at present. More large-sample high-quality clinical research is needed to provide evidence of clinical efficacy that is more in line with Chinese patients and to formulate standards and norms to guide disease diagnosis and treatment.
In addition, inhibition of inflammatory response by Nrf2 agonist (Bardoxolone), anti-fibrosis by Anti-miRNA-21 compound (Lademirsen), endothelin A receptor inhibitor (Atrasentan) and dual inhibitor of angiotensin II and endothelin A receptor New multi-channel drugs such as (Sparsentan) to reduce glomerular pressure are in clinical trials, as well as potential gene therapy programs such as CRISPR/Cas9 gene editing technology and exon skipping therapy, which will also bring benefits to the treatment of patients with Alport syndrome in the future. new Hope.
laminin-associated kidney disease
For example, laminin β2 (LAMB2) gene mutations lead to abnormal structure of laminin 521, which prevents the normal polymerization of laminin 521 molecules, or laminin 521 is replaced by other types of laminin, resulting in developmental and maturation disorders of GBM. Abnormal, increased permeability, with podocyte damage and massive proteinuria, namely Pierson syndrome.
Pierson syndrome is an autosomal recessive disorder characterized clinically by nephrotic syndrome with neurodevelopmental abnormalities (eg, hypotonia, muscle weakness) and ocular abnormalities .
In addition, in renal biopsy, under fluorescence detection, there is no immune complex deposition, and laminin β2 loss can be seen in typical patients; light microscopy shows increased mesangial matrix, and podocytes are cuboidal changes, which may be accompanied by focal segmental Glomerulosclerosis (FSGS)-like lesion, tubulointerstitial atrophy, and fibrosis; increased mesangial matrix on electron microscopy, diffuse foot process fusion of podocytes, irregular thickening and thinning of GBM, GBM layer compaction visible.
In clinical practice, LAMB2 mutation can be detected in some patients with Alport syndrome, and LAMB2-S580R mutation will accelerate the progression of the X-linked dominant Alport syndrome.
Other Type IV Collagen-Associated Kidney Diseases
Gene mutations related to IV collagen and podocytes also frequently occur in FSGS patients. After targeted panel sequencing of 135 sporadic adult patients with steroid-resistant nephrotic syndrome (SRNS), it was found that 14 patients (10.4%) carried 2 Among other pathogenic mutations, podocyte-related genes accounted for 56.3%, and type IV collagen gene mutations accounted for 43.7%. Carriers have a poorer prognosis than those who do not carry the gene mutation.
Collagen type IV gene mutations may also occur in familial IgA nephropathy. After whole exome sequencing of 46 IgA nephropathy families, type IV collagen gene mutations were detected in 9 cases (20%), and COL4A3/A4 heterozygous mutation was more common.
In addition to the above-mentioned kidney diseases, since α1α1α2(IV) is distributed in all basement membranes of the body, the COL4A1/A2 gene mutation can affect multiple systems. In addition to hematuria and renal cysts in kidney lesions, cerebrovascular diseases (such as cerebral perforating deformity, cerebrovascular disease, etc.), ocular lesions (such as cataracts, retinal hemorrhage, etc.), muscle lesions, and heart lesions. Therefore, when a patient is found to have a COL4A1/A2 variant, one should not focus solely on renal disease.
In conclusion, gene mutations have great reference value for the diagnosis and treatment of kidney disease and systemic symptoms. It is recommended to perform genetic testing for patients with the following conditions: steroid resistance refractory FSGS, familial IgA nephropathy, glomerular GBM Layer fracture, uneven thickness, irregular structure, and unexplained renal failure.
for more information:ali.ma@wecistanche.com
