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BACKGROUND: Molecular mechanisms of kidney stone formation remain unknown in most patients. Previous studies have shown a high heritability of nephrolithiasis, but data on the prevalence and characteristics of genetic disease in unselected adults with nephrolithiasis are lacking. This study was conducted to fill this important knowledge gap. METHODS: We performed whole exome sequencing in 787 participants in the Bern Kidney Stone Registry, an unselected cohort of adults with one or more past kidney stone episodes [kidney stone formers (KSFs)] and 114 non-kidney stone formers (NKSFs). An exome-based panel of 34 established nephrolithiasis genes was analysed and variants assessed according to American College of Medical Genetics and Genomics criteria. Pathogenic (P) or likely pathogenic (LP) variants were considered diagnostic. RESULTS: The mean age of KSFs was 47 ± 15 years and 18% were first-time KSFs. A Mendelian kidney stone disease was present in 2.9% (23/787) of KSFs. The most common genetic diagnoses were cystinuria (SLC3A1, SLC7A9; n = 13), vitamin D-24 hydroxylase deficiency (CYP24A1; n = 5) and primary hyperoxaluria (AGXT, GRHPR, HOGA1; n = 3). Of the KSFs, 8.1% (64/787) were monoallelic for LP/P variants predisposing to nephrolithiasis, most frequently in SLC34A1/A3 or SLC9A3R1 (n = 37), CLDN16 (n = 8) and CYP24A1 (n = 8). KSFs with Mendelian disease had a lower age at the first stone event (30 ± 14 versus 36 ± 14 years; P = .003), were more likely to have cystine stones (23.4% versus 1.4%) and less likely to have calcium oxalate monohydrates stones (31.9% versus 52.5%) compared with KSFs without a genetic diagnosis. The phenotype of KSFs with variants predisposing to nephrolithiasis was subtle and showed significant overlap with KSFs without diagnostic variants. In NKSFs, no Mendelian disease was detected and LP/P variants were significantly less prevalent compared with KSFs (1.8% versus 8.1%). CONCLUSION: Mendelian disease is uncommon in unselected adult KSFs, yet variants predisposing to nephrolithiasis are significantly enriched in adult KSFs.
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Cálculos Renais , Humanos , Cálculos Renais/genética , Cálculos Renais/epidemiologia , Cálculos Renais/etiologia , Feminino , Masculino , Prevalência , Pessoa de Meia-Idade , Adulto , Sequenciamento do Exoma , Sistema de Registros , Nefrolitíase/genética , Nefrolitíase/epidemiologia , Nefrolitíase/etiologiaRESUMO
SIGNIFICANCE STATEMENT: Thiazide diuretics (thiazides) are among the most widely prescribed drugs worldwide, but their use is associated with glucose intolerance and new-onset diabetes mellitus. The molecular mechanisms remain elusive. Our study reveals that thiazides attenuate insulin secretion through inhibition of the mitochondrial carbonic anhydrase isoform 5b (CA5b) in pancreatic ß cells. We furthermore discovered that pancreatic ß cells express only one functional carbonic anhydrase isoform, CA5b, which is critical in replenishing oxaloacetate in the mitochondrial tricarboxylic acid (TCA) cycle (anaplerosis). These findings explain the mechanism for thiazide-induced glucose intolerance and reveal a fundamental role of CA5b in TCA cycle anaplerosis and insulin secretion in ß cells. BACKGROUND: Thiazide diuretics are associated with glucose intolerance and new-onset diabetes mellitus. Previous studies demonstrated that thiazides attenuate insulin secretion, but the molecular mechanisms remain elusive. We hypothesized that thiazides attenuate insulin secretion via one of the known molecular thiazide targets in ß cells. METHODS: We performed static insulin secretion experiments with islets of wild-type, Sodium/chloride co-transporter (NCC) (SLC12A3), and sodium-driven chloride/bicarbonate exchanger (NDCBE) (SLC4A8) knock-out (KO) mice and with murine Min6 cells with individual knockdown of carbonic anhydrase (CA) isoforms to identify the molecular target of thiazides in ß cells. CA isoform 5b (CA5b) KO mice were then used to assess the role of the putative thiazide target CA5b in ß -cell function and in mediating thiazide sensitivity in vitro and in vivo . RESULTS: Thiazides inhibited glucose- and sulfonylurea-stimulated insulin secretion in islets and Min6 cells at pharmacologically relevant concentrations. Inhibition of insulin secretion by thiazides was CO 2 /HCO 3- -dependent, not additive to unselective CA inhibition with acetazolamide, and independent of extracellular potassium. By contrast, insulin secretion was unaltered in islets of mice lacking the known molecular thiazide targets NCC or NDCBE. CA expression profiling with subsequent knockdown of individual CA isoforms suggested mitochondrial CA5b as a molecular target. In support of these findings, thiazides significantly attenuated Krebs cycle anaplerosis through reduction of mitochondrial oxaloacetate synthesis. CA5b KO mice were resistant to thiazide-induced glucose intolerance, and thiazides did not alter insulin secretion in CA5b KO islets. CONCLUSIONS: Thiazides attenuate insulin secretion via inhibition of the mitochondrial CA5b isoform in ß cells of mice.
