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

Fibrosis caused by chronic inflammation progressively damages nephrons. Eventually, this process becomes irreversible and kidney function declines as nephron mass is lost.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

The current standard of care addresses renal hemodynamics and reducing proteinuria, but not the underlying chronic inflammation that drives disease progression.2

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.

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Behind the Mystery:
Progression

Watch this video to learn how the progression of Alport syndrome varies from patient to patient and how the condition can be monitored.

Highlight Alport syndrome by recognizing the following signs:

  • Persistent Hematuria
  • Underlying Inflammation
  • Reduced GFR
  • Family History of CKD or Alport Syndrome
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Alport Syndrome

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Genetic testing for Alport syndrome and several other rare forms of chronic kidney disease is more accessible than ever before. Find out the eligibility requirements for no-charge genetic testing through KIDNEYCODE.

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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.
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