RESUMO
RATIONALE & OBJECTIVE: Uromodulin (UMOD) is the most abundant protein found in urine and has emerged as a promising biomarker of tubule health. Circulating UMOD is also detectable, but at lower levels. We evaluated whether serum UMOD levels were associated with the risks of incident kidney failure with replacement therapy (KFRT) and mortality. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: Participants in AASK (the African American Study of Kidney Disease and Hypertension) with available stored serum samples from the 0-, 12-, and 24-month visits for biomarker measurement. PREDICTORS: Baseline log-transformed UMOD and change in UMOD over 2 years. OUTCOMES: KFRT and mortality. ANALYTICAL APPROACH: Cox proportional hazards and mixed-effects models. RESULTS: Among 500 participants with baseline serum UMOD levels (mean age, 54y; 37% female), 161 KFRT events occurred during a median of 8.5 years. After adjusting for baseline demographic factors, clinical factors, glomerular filtration rate, log-transformed urine protein-creatinine ratio, and randomized treatment groups, a 50% lower baseline UMOD level was independently associated with a 35% higher risk of KFRT (adjusted HR, 1.35; 95% CI, 1.07-1.70). For annual UMOD change, each 1-standard deviation lower change was associated with a 67% higher risk of KFRT (adjusted HR, 1.67; 95% CI, 1.41-1.99). Baseline UMOD and UMOD change were not associated with mortality. UMOD levels declined more steeply for metoprolol versus ramipril (P<0.001) as well as for intensive versus standard blood pressure goals (P = 0.002). LIMITATIONS: Small sample size and limited generalizability. CONCLUSIONS: Lower UMOD levels at baseline and steeper declines in UMOD over time were associated with a higher risk of subsequent KFRT in a cohort of African American adults with chronic kidney disease and hypertension. PLAIN-LANGUAGE SUMMARY: Prior studies of uromodulin (UMOD), the most abundant protein in urine, and kidney disease have focused primarily on urinary UMOD levels. The present study evaluated associations of serum UMOD levels with the risks of kidney failure with replacement therapy (KFRT) and mortality in a cohort of African American adults with hypertension and chronic kidney disease. It found that participants with lower levels of UMOD at baseline were more likely to experience KFRT even after accounting for baseline kidney measures. Similarly, participants who experienced steeper annual declines in UMOD also had a heightened risk of kidney failure. Neither baseline nor annual change in UMOD was associated with mortality. Serum UMOD is a promising biomarker of kidney health.
Assuntos
Hipertensão , Insuficiência Renal Crônica , Insuficiência Renal , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Uromodulina , Estudos Prospectivos , Negro ou Afro-Americano , Hipertensão/tratamento farmacológico , Hipertensão/epidemiologia , Hipertensão/complicações , Insuficiência Renal/complicações , Insuficiência Renal Crônica/complicações , Taxa de Filtração Glomerular/fisiologia , BiomarcadoresRESUMO
BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) results from mutations in various genes, including REN, UMOD, MUC1, and HNF1B. ADTKD due to REN mutations (ADTKD-REN) is often characterized as a proteinopathy that triggers the endoplasmic reticulum stress (ERS) cascade, potentially sharing similarities with ADTKD-UMOD and ADTKD-MUC1 at the cellular level. This study, inspired by a patient harboring a W17R mutation, investigates ERS activation by this mutation alongside two other renin variants, W10R and L381P. METHODS: We established stable cell lines expressing both wild-type and mutated renin forms (W17R, W10R, and L381P). Using luciferase reporter assays, RT-qPCR, and confocal microscopy, we evaluated ERS activation, determined the cellular localization of the renin variants, and characterized the mitochondrial network in the W17R line. RESULTS: The L381P line exhibited ERS activation, including transcriptional upregulation of MANF and CRELD2. No ERS activation was observed in the W17R line, while the W10R line exhibited intermediate characteristics. Notably, the W17R variant was misrouted to the mitochondria resulting in changes of the mitochondrial network organisation. CONCLUSIONS: ERS activation is not a universal response to different renin mutations in ADTKD-REN. The pathogenesis of the W17R mutation may involve mitochondrial dysfunction rather than the ER pathway, albeit further research is needed to substantiate this hypothesis fully. Testing CRELD2 and MANF as targeted therapy markers for a specific subgroup of ADTKD-REN patients is recommended. Additionally, fludrocortisone treatment has shown efficacy in stabilizing the renal function of our patient over a four-year period without significant side effects.
