Alport syndrome

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Alport syndrome
Alport haring loss.jpg
Hearing loss effect of Alport syndrome in 13-year-old boy
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Alport syndrome is a genetic disorder [1] affecting around 1 in 5,000-10,000 children, [2] characterized by glomerulonephritis, end-stage kidney disease, and hearing loss. [3] Alport syndrome can also affect the eyes, though the changes do not usually affect vision, except when changes to the lens occur in later life. Blood in urine is universal. Proteinuria is a feature as kidney disease progresses. [4]

Contents

The disorder was first identified in a British family by the physician Cecil A. Alport in 1927. [5] [6] Alport syndrome once also had the label hereditary nephritis, but this is misleading as there are many other causes of hereditary kidney disease and 'nephritis'.

Alport syndrome is caused by an inherited defect in type IV collagen—a structural material that is needed for the normal function of different parts of the body. Since type IV collagen is found in the ears, eyes, and kidneys, this explains why Alport syndrome affects different seemingly unrelated parts of the body (ears, eyes, kidneys, etc.).

Depending on where the mutation is located in the genome, Alport syndrome can present itself in many forms. This includes X-linked Alport syndrome (XLAS), autosomal recessive Alport syndrome (ARAS), and autosomal dominant Alport syndrome (ADAS). [7]

Signs and symptoms

These descriptions refer to 'classic' Alport syndrome, which usually causes significant disease from young adult or late childhood life. [8] Some individuals, usually with milder mutations or 'carrier' status, develop disease later, or show only some of the features of classic disease.[ citation needed ]

Chronic kidney disease

Blood in urine is a usual feature of Alport syndrome from early infancy, identifiable on urine dipsticks. In young children, episodes of visible (macroscopic) haematuria may occur. Protein begins to appear in urine as the disease progresses. This is now regarded as an indication for treatment with ACE inhibitorss. Progressive loss of kidney function (reflected clinically by increases in serum creatinine or decreases in estimated glomerular filtration rate) can occur and may require treatment with renal replacement: dialysis or a kidney transplant. [9]

Hearing loss

Alport syndrome can also cause hearing loss although some patients are not affected. [10] Hearing in Alport syndrome patients is normal at birth. Hearing loss in affected patients develops progressively, usually at the stage when kidney function is normal, but there is substantial proteinuria. However, in some patients, hearing loss is only noted after kidney function has been lost. Characteristically the early changes are reduced ability to hear high-frequency sounds, 'sensorineural deafness'. This becomes more severe and affects lower frequencies too. Hearing loss is not usually complete in Alport syndrome; good communication is almost always possible with the use of hearing aids. [11]

Eye changes

Various eye abnormalities are often seen including lenticonus, keratoconus, cataracts and corneal erosion as well as retinal flecks in the macula and mid-periphery. [12] These rarely threaten vision. Lenticonus (cone-shaped lens) can be treated by replacement of the lens, as for cataracts. Mild keratoconus can be managed with hard, scleral, piggy-back or other specialty medical contact lenses; progressive cases may be halted with corneal collagen cross linking; and severe cases may require a corneal transplant.[ citation needed ] Macular abnormalities such as incomplete foveal hypoplasia or staircase foveopathy are common in Alport syndrome. [13]

It may also be associated with retinitis pigmentosa. [14]

Leiomyomatosis

Diffuse leiomyomatosis of the oesophagus and tracheobronchial tree has been reported in some families with Alport syndrome. Symptoms usually appear in late childhood and include dysphagia, postprandial vomiting, substernal or epigastric pain, recurrent bronchitis, dyspnea, cough, and stridor. Leiomyomatosis is confirmed by computed tomography (CT) scanning or magnetic resonance imaging (MRI). [15]

Other abnormalities

Aortic dissection has been described very rarely in patients with early-onset disease. [8] Leiomyomas, tumours of smooth muscle affecting the oesophagus and female genital tract, may occur in a rare overlap syndrome involving the adjacent COL4A5 and COL4A6 genes. [16]

Pathophysiology

Alport Syndrome is a relatively common genetic disorder affecting around 1 in 5,000-10,000 children. [2]

Genetics

Alport syndrome is caused by mutations in COL4A3, COL4A4 , and COL4A5 , three of six human genes involved in basement membrane (type IV) collagen biosynthesis. Mutations in any of these genes prevent the proper production or assembly of the specialised type IV collagen '345' network which is an important structural component of basement membranes in the kidney, inner ear, and eye. [17] It is also found in other locations, including the alveoli of the lungs. Basement membranes are thin, sheet-like structures that separate and support cells in many tissues. Type IV collagen '112' type is found in both vertebrates and invertebrates and is the major isoform in most human basement membranes. When mutations prevent the formation of 345 type IV collagen network in the glomerulus, the 112 network, which is formed in fetal development but usually replaced by 345, persists into adult life. [18]

Inheritance patterns

Alport syndrome can have different inheritance patterns depending on which specific mutation is present.

