Mechanism of Injury in Uromodulin-Associated Kidney Disease
Satish Kumar
Division of Nephrology, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma
Address correspondence to: Dr. Satish Kumar, University of Oklahoma Health Science Center, 920 S.L.Young Blvd, WP2250, Oklahoma City, OK 73104. Phone: 405-650-1871; Fax: 405-271-6496; E-mail: satish-kumar{at}ouhsc.edu
Nephronophthisis (NPHP), medullary cystic kidney disease (MCKD),and familial juvenile hyperuricemic nephropathy (FJHN) are threerenal disorders with overlapping clinical features. Recent moleculargenetic studies have begun to clarify the similarities and differencesbetween these conditions. Moreover, the pathogenetic mechanismsof renal damage in these conditions are being clarified. Inthis issue of JASN, Jennings et al. (1) present one such study.
A syndrome first described in 1945 (2) was named NPHP by Fanconiet al. in 1951 (3). Characteristic findings include renal tubularatrophy, interstitial fibrosis, corticomedullary cysts, andprogressive renal failure (4). Gout is not a known feature.NPHP, unlike MCKD and FJHN, is inherited as an autosomal recessivetrait. Four major subtypes have been recognized. NPHP types1, 2, 3, and 4 are caused by gene mutations for the proteinsnephrocystin (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 meanages of 13, 1, 19, and 11 to 34 yr. Pathogenetic mechanismsinvolved in progression of NPHP are incompletely understood.Protein products of all four NPHP genes, which are located onthe renal tubular cilia, interact with each other and with othersignaling molecules (5).
MCKD is an autosomal dominant hereditary condition that leadsto progressive renal failure. First described by Thorn et al.as "salt losing nephritis" (6), MCKD is characterized by renalfibrosis and progressive renal failure reaching end-stage renaldisease (ESRD) in adulthood (age range, 30 to 60 yr). Hyperuricemiaand gout are frequently present. Renal histology is similarto that in NPHP. Genetic studies have identified two variantsof MCKD. Clinical features of MCKD type 1 and MCKD type 2 arevery similar except a slightly earlier progression to ESRD inMCKD type 2 (7,8). The gene for MCKD type 1 has not been isolatedbut has been localized to chromosome 1q21 (9). MCKD type 2 isassociated 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 chromosome16p12 (16,17).
FJHN was first described by Duncan and Dixon in 1960 (18). Sincethen, several additional families have been described. Its clinicaland histologic features are similar to those of MCKD type 2.In most but not all families with FJHN, genetic studies haverevealed mutations in the UMOD gene. Patients with FJHN whodo not have UMOD mutations still show decreased THP excretionin urine, which suggests involvement of a protein involved inTHP processing (19). A consensus is emerging in the literaturethat FJHN and MCKD type 2 are the same disease (20,21).
THP is urine’s most abundant protein (12–15). Itis synthesized exclusively and abundantly in the thick ascendinglimb of the loop of Henle. Its biologic function remains somewhatunclear more than a century after its first description in 1895(22). THP contains the most varied array of glycans of any humanglycoprotein, which suggests a capacity for adhesion to a varietyof 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 bacteriafrom the urinary bladder (25,26) and have a tendency to formcalcium oxalate stones under experimental hyperoxaluria (27).It has been hypothesized that THP may serve a physiologic rolein the binding and excretion of a variety of potentially injuriousproducts from the tubular fluid (24).
THP gene knockout mice, however, do not develop hyperuricemia(28) or histologic changes attributed to FJHN/MCKD (29). Patientswith FJHN/MCKD have not been reported to exhibit increased tendencyfor urinary tract infections (30). It appears that total absenceof THP increases susceptibility to urinary tract infections,whereas mutant THP causes FJHN/MCKD.
Investigators have begun to address how the mutant THP may leadto the changes of FJHN/MCKD. Renal histology from patients withFJHN shows patchy aggregation of THP in renal tubules (31,32).Electron microscopic examination shows accumulation of THP inthe endoplasmic reticulum of these kidneys (19). Several studieshave demonstrated reduced levels of THP in the urine of patientswith 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 reducedin 5 patients with FJHN and serum THP levels were increasedin 3 out of 4 patients. The authors also expressed wild-typeand mutant UMOD cDNA constructs in polarized monolayers of culturedkidney cell and found that both wild-type and mutant UMOD proteinswere secreted more on the apical than the basolateral side ofthe monolayers. The apical secretion of the mutant UMOD wasreduced, whereas the basal secretion was unaffected. The authorssuggest that the mutant THP in kidneys of patients with FJHNmight elicit an immune response to THP, which results in tubularinjury and interstitial fibrosis. It is therefore interestingthat in vitro studies have demonstrated the capacity of THPto activate lymphocytes (34), neutrophils (35), and antigen-presentingdendritic cells (36). Intravenous injection of THP has beenshown to cause tubulointerstitial nephritis in experimentalanimals (37,38), and human renal biopsy studies have shown interstitialdeposits of THP in tubulointerstitial diseases (39).
Future studies should not only define the pathogenesis of theuncommon but important condition of FJHN, but should also illuminatea new paradigm of renal injury that may apply to other diseasesas well.
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[Abstract][Full Text][PDF]
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