Familial Juvenile hyperuricemic nephropathy (FJHN) is a rare autosomal dominant disorder, characterized by early onset of hyperuricemia, gout and progressive kidney disease. Hyperuricemia prior to renal impairment and decreased fractional excretion of uric acid are hallmarks of FJHN. Renal dysfunction gradually appears early in life and results in end-stage renal disease usually between the ages of 20 and 70 years. FJHN is mostly caused by mutations in the uromodulin gene located at 16p12. The course of FJHN is highly variable. Treatment includes management for hyperuricemia, gout and progressive kidney disease. Individuals with gout have been usually treated with allopurinol. But controversy exists as to whether uric acid lowering therapy prevents the progression of chronic kidney disease.
Allopurinol ; Gout ; Hyperuricemia ; Kidney Diseases ; Kidney Failure, Chronic ; Renal Insufficiency, Chronic ; Uric Acid ; Uromodulin

Differentiation of renal(RH) and non-renal(NRH) hematuria is important in the diagnosis and treatment of the patients with hematuria. Recently, urine RBC immunoperoxidase(IPx) staining method was developed, but there was no report on the usefulness of IPx in Korea. We validated the usefulness of IPx by comparing with the PCM. Both PCM and IPx were performed at the same time in 26 patients with RH confirmed by renal biopsy and 23 patients with NRH confirmed by radiologic and/or pathologic studies who were admitted to Chungbuk National University Hospital from January 1996 to December 1996. The age of RH and NRH group were 36.6+/-15.0 and 56.5+/-22.2 years. 35.7+/-30.4% of urine RBC were stained by IPx in RH group and only 1.6+/-4.4% were stained in NRH group(P<0.001). 23.4+/-29.9% of urine RBC by PCM were counted as dysmorphic RBC in RH group and 5.7+/-13.6% were counted in NRH group(P<0.05). At the cut-off value of 20%, the sensitivity and specificity of IPx were 57.7% and 100%. At the cut-off value of 30%, those of PCM were 30.9% and 95.7%, respectively. When comparing overall test performance by calculating AUCs of ROC(receiver operating characteristics) curve, IPx was better than PCM. IPx was better than PCM in localizing the origin of hematuria. The NRH might be excluded when IPx(+) cells are more than 20% of total urine RBC.
Area Under Curve ; Biopsy ; Chungcheongbuk-do ; Diagnosis ; Hematuria* ; Humans ; Korea ; Microscopy, Phase-Contrast* ; Sensitivity and Specificity ; Uromodulin

The aim of this study was to characterize the morphology of a polycystic kidney which was found in 100% of the transgenic mice homozygous for inv mutation and to gain insight into the pathogenesis of inherited polycystic kidney disease during the pre- and postnatal periods. The fetal and postnatal kidneys from the homozygous and heterozygous transgenic mice were examined by the light, transmission and scanning electron microscopes, image analyzer, and an immunohistochemistry utilizing the antibodies specific for each segment of the renal tubules (Tetragonolobus purpureas, Arachis hypogaea, Tamm-Horsfall protein, AE1/AE3, EMA, vimentin, Phaseolus vulgaris) was performed to determine the site of origin of renal cysts. Two developmental phases of a cystic disease were identified. The first phase, seen in fetal kidneys, was characterized by dilatation mainly of the proximal tubules and a few distal tubules. The later phase, in postnatal period, was characterized by progressive enlargement of the kidneys due to mainly cystic change of the collecting ducts, which distorted the normal architecture of both cortex and medulla and almost completely replaced the renal parenchyma. The cystic dilatation involved all segments of the nephron and the collecting duct as well as the Bowman's spaces of glomeruli. The epithelial cell hyperplasia was found as a micropolyp formation within the renal cysts and an increase in PCNA positive cells. These findings suggest that a cyst is not simply a ballooning of a renal tubule and the stretching of cells, formerly thought to be due to an altered compliance of an abnormal basement membrane, but indeed the result of increased numbers of tubular epithelial cells.
Animals ; Antibodies ; Arachis ; Basement Membrane ; Compliance ; Dilatation ; Epithelial Cells ; Hyperplasia ; Immunohistochemistry ; Kidney ; Mice ; Mice, Transgenic* ; Microscopy, Electron ; Nephrons ; Phaseolus ; Polycystic Kidney Diseases* ; Proliferating Cell Nuclear Antigen ; Uromodulin ; Vimentin