  • In most people with Alport syndrome (about 85%), the condition is inherited in an X-linked pattern, [19] due to mutations in the COL4A5 gene. A condition is considered X-linked if the gene involved in the disorder is located on the X chromosome. In males, who have only one X chromosome, one altered copy of the COL4A5 gene is sufficient to cause severe Alport syndrome, explaining why most affected males eventually develop kidney failure. In females, who have two X chromosomes, a mutation in one copy of the COL4A5 gene usually results in blood in the urine, but most affected females do not develop kidney failure.
  • Alport syndrome can also be inherited in an autosomal recessive pattern if both copies of the COL4A3 or COL4A4 gene, located on chromosome 2, have been mutated. [17] Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene. [9]
  • Past descriptions of an autosomal dominant form are now usually categorized as other conditions. [20] Notably, conditions associated with giant platelets and associated with mutations of MYH9 are no longer considered to be Alport variants. However apparent autosomal dominant transmission of disease associated with mutations in COL4A3 and COL4A4 does occur. [21] [22]

Clinical utility gene card for: Alport syndrome. [23]

Diagnosis

The diagnosis can usually be made on a combination of clinical, family history, and biopsy criteria.

Biopsy of kidneys or skin

To be helpful, kidney biopsies need to be taken before the disease is too advanced. Changes on conventional (light) microscopy are not characteristic, and the possibility of other diagnoses, particularly focal segmental glomerulosclerosis (FSGS), may be raised. Electron microscopy shows a characteristic sequence of changes from thinning of the glomerular basement membrane (GBM), developing into areas of thinning and thickening, and finally into a complex appearance with apparent splitting, often described as a 'basketweave' appearance. Early or very localised changes on this spectrum are not diagnostic, but the later changes are considered diagnostic.[ citation needed ]

Immunohistochemistry or immunofluorescence studies to identify the COL3-4-5 proteins in GBM can be helpful. However, these studies may be normal in some patients with Alport syndrome, especially milder variants.[ citation needed ]

The skin contains type IV collagen in a '556' network. Skin biopsies have been used to show the absence of the COL4A5 gene product, but these techniques are not straightforward, only apply to patients with severe COL4A5 mutations, and are not widely available. Genetic testing is now a better alternative if kidney biopsy is not possible.[ citation needed ]

Family history

A family history of end-stage renal disease with hearing impairment is suggestive of Alport syndrome, but other conditions can cause this combination of abnormalities. Most can be distinguished by clinical features. The finding of haematuria in relatives is suggestive.[ citation needed ] While X-linked inheritance is the most common pattern, genetic testing is revealing that atypical presentations may be more common than currently thought.[ citation needed ]

Genetic testing

Genetic testing plays an increasingly important role in confirming the diagnosis where the clinical features do not amount to proof. [24]

Other tests

The use of eye examinations for screening has been proposed. [25] Other tests may include a urine or blood test. [4]

Treatment

Kidney disease and kidney failure

In addition to measures for chronic kidney disease (CKD) of any cause, there is evidence that ACE inhibitors can slow the deterioration of kidney function in Alport syndrome, delaying the need for dialysis or transplantation. [26] The development of proteinuria has been recommended as an indication for commencing treatment. [8]

Once kidney failure has developed, patients usually do well on dialysis or with a kidney transplant. Transplantation can rarely be associated with the formation of antibodies to type IV collagen in the donor kidney resulting in progressive graft failure as a result of Goodpasture syndrome ('Alport post-transplant anti-GBM disease'). [27] [28]

Gene therapy has been frequently discussed, but delivering it to the podocytes in the glomerulus that normally produce the type IV collagen in the glomerular basement membrane is challenging. [29]

Hearing loss

It is not known whether ACE inhibitors or other treatments affect hearing loss. For those with classic Alport syndrome, hearing aids are often required in teenage or young adult years. [30]

Prognosis

Studies of the life expectancy of patients with Alport syndrome are rare, but one 2012 study found that Alport patients receiving renal replacement therapy (dialysis or kidney transplantation) exhibited, on average, better survival compared with matched controls who had other kidney diseases (and who also received renal replacement therapy). [31]