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Anidrases Carbônicas , Diabetes Mellitus , Intolerância à Glucose , Células Secretoras de Insulina , Ilhotas Pancreáticas , Camundongos , Animais , Secreção de Insulina , Tiazidas/farmacologia , Inibidores de Simportadores de Cloreto de Sódio/metabolismo , Inibidores de Simportadores de Cloreto de Sódio/farmacologia , Cloretos/metabolismo , Glucose/metabolismo , Anidrases Carbônicas/metabolismo , Sódio/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/metabolismoRESUMO
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by a unique bone and mineral phenotype. The impact of tolvaptan treatment on mineral metabolism and bone mineral density (BMD) is unknown. METHODS: We conducted an analysis in the Bern ADPKD Registry, a prospective observational cohort study. Mineral metabolism parameters were measured at baseline and every 12 months thereafter. BMD was determined by dual-energy X-ray absorptiometry at baseline and after 3 years. Multivariable mixed-effects regression models were applied to assess changes in mineral metabolism parameters and BMD associated with tolvaptan treatment. RESULTS: A total of 189 participants (122 without and 67 with subsequent tolvaptan treatment) were included in the analysis. During follow-up, tolvaptan treatment was associated with increased BMD at the femoral neck {ß = 0.092 [95% confidence interval (CI) 0.001-0.183], P = .047}. In addition, tolvaptan treatment was associated with higher plasma magnesium [ß = 0.019 (95% CI 0.001-0.037), P = .037], bicarbonate [ß = 0.972 (95% CI 0.242-1.702), P = .009] and urine pH [ß = 0.214 (95% CI 0.056-0.372), P = .008] and lower parathyroid hormone [ß = -0.191 (95% CI -0.328 to -0.053), P = .006], 1,25(OH)D3 [ß = -0.126 (95% CI -0.235 to -0.164), P = .024] and fractional urinary magnesium excretion [ß = -0.473 (95% CI -0.622 to -0.324), P < .001]. CONCLUSIONS: Chronic tolvaptan treatment is associated with increased femoral BMD and significant changes in both mineral metabolism and acid-base parameters in ADPKD patients.
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Rim Policístico Autossômico Dominante , Humanos , Tolvaptan/uso terapêutico , Rim Policístico Autossômico Dominante/complicações , Rim Policístico Autossômico Dominante/tratamento farmacológico , Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Densidade Óssea , Estudos Prospectivos , MagnésioRESUMO
NHA2 is a sodium/proton exchanger associated with arterial hypertension in humans, but the role of NHA2 in kidney function and blood pressure homeostasis is currently unknown. Here we show that NHA2 localizes almost exclusively to distal convoluted tubules in the kidney. NHA2 knock-out mice displayed reduced blood pressure, normocalcemic hypocalciuria and an attenuated response to the thiazide diuretic hydrochlorothiazide. Phosphorylation of the thiazide-sensitive sodium/chloride cotransporter NCC and its upstream activating kinase Ste20/SPS1-related proline/alanine rich kinase (SPAK), as well as the abundance of with no lysine kinase 4 (WNK4), were significantly reduced in the kidneys of NHA2 knock-out mice. In vitro experiments recapitulated these findings and revealed increased WNK4 ubiquitylation and enhanced proteasomal WNK4 degradation upon loss of NHA2. The effect of NHA2 on WNK4 stability was dependent from the ubiquitylation pathway protein Kelch-like 3 (KLHL3). More specifically, loss of NHA2 selectively attenuated KLHL3 phosphorylation and blunted protein kinase A- and protein kinase C-mediated decrease of WNK4 degradation. Phenotype analysis of NHA2/NCC double knock-out mice supported the notion that NHA2 affects blood pressure homeostasis by a kidney-specific and NCC-dependent mechanism. Thus, our data show that NHA2 as a critical component of the WNK4-NCC pathway and is a novel regulator of blood pressure homeostasis in the kidney.
