What Is Alport Syndrome?

Alport syndrome, also known as eye-ear-renal syndrome, is the most common form of hereditary nephritis. Clinical manifestations seem to be chronic glomerulonephritis. First reported by DicRinson in a third-generation hematuria family in 1875. In 1902, Guthrie reported that hematuria occurred in many people in a family. In 1927, Alport described that in addition to hematuria, patients still had hearing impairment, and men were more likely to enter renal failure than women, thereby establishing the diagnosis of the disease.

Alport syndrome

Alport syndrome is also known as hereditary nephritis, familial nephritis, and hereditary progressive nephritis.

The main inheritance of this disease is x-linked dominant inheritance, and the pathogenic gene is located in the middle of the long arm of the X chromosome. Therefore, heredity is related to gender. It usually develops before the age of 10, and hematuria (deformed red blood cell hematuria) is prominent and first-onset. Intermittent or continuous gross or microscopic hematuria is usually caused by specific upper respiratory tract infections, fatigue, or exacerbation after pregnancy. Renal function is chronic and progressively impaired, especially in men, and often enters end-stage renal failure at the age of 20-30 years. Often accompanied by high-frequency neurological deafness. 10% -20% of patients have ocular lesions, including: myopia, strabismus, nystagmus, keratoconus, corneal pigmentation, spherical crystals, cataracts and fundus lesions. There are no effective treatments for this disease to prevent infection, fatigue, pregnancy and kidney damage. Once renal insufficiency, the amount of protein and phosphorus should be restricted, and hypertension should be actively controlled to prevent the acquired factors from accelerating the disease progression.

There is no epidemiological data of Alport syndrome based on demography, but heredity of hematuria appears clinically. Alport syndrome is more common in kidney disease. Alport syndrome is most common if it is characterized by progression to end-stage renal disease (ESRD). Data from parts of the United States show that the Alport syndrome gene frequency is approximately 1: 5 000 [31] or 1: 10 000 [32]. Among foreign kidney biopsy specimens, Alport syndrome accounts for 1.6% [33] to 4% [34]. Among the larger groups of renal biopsy pathology studies in China (including 13 519 cases, 2 315 cases and 1 100 cases), Alport syndrome was diagnosed in 0.729% [35], 1.2% [36], and 0.818% [37] of patients, respectively. Different data also show that among patients with end-stage renal disease, Alport syndrome accounts for 0.2% to 5% [38 to 43] and 1.8% to 3% of children with chronic renal failure [44 to 45], accounting for kidneys of all ages. 0.6% [46] to 2.3% of transplant patients [47]. However, in patients with persistent hematuria, especially in children, Alport syndrome is more common, accounting for 11% to 27% [48 ~ 51]. To date, ethnic and geographic differences in the incidence of Alport syndrome have not been identified, but are relatively rare among black Americans

Since the identification of the first gene that causes Alport syndrome in the late 1980s, it has been clear that no matter what type of Alport syndrome is caused by a mutation in the gene encoding type IV collagen a chain, some scholars even It is believed that Alport syndrome should be classified as a collagenous disease. Type IV collagen is the major extracellular matrix protein in the basement membrane of the kidney. After the endothelial cells and epithelial cells are secreted outside the cells, the type IV collagen molecules self-assemble into a type IV collagen network with a polygonal network structure. Type IV collagen network and laminin network, nestin (entactin), proteoglycan and other glycoprotein molecules are the main molecular components of GBM. The basement membrane can be used as a scaffold for cell attachment to maintain the normal structure and shape of the cell population. At the same time, the basement membrane interacts with neighboring cells and affects cell proliferation, differentiation, adhesion, migration, and molecular filtration [1]. As a member of the collagen family, type IV collagen molecules are also three-helix molecules formed by three a chains intertwined and tightly twisted [1-3]. Each Cc chain consists of a 350-nm collagen domain characterized by a glycine XY (Gly-XY) repeat, a spherical 3 'non-collagen domain (Ncl domain), and a short 7s domain at the 5' end. It has been confirmed that there are at least six types of a chains involved in the molecular structure of type collagen, named a1 () a6 () chains, respectively, which are encoded by six different genes head-to-head and in pairs on different chromosomes. COL4A1 can be COL4A2 on chromosome 13q34, COL4A3 and CDL4A4 on chromosome 2q35-37, and COL4A5 and COL4A6 are located on x chromosome Xq22 [4-8]. Six kinds of a chains spontaneously aggregate to form three different protomers, and different protoplasms construct three different collagen networks [1]. The first type is a type IV collagen network composed of a1ala2 () -a1a1a2 () chains, which are widely expressed in immature nephrons; during the development of glomeruli, the type IV collagen network in GBM changes, a3a4a5 (IV) The trimer replaces the a1a1a2 (IV) trimer. The second type is a type IV collagen network composed of a3a4a5 (IV) -a3a4a5 (IV) chains, which are expressed only in GBM, distal tubular basement membrane (TBM), and alveolar basement membrane, eye and cochlear basement membrane. The third type is a type IV collagen network composed of a1a1a2 (IV) -a5a5a6 () chains. They are expressed in the Bowman capsule wall of the kidney and the basement membrane of the collecting duct, but not in GBM. In addition, they are expressed in the epidermal basement membrane and smooth muscle cell base. Membrane is also not expressed (Figure 11-3-1).