See also

Related Research Articles

<span class="mw-page-title-main">Nephrology</span> Medical study concerned with the kidneys

Nephrology is a specialty for both adult internal medicine and pediatric medicine that concerns the study of the kidneys, specifically normal kidney function and kidney disease, the preservation of kidney health, and the treatment of kidney disease, from diet and medication to renal replacement therapy. The word "renal" is an adjective meaning "relating to the kidneys", and its roots are French or late Latin. Whereas according to some opinions, "renal" and "nephro" should be replaced with "kidney" in scientific writings such as "kidney medicine" or "kidney replacement therapy", other experts have advocated preserving the use of renal and nephro as appropriate including in "nephrology" and "renal replacement therapy", respectively.

<span class="mw-page-title-main">Kidney disease</span> Damage to or disease of a kidney

Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can be diagnosed by blood tests. Nephrosis is non-inflammatory kidney disease. Nephritis and nephrosis can give rise to nephritic syndrome and nephrotic syndrome respectively. Kidney disease usually causes a loss of kidney function to some degree and can result in kidney failure, the complete loss of kidney function. Kidney failure is known as the end-stage of kidney disease, where dialysis or a kidney transplant is the only treatment option.

<span class="mw-page-title-main">Goodpasture syndrome</span> Rare autoimmune disease

Goodpasture syndrome (GPS), also known as anti–glomerular basement membrane disease, is a rare autoimmune disease in which antibodies attack the basement membrane in lungs and kidneys, leading to bleeding from the lungs, glomerulonephritis, and kidney failure. It is thought to attack the alpha-3 subunit of type IV collagen, which has therefore been referred to as Goodpasture's antigen. Goodpasture syndrome may quickly result in permanent lung and kidney damage, often leading to death. It is treated with medications that suppress the immune system such as corticosteroids and cyclophosphamide, and with plasmapheresis, in which the antibodies are removed from the blood.

<span class="mw-page-title-main">Glomerulonephritis</span> Term for several kidney diseases

Glomerulonephritis (GN) is a term used to refer to several kidney diseases. Many of the diseases are characterised by inflammation either of the glomeruli or of the small blood vessels in the kidneys, hence the name, but not all diseases necessarily have an inflammatory component.

<span class="mw-page-title-main">Membranous glomerulonephritis</span> Medical condition

Membranous glomerulonephritis (MGN) is a slowly progressive disease of the kidney affecting mostly people between ages of 30 and 50 years, usually white people.

<span class="mw-page-title-main">Nephritic syndrome</span> Medical condition

Nephritic syndrome is a syndrome comprising signs of nephritis, which is kidney disease involving inflammation. It often occurs in the glomerulus, where it is called glomerulonephritis. Glomerulonephritis is characterized by inflammation and thinning of the glomerular basement membrane and the occurrence of small pores in the podocytes of the glomerulus. These pores become large enough to permit both proteins and red blood cells to pass into the urine. By contrast, nephrotic syndrome is characterized by proteinuria and a constellation of other symptoms that specifically do not include hematuria. Nephritic syndrome, like nephrotic syndrome, may involve low level of albumin in the blood due to the protein albumin moving from the blood to the urine.

Thin basement membrane disease is, along with IgA nephropathy, the most common cause of hematuria without other symptoms. The only abnormal finding in this disease is a thinning of the basement membrane of the glomeruli in the kidneys. Its importance lies in the fact that it has a benign prognosis, with patients maintaining a normal kidney function throughout their lives.

<span class="mw-page-title-main">Interstitial nephritis</span> Medical condition

Interstitial nephritis, also known as tubulointerstitial nephritis, is inflammation of the area of the kidney known as the renal interstitium, which consists of a collection of cells, extracellular matrix, and fluid surrounding the renal tubules. It is also known as intestinal nephritis because the clinical picture may include mesenteric lymphadenitis in some cases of acute pyelonephritis. More specifically, in case of recurrent urinary tract infection, secondary infection can spread to adjacent intestine. In addition to providing a scaffolding support for the tubular architecture, the interstitium has been shown to participate in the fluid and electrolyte exchange as well as endocrine functions of the kidney.

<span class="mw-page-title-main">Branchio-oto-renal syndrome</span> Medical condition

Branchio-oto-renal syndrome (BOR) is an autosomal dominant genetic disorder involving the kidneys, ears, and neck. It is also known as Melnick-Fraser syndrome.

