Alport is a disease of genetic defects in Type IV collagen that are pro-inflammatory
Variants in the COL4A3/4/5 genes result in faulty production of Type IV collagen, which is essential to the integrity and function of the glomerular basement membrane (GBM). This faulty collagen causes splitting, lamination, and other structural damage to the GBM, and the filtration barrier becomes leaky, allowing proteins to escape the glomerulus.2
A variety of kidney cells, including podocytes on the GBM, respond to this damage by producing cytokines and chemokines to recruit immune cells. Because the kidney is perpetually exposed to the injury of the faulty Type IV collagen, this inflammatory response is chronic. If it is not interrupted, the inflammation can create fibrosis both inside the glomerulus and interstitially.2,3
Not all Type IV collagen defects are the same, but chronic inflammation is the common thread
The affected gene (COL4A3, A4, or A5) and the type of mutation can influence the severity of the Type IV collagen defects that lead to fibrosis and Alport progression.2, 4
But all patients with mutations in these genes–not just young boys–are at risk of Type IV collagen defects and the pathogenic chronic inflammation that they create.5
CKD Pathological States and Targeted Interventions6, 7
CKD Pathological states
Increased Pressure (Hyperfiltration)
- Systemic hypertension
- Efferent constriction
- Afferent dilation
CKD Interventions
Reduced Pressure
- Antihypertensives
- ACEi/ARB – Efferent dilation
- SGLT2i – Afferent constriction
ACEi=angiotensin-converting enzyme inhibitor; ARB=angiotensin II receptor blocker; SLGT2i=sodium-glucose cotransporter-2 inhibitor.
See how advanced genetic testing can help diagnose Alport earlier
Look beneath the surface:
Chronic Inflammation
Watch this video to learn how the progression of Alport syndrome varies from patient to patient and how the condition can be monitored.
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Alport Syndrome
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1. Akchurin O, Kaskel F. Update on inflammation in chronic kidney disease. Blood Purif. 2015;39(1-3):84-92. 2. Warady B, Agarwal R, Bangalore S, et al. Alport syndrome classification and management. Kidney Med. 2020;2(5):639-649. 3. Savige J. Alport syndrome: its effects on the glomerular filtration barrier and implications for future treatment. J Physiol. 2014;592(18):4013-4023. 4. Kamura M, Yamamura T, Omachi K, et al. Trimerization and genotype-phenotype correlation of COL4A5 mutants in Alport syndrome. Kidney Int Rep. 2020;5(5):718-726. 5. Kashtan CE. Alport syndrome: achieving early diagnosis and treatment. Am J Kidney Dis. 2021;77(2):272-279. 6. Tonneijck L, Muskiet MHA, Smits MM, et al. Glomerular hyperfiltration in diabetes: mechanisms, clinical significance, and treatment. J Am Soc Nephrol. 2017;28(4):1023-1039. 7. Premaratne E, Verma S, Ekinci EI, Theverkalam G, Jerums G, MacIsaac RJ. The impact of hyperfiltration on the diabetic kidney. Diabetes Metab. 2015;41(1):5-17.