It is believed that there are three main types of Alport syndrome, which are caused by mutations in genes encoding different type IV collagen G chains.

The X-linked dominant hereditary type of Alport syndrome is the most common, accounting for about 85%. The causative gene is the COL4A5 gene encoding type IV collagen a5 chain. So far, more than 300 mutations have been reported. There are many types of mutations, including large rearrangement, even 5% to 15% of all gene deletions, small deletions, insertions, and point mutations. Missense mutations, non-sense mutations, and splicing-site mutations are more common [9-15]. The mutation positions were distributed throughout the gene, and no obvious hot spot was found. In addition, 10% to 15% of patients have new or de novo mutations (de novomutation [16, 17]. There is one subtype of x-linked dominant hereditary Alport syndrome involving mutations in two genes, COL4A5 and COL4A6 [18, 19]. So far, there have been more than 20 Alport syndrome families with such mutations reported abroad. Chinese scholars have also identified and reported such cases [20, 21]. Genetic analysis results confirmed that the COL4A6 gene had a break point. ) In addition to the clinical phenotype of Alport syndrome, patients in intron 2 are also accompanied by diffuse leiomyoma; patients with COL4A6 gene deletion breakpoints other than intron 2 only have general Alport synthesis The clinical manifestations of the symptoms are not accompanied by diffuse leiomyoma [16, 22, 23]. There have been no reports of Alport syndrome caused by mutations in the COL4A6 gene alone.

About 15% of Alport syndrome is an autosomal recessive genotype, the pathogenic gene is the COLL4A3 or COL4A4 gene, and the more severe cases are homozygous or complex heterozygous mutations of the COL4A3 or COL4A4 gene. Using polymerase chain reaction-single-strand conformation polymorphism analysis (PCR-SSCP) method, only about 50% of autosomal recessive Alport syndrome patients can detect mutations in the COL4A3 or COL4A4 gene, and the double genes have not been confirmed. (Digenic) mutation. It has been reported that COL4A3 or COL4A4 gene mutations found in autosomal recessive Alport syndrome families are small mutations, and the mutation position is distributed throughout the gene without obvious hot mutations. The mutation types are diverse, including glycine Replacement and deletion mutations, nonsense mutations, splice site mutations, insertion mutations, and other missense mutations [24-28]. Autosomal dominant hereditary Alport syndrome is very rare, and mutations in the COL4A3 or COL4A4 gene have been identified in only a few unrelated families.

1. The pathological changes of light microscopy are not characteristic. Before the application of electron microscopy, Alport syndrome was considered to be chronic interstitial nephritis, and renal interstitial foam cells were mistakenly used as the basis for diagnosis [53]. Other minor glomerular lesions include: segmental capillary wall sclerosis, mild irregular widening of the mesangial region, thickening of Bowman's capsule wall segments, and focal capillary endothelial cells and / or lines Membrane cells increased, etc. (Figure 11-3-2). Except for red blood cell casts, the renal tubules and interstitials in childhood are mostly normal. Most of the renal tissue specimens of patients with Alport syndrome from 5 to 10 years old showed mild lesions, but mesangial and capillary wall injuries were seen, including segmental or diffuse mesangial cell proliferation, increased mesangial matrix, and thickened capillary walls. . Glomerular sclerosis and TBM thickening, tubule dilation, atrophy, interstitial fibrosis and other damage are seen in late stages, and foam cells are common. In addition, segmental and occasionally diffuse crescents can occur in the glomeruli, and about 33.3% of renal biopsy specimens show balloon adhesions.