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Prótons , Sódio , Pressão Sanguínea , Rim/metabolismo , Fosforilação , Sódio/metabolismo , Simportadores de Cloreto de Sódio/metabolismo , Membro 3 da Família 12 de Carreador de Soluto/genética , Membro 3 da Família 12 de Carreador de Soluto/metabolismoRESUMO
Neuropilin1 (Nrp1) is a co-receptor best known to regulate the development of endothelial cells and is a target of anticancer therapies. However, its role in other vascular cells including pericytes is emergent. The kidney is an organ with high pericyte density and cancer patients develop severe proteinuria following administration of NRP1B-neutralizing antibody combined with bevacizumab. Therefore, we investigated whether Nrp1 regulates glomerular capillary integrity after completion of renal development using two mouse models; tamoxifen-inducible NG2Cre to delete Nrp1 specifically in pericytes and administration of Nrp1-neutralizing antibodies. Specific Nrp1 deletion in pericytes did not affect pericyte number but mutant mice developed hematuria with glomerular basement membrane defects. Despite foot process effacement, albuminuria was absent and expression of podocyte proteins remained unchanged upon Nrp1 deletion. Additionally, these mice displayed dilation of the afferent arteriole and glomerular capillaries leading to glomerular hyperfiltration. Nidogen-1 mRNA was downregulated and collagen4α3 mRNA was upregulated with no significant effect on the expression of other basement membrane genes in the mutant mice. These features were phenocopied by treating wild-type mice with Nrp1-neutralizing antibodies. Thus, our results reveal a postdevelopmental role of Nrp1 in renal pericytes as an important regulator of glomerular basement membrane integrity. Furthermore, our study offers novel mechanistic insights into renal side effects of Nrp1 targeting cancer therapies.
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Membrana Basal Glomerular/metabolismo , Taxa de Filtração Glomerular , Glomérulos Renais/metabolismo , Neuropilina-1/metabolismo , Pericitos/metabolismo , Albuminúria/genética , Albuminúria/metabolismo , Albuminúria/fisiopatologia , Animais , Anticorpos Neutralizantes/farmacologia , Arteríolas/metabolismo , Arteríolas/fisiopatologia , Autoantígenos/genética , Autoantígenos/metabolismo , Capilares/metabolismo , Capilares/fisiopatologia , Colágeno Tipo IV/genética , Colágeno Tipo IV/metabolismo , Regulação da Expressão Gênica , Genótipo , Membrana Basal Glomerular/efeitos dos fármacos , Membrana Basal Glomerular/fisiopatologia , Membrana Basal Glomerular/ultraestrutura , Hematúria/genética , Hematúria/metabolismo , Hematúria/fisiopatologia , Glomérulos Renais/irrigação sanguínea , Glomérulos Renais/efeitos dos fármacos , Glomérulos Renais/fisiopatologia , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neuropilina-1/antagonistas & inibidores , Neuropilina-1/deficiência , Neuropilina-1/genética , Pericitos/efeitos dos fármacos , Pericitos/ultraestrutura , Fenótipo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais , VasodilataçãoRESUMO
A heterozygous mutation (c.643C>A; p.Q215X) in the monocarboxylate transporter 12-encoding gene MCT12 (also known as SLC16A12) that mediates creatine transport was recently identified as the cause of a syndrome with juvenile cataracts, microcornea, and glucosuria in a single family. Whereas the MCT12 mutation cosegregated with the eye phenotype, poor correlation with the glucosuria phenotype did not support a pathogenic role of the mutation in the kidney. Here, we examined MCT12 in the kidney and found that it resides on basolateral membranes of proximal tubules. Patients with MCT12 mutation exhibited reduced plasma levels and increased fractional excretion of guanidinoacetate, but normal creatine levels, suggesting that MCT12 may function as a guanidinoacetate transporter in vivo However, functional studies in Xenopus oocytes revealed that MCT12 transports creatine but not its precursor, guanidinoacetate. Genetic analysis revealed a separate, undescribed heterozygous mutation (c.265G>A; p.A89T) in the sodium/glucose cotransporter 2-encoding gene SGLT2 (also known as SLC5A2) in the family that segregated with the renal glucosuria phenotype. When overexpressed in HEK293 cells, the mutant SGLT2 transporter did not efficiently translocate to the plasma membrane, and displayed greatly reduced transport activity. In summary, our data indicate that MCT12 functions as a basolateral exit pathway for creatine in the proximal tubule. Heterozygous mutation of MCT12 affects systemic levels and renal handling of guanidinoacetate, possibly through an indirect mechanism. Furthermore, our data reveal a digenic syndrome in the index family, with simultaneous MCT12 and SGLT2 mutation. Thus, glucosuria is not part of the MCT12 mutation syndrome.