Assuntos
Estresse do Retículo Endoplasmático , Retículo Endoplasmático , Mutação , Nefrite Intersticial , Renina , Humanos , Renina/genética , Renina/metabolismo , Estresse do Retículo Endoplasmático/genética , Nefrite Intersticial/genética , Nefrite Intersticial/patologia , Retículo Endoplasmático/metabolismo , Masculino , Linhagem CelularRESUMO
The clinical characteristics of autosomal dominant tubulointerstitial kidney disease (ADTKD) include bland urinary sediment, slowly progressive chronic kidney disease (CKD) with many patients reaching end stage renal disease (ESRD) between age 20 and 70 years, and autosomal dominant inheritance. Due to advances in genetic diagnosis, ADTKD is becoming increasingly recognized as a cause of CKD. Pathogenic variants in UMOD, MUC1, and REN are the most common causes of ADTKD. ADTKD-UMOD is also associated with hyperuricemia and gout. ADTKD-REN often presents in childhood with mild hypotension, CKD, hyperkalemia, acidosis, and anemia. ADTKD-MUC1 patients present only with CKD. This review describes the pathophysiology, genetics, clinical manifestation, and diagnosis for ADTKD, with an emphasis on genetic testing and genetic counseling suggestions for patients.
Assuntos
Testes Genéticos , Insuficiência Renal Crônica , Humanos , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Uromodulina/genética , MutaçãoRESUMO
Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD) is caused by mutations in one of at least five genes and leads to kidney failure usually in mid adulthood. Throughout the literature, variable numbers of families have been reported, where no mutation can be found and therefore termed ADTKD-not otherwise specified. Here, we aim to clarify the genetic cause of their diseases in our ADTKD registry. Sequencing for all known ADTKD genes was performed, followed by SNaPshot minisequencing for the dupC (an additional cytosine within a stretch of seven cytosines) mutation of MUC1. A virtual panel containing 560 genes reported in the context of kidney disease (nephrome) and exome sequencing were then analyzed sequentially. Variants were validated and tested for segregation. In 29 of the 45 registry families, mutations in known ADTKD genes were found, mostly in MUC1. Sixteen families could then be termed ADTKD-not otherwise specified, of which nine showed diagnostic variants in the nephrome (four in COL4A5, two in INF2 and one each in COL4A4, PAX2, SALL1 and PKD2). In the other seven families, exome sequencing analysis yielded potential disease associated variants in novel candidate genes for ADTKD; evaluated by database analyses and genome-wide association studies. For the great majority of our ADTKD registry we were able to reach a molecular genetic diagnosis. However, a small number of families are indeed affected by diseases classically described as a glomerular entity. Thus, incomplete clinical phenotyping and atypical clinical presentation may have led to the classification of ADTKD. The identified novel candidate genes by exome sequencing will require further functional validation.
Assuntos
Doenças Renais Policísticas , Rim Policístico Autossômico Dominante , Adulto , Testes Genéticos , Estudo de Associação Genômica Ampla , Humanos , Mutação , Doenças Renais Policísticas/genética , Rim Policístico Autossômico Dominante/genéticaRESUMO
Autosomal dominant tubulointerstitial kidney disease due to UMOD mutations (ADTKD-UMOD) results in chronic interstitial nephritis, which gradually develops into end-stage renal disease. It is believed that the accumulation of mutant uromodulin causes the endoplasmic reticulum (ER) stress, then leads to the kidney damage. But the underlying mechanism remains unclear. To find the ADTKD-UMOD patients, UMOD gene screening was performed in 26 patients with unexplained chronic interstitial nephritis, during the past 10 years in our department, and among them three ADTKD-UMOD cases were discovered. Routine pathological staining and electron microscopy sections were reviewed again to confirm their kidney lesions. Immunostaining of UMOD and ER stress marker GRP78, as well as CHOP have all been done. The strong colocalization of UMOD with GRP78 and CHOP in ADTKD-UMOD patients but not in other chronic interstitial nephritis patients had been found. Moreover in vitro experiments, ER stress induced by tunicamycin (TM) not only significantly increased the expression of GRP78 and CHOP, but also caused the epithelial to myofibroblast transformation (EMT) of renal tubular epithelial cells, evidenced by decreased expression of E-cadherin and increased expression of vimentin, and extracellular matrix (ECM) deposition, evidenced by increased expression of fibronectin (FN). CHOP knockdown could restore the upregulation of vimentin and FN induced by TM. Thus, specific activation of CHOP in renal tubular epithelial cells induced by UMOD protein might be the key reason of renal interstitial fibrosis in ADTKD-UMOD patients.
