Familial Juvenile Hyperuricemic Nephropathy Research Articles

Néphropathie hyperuricémique familiale juvénile

Familial juvenile hyperuricemic nephropathy is a rare autosomal dominant disease. It is characterized by abnormal handling of urate responsible for hyperuricaemia often complicated of gouty arthritis. Renal failure is due to tubulointerstitial nephritis. Ultrasonography sometimes finds renal cysts of variable size and number. Renal histology, although not specific, shows interstitial fibrosis, atrophic tubules, sometimes enlarged and with irregular membrane thickening. Renal failure progresses to end stage between 30 and 60 years of age. Allopurinol treatment is recommended at the early stages of the disease, its efficacy on slowing down the progression of the disease is however not proven. There is genetic heterogeneity in familial juvenile hyperuricemic nephropathy. Uromodulin encoding Tamm-Horsfall protein is the only gene to date identified, responsible in less than half of the families. The described mutations most often concern a cystein and are clustering in exon 4. These mutations result in abnormal retention of the protein in endoplasmic reticulum of Henle loop cells and in reduction of its urinary excretion. The pathophysiology of the disease is however still dubious. Indeed, Tamm-Horsfall protein functions are not well known (anti-infectious role, cristallisation inhibition, immunomodulating role). Knock-out mice do not develop renal phenotype but are more prone to E. coli urinary infections. Uromodulin gene mutations have also been described in medullary cystic kidney disease, an autosomal dominant tubulointerstitial nephropathy, considered at first as a distinct disorder. Genetic progress allowed us to consider familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease as the two facets of a same disease, we should call uromodulin associated kidney diseases. At least two other genes have been implicated in similar clinical presentation: TCF2 and the gene encoding renin.

Tophus gout and chronic kidney disease in a young female patient: report of familial juvenile hyperuricemic nephropathy in three generations of the same family

A 20-year-old female was admitted with tophus gout and chronic kidney disease (CKD), progressing to dialysis need and death. The familial investigation evidenced several cases of hyperuricemia, gout and CKD, as well as several cases of early death due to CKD. After analyzing these cases, it was concluded that the diagnosis was familial juvenile hyperuricemic nephropathy. This is an autosomal dominant disorder caused by mutations in the uromodulin gene, characterized by early beginning hyperuricemia and gout, in men and women, associated with progressive CKD.

Phenotype and Outcome in Hereditary Tubulointerstitial Nephritis Secondary to UMOD Mutations

UMOD mutations cause familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease (MCKD), although these phenotypes are nonspecific. We reviewed cases of UMOD mutations diagnosed in the genetic laboratories of Necker Hospital (Paris, France) and of Université Catholique de Louvain (Brussels, Belgium). We also analyzed patients with MCKD/FJHN but no UMOD mutation. To determine thresholds for hyperuricemia and uric-acid excretion fraction (UAEF) according to GFR, these parameters were analyzed in 1097 patients with various renal diseases and renal function levels. Thirty-seven distinct UMOD mutations were found in 109 patients from 45 families, all in exon 4 or 5 except for three novel mutations in exon 8. Median renal survival was 54 years. The type of mutation had a modest effect on renal survival, and intrafamilial variability was high. Detailed data available in 70 patients showed renal cysts in 24 (34.3%) of nonspecific localization in most patients. Uricemia was >75th percentile in 31 (71.4%) of 42 patients not under dialysis or allopurinol therapy. UAEF (n = 27) was <75th percentile in 70.4%. Among 136 probands with MCKD/FJHN phenotype, UMOD mutation was found in 24 (17.8%). Phenotype was not accurately predictive of UMOD mutation. Six probands had HNF1B mutations. Hyperuricemia disproportionate to renal function represents the hallmark of renal disease caused by UMOD mutation. Renal survival is highly variable in patients with UMOD mutation. Our data also add novel insights into the interpretation of uricemia and UAEF in patients with chronic kidney diseases.