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Glicina/análogos & derivados , Transportadores de Ácidos Monocarboxílicos/genética , Mutação , Adulto , Idoso , Feminino , Glicina/metabolismo , Glicosúria/genética , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Adulto JovemRESUMO
NHA2 is a sodium/hydrogen exchanger with unknown physiological function. Here we show that NHA2 is present in rodent and human ß-cells, as well as ß-cell lines. In vivo, two different strains of NHA2-deficient mice displayed a pathological glucose tolerance with impaired insulin secretion but normal peripheral insulin sensitivity. In vitro, islets of NHA2-deficient and heterozygous mice, NHA2-depleted Min6 cells, or islets treated with an NHA2 inhibitor exhibited reduced sulfonylurea- and secretagogue-induced insulin secretion. The secretory deficit could be rescued by overexpression of a wild-type, but not a functionally dead, NHA2 transporter. NHA2 deficiency did not affect insulin synthesis or maturation and had no impact on basal or glucose-induced intracellular Ca(2+) homeostasis in islets. Subcellular fractionation and imaging studies demonstrated that NHA2 resides in transferrin-positive endosomes and synaptic-like microvesicles but not in insulin-containing large dense core vesicles in ß-cells. Loss of NHA2 inhibited clathrin-dependent, but not clathrin-independent, endocytosis in Min6 and primary ß-cells, suggesting defective endo-exocytosis coupling as the underlying mechanism for the secretory deficit. Collectively, our in vitro and in vivo studies reveal the sodium/proton exchanger NHA2 as a critical player for insulin secretion in the ß-cell. In addition, our study sheds light on the biological function of a member of this recently cloned family of transporters.
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Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Trocadores de Sódio-Hidrogênio/metabolismo , Animais , Linhagem Celular Tumoral , Endocitose/efeitos dos fármacos , Endossomos/metabolismo , Exocitose/efeitos dos fármacos , Feminino , Glucose/farmacologia , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Secreção de Insulina , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Microscopia Confocal , Interferência de RNA , Trocadores de Sódio-Hidrogênio/genética , Compostos de Sulfonilureia/farmacologiaRESUMO
Thiazide and thiazide-like diuretics (thiazides) belong to the most frequently prescribed drugs worldwide. By virtue of their natriuretic and vasodilating properties, thiazides effectively lower blood pressure and prevent adverse cardiovascular outcomes. In addition, through their unique characteristic of reducing urine calcium, thiazides are also widely employed for the prevention of kidney stone recurrence and reduction of bone fracture risk. Since their introduction into clinical medicine in the early 1960s, thiazides have been recognized for their association with metabolic side effects, particularly impaired glucose tolerance, and new-onset diabetes mellitus. Numerous hypotheses have been advanced to explain thiazide-induced glucose intolerance, yet underlying mechanisms remain poorly defined. Regrettably, the lack of understanding and unpredictability of these side effects has prompted numerous physicians to refrain from prescribing these effective, inexpensive, and widely accessible drugs. In this review, we outline the pharmacology and mechanism of action of thiazides, highlight recent advances in the understanding of thiazide-induced glucose intolerance, and provide an up-to-date discussion on the role of thiazides in kidney stone prevention.
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Cálculos Renais , Tiazidas , Humanos , Cálculos Renais/induzido quimicamente , Cálculos Renais/prevenção & controle , Tiazidas/uso terapêutico , Tiazidas/efeitos adversos , Tiazidas/farmacologia , Animais , Intolerância à Glucose/induzido quimicamente , Inibidores de Simportadores de Cloreto de Sódio/efeitos adversos , Inibidores de Simportadores de Cloreto de Sódio/uso terapêutico , Diuréticos/efeitos adversos , Diuréticos/farmacologia , Diuréticos/uso terapêuticoRESUMO
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is associated with significant risk of forming kidney stones, especially those made of calcium oxalate and uric acid, compared with the general population. Since crystals are able to activate the inflammasome and lead to cell injury, crystalluria might worsen ADPKD natural history, acting as a third hit. METHODS: The Bern ADPKD registry is a prospective observational cohort study. Height-adjusted total kidney volume (ht-TKV) was measured at baseline and every 3 years. Twenty-four hour urinary solute excretions collected at baseline and eGFR measurements over time were included in this analysis. Twenty-four hour urinary supersaturations (SS) for calcium oxalate, calcium phosphate and uric acid were calculated using EQUIL-2. Linear regression models were used to assess linear and non-linear associations between slopes of ht-TKV and eGFR with SSs and 24 h urinary solute excretions. RESULTS: Seventy-seven participants (mean age 45.0 [SD 12.9] years, eGFR 76.4 [28.3] mL/min/1.73 m2) were included, with a median follow-up of 4 years. The median slopes of ht-TKV and eGFR were 3.9 percent/year and 2.9 mL/min/1.73 m2/year, respectively. SS for uric acid showed a direct, linear association (p value for linearity 0.035) with ht-TKV slope. When analyzing individual components, urinary uric acid, ammonium, magnesium and sulfate were all directly associated with ht-TKV slope. Urinary sulfate was also directly associated with eGFR slope. CONCLUSIONS: Uric acid supersaturation and several other urinary components are identified as predictors of cyst growth in patients with ADPKD. Future studies with a dedicated design are needed to investigate the pathophysiological mechanisms underlying these associations.
