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What is Nephro Genetics?

Advancements in genetic diagnostic technology have revealed multiple variants in various genes involved in kidney pathophysiology. This has led to a deeper understanding of several renal disorders.

Prevalence Genetic Renal Disorders (GRD)

Studies indicate that renal disorders are not just environmental but also genetic, affecting 5-15% of the total adult population. In fact, 20% of CKD cases are thought to be due to genetic forms of renal disease, as proved by familial clustering and differing prevalence rates across ethnic groups [2].The prevalence of renal diseases in children ranges from 21 to 55 per million age representative population. Countries with high rates of consanguinity and potentially greater risks of autosomal ESRD are reported to have hereditary renal diseases [3].

  1. [1] Gluba-Brzózka A, Franczyk B, Olszewski R, et al. Int J Mol Sci. 2017 Jun 10;18(6).
  2. [2] Mallett A, Patel C, Salisbury A, et al. Orphanet Journal of Rare Diseases. 2014;9:98.
  3. [3] Fletcher, J., McDonald, S., Alexander, S.I. et al. Pediatr Nephrol (2013) 28: 251.
  4. [* ]Hildebrandt F: Genetic kidney diseases. Lancet. 2010, 375 (9722): 1287-1295.

Highly penetrant mutations cause a wide range of renal phenotypes including:

  • Diseases of renal growth (eg: polycystic kidney disease)
  • Diseases of abnormal glomerular function (eg: congenital nephrotic syndrome)
  • Abnormalities of blood pressure and electrolyte homeostasis (eg: Bartter syndrome)

Correct diagnosis of GRD impacts

  • Leads to specific investigations
  • Optimization oftreatment regimens
  • Socioeconomic benefits to individual and family

Defects of the cilial system are closely related to the development of cystic kidney disease at any stage of life. Cystic kidney diseases are also known as renal cystic ciliopathies. Some of these are:

  • Polycystic Kidney Disease (ADPKD/ARPKD)
  • Tubulointerstitial Kidney Disease (ADTKD)
  • Meckel Gruber Syndrome and related disorders
  • Nephronophthisis

Renal tubular function governs reabsorption of water and solutes from the glomerular filtrate. In renal tubulopathies, the primary genetic defect causes loss of function of a specific renal-transport protein or signaling molecule. The following are classified under genetic renal tubular disorders:

  • Bartter syndrome
  • Gitelman syndrome
  • Pseudohypoaldosteronism (Type1/2)
  • Fanconi syndrome
  • dRTA

Examples

(i) Atypical Haemolytic Uraemic Syndrome (aHUS)

Until recently Atypical Hemolytic Uremic Syndrome (aHUS) wasan untreatable disease. Understanding the genetics of aHUS has revealed that most individuals carry mutations in complement genes. that result in the over-activation of the complement system. This resulted in thesuccessful clinical trial of the complement inhibitor Eculizumab. Proven mutations in complement genes predict response to Eculizumab, while mutations in the non-complement gene DGKE, is a marker of non-response in a subgroup of patients.

(ii) The Role of UMOD in Hypertension and Chronic
Kidney Disease

Mutations in UMOD that encodes uromodulin is associated with Medullary Cystic Kidney Disease Type 2, a rare, dominantly inherited cause of CKD. Recent GWAS studies have identified susceptibility variants for chronic kidney disease and hypertension in UMOD. Risk variants in UMOD directly increase UMOD expression, leading to salt-sensitive hypertension, secondary to activation of the renal sodium-potassium-chloride cotransporter NKCC2. Uromodulin may be a novel therapeutic target to control blood pressure and preserve renal function.

Examples

(i) Atypical Haemolytic Uraemic Syndrome (aHUS)

Until recently Atypical Hemolytic Uremic Syndrome (aHUS) wasan untreatable disease. Understanding the genetics of aHUS has revealed that most individuals carry mutations in complement genes. that result in the over-activation of the complement system. This resulted in thesuccessful clinical trial of the complement inhibitor Eculizumab. Proven mutations in complement genes predict response to Eculizumab, while mutations in the non-complement gene DGKE, is a marker of non-response in a subgroup of patients.

(ii) The Role of UMOD in Hypertension and Chronic
Kidney Disease

Mutations in UMOD that encodes uromodulin is associated with Medullary Cystic Kidney Disease Type 2, a rare, dominantly inherited cause of CKD. Recent GWAS studies have identified susceptibility variants for chronic kidney disease and hypertension in UMOD. Risk variants in UMOD directly increase UMOD expression, leading to salt-sensitive hypertension, secondary to activation of the renal sodium-potassium-chloride cotransporter NKCC2. Uromodulin may be a novel therapeutic target to control blood pressure and preserve renal function.

  • encodes uromodulin is associated with
  • encodes uromodulin is associated with
  • encodes uromodulin is associated with
  • Polycystic Kidney Disease Gene panel (ARPKD: PKHD1/ADPKD: PKD1 & PKD2)
  • Meckel Gruber Syndrome gene panel
  • VHL Gene analysis
  • Von Hippel-Lindau Syndrome (VHL) deletion/duplication analysis
  • Joubert Syndrome gene panel
  • Polycystic Kidney Disease Gene panel (ARPKD: PKHD1/ADPKD: PKD1 & PKD2)
  • VHL Gene analysis
  • Joubert Syndrome gene panel
  • Von Hippel-Lindau Syndrome (VHL) deletion/duplication analysis

Common Disorders

Defects of the cilial system are closely related to the development of cystic kidney disease at any stage of life. Cystic kidney diseases are also known as renal cystic ciliopathies. Some of these are:

  • Polycystic Kidney Disease (ADPKD/ARPKD)
  • Tubulointerstitial Kidney Disease (ADTKD)
  • Meckel Gruber Syndrome and related disorders
  • Nephronophthisis

Renal tubular function governs reabsorption of water and solutes from the glomerular filtrate. In renal tubulopathies, the primary genetic defect causes loss of function of a specific renal-transport protein or signaling molecule. The following are classified under genetic renal tubular disorders:

  • Bartter syndrome
  • Gitelman syndrome
  • Pseudohypoaldosteronism (Type1/2)
  • Fanconi syndrome
  • dRTA

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