Congenital nephrotic syndrome is a rare kidney disease which manifests in infants during the first 3 months of life, and is characterized by high levels of protein in the urine (proteinuria), low levels of protein in the blood, and swelling. This disease is primarily caused by genetic mutations which result in damage to components of the glomerular filtration barrier and allow for leakage of plasma proteins into the urinary space.

<span class="mw-page-title-main">Glomerular basement membrane</span>

The glomerular basement membrane of the kidney is the basal lamina layer of the glomerulus. The glomerular endothelial cells, the glomerular basement membrane, and the filtration slits between the podocytes perform the filtration function of the glomerulus, separating the blood in the capillaries from the filtrate that forms in Bowman's capsule. The glomerular basement membrane is a fusion of the endothelial cell and podocyte basal laminas, and is the main site of restriction of water flow. Glomerular basement membrane is secreted and maintained by podocyte cells.

Collagen IV is a type of collagen found primarily in the basal lamina. The collagen IV C4 domain at the C-terminus is not removed in post-translational processing, and the fibers link head-to-head, rather than in parallel. Also, collagen IV lacks the regular glycine in every third residue necessary for the tight, collagen helix. This makes the overall arrangement more sloppy with kinks. These two features cause the collagen to form in a sheet, the form of the basal lamina. Collagen IV is the more common usage, as opposed to the older terminology of "type-IV collagen". Collagen IV exists in all metazoan phyla, to whom they served as an evolutionary stepping stone to multicellularity.

<span class="mw-page-title-main">Rapidly progressive glomerulonephritis</span> Medical condition

Rapidly progressive glomerulonephritis (RPGN) is a syndrome of the kidney that is characterized by a rapid loss of kidney function, with glomerular crescent formation seen in at least 50% or 75% of glomeruli seen on kidney biopsies. If left untreated, it rapidly progresses into acute kidney failure and death within months. In 50% of cases, RPGN is associated with an underlying disease such as Goodpasture syndrome, systemic lupus erythematosus or granulomatosis with polyangiitis; the remaining cases are idiopathic. Regardless of the underlying cause, RPGN involves severe injury to the kidneys' glomeruli, with many of the glomeruli containing characteristic glomerular crescents.

<span class="mw-page-title-main">Nephrocalcinosis</span> Medical condition caused by the deposition of calcium salts in the kidneys

Nephrocalcinosis, once known as Albright's calcinosis after Fuller Albright, is a term originally used to describe the deposition of poorly soluble calcium salts in the renal parenchyma due to hyperparathyroidism. The term nephrocalcinosis is used to describe the deposition of both calcium oxalate and calcium phosphate. It may cause acute kidney injury. It is now more commonly used to describe diffuse, fine, renal parenchymal calcification in radiology. It is caused by multiple different conditions and is determined by progressive kidney dysfunction. These outlines eventually come together to form a dense mass. During its early stages, nephrocalcinosis is visible on x-ray, and appears as a fine granular mottling over the renal outlines. It is most commonly seen as an incidental finding with medullary sponge kidney on an abdominal x-ray. It may be severe enough to cause renal tubular acidosis or even end stage kidney disease, due to disruption of the kidney tissue by the deposited calcium salts.

<span class="mw-page-title-main">Collagen, type IV, alpha 5</span> Protein-coding gene in humans

Collagen alpha-5(IV) chain is a protein that in humans is encoded by the COL4A5 gene.

<span class="mw-page-title-main">Collagen, type IV, alpha 4</span> Protein found in humans

Collagen alpha-4(IV) chain is a protein that in humans is encoded by the COL4A4 gene.

<span class="mw-page-title-main">Mesangial proliferative glomerulonephritis</span> Medical condition

Mesangial proliferative glomerulonephritis (MesPGN) is a morphological pattern characterized by a numerical increase in mesangial cells and expansion of the extracellular matrix within the mesangium of the glomerulus. The increase in the number of mesangial cells can be diffuse or local and immunoglobulin and/or complement deposition can also occur. MesPGN is associated with a variety of disease processes affecting the glomerulus, though can be idiopathic. The clinical presentation of MesPGN usually consists of hematuria or nephrotic syndrome. Treatment is often consistent with the histologic pattern of and/or disease process contributing to mesangial proliferative glomerulonephritis, and usually involves some form of immunosuppressant.