Assuntos
Transição Epitelial-Mesenquimal/genética , Nefrite Intersticial/genética , Fator de Transcrição CHOP/metabolismo , Regulação para Cima/genética , Uromodulina/genética , Adulto , Estresse do Retículo Endoplasmático/genética , Feminino , Humanos , Masculino , Mutação , Adulto JovemRESUMO
The glycoprotein uromodulin (UMOD) is the most abundant protein in urine, and N-glycans are critical for many biological functions of UMOD. Comprehensive glycan profiling of UMOD provides valuable information to understand the exact mechanisms of glycan-regulated functions. To perform comprehensive glycosylation analysis of UMOD from urine samples with limited volumes, we developed a streamlined workflow that included UMOD isolation from 5 mL of urine from 6 healthy adult donors (3 males and 3 females) and a glycosylation analysis using a highly sensitive and reproducible nanoLC-MS/MS based glycomics approach. In total, 212 N-glycan compositions were identified from the purified UMOD, and 17% were high-mannose glycans, 2% were afucosylated/asialylated, 3% were neutral fucosylated, 28% were sialylated (with no fucose), 46% were fucosylated and sialylated, and 4% were sulfated. We found that isolation of UMOD resulted in a significant decrease in the relative quantity of high-mannose and sulfated glycans with a significant increase of neutral fucosylated glycans in the UMOD-depleted urine relative to the undepleted urine, but depletion had little impact on the sialylated glycans. To our knowledge, this is the first study to perform comprehensive N-glycan profiling of UMOD using nanoLC-MS/MS. This analytical workflow would be very beneficial for studies with limited sample size, such as pediatric studies, and can be applied to larger patient cohorts not only for UMOD interrogation but also for global glycan analysis.
Assuntos
Glicômica , Espectrometria de Massas em Tandem , Adulto , Criança , Feminino , Glicosilação , Humanos , Masculino , Polissacarídeos , UromodulinaRESUMO
For over 70 years, serum creatinine has remained the primary index for detection and monitoring of kidney disease. Tubulointerstitial damage and fibrosis are highly prognostic for subsequent kidney failure in biopsy studies, yet this pathology is invisible to the clinician in the absence of a biopsy. Recent discovery of biomarkers that reflect distinct aspects of kidney tubule disease have led to investigations of whether these markers can provide additional information on risk of chronic kidney disease (CKD) progression and associated adverse clinical end points, above and beyond estimated glomerular filtration rate and albuminuria. These biomarkers can be loosely grouped into those that mark tubule cell injury (eg, kidney injury molecule 1, monocyte chemoattractant protein 1) and those that mark tubule cell dysfunction (eg, α1-microglobulin, uromodulin). These kidney tubule biomarkers provide new opportunities to monitor response to therapeutics used to treat CKD patients. In this review, we describe results from some unique contributions in this area and discuss the current challenges and requirements in the field to bring these markers to clinical practice. We advocate for a broader assessment of kidney health that moves beyond a focus on the glomerulus, and we highlight how such tools can improve diagnostic accuracy and earlier assessment of therapeutic efficacy or harm in CKD patients.
Assuntos
Insuficiência Renal Crônica , Albuminúria , Biomarcadores , Taxa de Filtração Glomerular , Humanos , Túbulos Renais , Insuficiência Renal Crônica/diagnósticoRESUMO
INTRODUCTION AND HYPOTHESIS: Previous studies have indicated a hereditary component of stress urinary incontinence; however, evidence on candidate genes or single-nucleotide polymorphisms (SNPs) is scarce. We hypothesize a genetic association of female stress urinary incontinence based on significant differences of the urinary and serum proteomic pattern in the identical study population. METHODS: Case-control study of 19 patients and 19 controls. We searched for known SNPs of SUI candidate genes (COL1A1, MMP1, SERPINA5, UMOD) in the database of short genetic variations and PubMed. Genomic DNA was isolated using QIAamp DNA Blood Midi Kit (Qiagen). We performed Sanger sequencing of selected exons and introns. RESULTS: The rs885786 SNP of the SERPINA5 gene was identified in 15 cases and 10 controls (p = 0.09). The rs6113 SNP of the SERPINA5 gene was present in 4 controls compared to 0 cases (p = 0.105). The rs4293393, rs13333226 and rs13335818 SNPs of the UMOD gene were identified in five cases and two controls (p = 0.20), the rs1800012 SNP of the COL1A1 gene in five cases versus four controls (p = 0.24) and the homozygous rs1799750 SNP of the MMP1 gene in eight cases versus five controls (p = 0.18). The combination of the rs885786 SNP of the SERPINA5 gene and rs179970 SNP of the MMP1 gene was detected in ten cases versus five controls (p = 0.072). CONCLUSIONS: We found nonsignificant trends toward associations of SNPs on the SERPINA5, UMOD and MMP1 gene and SUI.