2. Immunofluorescence

No specific changes, it can be seen that C3 and IgM in the glomerular mesangial region and along the GBM (glomerular basement membrane) in the segmental or diffuse granular deposition, can also be completely negative [54], and help with IgA nephropathy , Membrane proliferative glomerulonephritis and other immune complex-mediated glomerulonephritis. Using specific antibodies against different a chains of type IV collagen to perform immunofluorescence detection in Figure 11-3-2 Alport syndrome and skin tissues, it can diagnose x-linked dominant hereditary men (Figure 11-3-3) and women And autosomal recessive Alpmt syndrome (Table 11-3-1).

3 Electron microscopy

The pathological changes characteristic of Alport syndrome can be observed under electron microscopy. GBM is widely thickened or thinned and the dense layer is divided into typical lesions (Figure 11-3-4). The irregular appearance of the GBM dense layer is the most prominent abnormality of the ultrastructure. The scope can cover all capillary ridges or all areas within the capillary ridges, or only part of the capillary ridges or capillary ridges. region. The GBM dense layer can be thickened to 1 200nm (normally 100-350nm), and has irregular inner and outer contour lines. Due to the fracture of the GBM dense layer, some "electronic dense particles" (diameters) in the GBM can also be seen under the electron microscope. (20-90nm), its properties are not clear enough, it may be the "residue" of the damaged dense layer, and some scholars believe that it may be derived from degenerative podocytes. GBM diffuse thinning (thinning below 100nm) is more common in young children, female patients or early disease, and occasionally in adult male patients.

It is still believed that diffuse thickening and tearing of GBM is the pathological basis for the diagnosis of Alport syndrome. Other pathological changes, such as thinning of GBM, should be diagnosed in combination with family history, the expression of type IV collagen a chain in GBM, and genetic information. Especially with thin basement membrane nephropathy.

Alport syndrome is essentially a hereditary, kidney-dominated clinical syndrome. Therefore, in clinical practice, it is necessary to pay attention to both the characteristics of renal abnormalities and the "extrarenal" manifestations. Try to infer the genetic type, because the clinical characteristics and prognosis of Alport syndrome are different.

1. Renal manifestations are most common in hematuria, mostly glomerular hematuria. Data from China have reported that 68% of patients with Alport syndrome have glomerular hematuria [21]. Male patients with the x-linked dominant hereditary type have persistent microscopic hematuria, which can even occur within a few days after birth; the penetrance of microscopic hematuria is 100%. About 67% of male patients with Alport syndrome have paroxysmal gross hematuria, most of which occur before the age of 10 to 15 years. Gross hematuria can occur after upper respiratory infection or fatigue. According to some authors, if a boy in a family of x-linked dominant Alport syndrome has no hematuria by age 10, the boy is likely not affected. More than 90% of women with x-linked dominant hereditary Alport syndrome have microscopic hematuria, and a few women have gross hematuria [55]. Almost all patients (men and women) with autosomal recessive genotypes exhibit hematuria; while heterozygous relatives of autosomal recessive genotypes, the incidence of hematuria is 50% to 60%, not exceeding 80% [56].

Male patients with x-linked dominant hereditary type Alport syndrome will all develop proteinuria, with continuous proteinuria with age or hematuria, and even nephrotic range proteinuria [57], the incidence of nephrotic syndrome is 30% 40%. Peking University First Hospital reported that 31.8% of patients had proteinuria with nephrotic syndrome [21], and suggested a poor prognosis. Similarly, the incidence and severity of hypertension also increase with age, and most often occur in male patients.

The renal prognosis of male patients with x-linked dominant hereditary Alport syndrome is extremely poor, and almost all of them progress to end-stage renal disease. The rate of progress varies from family to family, usually from 5 to 10 years from the start of renal dysfunction to renal failure. According to the authors, Alport syndrome families are divided into adolescent type (occurring before 31 years of age) and adult type (occurring after 31 years of age) according to the age of men with end-stage renal disease. Renal failure also develops in some women with x-linked dominant hereditary Alport syndrome. By the age of 40, about 12% of patients, and 30% to 40% of patients over 60 years of age have renal failure [17]. Many patients with autosomal recessive inheritance develop renal failure during adolescence, and almost all patients develop renal failure before the age of 30. Patients with autosomal dominant inheritance have relatively mild clinical manifestations and do not progress to end-stage renal disease until the age of 50 years.

