Renal genetics in transition

Abstract

In chronic kidney disease (CKD) the kidneys lose their ability to filter, reabsorb and secrete water, electrolytes and other small molecules from the blood into the urine, and keep larger molecules such as proteins in. 1 The prevalence of CKD is estimated to be 10-13%, and continually increasing. [2][3][4] Disease burden is high in CKD, as it is associated with increased risks of cardiovascular morbidity, premature mortality and decreased quality of life. [2][3][4] CKD is defined by decreased glomerular filtration rate (GFR) or the amount of protein lost in the urine (proteinuria), for at least 3 months. [5][6][7][8] GFR and degree of proteinuria are also used to determine the severity of renal disease, from mild disease in stage 1 to end-stage renal disease (ESRD) in stage 5. 5,[9][10][11] In ESRD the kidneys are failing, requiring renal replacement therapy in the form of dialysis or a renal transplant. 5,[9][10][11] Underlying causes of CKDThe criteria to stage CKD are based on laboratory findings, and do not depend on nor characterize the underlying cause for the renal disease. [5][6][7][8] Nevertheless, identifying the underlying cause is essential, because it gives information regarding the prognosis and can influence treatment decisions (addressed in detail below).To identify the underlying cause, the tools routinely used are blood and urine investigations, renal ultrasounds or computed tomography, and invasive renal biopsies. [5][6][7][8][12][13][14] However, accurately determining the underlying cause in a specific patient can prove difficult. This is because CKD can be caused by many different disorders that often have indistinguishable clinical features. The type of diseases that cause CKD range from highly prevalent diseases such as diabetes and hypertension, to less prevalent conditions like IgA nephropathy and finally to very rare disorders, for example Fabry disease. 1,15,16 Monogenic renal diseasesInterestingly, the very rare causes of CKD are often monogenic kidney diseases (MGKD). MGKD are the result of mutations in genes encoding proteins essential for renal structure or function. 17 Also called Mendelian diseases, after their discoverer Gregor Mendel (1822-1884), monogenic diseases are caused by defects in a single gene. 18,19 The defect can be in one autosomal allele (autosomal dominant disease), two autosomal alleles (autosomal recessive disease), or it can be in a gene on the X or Y chromosome (sex linked disease). 18,19 12 Chapter 1 Figure 1.1 | The process of gene panel testing for renal disease: gene panel design with the use of next-generation sequencing techniques, variant calling, and interpretation, as well as the infl uence of phenotyping and segregation analysis in variant interpretation and translating the result back to the individual patient.Defi nite calling of pathogenicity is impossible however, if a variant is detected in a gene that has not previously been associated with the patient's phenotype. 19,39 In those cases, in vitro or in vivo functional studies can be performed...