Diffuse proliferative glomerulonephritis (DPGN) is a type of glomerulonephritis that is the most serious form of renal lesions in SLE and is also the most common, occurring in 35% to 60% of patients. In absence of SLE, DPGN pathology looks more like Membranoproliferative glomerulonephritis

<span class="mw-page-title-main">Samoyed hereditary glomerulopathy</span>

Samoyed hereditary glomerulopathy (SHG) is a hereditary, X-linked, noninflammatory disease of the renal glomeruli, occurring in the Samoyed breed of dog. The disease has been shown to be a model for Alport syndrome in humans in that the disease resembles that of the human disease. Because of this, it is sometimes referred to by the name given to the disease in humans when referring to the conditions in Samoyed dogs. Alternatively, it may also be known as X-linked hereditary nephritis. Genetically, the trait is inherited as a sex-linked, genetically dominant disease, and thus affects male dogs to a greater degree than female dogs, since males only have one X chromosome.

<span class="mw-page-title-main">Epstein syndrome</span> Medical condition

Epstein syndrome is a rare genetic disease characterized by a mutation in the MYH9 gene in nonmuscle myosin. This disease affects the patient's renal system and can result in kidney failure. Epstein syndrome was first discovered in 1972 when two families had similar symptoms to Alport syndrome. Epstein syndrome and other Alport-like disorders were seen to be caused by mutations in the MYH9 gene, however, Epstein syndrome differs as it was more specifically linked to a mutation on the R702 codon on the MYH9 gene. Diseases with mutations on the MYH9 gene also include May–Hegglin anomaly, Sebastian syndrome and Fechtner syndrome.