2. Hearing impaired

Hearing impairment in patients with Alport syndrome manifests as sensorineural hearing loss, which occurs in the cochlea. Deafness is progressive, and the sides are not completely symmetrical. Hearing loss in the high-frequency area must be diagnosed with the aid of audiometry, which reaches the full range, and even affects daily dialogue and communication. No congenital deafness has been reported. Men with x-linked dominant Alport syndrome are more likely to develop deafness than women, and they are older than women. Deafness has been reported in men and women with X-linked dominant hereditary Alport syndrome at rates of approximately 81% and 19%, respectively [17, 58]. And about 66.6% of patients with autosomal recessive Alport syndrome exhibit sensorineural hearing loss before the age of 20 [16].

3 Eye lesions

The characteristic eye diseases of Alport syndrome include anterior lenticonus, perimaeular dot and fleck retinopathy, and midpmeripheral retinopthy of the retina [59, 60]. The anterior cone lens appears as the central part of the lens protruding into the anterior capsule. Patients may present with progressive myopia and even cause anterior polar cataracts or spontaneous perforation of the anterior capsule. Anterior cone lenses appear more than 20 to 30 years old. The smallest patients reported so far are 13-year-old men, 60% to 70% of x-linked men, 10% of x-linked dominant hereditary women, and about 70%. Patients with autosomal recessive Alport syndrome have an anterior cone lens [56]. Alport syndrome-specific retinopathy usually does not affect vision. With fundus mirrors or retinal imaging methods, there can be dim, even pale, punctate and spotted lesions around the macula of the fundus or retinal equator. The lesions will accompany the decline of renal function. progress. About 70% of X-linked dominant hereditary men, 10% of x-linked dominant hereditary women, and about 70% of autosomal recessive Alport syndrome patients develop retinopathy and often coexist with deafness and anterior cone lens. But retinopathy appeared earlier than the cone lens. Eye involvement has not been reported in patients with autosomal dominant hereditary Alport syndrome.

4 Abnormal blood system

AMME syndrome (AMME complex) is Alport syndrome with hematological abnormalities, which are mainly manifested as Alport, mental retardation, central facial dysplasia, and oval erythrocytosis. Studies have confirmed that all COL4A5 genes of this type of Alport syndrome are deleted, and the gene deletion range extends beyond the 3 'end. In addition, previously reported hematological abnormalities, such as giant platelets (Epstein syndrome), platelet abnormalities with leukocyte inclusions (Fechtner syndrome), and platelet abnormalities only (Sebastian syndrome), are accompanied by "Alport-like" manifestations. The disease has been confirmed to be caused by mutations in the gene encoding non-myosin heavy chain 9, MYH9, rather than mutations in the type IV collagen gene. Therefore, this type of disease is not Alport syndrome, known as MYHllA syndrome, and is autosomal dominant [61].

5. Diffuse leiomyomatosis. Some adolescent Alport syndrome families or patients are accompanied by significant smooth muscle hypertrophy. The esophagus, trachea, and female reproductive tract (such as the clitoris, labia majora, and uterus) are common affected areas and appear. Corresponding symptoms, such as dysphagia and dyspnea. In 2003, China also reported the first case of Alport syndrome with diffuse leiomyoma [20]. Alport syndrome with diffuse leiomyomas are all x-linked dominant genotypes, but women with heterozygotes have shown smooth muscle hypertrophy early, and the specific mechanism of this phenomenon is not clear.

6. Other authors have reported certain lesions, such as thyroid disease, IgA deficiency, postpontine neuritis, ascending aortic aneurysm, anorectal deformity, psychosis, fibromyopathy, type I neurofibromatosis [62], and Turner Like syndrome [63] and so on. The above-mentioned lesions have not yet been determined as specific clinical manifestations of Alport syndrome, and are likely to be only diseases coexisting with Alport syndrome.

With the deepening understanding of Alport syndrome, the diagnostic criteria of the disease have also gone through several stages. Forty years after Alport was named in 1927, the disease has always been diagnosed with the clinical syndrome criteria of "hematuria + deafness + family history of renal failure". The application of electron microscopy in the 1970s revealed the specific ultrastructural changes of GBM in this disease. Based on this, Flinter et al. [64] proposed 4 criteria for the diagnosis of Alport syndrome. If hematuria and / or chronic Patients with renal failure can be diagnosed if they meet 3 of the following 4 items: family history of hematuria or chronic renal failure; typical changes in renal biopsy electron microscopy; sensorineural hearing loss; eye changes. However, research shows that only 45% to 55% of patients with Alport syndrome have deafness and the incidence of eye abnormalities is only 30% to 40%. Therefore, the above criteria are too strict and many patients will be missed. In 1996, Gregory et al. [65] proposed ten criteria for the diagnosis of Alpot syndrome on the basis of comprehensive previous experience (Table 11-3-2).