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Rim Policístico Autossômico Dominante , Humanos , Pessoa de Meia-Idade , Sais , Estudos Prospectivos , Ácido Úrico , Oxalato de Cálcio , Taxa de Filtração Glomerular , Progressão da Doença , RimRESUMO
The SLC9 gene family encodes Na+/H+ exchangers (NHEs), a group of membrane transport proteins critically involved in the regulation of cytoplasmic and organellar pH, cell volume, as well as systemic acid-base and volume homeostasis. NHEs of the SLC9A subfamily (NHE 1-9) are well-known for their roles in human physiology and disease. Much less is known about the two members of the SLC9B subfamily, NHA1 and NHA2, which share higher similarity to prokaryotic NHEs than the SLC9A paralogs. NHA2 (also known as SLC9B2) is ubiquitously expressed and has recently been shown to participate in renal blood pressure and electrolyte regulation, insulin secretion and systemic glucose homeostasis. In addition, NHA2 has been proposed to contribute to the pathogenesis of polycystic kidney disease, the most common inherited kidney disease in humans. NHA1 (also known as SLC9B1) is mainly expressed in testis and is important for sperm motility and thus male fertility, but has not been associated with human disease thus far. In this review, we present a summary of the structure, function and regulation of expression of the SLC9B subfamily members, focusing primarily on the better-studied SLC9B paralog, NHA2. Furthermore, we will review the potential of the SLC9B subfamily as drug targets.
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BACKGROUND: Immune responses on SARS-CoV-2 vaccination in patients receiving anti-CD20 therapies are impaired but vary considerably. We conducted a systematic review and meta-analysis of the literature on SARS-CoV-2 vaccine induced humoral and cell-mediated immune response in patients previously treated with anti-CD20 antibodies. METHODS: We searched PubMed, Embase, Medrxiv and SSRN using variations of search terms 'anti-CD20', 'vaccine' and 'COVID' and included original studies up to 21 August 2021. We excluded studies with missing data on humoral or cell-mediated immune response, unspecified methodology of response testing, unspecified timeframes between vaccination and blood sampling or low number of participants (≤3). We excluded individual patients with prior COVID-19 or incomplete vaccine courses. Primary endpoints were humoral and cell-mediated immune response rates. Subgroup analyses included time since anti-CD20 therapy, B cell depletion and indication for anti-CD20 therapy. We used random-effects models of proportions. FINDINGS: Ninety studies were assessed. Inclusion criteria were met by 23 studies comprising 1342 patients. Overall rate of humoral response was 0.40 (95% CI 0.35 to 0.47). Overall rate of cell-mediated immune responses was 0.71 (95% CI 0.57 to 0.87). A time interval >6 months since last anti-CD20 therapy was associated with higher humoral response rates with 0.63 (95% CI 0.53 to 0.72) versus <6 months 0.2 (95% CI 0.03 to 0.43); p=0<01. Similarly, patients with circulating B cells more frequently showed humoral responses. Anti-CD20-treated kidney transplant recipients showed lower humoral response rates than patients with haematological malignancies or autoimmune disease. INTERPRETATION: Patients on anti-CD20 therapies can develop humoral and cell-mediated immune responses after SARS-CoV-2 vaccination, but subgroups such as kidney transplant recipients or those with very recent therapy and depleted B cell are at high risk for non-seroconversion and should be individually assessed for personalised SARS-CoV-2 vaccination strategies. Potential limitations are small patient numbers and heterogeneity of studies included. FUNDING: This study was funded by Bern University Hospital.
