Backgound Bartter's syndrome(BS)is a rare group of salt losing tubulopathies due to the impairment of transport mecha-nisms at the thick ascending limb of the Henle's loop.Data sources Literature reviews and o...Backgound Bartter's syndrome(BS)is a rare group of salt losing tubulopathies due to the impairment of transport mecha-nisms at the thick ascending limb of the Henle's loop.Data sources Literature reviews and original research articles were collected from database,including PubMed and Scopus.Results According to the time of onset and symptoms,BS can be classified into antenatal and classic BS.Molecular studies have identified different subtypes of BS.BS types Ⅰ,Ⅱ and Ⅲ are caused by mutations on genes encoding the luminal Na^(+)-K^(+)-2Cl^(-) co-transporter,the luminal K+ channel ROMK,and the basolateral chloride channel ClC-Kb(CLCNKB),respectively.Loss-of-function mutations of Barttin CLCNK type accessory beta subunit cause BS type Ⅳa.Simultaneous mutations of CLCNKB and CLCNKA cause BS type Ⅳb.BS type Ⅴ consists in a novel transient form characterized by antenatal presentation due to mutations in the MAGE family member D2.Severe gain-of-function mutations of the extracellular calcium sensing receptor gene can result in an autosomal dominant condition of BS.Main clinical and biochemical alterations in BS include polyuria,dehydration,hypokalemia,hypochloremic metabolic alka-losis,hyperreninemia,high levels of prostaglandins,normal or low blood pressure,hypercalciuria and failure to thrive.Treatment focuses mainly at correcting dehydration and electrolyte disturbances and in measures to reduce polyuria,including the use of nonsteroidal anti-inflammatory medications to control excessive renal prostaglandin E2 production.Conclusions Early diagnosis and treatment of BS may prevent long-term consequences such as growth failure,nephrocal-cinosis and end-stage renal disease.展开更多
The expression of calcium epithelium TRPV5, alcium binding protein Calbindin-D28k and Na＋/Ca2＋ exchanger NCX1 was detected in renal distal convoluted tubule, and their effects on urine calcium reabsorption and the p...The expression of calcium epithelium TRPV5, alcium binding protein Calbindin-D28k and Na＋/Ca2＋ exchanger NCX1 was detected in renal distal convoluted tubule, and their effects on urine calcium reabsorption and the possible pathogenic mechanism in idiopathic hypercalciuria （IH） were investigated. Genetic hypercalciuric stone-forming （GHS） rats were chosen as animal models to study urine calcium reabsorption and IH. The cognate female and male rats that had maximal urine calcium were matched to breed next generation. Twelve GHS rats and 12 normal control （NC） SD rats were selected. Western blot and real time quantitative PCR were used to detect the protein and gene expression of TRPV5, Calbindin-D28k and NCX1 respectively. The expression levels of TRPV5 protein and mRNA in GHS rats were significantly lower than in NC rats （P〈0.05）. Western blot revealed that the expression levels of Calbindin-D28k in GHS rats and NC rats were 0.49±0.02 and 0.20±0.01 respectively, with the difference being significant between them （P〈0.05）. By using real time quantitative PCR, it was found that there was no significant difference in Calbindin-28k mRNA expression levels between GHS rats and NC rats （P〉0.05）. There was no significant differ- ence in the NCX1 expression between GHS rats and NC rats （P〉0.05）. It was suggested that TRPV5 and Calbindin-D28k might play an important role in urine calcium reabsorption and IH, but they dif- ferently contributed to the pathogenesis： The down-regulation of TRPV5 decreases urine calcium reabsorption, directly leading to loss of the urine calcium and resulting in hypercalciuria, and the increased Calbindin-D28k expression could relieve, neutralize and decrease intracellular Ca2＋ concentration to maintain calcium balance. NCX1 is not the key protein in urine calcium reabsorption.展开更多