Tamm-Horsfall Glycoprotein Interacts with Renal Outer Medullary Potassium Channel ROMK2 and Regulates Its Function

Tamm-Horsfall glycoprotein (THGP) or Uromodulin is a membrane protein exclusively expressed along the thick ascending limb (TAL) and early distal convoluted tubule (DCT) of the nephron. Mutations in the THGP encoding gene result in Familial Juvenile Hyperuricemic Nephropathy (FJHN), Medullary Cystic Kidney Disease type 2 (MCKD-2), and Glomerulocystic Kidney Disease (GCKD). The physicochemical and biological properties of THGP have been studied extensively, but its physiological function in the TAL remains obscure. We performed yeast two-hybrid screening employing a human kidney cDNA library and identified THGP as a potential interaction partner of the renal outer medullary potassium channel (ROMK2), a key player in the process of salt reabsorption along the TAL. Functional analysis by electrophysiological techniques in Xenopus oocytes showed a strong increase in ROMK current amplitudes when co-expressed with THGP. The effect of THGP was specific for ROMK2 and did not influence current amplitudes upon co-expression with Kir2.x, inward rectifier potassium channels related to ROMK. Single channel conductance and open probability of ROMK2 were not altered by co-expression of THGP, which instead increased surface expression of ROMK2 as determined by patch clamp analysis and luminometric surface quantification, respectively. Despite preserved interaction with ROMK2, disease-causing THGP mutants failed to increase its current amplitude and surface expression. THGP(-/-) mice exhibited increased ROMK accumulation in intracellular vesicular compartments when compared with WT animals. Therefore, THGP modulation of ROMK function confers a new role of THGP on renal ion transport and may contribute to salt wasting observed in FJHN/MCKD-2/GCKD patients.

Genome-wide study of familial juvenile hyperuricaemic (gouty) nephropathy (FJHN) indicates a new locus, FJHN3, linked to chromosome 2p22.1-p21

Familial juvenile hyperuricaemic (gouty) nephropathy (FJHN), is an autosomal dominant disease associated with a reduced fractional excretion of urate, and progressive renal failure. FJHN is genetically heterogeneous and due to mutations of three genes: uromodulin (UMOD), renin (REN) and hepatocyte nuclear factor-1beta (HNF-1β) on chromosomes 16p12, 1q32.1, and 17q12, respectively. However, UMOD, REN or HNF-1β mutations are found in only approximately 45% of FJHN probands, indicating the involvement of other genetic loci in approximately 55% of probands. To identify other FJHN loci, we performed a single nucleotide polymorphism (SNP)-based genome-wide linkage analysis, in six FJHN families in whom UMOD, HNF-1β and REN mutations had been excluded. Parametric linkage analysis using a 'rare dominant' model established linkage in five of the six FJHN families, with a LOD score >+3, at 0% recombination, between FJHN and SNPs at chromosome 2p22.1-p21. Analysis of individual recombinants in two unrelated affected individuals defined a approximately 5.5 Mbp interval, flanked telomerically by SNP RS372139 and centromerically by RS896986 that contained the locus, designated FJHN3. The interval contains 28 genes, and DNA sequence analysis of the most likely candidate, solute carrier family 8 member 1 (SLC8A1), did not identify any abnormalities in the FJHN3 probands. FJHN3 is likely located within a approximately 5.5 Mbp interval on chromosome 2p22.1-p21, and identifying the genetic abnormality will help to further elucidate mechanisms predisposing to gout and renal failure.

Development of LC-MS Method for Detection of Mutant Uromodulin Protein

Mutations in the uromodulin gene cause the autosomal disorders familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease type 2 (MCKD2). However, methods to detect the mutant form of the uromodulin protein have not been developed. In this study, we developed a liquid chromatography-mass spectrometry (LC-MS) method for detection of the mutated uromodulin peptide (C148W). Our method can distinguish the mutant peptide, GWHWE, from wildtype peptide, GWHC*E. Using MS/MS analysis with a selected reaction monitoring (SRM) mode, peptide-specific fragment ions (m/z 714 → 381, 471, 567, and 679 for GWHWE and m/z 688 → 381, 445, 541, and 653 for GWHC*E) were detected.