Assuntos
Metaloproteinase 1 da Matriz/genética , Inibidor da Proteína C/genética , Proteoma , Incontinência Urinária por Estresse/genética , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Incontinência Urinária por Estresse/sangue , Incontinência Urinária por Estresse/urinaRESUMO
BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by a pathogenic variant in UMOD (ADTKD-UMOD) is a rare group of diseases characterized by hyperuricaemia with decreased urinary excretion of urate, gout and progressive chronic kidney disease. The mundane clinical characteristics often result in a failure to diagnose ADTKD-UMOD. CASE PRESENTATION: In this report, we describe a 12-year-old boy who presented with polyarthritis, hyperuricaemia and tophi with a family history of 8 affected individuals. Clinical data, blood and urine samples of 3 affected members and 8 unaffected members were collected. Genetic testing of the eight genes (UMOD, HPRT1, PRPS1, MTHFR, REN, HNF1b, URAT1 and G6PC) was performed using Sanger sequencing. A heterozygous missense variant (c.674C > G; p.T225R) in UMOD was found in this boy, his older brother with the same phenotype and his mother with hyperuricaemia, gout and chronic kidney disease. CONCLUSION: This case highlights the importance of family history and genetic testing for definite diagnosis. This novel variant extends the spectrum of known UMOD gene variants and further supports the allelic heterogeneity of ADTKD-UMOD.
Assuntos
Artrite/genética , Gota/genética , Hiperuricemia/genética , Rim/patologia , Nefrite Intersticial/genética , Uromodulina/genética , Criança , Feminino , Humanos , Rim/ultraestrutura , Masculino , Mães , Mutação de Sentido Incorreto , Nefrite Intersticial/patologia , IrmãosRESUMO
African Americans have a 2- to 4-fold greater incidence of end-stage kidney disease (ESKD) than whites, which has long raised the possibility of a genetic cause for this disparity. Recent advances in genetic studies have shown a causal association of polymorphisms at the apolipoprotein L1 gene (APOL1) with the markedly increased risk for the nondiabetic component of the overall disparity in ESKD in African Americans. Although APOL1-associated kidney disease is thought to account for a substantial proportion of ESKD in African Americans, not all the increased risk for ESKD is accounted for, and a complete cataloging of disparities in genetic causes of ESKD eludes our current understanding of genetic-associated kidney disease. Genetic testing aids the screening, diagnosis, prognosis, and treatment of diseases with a genetic basis. Widespread use of genetic testing in clinical practice is limited by the small number of actionable genetic variants, limited health literacy of providers and patients, and underlying complex ethical, legal, and social issues. This perspective reviews racial and ethnic differences associated with genetic diseases and the development of ESKD in African Americans and discusses potential uncertainties associated with our current understanding of penetrance of genetically linked kidney disease and population-attributable risk percent.
Assuntos
Apolipoproteína L1/genética , Negro ou Afro-Americano/genética , Predisposição Genética para Doença/epidemiologia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Falência Renal Crônica/etnologia , Falência Renal Crônica/genética , Negro ou Afro-Americano/estatística & dados numéricos , Estudos de Casos e Controles , Feminino , Testes Genéticos , Disparidades nos Níveis de Saúde , Humanos , Falência Renal Crônica/terapia , Transplante de Rim/estatística & dados numéricos , Masculino , Avaliação das Necessidades , Diálise Renal/estatística & dados numéricos , Estados UnidosRESUMO
BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by UMOD gene mutation (ADTKD-UMOD) is rare in children, characterized by hyperuricemia, gout, and progressive chronic kidney disease. It usually leads to end-stage renal failure at fiftieth decades. Here, we report a 3-year-old Chinese boy in an ADTKD family caused by a novel UMOD gene mutation. CASE PRESENTATION: A 3-year-old boy was admitted to our hospital because of persistent hematuria. Urinalysis showed BLD 2+ without proteinuria. The serum levels of uric acid, creatinine and electrolytes were normal. No renal cyst or calculus was found by ultrasonography. Renal biopsy was performed and focal and segmental glomerulosclerosis was found in 4 glomeruli among 35 glomeruli examined. His father was found with end-stage renal disease (ESRD) at the age of 29, and renal ultrasound showed several cysts in both kidneys. A novel heterozygous mutation (c.1648G > A,p.V550I) in exon 8 of UMOD gene was identified by whole exome sequencing in the family. SCBC Genome Browser alignment showed that V550 were highly conserved in uromodulin among different species. Software predicted that the mutation is suspected to be harmful. By literature review, there are 12 mutations of UMOD gene in 14 Chinese families including only one pediatric case(a 16-year-old girl). CONCLUSIONS: A novel heterozygous mutation (c.1648G > A,p.V550I) in exon 8 of UMOD gene was found in in a Chinese child case with ADTKD-UMOD, which extends our understanding of UMOD gene mutation spectrum and phenotype of ADTKD-UMOD in children.
