Uromodulin and Chronic Kidney Disease

Uromodulin (Tamm-Horsfall protein) is produced in the kidney by cells of the thick ascending limb and distal tubule. Recent genetic studies suggest a role of uromodulin in chronic kidney disease. Mutations in the UMOD gene cause uromodulin storage disease. They code for amino acid substitutions that lead to misfolding of the molecule and its retention in the endoplasmic reticulum. Single nucleotide polymorphisms in the region of the UMOD gene have been shown to be associated with chronic kidney disease and reduced glomerular filtration rate. These polymorphisms affect uromodulin concentration in the urine, and lower genetically determined urinary uromodulin concentrations seem to protect against renal disease. Chronic kidney disease is associated with higher serum levels of uromodulin. From animal experiments and human studies it is hypothesized that uromodulin entering the renal interstitium either by basolateral secretion or urinary back-leakage in damaged tubuli interacts with and stimulates cells of the immune system and thereby causes inflammation and progression of chronic kidney disease. Copyright © 2010 S. Karger AG, Basel Published online: October 14, 2010 Dr. Karl Lhotta Academic Teaching Hospital Feldkirch Carinagasse 47 AT–6800 Feldkirch (Austria) Tel. +43 5522 303 2700, Fax +43 5522 303 7506, E-Mail karl.lhotta @ lkhf.at © 2010 S. Karger AG, Basel 1420–4096/10/0335–0393$26.00/0 Accessible online at: www.karger.com/kbr D ow nl oa de d by : 54 .7 0. 40 .1 1 11 /2 3/ 20 17 2 :4 3: 49 A M Lhotta Kidney Blood Press Res 2010;33:393–398 394 nome-wide association studies in the general population showed that several significant single nucleotide polymorphisms in the UMOD gene region were associated with chronic kidney disease (CKD) and estimated glomerular filtration rate [11, 12] . Uromodulin Storage Diseases These autosomal dominant diseases clinically present with hyperuricemia and gout with a low renal fractional excretion of uric acid, and progressive renal failure leading to ESRD in adulthood [13] . Renal cysts are a frequent finding and renal histology shows tubular atrophy and interstitial fibrosis with mild inflammatory infiltration. Urinary uromodulin excretion decreases during childhood and reaches very low levels in adulthood [14, 15] . To date, more than 50 UMOD mutations have been identified. They are mainly localized in exons 3 and 4, and most of them are missense mutations or small inframe deletions. Many of them cause an amino acid change at cysteine sites. Cysteine residues form disulfide bonds and determine correct protein folding. Therefore, it is assumed that UMOD mutations causing uromodulin storage disease lead to defective protein folding. Misfolded immature uromodulin is retained in the ER and not expressed at or released by the apical cell membrane. In renal biopsies large, dense intracellular deposits of uromodulin in TAL cells can be visualized by immuno s taining using antiuromodulin antibodies [9] . Electron microscopy of TAL cells shows bundles of hyperplastic ER containing moderately electron-dense storage material [16] . In vitro experiments of various renal epithelial cell lines transfected with mutant UMOD cDNAs indeed showed that mutated uromodulin is retained intracellularly [17–21] . Depending on the extent of maturation, Williams et al. [20] classified mutants into group A with reduced (50%) and group B with almost absent (25%) maturation. Group A mutants were also localized to the cell membrane, whereas group B mutants continued to be completely retained by the ER. There is, however, no correlation between the severity of the maturation defect and the clinical expression of the disease. Accumulation of misfolded proteins in the ER causes ER stress and the unfolded protein response with increased synthesis of chaperones and foldases and activation of ER-associated degradation in order to eliminate the misfolded proteins [22] . When the capacity of the cell to remove these molecules is working to full capacity, the unfolded protein response may trigger apoptosis and autophagy or alternatively lead to cell activation via MAP kinases and NF B. It is highly likely that these pathways eventually result in TAL cell damage and loss with progressive renal failure. We were able to show a significant number of apoptotic tubular epithelial cells in a biopsy of a patient with uromodulin storage disease [23] . In vitro, chaperones such as colchicine and sodium 4-phenylbutyrate increased uromodulin transport to the cell membrane and secretion in transfected cell lines and reduced apoptosis [17] . Therefore, such substances may be good candidates for the treatment of uromodulin storage disease. Jennings et al. [19] reported normal basolateral secretion of mutated uromodulin and increased serum levels in some patients. Higher basolateral secretion of uromodulin may cause an inflammatory response and tubulointerstitial damage (see below). Uromodulin is also located in primary cilia of TAL cells [24] . Studies in renal biopsies of patients and cell culture experiments in transfected cells showed decreased ciliary uromodulin expression in uromodulin storage disease [24] . As hereditary renal cystic diseases are caused by defects in ciliary proteins, this finding may explain the frequent presence of renal cysts in uromodulin storage diseases. Why patients with uromodulin storage disease have a low fractional renal excretion of uric acid and consequent hyperuricemia remains a matter of debate. The common view is that hyperuricemia is a consequence of volume depletion. Scolari et al. [13] hypothesize that due to the lack of uromodulin on the luminal surface of the TAL, water reabsorption is increased. This would lead to a reduction of sodium and chloride reabsorption by the TAL, which is compensated by an increase in proximal tubular uptake, a process that is coupled to urate reabsorption. They also showed that a reduction in urine-concentrating capability was associated with higher uric acid serum levels in these patients. In contrast, Kotanko et al. [25] did not find any signs of volume depletion in their patients, who had normal renin and aldosterone levels. In addition, despite saline infusion they retained their low fractional uric acid excretion. Whatever the cause of hyperuricemia, treatment with uricosuric drugs such as benzbromarone can normalize renal uric acid excretion in these patients [23] .