An aid to the diagnosis of genetic disorders underlying adult-onset renal failure: a literature review

Several genetic disorders can present in adult patients with renal insufficiency. Genetic renal disease other than ADPKD accounts for ESRD in 3% of the adult Dutch population. Because of this low prevalence and their clinical heterogeneity most adult nephrologists are less familiar with these disorders. As a guideline to differential diagnosis, we provide an overview of the clinical manifestations and the pathogenesis of the main genetic disorders with chronic renal insufficiency surfacing in adulthood and add an algorithm plus 4 tables. We also indicate where molecular genetics nowadays can be of aid in the diagnostic process. The following disorders are discussed by mode of inheritance: 1) Autosomal dominant: autosomal dominant polycystic kidney disease, nephropathies associated with uromodulin (medullary cystic disease and familial juvenile hyperuricemic nephropathy), renal cysts and diabetes syndrome, nail-patella syndrome, glomerulopathy with fibronectin deposits. 2) Not autosomal dominant: Nephronophthisis, Fabry disease, primary oxalosis, Adenine Phosphoribosyl Transferase deficiency, Alport syndrome, Lecithin-cholesterol acyltransferase deficiency, adult-onset cystinosis.

More on Clinical Renal Genetics

Surprisingly, inherited disorders due to mutations of the genes coding for the renin-angiotensin system (RAS) have been rarely reported. The most striking example is autosomal recessive tubular dysgenesis, characterized by the absence or paucity of proximal tubules and caused by various mutations involving renin, angiotensinogen, angiotensin converting enzyme (ACE), and angiotensin AT1 receptor (1). In most cases this disease results in early end-stage renal failure. This disease is reminiscent of the cases of renal tubular dysgenesis occurring in fetuses exposed to ACE inhibitors or angiotensin receptor blockers, or in ischemic fetal kidneys in the twin-to-twin transfusion syndrome (1). Zivna et al. have studied three families with dominant renin gene mutations: a deletion in two unrelated families, and a missense mutation in the exon 1 coding for the signal sequence in the third family. The gene responsible for renin production is located on chromosome 1 and is primarily expressed by granular cells in the juxtaglomerular apparatus. The gene product, preprorenin, contains a signal sequence that directs endoplasmic reticulum (ER) targeting, glycosylation, and proteolytic processing of the nascent preprorenin, resulting in prorenin and renin. Transfection and in vitro studies have demonstrated that both mutations affect ER translocation and processing of nascent preprorenin, accounting for reduced or abolished biosynthesis and secretion. Kidney biopsies were available in three patients with the deletion. Light microscopy examination revealed focal tubular atrophy and dystrophy, focal segmental glomerulosclerosis, and interstitial fibrosis. Immunohistochemical study showed decreased staining for renin and prorenin in juxtaglomerular granular cells and tubular epithelia. However, abnormal localization of renin and prorenin inside of the vessel wall of several arterioles and small arteries was detected. Staining intensities of the other RAS components were decreased. The description of the phenotype of this disease was based on the study of 16 affected subjects. The ages at diagnosis ranged from 4 to 59 years. The phenotype included anemia (responsive to erythropoietin), hyperuricemia (usually mild, not accompanied by gout, present in many but not all patients), and slowly progressive chronic kidney disease. Plasma renin and aldosterone levels were low but not entirely suppressed. Increased proximal tubular reabsorption due to mild volume depletion may be responsible for reduced fractional excretion of uric acid and hyperuricemia. By ultrasonography, kidneys were atrophic with no evidence of cysts. End-stage kidney disease developed between 43 and 68 years of age. Although hyperuricemia is mild and inconstant, this disease should be added to the group of inherited kidney diseases with early hyperuricemia: familial juvenile hyperuricemic nephropathy due to UMOD mutations, which codes for uromodulin, and hepatocyte nuclear factor 1, homeobox β (HNF 1-β) mutations disease, which is characterized by renal cysts, diabetes mellitus, genital or renal malformations, early gout, and liver test abnormalities (but the phenotype is rarely complete). These two diseases have an autosomal dominant inheritance.