Assuntos
Predisposição Genética para Doença , Mutação/genética , Nefrite Intersticial/genética , Uromodulina/genética , Biópsia por Agulha , Pré-Escolar , China , Seguimentos , Hematúria/diagnóstico , Hematúria/etiologia , Heterozigoto , Humanos , Imuno-Histoquímica , Testes de Função Renal , Masculino , Nefrite Intersticial/fisiopatologia , Linhagem , Ultrassonografia Doppler , Urinálise/métodosRESUMO
Introduction: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare genetic cause of renal impairment resulting from mutations in the MUC1, UMOD, HNF1B, REN, and SEC61A1 genes. Neither the national or global prevalence of these diseases has been determined. We aimed to establish a database of patients with ADTKD in Ireland and report the clinical and genetic characteristics of these families. Methods: We identified patients via the Irish Kidney Gene Project and referral to the national renal genetics clinic in Beaumont Hospital who met the clinical criteria for ADTKD (chronic kidney disease, bland urinary sediment, and autosomal dominant inheritance). Eligible patients were then invited to undergo genetic testing by a variety of methods including panel-based testing, whole exome sequencing and, in five families who met the criteria for diagnosis of ADTKD but were negative for causal genetic mutations, we analyzed urinary cell smears for the presence of MUC1fs protein. Results: We studied 54 individuals from 16 families. We identified mutations in the MUC1 gene in three families, UMOD in five families, HNF1beta in two families, and the presence of abnormal MUC1 protein in urine smears in three families (one of which was previously known to carry the genetic mutation). We were unable to identify a mutation in 4 families (3 of whom also tested negative for urinary MUC1fs). Conclusions: There are 4443 people with ESRD in Ireland, 24 of whom are members of the cohort described herein. We observe that ADTKD represents at least 0.54% of Irish ESRD patients.
Assuntos
Genes Dominantes , Falência Renal Crônica/genética , Túbulos Renais/patologia , Adulto , Idoso , Estudos Transversais , Feminino , Testes Genéticos/estatística & dados numéricos , Fator 1-beta Nuclear de Hepatócito/genética , Humanos , Irlanda/epidemiologia , Falência Renal Crônica/epidemiologia , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Mucina-1/genética , Mutação , Prevalência , Uromodulina/genéticaRESUMO
RATIONALE & OBJECTIVE: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare underdiagnosed cause of end-stage renal disease (ESRD). ADTKD is caused by mutations in at least 4 different genes: MUC1, UMOD, HNF1B, and REN. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 56 families (131 affected individuals) with ADTKD referred from different Spanish hospitals. Clinical, laboratory, radiologic, and pathologic data were collected, and genetic testing for UMOD, MUC1, REN, and HNF1B was performed. PREDICTORS: Hyperuricemia, ultrasound findings, renal histology, genetic mutations. OUTCOMES: Age at ESRD, rate of decline in estimated glomerular filtration rate. RESULTS: ADTKD was diagnosed in 25 families (45%), 9 carried UMOD pathogenic variants (41 affected members), and 16 carried the MUC1 pathogenic mutation c.(428)dupC (90 affected members). No pathogenic variants were identified in REN or HNF1B. Among the 77 individuals who developed ESRD, median age at onset of ESRD was 51 years for those with ADTKD-MUC1 versus 56 years (P=0.1) for those with ADTKD-UMOD. Individuals with the MUC1 duplication presented higher risk for developing ESRD (HR, 2.24; P=0.03). The slope of decline in estimated glomerular filtration rate showed no significant difference between groups (-3.0mL/min/1.73m2 per year in the ADTKD-UMOD group versus -3.9mL/min/1.73m2 per year in the ADTKD-MUC1 group; P=0.2). The prevalence of hyperuricemia was significantly higher in individuals with ADTKD-UMOD (87% vs 54%; P=0.006). Although gout occurred more frequently in this group, the difference was not statistically significant (24% vs 7%; P=0.07). LIMITATIONS: Relatively small Spanish cohort. MUC1 analysis limited to cytosine duplication. CONCLUSIONS: The main genetic cause of ADTKD in our Spanish cohort is the MUC1 pathogenic mutation c.(428)dupC. Renal survival may be worse in individuals with the MUC1 mutation than in those with UMOD mutations. Clinical presentation does not permit distinguishing between these variants. However, hyperuricemia and gout are more frequent in individuals with ADTKD-UMOD.