Diagnosis of family members of Alport syndrome: In the immediate family members, 4 of the criteria should be met, with exceptions; of course, there are exceptions; but the diagnosis of peripheral members and individuals who only show unknown causes of hematuria, end-stage renal disease or hearing impairment should be very careful. Determine whether family members in Alport syndrome families are affected: If the individual meets the corresponding genotype, and then meets one of the criteria 2 to 10, a diagnosis can be proposed, and two can be confirmed. For individuals without family history, at least four of the above indicators should be met.

With the understanding and recognition of the pathogenic genes of Alport syndrome and the expression characteristics of related protein molecules, American scholars have proposed the "2/6" criteria for the diagnosis of Alport syndrome, that is, if they meet two of the following six criteria, they can Diagnosis of Alport syndrome: family history of hematuria, men progress to end-stage renal disease; detection of special Alport syndrome diagnostic criteria 1 family history of nephritis, or first-degree relatives of probands or male relatives with unexplained hematuria 2 Persistent hematuria, no evidence of other hereditary kidney diseases, such as thin basement membrane nephropathy, polycystic kidney disease, or IgA nephropathy 3 bilateral sensorineural deafness at 2 000 to 8 000 Hz, deafness is progressive, normal in early infants, but 4 COL4A4 or COL4A5 gene mutations appear before the age of 30 5 Immunofluorescence examination shows that the glomerulus and / or skin basement membrane does not express the Alport epitope completely or partially 6 The ultrastructure of the glomerular basement membrane is extensively abnormal, especially Is thickening, thinning, and splitting 7 eye lesions, including 8 probands including anterior cone lens, posterior capsule cataract, and retinal spots, or at least two family members who have gradually progressed to the end stage ' 9 Giant thrombocytopenia disease, inclusion bodies, or leukocytes esophagus 10 and (or) female. Diffuse leiomyoma of the sexual genital tract Table 11-3-2 Thickening and stratification of GBM diagnostic criteria for Alport syndrome; Progressive, high-frequency, sensorineural hearing loss; Anterior cone lens and Spots around the macula; Type IV collagen a3, a4, and a5 chains are abnormally expressed in the basement membrane; and Type IV collagen type a3, a4, and a5 chain mutations.

In short, whether it is the 4 criteria of Flinter or the 10 or 6 criteria proposed later, the diagnosis of Alport syndrome requires comprehensive clinical and laboratory information. Not only the diagnosis of clinical syndromes, but also the diagnosis of genotypes and mutations should be made as far as possible, so that it is possible to not only diagnose the proband, but also provide objective genetic counseling to the family, and then it is possible to produce the family with needs. Before diagnosis.

In addition to paying attention to the symptoms of kidney disease, such as urine routine and renal function, the diagnosis of clinical symptom syndrome should also be based on pure tone audiometry and eye slit lamp examination to determine whether there are "extrarenal symptoms" such as sensorineural deafness and Eye abnormalities. So far, the characteristic thickening and stratification of GBM is still considered to be the "gold standard" for the diagnosis of Alport syndrome, but it does have limitations. For some atypical families, although renal pathology can be diagnosed as Alport syndrome, it is not possible to determine whether the genetic pattern is an x-linked dominant genotype or an autosomal recessive genotype; as for some young people who are highly suspected of the disease In patients and female patients, GBM has no typical pathological changes, only showing that GBM becomes thin. Domestic and foreign studies believe that through simple skin biopsy, detection of epidermal GBM type IV collagen a5 chain expression can be used to diagnose male patients with x-linked Alport syndrome, and x-linked dominant genetic Alport synthesis carrying disease-causing genes. Enroll female patients [66, 67]. When judging the results, please pay attention to: male patients can be diagnosed as x-linked dominant hereditary type Alport syndrome if the epidermal basement membrane is not expressing a5 () chain; female patients can be diagnosed as x-linked dominant hereditary type Alport syndrome Syndrome. Because some patients with x-linked dominant hereditary Alport syndrome or gene carriers may have normal expression of the GBM type IV collagen a5 chain [67,68], the expression of the GBM type IV collagen a5 chain is normal and cannot be completely Excluding the diagnosis of Alport syndrome. Asymptomatic gene carriers, the epidermal type IV collagen a5 chain is normally expressed. In addition, some authors believe that the reduced expression of type IV collagen a3-5 chain in GBM may also be helpful in the diagnosis of Alport syndrome [69].

