ARRA IMPACT REPORT:
Chronic Kidney Disease – Genetics
Public Health Burden
The number of Americans with chronic kidney disease (CKD)—that is, some degree of impaired kidney function—has been estimated to be more than 23 million.1 The prevalence of CKD is increasing in the population—from 10 percent between 1988 and 1994 to 13 percent between 1999 and 2004—due largely to increasing rates of diabetes and hypertension, both of which are likely to be a consequence of obesity.2
Advancing Insight into the Genetic Causes of CKD
New gene identification will make possible 1) screening and early detection of CKD; 2) the generation of novel molecular targets of CDK; and 3) further development of disease models in which to study disease process and potential therapeutics. ARRA-funded research has identified several new genetic mutations of CKD, described below:
Immunoglobulin A (IgA) Nephropathy: For the first time, researchers have found five regions in the human genome that increase susceptibility to immunoglobulin A (IgA) nephropathy, a major cause of kidney failure worldwide – systematically identifying those that point to a tendency for IgA nephropathy, or a protection against it.3 IgA nephropathy occurs when IgA, a protein that helps the body fight infections, settles in the kidneys. After many years, the IgA deposits may cause the kidneys to leak blood and sometimes protein in the urine.
Focal Segmental Glomerulosclerosis (FSGS): An international group of researchers has identified two novel myosin 1E (MYO1E) gene mutations in patients with childhood-onset, steroid-resistant focal segmental glomerulosclerosis (FSGS).8 FSGS is one of the leading causes of kidney failure. It is most often diagnosed in children and young adults. The disease is characterized by scarring in scattered regions of the kidney. Kidney damage resulting from this disease can allow protein in the blood to leak into the urine, a condition termed proteinuria. Initial treatment of FSGS generally involves corticosteroids, a class of hormones that reduces inflammation. This therapy results in reversal of proteinuria in approximately one-fourth of patients. For the majority of patients, whose FSGS does not respond to this treatment, there is no agreed-upon next step.
Congenital Nephrotic Syndrome: An international group of investigators has identified nineteen novel nephrosis 1 gene mutations in patients with congenital nephrotic syndrome.4 Nephrotic syndrome is a condition in which damage to the filtering units of the kidneys, called glomeruli, causes large amounts of protein to leak from the blood into the urine. Over time, this condition may lead to kidney failure and the need for dialysis or kidney transplantation.
Researchers have identified a novel mutation in the heparanase 2 gene in a child with Ochoa syndrome, a disorder that causes urinary problems and unusual facial expressions.5 The urinary problems arise when urine does not travel in the correct direction from kidney to bladder; but rather flows back from the bladder to the kidney. This “reflux” may lead to scarring of the kidney, which is associated with high blood pressure and kidney failure.
Nephrotic Syndrome: An international group of investigators has identified 6 different novel coenzyme Q10 biosynthesis monooxygenase 6 (COQ6) gene mutations in 13 individuals with nephrotic syndrome.6 In addition, each of the human COQ6 mutations was linked to sensorineural deafness. In rats, the COQ6 protein was found to be present in kidney cells called podocytes as well as in cells of the inner ear.
Genetic Insight into Proteinuria: A novel small deletion of the cubilin (CUBN) gene has been identified as the cause of a type of kidney damage which allows protein in the blood to leak into the urine (proteinuria).7 Cubilin normally functions to reabsorb protein in the proximal tubule of the kidney. This cubulin mutation is a single-gene cause of proteinuria in a subset of patients with nephrotic syndrome.
Nephronophthisis: Researchers have identified mutations of MRE11, ZNF423, and CEP164 genes in a rare but devastating form of kidney disease called nephronophthisis-related ciliopathies (NPHP-RC).9 All three genes encode proteins that participate in the DNA damage response pathway which directs activation of DNA repair networks. NPHP-RC are genetic cystic disorders that manifest in the kidney, eye, brain, and liver and lead to tissue degeneration. Collectively, nephronophthisis is the most common genetic cause of end-stage renal failure in people under age 30.
Contributing NIH Institutes & Centers
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)