Autosomal dominant tubulointerstitial kidney disease (ADTKD) refers to a group of disorders with a bland urinary sediment, slowly progressive chronic kidney disease (CKD), and autosomal dominant inheritance. Due to advances in genetic diagnosis, ADTKD is becoming increasingly recognized as a cause of CKD in both children and adults. ADTKD-REN presents in childhood with mild hypotension, CKD, hyperkalemia, acidosis, and anemia. ADTKD-UMOD is associated with gout and CKD that may present in adolescence and slowly progresses to kidney failure. HNF1β mutations often present in childhood with anatomic abnormalities such as multicystic or dysplastic kidneys, as well as CKD and a number of other extra-kidney manifestations. ADTKD-MUC1 is less common in childhood, and progressive CKD is its sole clinical manifestation, usually beginning in the late teenage years. This review describes the pathophysiology, genetics, clinical characteristics, diagnosis, and treatment of the different forms of ADTKD, with an emphasis on diagnosis. We also present data on kidney function in children with ADTKD from the Wake Forest Rare Inherited Kidney Disease Registry.

• Klíčová slova
• Autosomal dominant, Chronic kidney disease, HNF1β, Inherited, Mucin-1, Pediatric, Renin, Uromodulin,
• MeSH
• chronická renální insuficience * MeSH
• dítě MeSH
• dna (nemoc) * MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mutace MeSH
• polycystická choroba ledvin * MeSH
• uromodulin genetika   MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• uromodulin MeSH

The OAT1 (SLC22A6) and OAT3 (SLC22A8) urate transporters are located on the basolateral membrane of the proximal renal tubules, where they ensure the uptake of uric acid from the urine back into the body. In a cohort of 150 Czech patients with primary hyperuricemia and gout, we examined the coding regions of both genes using PCR amplification and Sanger sequencing. Variants p.P104L (rs11568627) and p.A190T (rs146282438) were identified in the gene for solute carrier family 22 member 6 (SLC22A6) and variants p.R149C (rs45566039), p.V448I (rs11568486) and p.R513Q (rs145474422) in the gene solute carrier family 22 member 8 (SLC22A8). We performed a functional study of these rare non-synonymous variants using the HEK293T cell line. We found that only p.R149C significantly reduced uric acid transport in vitro. Our results could deepen the understanding of uric acid handling in the kidneys and the molecular mechanism of uric acid transport by the OAT family of organic ion transporters.

• Klíčová slova
• OAT1, OAT3, gout, hyperuricemia, urate transport,
• MeSH
• biologický transport MeSH
• dna (nemoc) * genetika   metabolismus   MeSH
• HEK293 buňky MeSH
• hyperurikemie * genetika   MeSH
• kyselina močová metabolismus   MeSH
• lidé MeSH
• přenašeče organických aniontů nezávislé na sodíku * genetika   MeSH
• protein 1 přenášející organické anionty * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• kyselina močová MeSH
• organic anion transport protein 3 MeSH Prohlížeč
• přenašeče organických aniontů nezávislé na sodíku * MeSH
• protein 1 přenášející organické anionty * MeSH

Renal hypouricemia (RHUC) is caused by an inherited defect in the main reabsorption system of uric acid, SLC22A12 (URAT1) and SLC2A9 (GLUT9). RHUC is characterized by a decreased serum uric acid concentration and an increase in its excreted fraction. Patients suffer from hypouricemia, hyperuricosuria, urolithiasis, and even acute kidney injury. We report clinical, biochemical, and genetic findings in a cohort recruited from the Košice region of Slovakia consisting of 27 subjects with hypouricemia and relatives from 11 families, 10 of whom were of Roma ethnicity. We amplified, directly sequenced, and analyzed all coding regions and exon-intron boundaries of the SLC22A12 and SLC2A9 genes. Sequence analysis identified dysfunctional variants c.1245_1253del and c.1400C>T in the SLC22A12 gene, but no other causal allelic variants were found. One heterozygote and one homozygote for c.1245_1253del, nine heterozygotes and one homozygote for c.1400C>T, and two compound heterozygotes for c.1400C>T and c.1245_1253del were found in a total of 14 subjects. Our result confirms the prevalence of dysfunctional URAT1 variants in Roma subjects based on analyses in Slovak, Czech, and Spanish cohorts, and for the first time in a Macedonian Roma cohort. Although RHUC1 is a rare inherited disease, the frequency of URAT1-associated variants indicates that this disease is underdiagnosed. Our findings illustrate that there are common dysfunctional URAT1 allelic variants in the general Roma population that should be routinely considered in clinical practice as part of the diagnosis of Roma patients with hypouricemia and hyperuricosuria exhibiting clinical signs such as urolithiasis, nephrolithiasis, and acute kidney injury.