The most important clue for the diagnosis of hereditary type comes from family history, so it is important to conduct family hematuria and renal failure investigations. In addition to detailed inquiries about whether there is a close marriage, you should also try to perform morning urine urine sediment microscopy on first-degree relatives To find asymptomatic hematuria and even proteinuria family members. Regardless of whether there is a family history, the results of the investigation of the patients and their family history should be clearly and unambiguously displayed using a pedigree. Also, combine the epidermis as well. The expression of GBM type IV collagen a chain in renal tissue can also objectively diagnose Alport syndrome hereditary types, such as autosomal recessive Alport syndrome GBM, TBM, and Bowman's sac wall a3 and a4 chains have disappeared; a5 chain in GBM disappears, but it still exists in TBM, Bowman's capsule wall, and epidermal basement membrane (Table 11-3-1) [70-72].

Screening and analysis of the COL4A3-5 gene of Alport syndrome families for genetic diagnosis can provide accurate genetic information, not only genetic counseling, but also the only method to identify asymptomatic gene carriers, and to Before diagnosis becomes possible. But the COL4A5 gene is about 240 base pairs long and has 51 exons. Therefore, this inspection is time-consuming and labor-intensive and requires more complete laboratory equipment. We look forward to the introduction of automated, small sample DNA analysis technologies and instruments to accelerate and simplify the workload and process of genetic analysis. Chinese scholars have established a set of methods for detecting gene mutations with relatively low cost and high detection rate, that is, culturing fibroblasts from skin biopsy, extracting RNA, and using RT-PcR method to amplify and analyze type IV collagen a5 chain mRNA sequence. The mutation detection rate reached 90% [73]. In 1995, European and American scholars have successfully performed the prenatal diagnosis of x-linked dominant hereditary Alport syndrome [74]. However, due to the diversity of genetic mutations in the x-linked dominant hereditary Alport syndrome, the researchers first identified the COL4A5 gene mutation in the family, and then used the nucleotide sequence of the mutation region as a probe to conceive with a pregnant woman of the family. At 10 weeks, the chorionic villus DNA was hybridized, and a genetically altered fetus was detected to terminate the pregnancy. In 2006, Chinese scholars also successfully performed the prenatal diagnosis of Alport syndrome.

For patients with end-stage renal disease in Alport syndrome, one of the effective treatments is kidney transplantation. Regarding the choice of donors for Alport syndrome kidney transplantation, living donor kidneys are generally recommended; however, if anti-glomerular basement membrane nephritis has occurred after transplantation, it is best not to use a living kidney for another kidney transplant. Some researchers believe that female carriers of the heterozygous COL4A5 gene have no clinical manifestations such as proteinuria, hypertension, renal failure, and deafness, and can be used as donors, but the risk of renal insufficiency after transplantation is higher than that of healthy donors. Body kidney [76].

Many reports indicate that patients with Alport syndrome who have undergone renal transplantation produce antibodies against the normal GBM transplanted in the body and develop anti-glomerular basement membrane nephritis, which leads to transplant failure. The incidence of anti-glomerular basement membrane nephritis after transplantation is 3% to 4% [77-79], and about 75% occurs within 1 year after transplantation. Patients with x-linked dominant genotypes and autosomal recessive genotypes of Alport syndrome have anti-glomerular basement membrane after transplantation. Report of nephritis. It has also been reported that due to the failure of anti-glomerular basement membrane nephritis transplantation, re-transplantation can occur again.

Many researchers have done a lot of research on the essence of anti-GBM antibodies after Alport syndrome kidney transplantation, and the results are mixed. The anti-GBM component is considered to be type VI collagen a3 chain NC1 fragment [80], or type IV collagen. a5 chain NCl fragment [79,81,82]. Among the genetic mutations in Alport syndrome that produce anti-glomerular basement membrane nephritis after transplantation, 50% are all or part of the COL4A5 gene deletion, which is significantly higher than the frequency of gene deletion in the overall Alport syndrome (16%). The production of GBM antibodies may be due to the COL4A5 gene mutation that hinders the expression of molecules that are immunogenic and fails to form immune tolerance.

