Hints to the diagnosis of uromodulin kidney disease

Abstract

BackgroundUromodulin kidney disease (UKD) is an inherited kidney disease caused by a uromodulin (UMOD) gene mutation. The UMOD gene encodes the Tamm–Horsfall protein (THP), which is the most abundant protein in healthy human urine. Because of its rarity, the incidence of UKD has not been fully elucidated. The purpose of the present study is to clarify the frequency of UKD among patients who underwent renal biopsy.MethodsImmunostaining for THP was performed for patients <50 years of age with renal insufficiency and hyperuricemia without overt urinalysis abnormality from renal biopsy databases. Serum and urinary THP concentrations were evaluated in available individuals.ResultsFifteen patients were selected for immunostaining from a total of 3787 patients. In three independent patients, abnormal THP accumulation in renal tubular cells was observed. A novel missense A247P UMOD mutation was detected in two of the three patients, including one having a typical family history of familial juvenile hyperuricemic nephropathy. Serum and urinary THP concentrations of all available patients with UMOD A247P mutation were significantly lower than those of controls.ConclusionsIn the present study, UKD was detected in <1 in 1000 subjects who underwent renal biopsies. However, in subjects meeting all of the above criteria, abnormal THP accumulation was detected in 20% (3/15), suggesting that renal biopsy with immunostaining for THP is a good tool for diagnosing UKD. Also, low serum THP concentration detected in the present subjects might be a good diagnostic marker or important in understanding the pathogenesis of UKD.

UMOD Geneassociated Renal Failure Patients have Unusual minerals and Nitrogenous Wastes Levels after hemodialysis

“…Uromodulin is essential protein encoded by UMOD gene and produced in the kidney and contribute to colloid osmotic pressure, retards passage of positively charged electrolytes, prevents urinary tract infection and modulates formation of supersaturated salts and their crystals. 16,17 In the present study we identified 9 patients (5 were relatives) with AMOD gene mutation and our prior hypothesis, patients with UMOD gene mutation have more deterioration effects than others. These worsening effects may lead to hemodialysis impaired control of nitrogenous wastes and minerals.…”

“…UMOD gene mutation also associates with serum urea (P=1.0x10(-6)), uric acid (P=0.0064). 17,18 Although, several studies have suggested that the level of uromodulin in the urine could represent a valuable biomarker for the development of CKD, 19 but we suggest the use of the levels of nitrogenous products during dialysis as indicators of UMOD gene mutation. Such patients with constant biomarkers elevation can be further submitted to gene analysis.…”

Significance of kidney biopsy in autosomal dominant tubulointerstitial kidney disease-UMOD: is kidney biopsy truly nonspecific?

“…Case #3 was one of 15 patients with renal insufficiency, hyperuricemia and normal urine tests without glomerular abnormalities under 50 years old extracted from the 3787 patients. Abnormal UMOD accumulation was detected in the kidney of case #3, and subsequently UMOD mutation was detected [13]. Another patient without a family history (case #9) was suspected to have ADTKD from the clinical history and kidney pathological findings which prompted genetic testing.…”

Tamm–Horsfall Protein is a Potent Immunomodulatory Molecule and a Disease Biomarker in the Urinary System

“…Investigations have demonstrated decreased urinary THP excretion in endemic nephropathy [ 81 , 82 ], diabetic nephropathy [ 54 , 56 , 70 ], and lupus nephritis [ 53 ]. The decreased urinary THP production is not only a useful biomarker of renal tubular damage [ 56 , 57 , 58 ] but also an indicator of decreased clearance of systemic and renal proinflammatory cytokines, and it can thus accelerate renal inflammation.…”