Uromodulin is expressed in renal primary cilia and UMOD mutations result in decreased ciliary uromodulin expression

Uromodulin (UMOD) mutations are responsible for three autosomal dominant tubulo-interstitial nephropathies including medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy and glomerulocystic kidney disease. Symptoms include renal salt wasting, hyperuricemia, gout, hypertension and end-stage renal disease. MCKD is part of the 'nephronophthisis-MCKD complex', a group of cystic kidney diseases. Both disorders have an indistinguishable histology and renal cysts are observed in either. For most genes mutated in cystic kidney disease, their proteins are expressed in the primary cilia/basal body complex. We identified seven novel UMOD mutations and were interested if UMOD protein was expressed in the primary renal cilia of human renal biopsies and if mutant UMOD would show a different expression pattern compared with that seen in control individuals. We demonstrate that UMOD is expressed in the primary cilia of renal tubules, using immunofluorescent studies in human kidney biopsy samples. The number of UMOD-positive primary cilia in UMOD patients is significantly decreased when compared with control samples. Additional immunofluorescence studies confirm ciliary expression of UMOD in cell culture. Ciliary expression of UMOD is also confirmed by electron microscopy. UMOD localization at the mitotic spindle poles and colocalization with other ciliary proteins such as nephrocystin-1 and kinesin family member 3A is demonstrated. Our data add UMOD to the group of proteins expressed in primary cilia, where mutations of the gene lead to cystic kidney disease.

Uromodulin and Translational Medicine

Tamm-Horsfall protein (THP) was originally described in 1895 as “urinary mucoprotein” and biochemically characterized approximately 50 years ago. Kidney epithelial cells of all placental mammals synthesize THP, and it is the most abundant protein in normal urine.1,2 Pirica, a novel THP-like gene that is induced in response to predation, was recently identified in tadpoles, suggesting that THP family proteins are also present in invertebrate species.3 Uromodulin was originally reported as a unique immunosuppressive glycoprotein from the urine of pregnant women,4 and its amino acid composition is identical to THP.5 Standard nomenclature for THP is now uromodulin. Uromodulin provides a protein infrastructure for urinary casts used to diagnosis various kidney diseases in the clinic. Experimentalists have used both in vitro and in vivo models to define the biology of uromodulin in the urinary tract, and protein chemists have extensively characterized its biochemical properties and domains.6–10 Despite these efforts, the function of uromodulin remains an enigma. Published data suggest uromodulin is glycosyl phosphatidyl inositol-anchored along the apical domain of some kidney epithelia and secreted into urine and blood. It inhibits both bacterial colonization of the urinary track and stone formation, binds and activates leukocytes, and generates the water impermeability of the thick ascending limb of Henle by assembly into filaments through its zona pelucida domain. Tissue distribution of pirica, the amphibian uromodulin-like protein, also supports the hypothesis that uromodulin regulates the water permeability of tissue.3 Mutations in UMOD , the gene that encodes uromodulin, cause rare, autosomal dominant, primary tubulointerstitialkidney diseases, particularly familial juvenile hyperuricemicnephropathy (FJHN; OMIM 191845) and a form of medullary cystic kidney disease (MCKD2; …

A Case of Familial Juvenile Hyperuricemic Nephropathy with Novel Uromodulin Gene Mutation, a Novel Heterozygous Missense Mutation in Korea

Familial Juvenile hyperuricemic nephropathy (FJHN, OMIM #162000) is a rare autosomal dominant disorder characterized by hyperuricemia with renal uric acid under-excretion, gout and chronic kidney disease. In most but not all families with FJHN, genetic studies have revealed mutations in the uromodulin (UMOD) gene located on chromosome 16p11-p13. We here described a novel heterozygous missense mutation (c.1382C>A causing p.Ala461Glu) in an affected 16-year-old male with hyperuricemia, gout and chronic kidney disease. His father was also affected and the UMOD mutation was found to segregate with the disease. There has been only one case report of Korean family with FJHN, which has not been diagnosed by genetic study. This is the first report of genetically diagnosed FJHN in Korea.

Uromodulin mutations causing familial juvenile hyperuricaemic nephropathy lead to protein maturation defects and retention in the endoplasmic reticulum

