Mechanism of Injury in Uromodulin-Associated Kidney Disease
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Editorial Mechanism of Injury in Uromodulin-Associated Kidney Disease Satish Kumar Division of Nephrology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma J Am Soc Nephrol 18: 10–12, 2007. doi: 10.1681/ASN.2006111234 ephronophthisis (NPHP), medullary cystic kidney Since then, several additional families have been described. Its disease (MCKD), and familial juvenile hyperurice- clinical and histologic features are similar to those of MCKD N mic nephropathy (FJHN) are three renal disorders type 2. In most but not all families with FJHN, genetic studies with overlapping clinical features. Recent molecular genetic have revealed mutations in the UMOD gene. Patients with studies have begun to clarify the similarities and differences FJHN who do not have UMOD mutations still show decreased between these conditions. Moreover, the pathogenetic mecha- THP excretion in urine, which suggests involvement of a pro- nisms of renal damage in these conditions are being clarified. In tein involved in THP processing (19). A consensus is emerging this issue of JASN, Jennings et al. (1) present one such study. in the literature that FJHN and MCKD type 2 are the same A syndrome first described in 1945 (2) was named NPHP by disease (20,21). Fanconi et al. in 1951 (3). Characteristic findings include renal THP is urine’s most abundant protein (12–15). It is synthe- tubular atrophy, interstitial fibrosis, corticomedullary cysts, sized exclusively and abundantly in the thick ascending limb of and progressive renal failure (4). Gout is not a known feature. the loop of Henle. Its biologic function remains somewhat NPHP, unlike MCKD and FJHN, is inherited as an autosomal unclear more than a century after its first description in 1895 recessive trait. Four major subtypes have been recognized. (22). THP contains the most varied array of glycans of any NPHP types 1, 2, 3, and 4 are caused by gene mutations for the human glycoprotein, which suggests a capacity for adhesion to proteins nephrocystin (chromosome 2), inversin (chromosome a variety of ligands (23). Indeed, THP has been shown to bind 9), NPHP 3 (chromosome 3), and nephroretinin (chromosome cells, crystals, ions, immunoglobulins, myeloma proteins, and 1), respectively. Renal failure in NPHP types 1, 2, 3, and 4 cytokines (24). UMOD gene knockout mice show difficulty in develops at mean ages of 13, 1, 19, and 11 to 34 yr. Pathogenetic clearing bacteria from the urinary bladder (25,26) and have a mechanisms involved in progression of NPHP are incompletely tendency to form calcium oxalate stones under experimental understood. Protein products of all four NPHP genes, which hyperoxaluria (27). It has been hypothesized that THP may are located on the renal tubular cilia, interact with each other serve a physiologic role in the binding and excretion of a and with other signaling molecules (5). variety of potentially injurious products from the tubular fluid MCKD is an autosomal dominant hereditary condition that (24). leads to progressive renal failure. First described by Thorn et al. THP gene knockout mice, however, do not develop hyper- as “salt losing nephritis” (6), MCKD is characterized by renal uricemia (28) or histologic changes attributed to FJHN/MCKD fibrosis and progressive renal failure reaching end-stage renal (29). Patients with FJHN/MCKD have not been reported to disease (ESRD) in adulthood (age range, 30 to 60 yr). Hyper- exhibit increased tendency for urinary tract infections (30). It uricemia and gout are frequently present. Renal histology is appears that total absence of THP increases susceptibility to similar to that in NPHP. Genetic studies have identified two urinary tract infections, whereas mutant THP causes FJHN/ variants of MCKD. Clinical features of MCKD type 1 and MCKD. MCKD type 2 are very similar except a slightly earlier progres- Investigators have begun to address how the mutant THP sion to ESRD in MCKD type 2 (7,8). The gene for MCKD type may lead to the changes of FJHN/MCKD. Renal histology from 1 has not been isolated but has been localized to chromosome patients with FJHN shows patchy aggregation of THP in renal 1q21 (9). MCKD type 2 is associated with mutations in the gene tubules (31,32). Electron microscopic examination shows accu- for Tamm-Horsfall protein (THP) (10,11). THP is also known as mulation of THP in the endoplasmic reticulum of these kidneys uromodulin (12–15). The gene for THP/uromodulin, known as (19). Several studies have demonstrated reduced levels of THP UMOD, is located on chromosome 16p12 (16,17). in the urine of patients with FJHN/MCKD (19,31,33). FJHN was first described by Duncan and Dixon in 1960 (18). In the study by Jennings et al. reported in this issue of JASN (1), the authors report that urinary THP levels were reduced in Published online ahead of print. Publication date available at www.jasn.org. 5 patients with FJHN and serum THP levels were increased in 3 out of 4 patients. The authors also expressed wild-type and Address correspondence to: Dr. Satish Kumar, University of Oklahoma Health Science Center, 920 S.L.Young Blvd, WP2250, Oklahoma City, OK 73104. Phone: mutant UMOD cDNA constructs in polarized monolayers of 405-650-1871; Fax: 405-271-6496; E-mail: [email protected] cultured kidney cell and found that both wild-type and mutant Copyright © 2007 by the American Society of Nephrology ISSN: 1046-6673/1801-0010 J Am Soc Nephrol 18: 10–12, 2007 Uromodulin-Associated Kidney Disease 11 UMOD proteins were secreted more on the apical than the 11. Turner JJ, Stacey JM, Harding B, Kotanko P, Lhotta K, Puig basolateral side of the monolayers. The apical secretion of the JG, Roberts I, Torres RJ, Thakker RV: Uromodulin muta- mutant UMOD was reduced, whereas the basal secretion was tions cause familial juvenile hyperuricemic nephropathy. unaffected. The authors suggest that the mutant THP in kid- J Clin Endocrinol Metab 88: 1398–1401, 2003 neys of patients with FJHN might elicit an immune response to 12. Tamm I, Horsfall FL Jr: A mucoprotein derived from hu- THP, which results in tubular injury and interstitial fibrosis. It man urine which reacts with influenza, mumps, and New- castle disease viruses. J Exp Med 95: 71–97, 1952 is therefore interesting that in vitro studies have demonstrated 13. Muchmore AV, Decker JM: Uromodulin: An immunosup- the capacity of THP to activate lymphocytes (34), neutrophils pressive 85-kilodalton glycoprotein isolated from human (35), and antigen-presenting dendritic cells (36). Intravenous pregnancy urine is a high affinity ligand for recombinant injection of THP has been shown to cause tubulointerstitial interleukin 1 alpha. J Biol Chem 261: 13404–13407, 1986 nephritis in experimental animals (37,38), and human renal 14. Kumar S: Are Tamm-Horsfall protein and uromodulin biopsy studies have shown interstitial deposits of THP in tu- identical? Eur J Clin Invest 28: 483–484, 1998 bulointerstitial diseases (39). 15. Serafini-Cessi F, Malagolini N, Cavallone D: Tamm-Hors- Future studies should not only define the pathogenesis of the fall glycoprotein: Biology and clinical relevance. Am J Kid- uncommon but important condition of FJHN, but should also ney Dis 42: 658–676, 2003 illuminate a new paradigm of renal injury that may apply to 16. Pook MA, Jeremiah S, Scheinman SJ, Povey S, Thakker RV: other diseases as well. Localization of the Tamm-Horsfall glycoprotein (uro- modulin) gene to chromosome 16p12.3–16p13.11. Ann Hum Genet 57: 285–290, 1993 Disclosures 17. 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