Effective clearance of inflammatory cells is required for resolution of inflammation. Here, we show in vivo evidence that apoptosis and reverse transendothelial migration (rTEM) are important mechanisms in eliminating neutrophils and facilitating recovery following ischemia/reperfusion injury (IRI) of the kidney. The clearance of neutrophils was delayed in the Bax knockout (KO)BM → wild-type (WT) chimera in which bone marrow derived cells are partially resistant to apoptosis, compared to WTBM → WT mice. These mice also showed delayed functional, histological recovery, increased tissue cytokines, and accelerated fibrosis. The circulating intercellular adhesion molecule-1 (ICAM-1)+ Gr-1+ neutrophils displaying rTEM phenotype increased during the recovery phase and blockade of junctional adhesion molecule-C (JAM-C), a negative regulator of rTEM, resulted in an increase in circulating ICAM-1+ neutrophils, faster resolution of inflammation and recovery. The presence of Tamm-Horsfall protein (THP) in circulating ICAM-1+ neutrophils could suggest that they are derived from injured kidneys. In conclusion, we suggest that apoptosis and rTEM are critically involved in the clearance mechanisms of neutrophils during the recovery phase of IRI.
Acute Kidney Injury* ; Animals ; Apoptosis ; Bone Marrow ; Chimera ; Cytokines ; Fibrosis ; Inflammation ; Intercellular Adhesion Molecule-1 ; Kidney ; Mice ; Neutrophils* ; Phenotype ; Transendothelial and Transepithelial Migration ; Uromodulin

Much has changed in our understanding of the interstitial cystitis/painful bladder syndrome (IC/PBS) over time. The International Continence Society (ICS) prefers the term Painful Bladder Syndrome (PBS) defined as "the complaint of suprapubic pain related to bladder filling, accompanied by other symptoms such as increased daytime and night-time frequency, in the absence of proven urinary infection or other obvious pathology". Interstitial cystitis is a clinical diagnosis primarily based on symptoms of urgency/frequency and pain in the bladder and or pelvis. The pathogenesis of IC is still not completely understood, but it is likely multifactorial. The major etiologic theories include abnormality of the bladder urothelium, bladder mast cell activation, bladder inflammation, and altered bladder innervation. The sensitivity and specificity of urinary markers and the potassium sensitivity test have not been prospectively studied. Antiproliferative factor and Tamm-Horsfall protein are novel tests that may prove to be worthwhile pending future studies. Management includes patient education, dietary and lifestyle counseling, oral therapy, intravesical therapy, and surgery. Recently, the European Society for the Study of Interstitial Cystitis (ESSIC) proposed a new nomenclature and classification system. This article discusses recent data and outlines current concepts of IC/PBS.
Classification ; Counseling ; Cystitis, Interstitial* ; Diagnosis* ; Inflammation ; Life Style ; Mast Cells ; Patient Education as Topic ; Pelvis ; Potassium ; Sensitivity and Specificity ; Urinary Bladder ; Uromodulin ; Urothelium

INTRODUCTION: Urinary proteomics provides a wealth of information in the identification of protein markers associated with various diseases such as in carcinoma. With the increasing incidence of prostate cancer and the lack of sensitivity and specificity of prostate specific antigen, the simultaneous identification of an alternative protein biomarker through urinary proteomics is encouraging. Urine, which has similar proteins with serum, makes it an ideal alternative biofluid wherein the collection is easy and non-invasive.
METHODS: Urinary proteins were separated by gradient SDS-PAGE followed by in-gel digestion and organic/buffer peptide extraction. The protein biomarkers in prostate cancer patients and control subjects were identified via LC-MS/MS and submitted to Protein Prospector where the peptide fragmentation of sequence was analyzed and compared with the SwissProt database.
RESULTS: A panel of three protein biomarkers for the early detection of prostate cancer were identified: transthyretin, hemoglobin subunit alpha and hemoglobin sububit beta. The presence of these three biomarkers is associated with high Gleason scores and TNM stages but not with PSA level. Uromodulin and mannan binding lectin serine protease cancer from BPH. The study also revealed the divergence of the urinary proteome of the cancer patients from the urinary proteome of the control with BPH suggesting the fundamental differences in benign and malignant growth of the prostate epithelial cells. Another highlight of the study was the identification of oxidation of pro63 of transthyretin in patient 3. The proposed role of the post translational modification in pro63 of transthyretinin in the mechanism of prostate carcinogenesis remains to be defined and warrants further study.
CONCLUSION: Our study was able to establish the homology of urine proteome among the controls and its divergence from the patients afflicted with prostate cancer by simultaneously comparing their urine proteomes leading to the identification of a distinct panel of biomarkers, namely, transthyretin, hemoglobin subunit alpha and hemoglobin subunit beta. Uromodulin and mannan binding lectin serine protease 2 are the additional biomarkers that can distinguish prostate cancer from BPH. Due to limitations in the number of controls and patients, only preliminary findings and their significance were shown. These findings need to be confirmed in future investigations using larger sample size for both the controls and the patients.