Assuntos
Falência Renal Crônica/diagnóstico , Falência Renal Crônica/genética , Mucina-1/genética , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/genética , Uromodulina/genética , Adulto , Feminino , Humanos , Falência Renal Crônica/epidemiologia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Nefrite Intersticial/diagnóstico , Nefrite Intersticial/epidemiologia , Nefrite Intersticial/genética , Rim Policístico Autossômico Dominante/epidemiologia , Espanha/epidemiologiaRESUMO
BACKGROUND: Acute kidney injury (AKI) is a common complication of cardiopulmonary bypass surgery (CPB) in children. Several promising postoperative AKI biomarkers have been identified, but no preoperative biomarkers are available. We evaluated the association of urinary uromodulin (uUMOD) with postoperative AKI. METHODS: One hundred and one children undergoing CPB were enrolled. Urine was collected prior to CPB, and AKI was defined as â§50% increase in serum creatinine from preoperative baseline within 48 h of surgery. RESULTS: Forty-seven patients (47%) developed AKI, and 92% of participants in the lowest quartile of preoperative uUMOD concentrations developed AKI compared with 8% in the highest quartile. Patients with preoperative uUMOD levels in the lowest quartile had 132.3× increased risk of postoperative AKI versus the highest quartile. Raw uUMOD levels were significantly lower in patients with AKI vs. no AKI. Significance was unchanged after correcting uUMOD levels for urinary creatinine. Receiver operating characteristic analysis showed preoperative uUMOD strongly predicted postoperative AKI, with area under the curve (AUC) 0.90. Stepwise logistic regression analysis revealed a model combining uUMOD, and bypass time predicted AKI at p<0.001. Neither Risk Adjustment for Congenital Heart Surgery 1 (RACHS) score nor age improved the model's ability to predict AKI. Independent analysis demonstrated that while bypass time was associated with AKI, the predictive ability of bypass time (AUC 0.77) was less than that of preoperative uUMOD levels (AUC 0.9). CONCLUSIONS: Children with lowest preoperative levels of uUMOD have greatly increased risk of AKI post-CPB. If uUMOD were used to risk-stratify patients undergoing CPB, clinical measures could be taken to minimize AKI development.
Assuntos
Injúria Renal Aguda/etiologia , Biomarcadores/urina , Ponte Cardiopulmonar/efeitos adversos , Uromodulina/urina , Injúria Renal Aguda/urina , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Testes de Função Renal , Masculino , Complicações Pós-Operatórias , Período Pré-Operatório , Curva ROC , Medição de Risco/métodosRESUMO
BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by mutations in the UMOD gene (ADTKD-UMOD) is considered rare and often remains unrecognised. We aimed to establish the prevalence of genetic kidney diseases, ADTKD and ADTKD-UMOD in adult chronic kidney disease (CKD) patients, and to investigate characteristic features. METHODS: We sent questionnaires on family history to all patients with CKD stages 3-5 in our tertiary renal centre to identify patients with inherited renal disease. Details on clinical and family history were obtained from patient interviews and clinical records. Sanger sequencing of the UMOD gene was performed from blood or saliva samples. RESULTS: 2027 of 3770 sent questionnaires were returned. 459 patients reported a family history, which was consistent with inherited kidney disease in 217 patients. 182 non-responders with inherited kidney diseases were identified through a database search. Of these 399 individuals, 252 had autosomal dominant polycystic kidney disease (ADPKD), 28 had ADTKD, 25 had Alports, and 44 were unknown, resulting in 11% of CKD 3-5 patients and 19% of end-stage renal disease patients with genetic kidney diseases. Of the unknown, 40 were genotyped, of whom 31 had findings consistent with ADTKD. 30% of unknowns and 39% of unknowns with ADTKD had UMOD mutations. Altogether, 35 individuals from 18 families were found to have ten distinct UMOD mutations (three novel), making up 1% of patients with CKD 3-5, 2% of patients with end-stage renal disease, 9% of inherited kidney diseases and 56% with ADTKD. ADTKD-UMOD was the most common genetic kidney disease after ADPKD with a population prevalence of 9 per million. Less proteinuria and haematuria, but not hyperuricaemia or gout were predictive of ADTKD-UMOD. The main limitations of the study are the single-centre design and a predominantly Caucasian population. CONCLUSIONS: The prevalence of genetic kidney diseases and ADTKD-UMOD is significantly higher than previously described. Clinical features poorly predicted ADTKD-UMOD, highlighting the need for genetic testing guided by family history alone.