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Vacinas contra COVID-19 , COVID-19 , Anticorpos Antivirais , Humanos , Imunidade Celular , SARS-CoV-2RESUMO
The sodium/hydrogen exchanger 6 (NHE6) localizes to recycling endosomes, where it mediates endosomal alkalinization through K+/H+ exchange. Mutations in the SLC9A6 gene encoding NHE6 cause severe X-linked mental retardation, epilepsy, autism and corticobasal degeneration in humans. Patients with SLC9A6 mutations exhibit skeletal malformations, and a previous study suggested a key role of NHE6 in osteoblast-mediated mineralization. The goal of this study was to explore the role of NHE6 in bone homeostasis. To this end, we studied the bone phenotype of NHE6 knock-out mice by microcomputed tomography, quantitative histomorphometry and complementary ex vivo and in vitro studies. We detected NHE6 transcript and protein in both differentiated osteoclasts and mineralizing osteoblasts. In vitro studies with osteoclasts and osteoblasts derived from NHE6 knock-out mice demonstrated normal osteoclast differentiation and osteoblast proliferation without an impairment in mineralization capacity. Microcomputed tomography and bone histomorphometry studies showed a significantly reduced bone volume and trabecular number as well as an increased trabecular space at lumbar vertebrae of 6 months old NHE6 knock-out mice. The bone degradation marker c-terminal telopeptides of type I collagen was unaltered in NHE6 knock-out mice. However, we observed a reduction of the bone formation marker procollagen type 1 N-terminal propeptide, and increased circulating sclerostin levels in NHE6 knock-out mice. Subsequent studies revealed a significant upregulation of sclerostin transcript expression in both primary calvarial cultures and femora derived from NHE6 knock-out mice. Thus, loss of NHE6 in mice causes an increase of sclerostin expression associated with reduced bone formation and low bone volume.
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Osteoblastos , Trocadores de Sódio-Hidrogênio , Animais , Hidrogênio , Camundongos , Camundongos Knockout , Osteoclastos , Sódio , Trocadores de Sódio-Hidrogênio/genética , Microtomografia por Raio-XRESUMO
BACKGROUND AND OBJECTIVES: Nephrolithiasis is a common health problem in autosomal dominant polycystic kidney disease (ADPKD) and significantly contributes to patient morbidity. Recently, Tolvaptan has been introduced for the treatment of ADPKD, but whether it is associated with alterations of the urinary lithogenic risk profile remains unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted an analysis of participants enrolled in the Bern ADPKD registry, a prospective observational cohort study. Twenty-four-hour urine analyses were performed at baseline and then at yearly follow-ups. Relative supersaturation ratios for calcium oxalate, brushite, and uric acid were calculated with the program EQUIL2. Unadjusted and multivariable mixed-effects linear regression models, adjusted for age, sex, body mass index, eGFR, net acid excretion, and height-adjusted total kidney volume, were used to assess the association of Tolvaptan with urinary parameters relevant for kidney stone formation. The maximum individual follow-up time was 3 years, median follow-up time 1.9 years, and cumulative follow-up time 169 years. RESULTS: In total, 125 participants (38 with and 87 without Tolvaptan treatment) were included in the analysis. In multivariable analysis, Tolvaptan treatment was associated [adjusted estimate of the difference between Tolvaptan and no Tolvaptan; 95% confidence interval (CI)] with lower urine relative supersaturation ratios for calcium oxalate (-0.56; 95% CI, -0.82 to -0.3; P<0.001), brushite (-0.33; 95% CI, -0.54 to -0.11; P=0.004), and uric acid (-0.62; 95% CI, -0.88 to -0.37; P<0.001), and with higher urine citrate in mmol/mmol creatinine per day (0.25; 95% CI, 0.05 to 0.46; P=0.02) and calcium in mmol/mmol creatinine per day (0.31; 95% CI, 0.09 to 0.53; P=0.006) excretion. In addition, Tolvaptan treatment was associated with lower net acid excretion in mEq/mmol creatinine per day (-0.54; 95% CI, -0.90 to -0.17; P=0.004) and higher net gastrointestinal alkali absorption in mEq/mmol creatinine per day (0.57; 95% CI, 0.26 to 0.88; P<0.001). CONCLUSIONS: Tolvaptan treatment is associated with a significantly improved urinary lithogenic risk profile in patients with ADPKD.