Over 1%-15% of the population worldwide is affected by nephrolithiasis,which remains the most common and costly disease that urologists manage today.Identification of atrisk individuals remains a theoretical and techn...Over 1%-15% of the population worldwide is affected by nephrolithiasis,which remains the most common and costly disease that urologists manage today.Identification of atrisk individuals remains a theoretical and technological challenge.The search for monogenic causes of stone disease has been largely unfruitful and a technological challenge;however,several candidate genes have been implicated in the development of nephrolithiasis.In this review,we will review current data on the genetic inheritance of stone disease,as well as investigate the evolving role of genetic analysis and counseling in the management of nephrolithiasis.展开更多
目的探讨家族性低镁血症高钙尿症与肾钙质沉着症（familial hypomagnesaemia with hypercalciuria and nephrocalcinosis，FHHNC）患者的临床特点和致病基因特征。方法2016年2月收治1例女性患者，年龄24岁。入院前1个月外院腹部X线片（...目的探讨家族性低镁血症高钙尿症与肾钙质沉着症（familial hypomagnesaemia with hypercalciuria and nephrocalcinosis，FHHNC）患者的临床特点和致病基因特征。方法2016年2月收治1例女性患者，年龄24岁。入院前1个月外院腹部X线片（KUB）检查示左肾结石，双肾钙质沉着。患者于外院行经皮肾镜取石术清除大部分左肾结石。本次入院后实验室检查：血镁0.65 mmol/L，24 h尿钙364.0 mg，血甲状旁腺激素187.4 pg/ml，血肌酐101.5μmol/L。行输尿管软镜碎石术清除左肾残余结石。考虑患者为FHHNC，对患者及其父母行外周血CLDN16和CLDN19基因测序分析。结果基因测序结果显示患者CLDN16基因的第2外显子第123密码子一个碱基缺失（c.368delA），第2外显子第139密码子发生错义突变[c.416C→T（p.A139V）]。患者母亲的第139密码子第2个碱基胞嘧啶变为胸腺嘧啶（c.416C→T）；患者父亲的第123密码子第2个碱基腺嘌呤缺失（c.368delA）。该患者确诊为FHHNC，口服氢氯噻嗪、枸橼酸钾、钙镁片治疗。随访6个月，复查血镁1.0 mmol/L，24 h尿钙156.0 mg，血甲状旁腺激素139.6 pg/ml，泌尿系结石无复发，双肾钙质沉着症及肾功能损伤无明显加重。结论CLDN16基因复合杂合突变致FHHNC的临床三联症为低镁血症、高钙尿症和肾钙质沉着症，确诊依靠CLDN16和CLDN19基因测序。肾功能严重受损前以对症治疗为主，给予氢氯噻嗪、枸橼酸钾、钙镁片治疗有可能明显改善低镁血症和高钙尿症。展开更多
Background: Renal stone (RS) is a highly prevalent disease in our societies and is mostly secondary to lifestyle habits. HIV<sub>1</sub> patients often experience RS, although specific risk factors are not...Background: Renal stone (RS) is a highly prevalent disease in our societies and is mostly secondary to lifestyle habits. HIV<sub>1</sub> patients often experience RS, although specific risk factors are not known. Despite other priorities, comprehensive work-up should be offered to avoid recurrences (50% risk in 5 years). Purpose and Methods: The aim of the study is to describe how to handle RS in persons living with HIV<sub>1</sub> and to suggest how the understanding of mechanisms involved in stone composition helps customize therapy and prevent recurrences. We prospectively performed a complete work-up in a cohort of 23 prevalent HIV<sub>1</sub> patients referred to our highly-specialized center by HIV physicians. Results: Inclusion was secondary to a colic episode with spontaneous elimination of the stone (74%), bilateral (67%), not obstructive (67%);53% underwent urologic interventions. Mean age was 34 ± 16 years old and BMI was 22.5 ± 3 (one-third with metabolic syndrome). History of RS showed only one episode (22%), >one (74%) or >4 (4%). Estimated GFR was 78 ± 24 