Assuntos
Nefrite Intersticial/genética , Rim Policístico Autossômico Dominante/genética , Insuficiência Renal Crônica/genética , Inquéritos e Questionários , Uromodulina/genética , Idoso , Feminino , Testes Genéticos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/diagnóstico , Nefrite Intersticial/epidemiologia , Rim Policístico Autossômico Dominante/diagnóstico , Rim Policístico Autossômico Dominante/epidemiologia , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologiaRESUMO
BACKGROUND: Laboratory studies suggest that urinary uromodulin, the most common protein in the urine of healthy adults, may protect against urinary tract infection (UTI). Epidemiologic studies evaluating this relationship in humans are lacking. STUDY DESIGN: Prospective longitudinal cohort study. SETTING & PARTICIPANTS: 953 participants enrolled in the Cardiovascular Health Study. PREDICTOR: Uromodulin assayed using enzyme-linked immunosorbent assay in spot urine samples. OUTCOMES: Composite of outpatient UTI events or UTI-related hospitalizations and each of them individually identified using International Classification of Diseases, Ninth Revision (ICD-9) codes using negative binomial regression with robust standard errors adjusted for age, race, sex, body mass index, diabetes, estimated glomerular filtration rate, and urinary albumin and urinary creatinine excretion. RESULTS: Median uromodulin level was 25.9 (IQR, 17.3-38.9) µg/mL, mean age of participants was 78 years, 61% were women, and 15% were black. There were 331 outpatient UTI events and 87 UTI-related hospitalizations among 186 participants during a median 9.9 years of follow-up. Persons in the highest quartile (>38.93µg/mL) of uromodulin concentration had a significantly lower risk for the composite outcome (incidence rate ratio [IRR], 0.47; 95% CI, 0.29-0.79) compared with those in the lowest quartile (≤17.26µg/mL). This association remained significant for outpatient UTI events (highest vs lowest quartile even after excluding those with prior UTI: IRR, 0.42; 95% CI, 0.23-0.77). The direction of association with UTI hospitalization was similar, but not statistically significant (IRR, 0.78; 95% CI, 0.39-1.58). LIMITATIONS: Use of ICD-9 codes to identify outcomes and lack of generalizability to younger populations. CONCLUSIONS: High urinary uromodulin levels are associated with lower risk for UTI in older community-dwelling adults independent of traditional UTI risk factors. This finding supports prior laboratory data indicating a protective role of uromodulin against UTI. Further research is needed to understand if this may lead to new treatments to prevent or treat UTI.
Assuntos
Infecções Urinárias/urina , Uromodulina/urina , Idoso , Idoso de 80 Anos ou mais , Albuminúria/urina , Estudos de Coortes , Creatinina/urina , Ensaio de Imunoadsorção Enzimática , Feminino , Taxa de Filtração Glomerular , Hospitalização/estatística & dados numéricos , Humanos , Vida Independente , Estudos Longitudinais , Masculino , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Proteção , Fatores de Risco , Infecções Urinárias/epidemiologiaRESUMO
BACKGROUND: In the absence of cytogenetic abnormality, fetuses with congenital anomalies of the kidney and urinary tract (CAKUT) with/without other structural anomalies show a higher likelihood of monogenic causes; however, defining the underlying pathology can be challenging. Here, we investigate the value of whole-exome sequencing (WES) in fetuses with CAKUT but normal findings upon karyotyping and chromosome microarray analysis. METHODS: WES was performed on DNA from the cord blood of 30 fetuses with unexplained CAKUT with/without other structural anomalies. In the first 23 cases, sequencing was initially performed on fetal DNA only; for the remaining seven cases, the trio of fetus, mother and father was sequenced simultaneously. RESULTS: Of the 30 cases, pathogenic variants were identified in 4 (13%) (UMOD, NEK8, HNF1B and BBS2) and incidental variants in 2 (7%) (HSPD1 and GRIN2B). Furthermore, two of the above four cases had other anomalies in addition to CAKUT. Thus, the detection rate was only 2/22 (9.1%) for isolated CAKUT and 2/8 (25%) for CAKUT with other abnormalities. CONCLUSIONS: Applying WES to the prenatal diagnostic approach in CAKUT fetuses with or without other anomalies allows for an accurate and early etiology-based diagnosis and improved clinical management. To expedite interpretation of the results, trio sequencing should be employed; however, interpretation may nevertheless be compromised by incomplete coverage of all relevant genes.