Human ; Male ; Prostate-specific Antigen ; Proteome ; Proteomics ; Prealbumin ; Uromodulin ; Serine Proteases ; Mannose-binding Lectin ; Prostatic Neoplasms ; Carcinogenesis ; Peptides ; Hemoglobins ; Epithelial Cells

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.
Adolescent ; Asian Continental Ancestry Group/*genetics ; Chromosomes, Human, Pair 16 ; Chronic Disease ; DNA Mutational Analysis ; Genes, Dominant ; Heterozygote ; Humans ; Hyperuricemia/*genetics ; Kidney Diseases/genetics ; Male ; *Mutation, Missense ; Pedigree ; Republic of Korea ; Uric Acid/blood ; Uromodulin/*genetics

Familial juvenile hyperuricemic nephropathy (FJHN; OMIM 162000) is an autosomal dominant disorder characterized by hyperuricemia and gouty arthritis due to reduced kidney excretion of uric acid and progressive renal failure. Gradual progressive interstitial renal disease, with basement membrane thickening and glomerulosclerosis resulting from fibrosis, starts in early life. In most cases of FJHN, uromodulin gene (UMOD) is responsible for the disease; however, there has been only one report of a genetically confirmed FJHN family in Korea. Here we report another Korean family with FJHN, in which three male members. a father and 2 sons.developed gout and progressive renal insufficiency. The clinical, laboratory, and radiological findings were consistent with FJHN, and renal biopsy showed chronic parenchymal damage, which can be found in FJHN but is not specific to this disease. In order to confirm the diagnosis, sequence analysis of the UMOD was performed, and a novel heterozygous missense variant (c.187T>C; p.Cys63Arg) in exon 3 was identified. We assume that this variant is likely to be the causative mutation in this family, as the variant segregated with the disease. In addition, approximately two-thirds of the known mutations lead to a cysteine amino acid change in uromodulin, and all such variants have been shown to cause UMOD-associated kidney disease. In summary, we report a Korean FJHN family with three affected members by genetic analysis of the UMOD, and provide the first report of a novel heterozygous missense mutation.
Adolescent ; Adult ; Base Sequence ; DNA Mutational Analysis ; Exons ; Gout/*genetics ; Heterozygote ; Humans ; Hyperuricemia/*genetics ; Kidney Diseases/*genetics ; Male ; *Mutation, Missense ; Pedigree ; Polymorphism, Single Nucleotide ; Republic of Korea ; Uromodulin/chemistry/*genetics

The effects of mangiferin on uric acid excretion, kidney function and related renal transporters were investigated in hyperuricemic mice induced by potassium oxonate. Mice were divided into normal control group, and 5 hyperuricemic groups with model control, 50, 100, and 200 mg x kg(-1) mangiferin, and 5 mg x kg(-1) allopurinol. Mice were administered by gavage once daily with 250 mg x kg(-1) potassium oxonate for seven consecutive days to create the model. And 3 doses of mangiferin were orally initiated on the day 1 h after potassium oxonate was given, separately. Serum uric acid, creatinine and urea nitrogon levels, as well as urinary uric acid creatinine levels were measured. Mouse uromodulin (mUMOD) levels in serum, urine and kidney were determined by ELISA method. The mRNA and protein levels of related renal transporters were assayed by RT-PCR and Western blotting methods, respectively. Compared to model group, mangiferin significantly reduced serum uric acid, creatinine and urea nitrogon levels, increased 24 h uric acid and creatinine excretion, and fractional excretion of uric acid in hyperuricemic mice, exhibiting uric acid excretion enhancement and kidney function improvement. Mangiferin was found to down-regulate mRNA and protein levels of urate transporter 1 (mURAT1) and glucose transporter 9 (mGLUT9), as well as up-regulate organic anion transporter 1 (mOAT1) in the kidney of hyperuricemic mice. These findings suggested that mangiferin might enhance uric acid excretion and in turn reduce serum uric acid level through the decrease of uric acid reabsorption and the increase of uric acid secretion in hyperuricemic mice. Moreover, mangiferin remarkably up-regulated expression levels of renal organic cation and carnitine transporters (mOCT1, mOCT2, mOCTN1 and mOCTN2), increased urine mUMOD levels, as well as decreased serum and kidney mUMOD levels in hyperuricemic mice, which might be involved in mangiferin-mediated renal protective action.
Animals ; Blood Urea Nitrogen ; Carrier Proteins ; genetics ; metabolism ; Creatinine ; blood ; Glucose Transport Proteins, Facilitative ; genetics ; metabolism ; Hyperuricemia ; blood ; chemically induced ; physiopathology ; urine ; Kidney ; metabolism ; physiopathology ; Male ; Membrane Proteins ; genetics ; metabolism ; Mice ; Octamer Transcription Factor-1 ; genetics ; metabolism ; Organic Anion Transport Protein 1 ; genetics ; metabolism ; Organic Anion Transporters ; genetics ; metabolism ; Organic Cation Transport Proteins ; genetics ; metabolism ; Organic Cation Transporter 2 ; Oxonic Acid ; Protective Agents ; pharmacology ; RNA, Messenger ; metabolism ; Random Allocation ; Solute Carrier Family 22 Member 5 ; Uric Acid ; blood ; urine ; Uromodulin ; blood ; urine ; Xanthones ; pharmacology