Genetic Renal Disease Easily Missed
Anthony J. Bleyer, MD, MS
Autosomal dominant interstitial kidney disease, which can lead to renal failure, is tricky to diagnose.
Autosomal dominant interstitial kidney disease is an under-recognized cause of kidney failure. Characterized by a very strong family history of kidney disease, it is a slowly progressive condition that leads to dialysis when patients are in their 40s or older. Mild renal insufficiency usually first appears in the late teenage years through the third decade of life. Patients have a bland urinary sediment, and renal ultrasound is frequently unremarkable.
Most nephrologists know little about autosomal dominant interstitial kidney disease because of its relative rarity and mundane clinical features. The absence of any systemic manifestations besides gout, the presence of a bland urinary sediment, and the absence of distinctive changes on renal ultrasound provide no pathognomonic clues that would alert the physician to the presence of the disease.
In addition, when kidney biopsies are performed, pathologists usually focus on secondary glomerular changes, and patients typically are diagnosed with some form of focal sclerosis or nephrosclerosis. Autoso-mal dominant interstitial kidney disease is one of the few kidney diseases for which renal biopsy is unable to clinch a diagnosis and may actually provide misleading results.
Medical terminology also contributes to diagnostic confusion: There is no generally accepted term for the various forms of the condition. It has previously been referred to as familial juvenile hyperuricemia as well as medullary cystic kidney disease. The latter actually is a misnomer. Medullary cysts may be seen on pathologic examination at autopsy of individuals who have end-stage renal disease, but they frequently are not present on routine renal ultrasound in individuals with autosomal dominant interstitial kidney disease.
There are at least two types of autosomal dominant interstitial kidney disease. Type 1 has been linked to Chromosome 1, but the genetic cause has not been identified. Gout develops with worsening kidney disease in some patients. Gout is less prevalent in type 1 disease than in type 2. Type 2 disease is linked to a mutation in the gene that produces the Tamm-Horsfall protein (also known as uromodulin). The mutated Tamm-Horsfall protein collects in the thick ascending limb, leading to premature tubular cell death.
Over time, tubular degradation and interstitial fibrosis lead to renal failure. The absence of Tamm-Horsfall protein results in a defect in urinary concentration in the thick ascending limb. This is compensated for by increased proximal tubular uptake of uric acid, resulting in hyperuricemia. Gout presents in the teenage years in boys and in the early 20s in women.
Autosomal dominant interstitial kidney disease has a mundane presentation, leading to difficulties in its identification. Cardinal features include slowly progressive CKD of unknown cause and the development of gout in many, but not all, cases. Urinary sediment is benign with minimal proteinuria and absence of hematuria. Renal ultrasound examinations usually are unremarkable. At disease onset, the kidneys are of normal size, but as patients age, the organs become contracted. Renal cysts occasionally may be observed.
In families with the disease, it typically afflicts one parent and approximately half of all siblings and half of all children of affected individuals. Screening for mutations in the uromodulin gene can be performed through Athena Diagnostics in Worcester, Mass. If no mutations in the uromodulin gene are present, families should be referred for genetic linkage studies to help identify the cause of their disease.
Identification is beneficial because it satisfies the wish to understand why this condition has occurred. Second, if families have a mutation in the Tamm-Horsfall protein gene, screening can be performed on potential kidney donors. In type 2 disease, allopurinol may be effective in preventing gout and possibly may slow disease progression. My colleagues and I are interested in conducting clinical studies of families with either type of autosomal dominant interstitial kidney disease and invite
physicians to refer such families to us. Physicians or affected family members may contact me at
Dr. Bleyer is professor of medicine in the section of nephrology at Wake Forest University School of Medicine in Winston-Salem, N.C.