Familial juvenile hyperuricaemic nephropathy (FJHN), an autosomal dominant disorder, is caused by mutations in the UMOD gene, which encodes Uromodulin, a glycosylphosphatidylinositol-anchored protein that is expressed in the thick ascending limb of the loop of Henle and excreted in the urine. Uromodulin contains three epidermal growth factor (EGF)-like domains, a cysteine-rich region which includes a domain of eight cysteines and a zona pellucida (ZP) domain. Over 90% of UMOD mutations are missense, and 62% alter a cysteine residue, implicating a role for protein misfolding in the disease. We investigated 20 northern European FJHN probands for UMOD mutations. Wild-type and mutant Uromodulins were functionally studied by expression in HeLa cells and by the use of western blot analysis and confocal microscopy. Six different UMOD missense mutations (Cys32Trp, Arg185Gly, Asp196Asn, Cys217Trp, Cys223Arg and Gly488Arg) were identified. Patients with UMOD mutations were phenotypically similar to those without UMOD mutations. The mutant Uromodulins had significantly delayed maturation, retention in the endoplasmic reticulum (ER) and reduced expression at the plasma membrane. However, Gly488Arg, which is the only mutation we identified in the ZP domain, was found to be associated with milder in vitro abnormalities and to be the only mutant Uromodulin detected in conditioned medium from transfected cells, indicating that the severity of the mutant phenotypes may depend on their location within the protein. Thus, FJHN-causing Uromodulin mutants are retained in the ER, with impaired intracellular maturation and trafficking, thereby indicating mechanisms whereby Uromodulin mutants may cause the phenotype of FJHN.

Familial juvenile hyperuricemic nephropathy: report on a new mutation and a pregnancy

Familial juvenile hyperuricemic nephropathy (FJHN) is a rare autosomal dominant disease caused by mutations in the uromodulin gene (UMOD) and leading to gout, tubulointerstitial nephropathy and end-stage renal disease. A Latvian family suffering from FJHN is described. The father of the family developed ESRD at age 36. His daughter was diagnosed with gout and chronic kidney disease at age 14 years. A renal biopsy revealed tubulointerstitial disease; 2 sons were diagnosed at age 9 and 4 with elevated uric acid levels and reduced fractional uric acid excretion. Urinary uromodulin was normal in the younger boy, but markedly decreased in the 2 other patients. Genetic analysis revealed a previously undescribed D196Y mutation in the UMOD gene. The female patient became pregnant at age 23. During pregnancy serum creatinine decreased from 2.0 to 1.5 mg/dl and blood pressure remained low. Analysis of the baby's umbilical cord blood and a mouth swab showed the presence of the D196Y mutation. Its urinary uromodulin excretion was in the low normal range. The uromodulin excretion pattern observed in the investigated family suggests that urinary uromodulin decreases in FJHN from low normal values at childhood to extremely low levels in early adulthood. In addition, this first report on pregnancy in a patient with FJHN shows normal adaptation despite markedly reduced renal function.

Mutation analysis of the Uromodulin gene in 96 individuals with urinary tract anomalies (CAKUT).

Uromodulin (UMOD) mutations were described in patients with medullary cystic kidney disease (MCKD2), familial juvenile hyperuricemic nephropathy (FJHN), and glomerulocystic kidney disease (GCKD). UMOD transcription is activated by the transcription factor HNF1B. Mutations in HNF1B cause a phenotype similar to FJHN/GCKD but also congenital anomalies of the kidney and the urinary tract (CAKUT). Moreover, we recently detected UMOD mutations in two patients with CAKUT. As HNF1B and UMOD act in the same pathway and cause similar phenotypes, we here examined whether UMOD mutations would be found in patients with CAKUT. Mutation analysis of UMOD was performed in 96 individuals with CAKUT by direct sequencing of exons 4 and 5 and by heteroduplex analysis following CEL I digestion assay of exons 3 and 6-12. Mean patient age was 11.4 years, and in 36.4% of patients, family history was positive for CAKUT. In the CEL I assay, 12 aberrant bands were detected in 103 of 960 polymerase chain reaction (PCR) products and were sequenced. Six previously known and seven new single nucleotide polymorphisms (SNPs) were detected. As no UMOD mutations were identified in these 96 patients with CAKUT, UMOD mutations do not seem to be a significant cause of CAKUT in this cohort.