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Antagonistas dos Receptores de Hormônios Antidiuréticos/uso terapêutico , Nefrolitíase/urina , Rim Policístico Autossômico Dominante/tratamento farmacológico , Rim Policístico Autossômico Dominante/urina , Tolvaptan/uso terapêutico , Adulto , Oxalato de Cálcio/urina , Fosfatos de Cálcio/urina , Ácido Cítrico/urina , Creatinina/urina , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Nefrolitíase/etiologia , Rim Policístico Autossômico Dominante/complicações , Sistema de Registros , Fatores de Risco , Ácido Úrico/urinaRESUMO
RATIONALE & OBJECTIVE: The impact of tolvaptan on health-related quality-of-life (HRQoL) in patients with autosomal dominant polycystic kidney disease (ADPKD) is unknown. To address this knowledge gap, we studied patient-reported HRQoL in patients enrolled in the Bern ADPKD registry. STUDY DESIGN: Prospective cohort study. SETTINGS & PARTICIPANTS: Inclusion criteria were age 18 years or older, clinical diagnosis of ADPKD, and informed consent. The main exclusion criterion was need for kidney replacement therapy. OUTCOME: HRQoL was assessed using the standardized Kidney Disease Quality of Life Short Form (KDQOL-SF) questionnaire at start of the study (baseline) and after 1 year (follow-up). The KDQOL-SF has 2 parts: a generic 36-Item Health Survey instrument with 8 subscores and 2 summary scores and a kidney disease-specific instrument to assess health concerns. Higher scores indicate better HRQoL. The influence of tolvaptan treatment on HRQoL and kidney-specific health concerns was analyzed using analysis of covariance, adjusting for HRQoL and health concerns before the start of the study, sex, and age. RESULTS: In 38 of 121 registry patients, tolvaptan treatment was initiated. Within the first 3 months, treatment had to be discontinued in 6 (16%) patients due to aquaretic side effects (n = 4; 11%) or elevated liver enzyme levels (n = 2; 5%), and a dose reduction was necessary in 8 (21%) patients. We included 98 patients (30 with and 68 without tolvaptan treatment) in the analysis for which baseline and 1-year follow-up data were available. At follow-up, and after adjusting for baseline scores, sex, and age, HRQoL and kidney-specific health concerns were not influenced by tolvaptan treatment, except for patient satisfaction, which was increased. LIMITATIONS: Observational study design, monocentric study at tertiary referral hospital, almost exclusively white study population, grant support by Otsuka Pharmaceuticals. CONCLUSIONS: Our results indicate that tolvaptan does not significantly affect HRQoL in patients with ADPKD who tolerate treatment beyond the first 3 months of therapy.
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Fibroblast growth factor 23 (FGF23) participates in the orchestration of mineral metabolism by inducing phosphaturia and decreasing the production of 1,25(OH)2D3. It is known that FGF23 release is stimulated by aldosterone and extracellular volume depletion. To characterize this effect further in a model of mild hypovolemia, we studied mice lacking the thiazide sensitive NaCl cotransporter (NCC). Our data indicate that NCC knockout mice (KO) have significantly higher FGF23, PTH and aldosterone concentrations than corresponding wild type (WT) mice. However, 1,25(OH)2D3, fractional phosphate excretion and renal brush border expression of the sodium/phosphate co-transporter 2a were not different between the two genotypes. In addition, renal expression of FGF23 receptor FGFR1 and the co-receptor Klotho were unaltered in NCC KO mice. FGF23 transcript was increased in the bone of NCC KO mice compared to WT mice, but treatment of primary murine osteoblasts with the NCC inhibitor hydrochlorothiazide did not elicit an increase of FGF23 transcription. In contrast, the mineralocorticoid receptor blocker eplerenone reversed excess FGF23 levels in KO mice but not in WT mice, indicating that FGF23 upregulation in NCC KO mice is primarily aldosterone-mediated. Together, our data reveal that lack of renal NCC causes an aldosterone-mediated upregulation of circulating FGF23.
