Mechanism of Injury in Uromodulin-Associated Kidney Disease

Nephronophthisis (NPHP), medullary cystic kidney disease (MCKD), and familial juvenile hyperuricemic nephropathy (FJHN) are three renal disorders with overlapping clinical features. Recent molecular genetic studies have begun to clarify the similarities and differences between these conditions. Moreover, the pathogenetic mechanisms of renal damage in these conditions are being clarified. In this issue of JASN, Jennings et al. (1) present one such study. A syndrome first described in 1945 (2) was named NPHP by Fanconi et al. in 1951 (3). Characteristic findings include renal tubular atrophy, interstitial fibrosis, corticomedullary cysts, and progressive renal failure (4). Gout is not a known feature. NPHP, unlike MCKD and FJHN, is inherited as an autosomal recessive trait. Four major subtypes have been recognized. NPHP types 1, 2, 3, and 4 are caused by gene mutations for the proteins nephrocystin (chromosome 2), inversin (chromosome 9), NPHP 3 (chromosome 3), and nephroretinin (chromosome 1), respectively. Renal failure in NPHP types 1, 2, 3, and 4 develops at mean ages of 13, 1, 19, and 11 to 34 yr. Pathogenetic mechanisms involved in progression of NPHP are incompletely understood. Protein products of all four NPHP genes, which are located on the renal tubular cilia, interact with each other and with other signaling molecules (5). MCKD is an autosomal dominant hereditary condition that leads to progressive renal failure. First described by Thorn et al. as “salt losing nephritis” (6), MCKD is characterized by renal fibrosis and progressive renal failure reaching end-stage renal disease (ESRD) in adulthood (age range, 30 to 60 yr). Hyperuricemia and gout are frequently present. Renal histology is similar to that in NPHP. Genetic studies have identified two variants of MCKD. Clinical features of MCKD type 1 and MCKD type 2 are very similar except a slightly earlier progression to ESRD in MCKD type 2 (7,8). The gene for MCKD type 1 has not been isolated but has been localized to chromosome 1q21 (9). MCKD type 2 is associated with mutations in the gene for Tamm-Horsfall protein (THP) (10,11). THP is also known as uromodulin (12–15). The gene for THP/uromodulin, known as UMOD, is located on chromosome 16p12 (16,17). FJHN was first described by Duncan and Dixon in 1960 (18). Since then, several additional families have been described. Its clinical and histologic features are similar to those of MCKD type 2. In most but not all families with FJHN, genetic studies have revealed mutations in the UMOD gene. Patients with FJHN who do not have UMOD mutations still show decreased THP excretion in urine, which suggests involvement of a protein involved in THP processing (19). A consensus is emerging in the literature that FJHN and MCKD type 2 are the same disease (20,21). THP is urine’s most abundant protein (12–15). It is synthesized exclusively and abundantly in the thick ascending limb of the loop of Henle. Its biologic function remains somewhat unclear more than a century after its first description in 1895 (22). THP contains the most varied array of glycans of any human glycoprotein, which suggests a capacity for adhesion to a variety of ligands (23). Indeed, THP has been shown to bind cells, crystals, ions, immunoglobulins, myeloma proteins, and cytokines (24). UMOD gene knockout mice show difficulty in clearing bacteria from the urinary bladder (25,26) and have a tendency to form calcium oxalate stones under experimental hyperoxaluria (27). It has been hypothesized that THP may serve a physiologic role in the binding and excretion of a variety of potentially injurious products from the tubular fluid (24). THP gene knockout mice, however, do not develop hyperuricemia (28) or histologic changes attributed to FJHN/MCKD (29). Patients with FJHN/MCKD have not been reported to exhibit increased tendency for urinary tract infections (30). It appears that total absence of THP increases susceptibility to urinary tract infections, whereas mutant THP causes FJHN/MCKD. Investigators have begun to address how the mutant THP may lead to the changes of FJHN/MCKD. Renal histology from patients with FJHN shows patchy aggregation of THP in renal tubules (31,32). Electron microscopic examination shows accumulation of THP in the endoplasmic reticulum of these kidneys (19). Several studies have demonstrated reduced levels of THP in the urine of patients with FJHN/MCKD (19,31,33). In the study by Jennings et al. reported in this issue of JASN (1), the authors report that urinary THP levels were reduced in 5 patients with FJHN and serum THP levels were increased in 3 out of 4 patients. The authors also expressed wild-type and mutant UMOD cDNA constructs in polarized monolayers of cultured kidney cell and found that both wild-type and mutant UMOD proteins were secreted more on the apical than the basolateral side of the monolayers. The apical secretion of the mutant UMOD was reduced, whereas the basal secretion was unaffected. The authors suggest that the mutant THP in kidneys of patients with FJHN might elicit an immune response to THP, which results in tubular injury and interstitial fibrosis. It is therefore interesting that in vitro studies have demonstrated the capacity of THP to activate lymphocytes (34), neutrophils (35), and antigen-presenting dendritic cells (36). Intravenous injection of THP has been shown to cause tubulointerstitial nephritis in experimental animals (37,38), and human renal biopsy studies have shown interstitial deposits of THP in tubulointerstitial diseases (39). Future studies should not only define the pathogenesis of the uncommon but important condition of FJHN, but should also illuminate a new paradigm of renal injury that may apply to other diseases as well. Disclosures None.