Immature Renal Structures Associated With a Novel UMOD Sequence Variant

Mutations of the UMOD gene, encoding uromodulin, have been associated with medullary cystic kidney disease 2, familial juvenile hyperuricemic nephropathy, and glomerulocystic kidney disease. We report on a 13-year-old boy presenting with chronic reduced kidney function, hyperuricemia, and impairment in urine-concentrating ability. His father was affected by an undefined nephropathy that required transplantation. The boy's renal ultrasonography showed reduced bilateral kidney volumes and cortical hyperechogenicity, with 2 tiny cysts in the left kidney. Renal biopsy showed up to 60% of glomeruli featuring an enlargement of Bowman space (glomerular cysts), with mild interstitial fibrosis (alpha-smooth muscle actin [alphaSMA] positive), inflammatory infiltrate, and focal tubular atrophy at the cortical level. At the corticomedullary junction, immature tubules (some dilated) with cytokeratin- and paired box gene 2 (PAX2)-positive immunostaining were seen, surrounded by vimentin-positive mesenchymal tissue. Unlike previously reported cases, no uromodulin-positive globular aggregates within the cytoplasm of tubular cells were observed. Uromodulin urinary excretion was absent. Genetic analysis showed a novel heterozygous sequence change in the UMOD gene (NM_003361.2:c.149G-->C; p.Cys50Ser) involving the first epidermal growth factor-like domain of the protein in both the boy and his father. This novel UMOD sequence variant, which is associated with an immunohistochemical pattern different from previous reports and a histological picture characterized by immature renal structures, suggests a possible role for UMOD in renal development.

Abnormal expression and processing of uromodulin in Fabry disease reflects tubular cell storage alteration and is reversible by enzyme replacement therapy

Uromodulin (UMOD) malfunction has been found in a range of autosomal dominant tubulointerstitial nephropathies associated with hyperuricaemia, gouty arthritis, medullary cysts and renal failure-labelled as familial juvenile hyperuricaemic nephropathy, medullary cystic disease type 2 and glomerulocystic kidney disease. To gain knowledge of the spectrum of UMOD changes in various genetic diseases with renal involvement we examined urinary UMOD excretion and found significant quantitative and qualitative changes in 15 male patients at various clinical stages of Fabry disease. In untreated patients, the changes ranged from normal to a marked decrease, or even absence of urinary UMOD. This was accompanied frequently by the presence of aberrantly processed UMOD lacking the C-terminal part following the K432 residue. The abnormal patterns normalized in all patients on enzyme replacement therapy and in some patients on substrate reduction therapy. Immunohistochemical analysis of the affected kidney revealed abnormal UMOD localization in the thick ascending limb of Henle's loop and the distal convoluted tubule, with UMOD expression inversely proportional to the degree of storage. Our observations warrant evaluation of tubular functions in Fabry disease and suggest UMOD as a potential biochemical marker of therapeutic response of the kidney to therapy. Extended comparative studies of UMOD expression in kidney specimens obtained during individual types of therapies are therefore of great interest.

Production and Characterization of Transgenic Mice Harboring Mutant Human UMOD Gene

Familial juvenile hyperuricemic nephropathy is caused by mutations in the UMOD gene encoding uromodulin. A transgenic mouse model was developed by introducing a human mutant UMOD (C148W) cDNA under control of the mouse umod promoter. Uromodulin accumulation was observed in the thick ascending limb cells in the kidney of transgenic mice. However, the urinary excretion of uromodulin in transgenic mice did not decrease and LC-MS/MS analysis indicated it was of mouse origin. Moreover, the creatinine clearance was not different between wildtype and transgenic animals. Consequently, the onset of the disease was not observed in transgenic mice until 24 weeks of age.

Control of renal uric acid excretion and gout

Impaired renal uric acid excretion is the major mechanism of hyperuricemia in patients with primary gout. This review highlights recent advances in the knowledge of normal mechanisms of renal uric acid handling and derangement of these mechanisms in uric acid underexcretion. The discovery of URAT1 has facilitated identification of other molecules potentially involved in uric acid transport in the renal tubules. Some of these molecules show gender differential expression in animal experiments. Sodium-dependent monocarboxylate cotransporters have been shown to transport lactate and butyrate, and may have roles in hyperuricemia associated with diabetic ketoacidosis and alcohol ingestion. Certain polymorphisms in SLC22A12 may be associated with the development of hyperuricemia or gout, although confirmation is needed. Mechanisms of hyperuricemia associated with uric acid underexcretion in patients with familial juvenile hyperuricemic nephropathy also remain to be clarified. Distal tubular salt wasting and compensatory upregulation of the resorption of sodium and uric acid in the proximal tubule may explain the hyperuricemia associated with this disorder. Much progress has been made in understanding the mechanisms of renal uric acid handling. Elucidation of the mechanisms of hyperuricemia in patients with familial juvenile hyperuricemic nephropathy will shed light on the function of uromodulin, functional impairment of which eventually results in diminished uric acid excretion.