Assuntos
Fatores de Crescimento de Fibroblastos/metabolismo , Receptores de Droga/genética , Receptores de Droga/metabolismo , Simportadores de Cloreto de Sódio/genética , Simportadores de Cloreto de Sódio/metabolismo , Aldosterona/metabolismo , Análise de Variância , Animais , Cálcio/metabolismo , Modelos Animais de Doenças , Eplerenona/farmacologia , Fêmur/metabolismo , Fator de Crescimento de Fibroblastos 23 , Síndrome de Gitelman/metabolismo , Glucuronidase/metabolismo , Hidroclorotiazida/farmacologia , Hipovolemia/metabolismo , Proteínas Klotho , Masculino , Camundongos , Camundongos Knockout , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Hormônio Paratireóideo/metabolismo , Fosfatos/metabolismo , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Receptores de Droga/antagonistas & inibidores , Tiazidas/metabolismoRESUMO
BACKGROUND AND OBJECTIVES: Incomplete distal renal tubular acidosis is a well known cause of calcareous nephrolithiasis but the prevalence is unknown, mostly due to lack of accepted diagnostic tests and criteria. The ammonium chloride test is considered as gold standard for the diagnosis of incomplete distal renal tubular acidosis, but the furosemide/fludrocortisone test was recently proposed as an alternative. Because of the lack of rigorous comparative studies, the validity of the furosemide/fludrocortisone test in stone formers remains unknown. In addition, the performance of conventional, nonprovocative parameters in predicting incomplete distal renal tubular acidosis has not been studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a prospective study in an unselected cohort of 170 stone formers that underwent sequential ammonium chloride and furosemide/fludrocortisone testing. RESULTS: Using the ammonium chloride test as gold standard, the prevalence of incomplete distal renal tubular acidosis was 8%. Sensitivity and specificity of the furosemide/fludrocortisone test were 77% and 85%, respectively, yielding a positive predictive value of 30% and a negative predictive value of 98%. Testing of several nonprovocative clinical parameters in the prediction of incomplete distal renal tubular acidosis revealed fasting morning urinary pH and plasma potassium as the most discriminative parameters. The combination of a fasting morning urinary threshold pH <5.3 with a plasma potassium threshold >3.8 mEq/L yielded a negative predictive value of 98% with a sensitivity of 85% and a specificity of 77% for the diagnosis of incomplete distal renal tubular acidosis. CONCLUSIONS: The furosemide/fludrocortisone test can be used for incomplete distal renal tubular acidosis screening in stone formers, but an abnormal furosemide/fludrocortisone test result needs confirmation by ammonium chloride testing. Our data furthermore indicate that incomplete distal renal tubular acidosis can reliably be excluded in stone formers by use of nonprovocative clinical parameters.
Assuntos
Acidose Tubular Renal/diagnóstico , Cloreto de Amônio/administração & dosagem , Fludrocortisona/administração & dosagem , Furosemida/administração & dosagem , Cálculos Renais/diagnóstico , Testes de Função Renal , Inibidores de Simportadores de Cloreto de Sódio e Potássio/administração & dosagem , Acidose Tubular Renal/complicações , Acidose Tubular Renal/epidemiologia , Adulto , Feminino , Humanos , Cálculos Renais/epidemiologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Estudos Prospectivos , Reprodutibilidade dos Testes , Suíça/epidemiologiaRESUMO
We previously demonstrated that the sodium/hydrogen exchanger NHA2, also known as NHEDC2 or SLC9B2, is critical for insulin secretion by ß-cells. To gain more insights into the role of NHA2 on systemic glucose homeostasis, we studied the impact of loss of NHA2 during the physiological aging process and in the setting of diet-induced obesity. While glucose tolerance was normal at 2 months of age, NHA2 KO mice displayed a significant glucose intolerance at 5 and 12 months of age, respectively. An obesogenic high fat diet further exacerbated the glucose intolerance of NHA2 KO mice. Insulin levels remained similar in NHA2 KO and WT mice during aging and high fat diet, but fasting insulin/glucose ratios were significantly lower in NHA2 KO mice. Peripheral insulin sensitivity, measured by insulin tolerance tests and hyperinsulinemic euglycemic clamps, was unaffected by loss of NHA2 during aging and high fat diet. High fat diet diminished insulin secretion capacity in both WT and NHA2 KO islets and reduced expression of NHA2 in WT islets. In contrast, aging was characterized by a gradual increase of NHA2 expression in islets, paralleled by an increasing difference in insulin secretion between WT and NHA2 KO islets. In summary, our results demonstrate that loss of the sodium/hydrogen exchanger NHA2 exacerbates obesity- and aging-induced glucose intolerance in mice. Furthermore, our data reveal a close link between NHA2 expression and insulin secretion capacity in islets.
RESUMO
Children conceived by assisted reproductive technologies (ART) display a level of vascular dysfunction similar to that seen in children of mothers with preeclamspia. The long-term consequences of ART-associated vascular disorders are unknown and difficult to investigate in healthy children. Here, we found that vasculature from mice generated by ART display endothelial dysfunction and increased stiffness, which translated into arterial hypertension in vivo. Progeny of male ART mice also exhibited vascular dysfunction, suggesting underlying epigenetic modifications. ART mice had altered methylation at the promoter of the gene encoding eNOS in the aorta, which correlated with decreased vascular eNOS expression and NO synthesis. Administration of a deacetylase inhibitor to ART mice normalized vascular gene methylation and function and resulted in progeny without vascular dysfunction. The induction of ART-associated vascular and epigenetic alterations appeared to be related to the embryo environment; these alterations were possibly facilitated by the hormonally stimulated ovulation accompanying ART. Finally, ART mice challenged with a high-fat diet had roughly a 25% shorter life span compared with control animals. This study highlights the potential of ART to induce vascular dysfunction and shorten life span and suggests that epigenetic alterations contribute to these problems.