• Klíčová slova
• Roma, SLC22A12, URAT1, ethnic specificity, renal hypouricemia,
• Publikační typ
• časopisecké články MeSH

The ABCG2 gene is a well-established hyperuricemia/gout risk locus encoding a urate transporter that plays a crucial role in renal and intestinal urate excretion. Hitherto, p.Q141K-a common variant of ABCG2 exhibiting approximately one half the cellular function compared to the wild-type-has been reportedly associated with early-onset gout in some populations. However, compared with adult-onset gout, little clinical information is available regarding the association of other uricemia-associated genetic variations with early-onset gout; the latent involvement of ABCG2 in the development of this disease requires further evidence. We describe a representative case of familial pediatric-onset hyperuricemia and early-onset gout associated with a dysfunctional ABCG2, i.e., a clinical history of three generations of one Czech family with biochemical and molecular genetic findings. Hyperuricemia was defined as serum uric acid (SUA) concentrations 420 μmol/L for men or 360 μmol/L for women and children under 15 years on two measurements, performed at least four weeks apart. The proband was a 12-year-old girl of Roma ethnicity, whose SUA concentrations were 397-405 µmol/L. Sequencing analyses focusing on the coding region of ABCG2 identified two rare mutations-c.393G>T (p.M131I) and c.706C>T (p.R236X). Segregation analysis revealed a plausible link between these mutations and hyperuricemia and the gout phenotype in family relatives. Functional studies revealed that p.M131I and p.R236X were functionally deficient and null, respectively. Our findings illustrate why genetic factors affecting ABCG2 function should be routinely considered in clinical practice as part of a hyperuricemia/gout diagnosis, especially in pediatric-onset patients with a strong family history.

• Klíčová slova
• ABCG2 genotype, Roma, SUA-lowering therapy, clinico-genetic analysis, ethnic specificity, genetic variations, precision medicine, rare variant, serum uric acid, urate transporter,
• MeSH
• ABC transportér z rodiny G, člen 2 genetika   metabolismus   MeSH
• dítě MeSH
• dna (nemoc) komplikace   genetika   MeSH
• dospělí MeSH
• fenotyp MeSH
• genetická predispozice k nemoci MeSH
• HEK293 buňky MeSH
• hyperurikemie krev   komplikace   genetika   MeSH
• jednonukleotidový polymorfismus * MeSH
• kyselina močová krev   MeSH
• lidé MeSH
• mutace MeSH
• nádorové proteiny genetika   metabolismus   MeSH
• přenašeče organických aniontů genetika   metabolismus   MeSH
• rodokmen MeSH
• transfekce MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 MeSH
• ABCG2 protein, human MeSH Prohlížeč
• kyselina močová MeSH
• nádorové proteiny MeSH
• přenašeče organických aniontů MeSH
• urate transporter MeSH Prohlížeč

OBJECTIVE: Uric acid is the end product of purine metabolism in humans, and increased serum uric acid concentrations lead to gout. The objective of the current study was to identify factors that are independently associated with serum uric acid concentrations in a cohort of Czech control individuals. METHODS: The cohort consisted of 589 healthy subjects aged 18-65 years. We studied the associations between the serum uric acid concentration and the following: (i) demographic, anthropometric and other variables previously reported to be associated with serum uric acid concentrations; (ii) the presence of metabolic syndrome and the levels of metabolic syndrome components; and (iii) selected genetic variants of the MTHFR (c.665C>T, c.1286A>C), SLC2A9 (c.844G>A, c.881G>A) and ABCG2 genes (c.421C>A). A backward model selection procedure was used to build two multiple linear regression models; in the second model, the number of metabolic syndrome criteria that were met replaced the metabolic syndrome-related variables. RESULTS: The models had coefficients of determination of 0.59 and 0.53. The serum uric acid concentration strongly correlated with conventional determinants including male sex, and with metabolic syndrome-related variables. In the simplified second model, the serum uric acid concentration positively correlated with the number of metabolic syndrome criteria that were met, and this model retained the explanatory power of the first model. Moderate wine drinking did not increase serum uric acid concentrations, and the urate transporter ABCG2, unlike MTHFR, was a genetic determinant of serum uric acid concentrations. CONCLUSION: Metabolic syndrome, moderate wine drinking and the c.421C>A variant in the ABCG gene are independently associated with the serum uric acid concentration. Our model indicates that uric acid should be clinically monitored in persons with metabolic syndrome.

• MeSH
• ABC transportér z rodiny G, člen 2 MeSH
• ABC transportéry krev   genetika   MeSH
• dospělí MeSH
• exprese genu MeSH
• jednonukleotidový polymorfismus * MeSH
• kohortové studie MeSH
• kyselina močová krev   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metabolický syndrom krev   genetika   patologie   MeSH
• methylentetrahydrofolátreduktasa (NADPH2) krev   genetika   MeSH
• mladiství MeSH
• modely genetické MeSH
• nádorové proteiny krev   genetika   MeSH
• pití alkoholu krev   genetika   patologie   MeSH
• proteiny usnadňující transport glukosy krev   genetika   MeSH
• regresní analýza MeSH
• senioři MeSH
• sexuální faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladiství MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ABC transportér z rodiny G, člen 2 MeSH
• ABC transportéry MeSH
• ABCG2 protein, human MeSH Prohlížeč
• kyselina močová MeSH
• methylentetrahydrofolátreduktasa (NADPH2) MeSH
• MTHFR protein, human MeSH Prohlížeč
• nádorové proteiny MeSH
• proteiny usnadňující transport glukosy MeSH
• SLC2A9 protein, human MeSH Prohlížeč