Progressive Accumulation of Intrinsic Mouse Uromodulin in the Kidneys of Transgenic Mice Harboring the Mutant Human Uromodulin Gene

Familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease type 2 (MCKD2) are autosomal dominant disorders characterized by juvenile hyperuricemia of the underexcretion type, juvenile gout and chronic renal failure in the adult. FJHN/MCKD2 constitute diseases caused by mutations of the human uromodulin (UMOD) gene that encodes uromodulin, the most abundant glycoprotein in normal human urine. The mutations affect the transport of uromodulin, resulting in the accumulation of uromodulin in the kidneys of FJHN/MCKD2 patients. The purpose of this study was to confirm the accumulation of uromodulin in the kidneys of transgenic mice harboring the mutant human UMOD gene with mouse UMOD gene promoter, and to determine the relationship between its accumulation and the effect on uromodulin transport. The mutant human UMOD mRNA and its protein were expressed in the kidneys of transgenic mice. Moreover, the staining of human uromodulin was colocalized with that of mouse uromodulin. Although the human UMOD mRNA levels increased, the protein levels did not change and the accumulation of human uromodulin was not observed. However, the mouse uromodulin consists of two forms, 103 and 117 kDa, and the 103 kDa protein was gradually increased in the kidneys of transgenic mice. Human and mouse uromodulins in the kidneys of transgenic mice were mainly detected in the Triton X-100 insoluble microsomal fraction. Therefore, the progressive accumulation of uromodulin was observed in the plasma membrane of the kidneys of transgenic mice but the accumulated uromodulin protein was not that encoded by the transgene.

Outcome of kidney transplantation in familial juvenile hyperuricaemic nephropathy

Familial juvenile hyperuricaemic nephropathy (FJHN) and medullary cystic kidney disease (MCKD) are rare autosomal-dominant disorders, both characterized by early hyperuricaemia due to reduced urinary excretion of urate and the development of chronic interstitial nephropathy, most often leading to end-stage renal failure (ESRF) in adulthood. Although a history of gout is more frequently reported in FJHN and corticomedullary renal cysts more frequently found in MCKD, both phenotypes overlap [1]. Two loci for MCKD (MCKD1 and MCKD2) were localized to chromosome 1q21 and 16p12, respectively [2,3]. A locus for FJHN was mapped to chromosome 16p11.2, in a region overlapping with the MCKD2 locus, raising the hypothesis that FJHN and MCKD2 were two facets of the same disease [4]. This was demonstrated by the identification of mutations in the UMOD gene encoding uromodulin (or Tamm-Horsfall protein) in three families with FJHN and one with MCKD2 [5]. Several groups soon confirmed the role of the UMOD gene as the cause of FJHN, with a cluster of mutations in exons 4 and 5 (reviewed in [1]). The cause of the onset and progression of chronic interstitial nephritis in UMOD-related disorders remains a moot point. Uromodulin is a kidney-specific protein produced in the thick ascending limb (TAL) of the loop of Henle and excreted in the urine [1]. Mutant uromodulin has been shown to accumulate in the endoplasmic reticulum of TAL cells, with only wildtype uromodulin found in the urine of affected patients [6,7]. Intratubular accumulated uromodulin is thought to induce cell death and interstitial fibrosis, through unidentified mechanisms. If this is true, the transplantation of a normal kidney producing only wild-type uromodulin should cure the disease, without fear of recurrence. The earliest manifestation of the disease is a decreased fractional urinary excretion of urate (FEur), expressed as a function of age and sex. The most likely explanation for this abnormality is an increased reabsorption of urate in the proximal tubule along with sodium, the latter thought to be a compensation for the decreased sodium uptake in the TAL related to the uromodulin defect [1]. This abnormality should be reversed after kidney transplantation. There is so far no data in the literature on the results of kidney transplantation in this condition. This prompts us to report on the outcome of kidney transplantation in six patients with FJHN due to a documented mutation in the UMOD gene, with emphasis on the post-transplant renal handling of uric acid.