Assuntos
Exoma , Anormalidades Urogenitais/genética , Adulto , Sequência de Aminoácidos , Amniocentese , Sequência de Bases , Análise Mutacional de DNA , Feminino , Feto , Humanos , Rim/anormalidades , Rim/diagnóstico por imagem , Técnicas de Diagnóstico Molecular , Gravidez , Ultrassonografia Pré-Natal , Sistema Urinário/anormalidades , Sistema Urinário/diagnóstico por imagem , Anormalidades Urogenitais/diagnóstico por imagem , Sequenciamento do Exoma , Adulto JovemRESUMO
The renal phenotype in Bardet-Biedl syndrome (BBS) is highly variable. The present study describes renal findings in 41 BBS patients and analyzes the pathogenesis of hyposthenuria, the most common renal dysfunction. Five of 41 patients (12%) showed an estimated glomerular filtration rate < 60 ml·min-1·1.73 m-2 Urine protein and urine albumin-to-creatinine ratio were over 200 and 30 mg/g in 9/24 and 7/23 patients, respectively. Four of 41 patients showed no renal anomalies on ultrasound. Twenty of 34 patients had hyposthenuria in the absence of renal insufficiency. In all 8 of the hyposthenuric patients studied, dDAVP failed to elevate urine osmolality (Uosm), suggesting a nephrogenic origin. Interestingly, water loading (WL) did not result in a significant reduction of Uosm, indicating combined concentrating and diluting defects. dDAVP infusion induced a significant increase of plasma Factor VIII and von Willebrand Factor levels, supporting normal function of the type 2 vasopressin receptor at least in endothelial cells. While urinary aquaporin 2 (u-AQP2) abundance was not different between patients and controls at baseline, the dDAVP-induced increased u-AQP2 and the WL-induced reduction of u-AQP2 were blunted in patients with a combined concentrating and diluting defect, suggesting a potential role of AQP2 in the defective regulation of water absorption. Urine Uromodulin excretion was reduced in all hyposthenuric patients, suggesting a thick ascending limb defect. Interestingly, renal Na, Cl, Ca, but not K handling was impaired after acute WL but not at basal. In summary, BBS patients show combined urinary concentration and dilution defects; a thick ascending limb and collecting duct tubulopathy may underlie impaired water handling.
Assuntos
Aquaporina 2/urina , Síndrome de Bardet-Biedl/fisiopatologia , Taxa de Filtração Glomerular/fisiologia , Rim/fisiopatologia , Uromodulina/urina , Adolescente , Adulto , Síndrome de Bardet-Biedl/urina , Criança , Pré-Escolar , Feminino , Humanos , Capacidade de Concentração Renal/fisiologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto JovemRESUMO
BACKGROUND: Several genome-wide association studies revealed that several variants of UMOD gene were related to the estimated glomerular filtration rate (eGFR), CKD or hypertension. In this study, we investigated the association between a common variant rs13333226 in the promoter region of UMOD gene and end stage renal disease (ESRD). METHODS: Variant rs13333226 of UMOD gene was genotyped by using the ABI Real time TaqMan allelic discrimination assay in a case-control study including 638 unrelated patients with ESRD and 366 controls. RESULTS: The frequency of UMOD SNP rs13333226 GG/GA genotype was significantly higher (36.83% vs. 20.22%, P = 4.02 × 10-8) and the frequency of G allele was much higher (19.04% vs. 11.20%, P = 4.00 × 10-6) in the patients with ESRD than in the controls. The G allele was associated with an increased risk of ESRD (odds ratio 2.30, 95% confidence interval 1.70-3.11, P = 6.10 × 10-8). And G allele (odds ratio 2.33, 95% confidence interval 1.32-4.13, P = 3.65 × 10-3) was associated independently with ESRD. CONCLUSIONS: A common variation rs13333226 in the promoter region of UMOD gene was independently associated with ESRD in Han Chinese.
Assuntos
Falência Renal Crônica/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas/genética , Uromodulina/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Falência Renal Crônica/patologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Adulto JovemRESUMO
Uromodulin (UMOD)-associated kidney disease (UAKD) belongs to the hereditary progressive ER storage diseases caused by maturation defects of mutant UMOD protein. Current treatments of UAKD patients are symptomatic and cannot prevent disease progression. Two in vitro studies reported a positive effect of the chemical chaperone sodium 4-phenylbutyrate (4-PBA) on mutant UMOD maturation. Thus, 4-PBA was suggested as a potential treatment for UAKD. This study evaluated the effects of 4-PBA in two mouse models of UAKD. In contrast to previous in vitro studies, treatment with 4-PBA did not increase HSP70 expression or improve maturation and trafficking of mutant UMOD in vivo. Kidney function of UAKD mice was actually deteriorated by 4-PBA treatment. In transfected tubular epithelial cells, 4-PBA did not improve maturation but increased the expression level of both mutant and wild-type UMOD protein. Activation of NF-κB pathway in thick ascending limb of Henle's loop cells of UAKD mice was detected by increased abundance of RelB and phospho-IκB kinase α/ß, an indirect activator of NF-κB. Furthermore, the abundance of NF-κB1 p105/p50, NF-κB2 p100/p52, and TRAF2 was increased in UAKD. NF-κB activation was identified as a novel disease mechanism of UAKD and might be a target for therapeutic intervention.