Clinical practice experience and animal experiments have shown that drug intervention can be tried in patients who have not had renal failure but who already have proteinuria. The objective is to reduce urinary protein and protect renal function to delay or prevent the occurrence and development of end-stage renal disease in patients with Alpoil syndrome. However, due to the lack of strict experimental controls and the relatively small number of cases, its efficacy is inconclusive. For example, in 1996, Cohen et al. [83] reported the use of angiotensin-converting enzyme inhibitor (AcEI) to treat three Alport patients for 3.5 to 6 years, and found that the rate of decrease in endogenous creatinine clearance has slowed down. In 2004, Proesmans et al. [84] reported 10 years of experience with ACEI in the treatment of Alport syndrome, and the results showed that the levels of urinary protein and glomerular filtration rate remained unchanged; those with urinary protein> 50 mg / (kg · 24h) ( 5 cases) After 10 years, the glomerular filtration rate remained unchanged in 2 cases, decreased by 50% in 2 cases, and decreased by 30% in 1 case. This result suggests that there may be individual differences in the renal protective effect of ACET on Alport syndrome, and it also suggests that drug intervention may be carried out earlier. The experimental results of using animal models to explore the effects of drug intervention are also of great reference value for the treatment of human Alport syndrome. Gross et al. [85] reported that early (preemptive, administration starting 4 weeks after birth) treatment of COL4A3-gene knockout mice with ramipril (ACEI) can effectively prevent renal fibrosis, delay renal failure, and ultimately Extend the survival time of treated mice to (150 ± 21) days, while untreated COL4A3-/-gene knockout mice survived only (71 ± 6) days, and then received ramipril-treated COL4A3- / 7 weeks after birth. Although the knockout mice had less urine protein than the untreated mice, their survival time was the same as that of the untreated mice. This result suggests that early diagnosis and early initiation of drug intervention are essential for Alport syndrome.

In 1999, Callis et al. [86] reported the use of cyclosporine in the treatment of 8 cases of Alport syndrome, with a cyclosporine dose of 5 mg / (kg.d), maintaining an average blood concentration of (82 ± 13) ng / ml, and an average course of treatment of 8.4 Years, the patient's renal function remained normal, and no proteinuria or proteinuria was lower than the pre-treatment level. After 5 years of treatment, 8 patients underwent a second renal biopsy, and the results showed that the renal pathological changes did not worsen. However, most scholars do not approve the use of cyclosporine to interfere with Alport syndrome. Charbit et al. [87] observed 9 patients and found that although cyclosporine can reduce urinary protein, the glomerular filtration rate was reduced. 20 to 23 medications were used. A renal biopsy was performed again one month later, showing cyclosporine nephrotoxicity.

Valli et al. [88] reported that restricting the diet of x-linked dominant hereditary Alport syndrome model dogs and strictly controlling the intake of protein, fat, calcium and phosphorus in the diet can make the experimental dogs have less GBM tear than the control Group, and the rate of renal failure was also delayed.

Although the pathogenic genes of Alport syndrome have been identified and laid a certain foundation for gene therapy, further efforts are needed to implement gene therapy. Professor Kashtan and Michael of the United States discussed the gene therapy of Alport syndrome as early as 1996, including how to use appropriate vectors and transmission methods to transfect genes into glomerular podocytes and express them; how to express them in a timely manner How to control ectopic expression, because the excessive expression of type VI collagen in multiple tissues may cause multiple organ fibrosis; whether the peptide chain expressed by the foreign gene will be immunogenic to the individual, resulting in resistance. Glomerular basement membrane nephritis, etc. [89]. Therefore, gene therapy of Alport syndrome still has many problems. Fortunately, in 2001, Heikkila et al. [90] reported adoption. Local renal perfusion can introduce adenovirus-mediated collagen collagen a5 chain cDNA into pig kidney; after that, the method of local renal perfusion in Alport model dogs was also used to achieve the implementation of adenoviral vector type collagen a5 chain cDNA. Locally introduced into the kidney [91] The results not only detected the expression of type IV collagen a5 chains in the kidney tissue, but also the introduced type IV collagen a5 chains could be combined with the type IV collagen a3 and type IV collagen a4 chains in the kidney. Renal pathology also improved, but renal function did not improve, probably due to a strong immune response caused by adenovirus.