References

  1. ↑ "Diseases of the Kidney: Alport Syndrome". Archived from the original on 2004-06-12. Retrieved 2004-06-16.
  2. 1 2 "What is Alport syndrome?". Alport syndrome. Archived from the original on 2019-01-06. Retrieved 2019-01-06.
  3. ↑ "Alport syndrome" at Dorland's Medical Dictionary
  4. 1 2 "Alport Syndrome". National Kidney Foundation. 2015-12-24. Retrieved 2022-08-01.
  5. ↑ Lagona E, Tsartsali L, Kostaridou S, Skiathitou A, Georgaki E, Sotsiou F (April 2008). "Skin biopsy for the diagnosis of Alport syndrome". Hippokratia. 12 (2): 116–8. PMC   2464308 . PMID   18923659.
  6. ↑ Alport AC (March 1927). "Hereditary familial congenital haemorrhagic nephritis". British Medical Journal. 1 (3454): 504–6. doi:10.1136/bmj.1.3454.504. JSTOR   25322864. PMC   2454341 . PMID   20773074.
  7. ↑ Zaunbrecher, Nicole. "Types of Alport Syndrome". Alport Syndrome News. Retrieved 2022-08-01.
  8. 1 2 3 UK Alport Group (2013-07-25). "Alport SyndromeL Clinician information". RareRenal. Renal Rare Diseases Registry. Retrieved 17 February 2016.
  9. 1 2 "Alport syndrome". MedlinePlus. Retrieved 28 June 2021.
  10. ↑ Zhou J, Hertz JM, Tryggvason K (June 1992). "Mutation in the alpha 5(IV) collagen chain in juvenile-onset Alport syndrome without hearing loss or ocular lesions: detection by denaturing gradient gel electrophoresis of a PCR product". American Journal of Human Genetics. 50 (6): 1291–300. PMC   1682577 . PMID   1598909.
  11. ↑ Watson S, Padala SA, Bush JS (28 May 2020). "Alport Syndrome". StatPearls. PMID   29262041 . Retrieved 30 May 2020.{{cite journal}}: Cite journal requires |journal= (help)
  12. ↑ Chugh KS, Sakhuja V, Agarwal A, Jha V, Joshi K, Datta BN, et al. (1993). "Hereditary nephritis (Alport's syndrome)--clinical profile and inheritance in 28 kindreds". Nephrology, Dialysis, Transplantation. 8 (8): 690–5. doi:10.1093/ndt/8.8.690. PMID   8414153.
  13. ↑ Hess K, Pfau M, Wintergerst MW, Loeffler KU, Holz FG, Herrmann P (February 2020). "Phenotypic Spectrum of the Foveal Configuration and Foveal Avascular Zone in Patients With Alport Syndrome". Invest Ophthalmol Vis Sci. 61 (2): 5. doi:10.1167/iovs.61.2.5. PMC   7324255 . PMID   32031577.
  14. ↑ Columbia University, Department of Ophthalmology. Link https://www.columbiaeye.org/content/retinitis-pigmentosa
  15. ↑ Alport Syndrome~clinical at eMedicine
  16. ↑ Kashtan CE (February 2019). "Alport Syndrome". In Adam MP, Ardinger HH, Pagon RA, et al. (eds.). Gene Reviews. Seattle (WA): University of Washington, Seattle. PMID   20301386.
  17. 1 2 Nozu K, Nakanishi K, Abe Y, Udagawa T, Okada S, Okamoto T, et al. (February 2019). "A review of clinical characteristics and genetic backgrounds in Alport syndrome". Clinical and Experimental Nephrology. 23 (2): 158–168. doi:10.1007/s10157-018-1629-4. PMC   6510800 . PMID   30128941.
  18. ↑ "Alport Syndrome". The Lecturio Medical Concept Library. Retrieved 28 June 2021.
  19. ↑ Jais JP, Knebelmann B, Giatras I, De Marchi M, Rizzoni G, Renieri A, et al. (October 2003). "X-linked Alport syndrome: natural history and genotype-phenotype correlations in girls and women belonging to 195 families: a "European Community Alport Syndrome Concerted Action" study". Journal of the American Society of Nephrology. 14 (10): 2603–10. doi: 10.1097/01.ASN.0000090034.71205.74 . PMID   14514738.
  20. ↑ "Alport Syndrome, Autosomal Dominant". Online Mendelian Inheritance in Man (OMIM). Johns Hopkins University. Retrieved 2008-11-24.
  21. ↑ Kharrat M, Makni S, Makni K, Kammoun K, Charfeddine K, Azaeiz H, et al. (September 2006). "Autosomal dominant Alport's syndrome: study of a large Tunisian family". Saudi Journal of Kidney Diseases and Transplantation. 17 (3): 320–5. PMID   16970251.
  22. ↑ Pescucci C, Mari F, Longo I, Vogiatzi P, Caselli R, Scala E, et al. (May 2004). "Autosomal-dominant Alport syndrome: natural history of a disease due to COL4A3 or COL4A4 gene". Kidney International. 65 (5): 1598–603. doi: 10.1111/j.1523-1755.2004.00560.x . PMID   15086897.
  23. ↑ Hertz JM, Thomassen M, Storey H, Flinter F (June 2012). "Clinical utility gene card for: Alport syndrome". European Journal of Human Genetics. 20 (6): 713. doi:10.1038/ejhg.2011.237. PMC   3355248 . PMID   22166944.
  24. ↑ "Alport Syndrome". The Lecturio Medical Concept Library. Retrieved 8 July 2021.
  25. ↑ Zhang KW, Colville D, Tan R, Jones C, Alexander SI, Fletcher J, Savige J (August 2008). "The use of ocular abnormalities to diagnose X-linked Alport syndrome in children". Pediatric Nephrology. 23 (8): 1245–50. doi:10.1007/s00467-008-0759-4. PMID   18343956. S2CID   28650514.
  26. ↑ Alport Syndrome~treatment at eMedicine
  27. ↑ "Alport syndrome". Renal Unit at the Royal Infirmary of Edinburgh, Scotland. Archived from the original on 2010-04-17. Retrieved 2010-03-24.
  28. ↑ "EdRen - Edinburgh Royal Infirmary Renal Unit - Alport anti-GBM disease". www.edren.org. Archived from the original on 2016-02-10. Retrieved 2016-02-17.
  29. ↑ Tryggvason K, Heikkilä P, Pettersson E, Tibell A, Thorner P (May 1997). "Can Alport syndrome be treated by gene therapy?". Kidney International. 51 (5): 1493–9. doi: 10.1038/ki.1997.205 . PMID   9150464.
  30. ↑ "Alport Syndrome". The Lecturio Medical Concept Library. Retrieved 28 June 2021.
  31. ↑ Temme J, Kramer A, Jager KJ, Lange K, Peters F, Müller GA, et al. (December 2012). "Outcomes of male patients with Alport syndrome undergoing renal replacement therapy". Clinical Journal of the American Society of Nephrology. 7 (12): 1969–76. doi:10.2215/CJN.02190312. PMC   3513741 . PMID   22997344.
  32. ↑ Chen D, Jefferson B, Harvey SJ, Zheng K, Gartley CJ, Jacobs RM, Thorner PS (March 2003). "Cyclosporine a slows the progressive renal disease of alport syndrome (X-linked hereditary nephritis): results from a canine model". Journal of the American Society of Nephrology. 14 (3): 690–8. doi: 10.1097/01.ASN.0000046964.15831.16 . PMID   12595505.

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