ml/min/1.73m<sup>2</sup> (mean Cr 101 ± 24 μmol/L), and 5 were classified CKD stage 3. Stone analysis was only available for 7 patients and in 6/7 patients, and calcium metabolism was fully explored (2 absorptive hypercalciuria, 4 renal primitive hypercalciuria). Retained mechanism for RS was uric acid dependent for one, oxalic acid dependent for three and calcium dependent for three. Very few patients were exposed to known environmental risk factors for RS, 3 were/had been exposed to darunavir and 3 to atazanavir, 1 to efavirenz, 1 to acetazolamide, 2 to allopurinol. Conclusion: RS in HIV<sub>1</sub> patients is mostly not related to ARV. Understanding of renal stone composition is critical to prevent recurrences by offering specific dietetic counselling and therapy. The role of HIV physicians is important due to the high prevalence of RS in the context of HIV disease.展开更多
特发性高钙尿症(idiopathic hypercalciuria,IH)是病因未明的尿钙增多而血清钙正常的钙代谢异常,是尿路结石形成的重要危险因素。患者肠道钙吸收增加、骨再吸收增加及肾尿钙再吸收减少而导致高钙尿。目前利用动物模型对该病发病机制进...特发性高钙尿症(idiopathic hypercalciuria,IH)是病因未明的尿钙增多而血清钙正常的钙代谢异常,是尿路结石形成的重要危险因素。患者肠道钙吸收增加、骨再吸收增加及肾尿钙再吸收减少而导致高钙尿。目前利用动物模型对该病发病机制进行了较深入的研究,发现维生素D受体(Vitamin D receptor,VDR)基因多态性、VDR表达增加及其调控蛋白的异常在IH基本的发病机制中起重要作用。展开更多
Proximal tubule(PT)transports most of the renal Ca^(2+),which was usually described as paracellular(passive).We found a regulated Ca^(2+)entry pathway in PT cells via the apical transient receptor potential canonical ...Proximal tubule(PT)transports most of the renal Ca^(2+),which was usually described as paracellular(passive).We found a regulated Ca^(2+)entry pathway in PT cells via the apical transient receptor potential canonical 3(TRPC3)channel,which initiates transcellular Ca^(2+)transport.Although TRPC3 knockout(−/−)mice were mildly hypercalciuric and displayed luminal calcium phosphate(CaP)crystals at Loop of Henle(LOH),no CaP+calcium oxalate(CaOx)mixed urine crystals were spotted,which are mostly found in calcium nephrolithiasis(CaNL).Thus,we used oral calcium gluconate(CaG;2%)to raise the PT luminal[Ca^(2+)]o further in TRPC3−/−mice for developing such mixed stones to understand the mechanistic role of PT-Ca^(2+)signaling in CaNL.Expectedly,CaG-treated mice urine samples presented with numerous mixed crystals with remains of PT cells,which were pronounced in TRPC3−/−mice,indicating PT cell damage.Notably,PT cells from CaG-treated groups switched their mode of Ca^(2+)entry from receptor-operated to store-operated pathway with a sustained rise in intracellular[Ca^(2+)]([Ca^(2+)]i),indicating the stagnation in PT Ca^(2+)transport.Moreover,those PT cells from CaG-treated groups demonstrated an upregulation of calcification,inflammation,fibrotic,oxidative stress,and apoptotic genes;effects of which were more robust in TRPC3 ablated condition.Furthermore,kidneys from CaG-treated groups exhibited fibrosis,tubular injury and calcifications with significant reactive oxygen species generation in the urine,thus,indicating in vivo CaNL.Taken together,excess PT luminal Ca^(2+)due to escalation of hypercalciuria in TRPC3 ablated mice induced surplus CaP crystal formation and caused stagnation of PT[Ca^(2+)]i,invoking PT cell injury,hence mixed stone formation.展开更多
In the past few decades pediatric urolithiasis has become more frequent. The reason for this increase is not completely clear but has been attributed to changes in climate, nutritional habits and possibly other enviro...In the past few decades pediatric urolithiasis has become more frequent. The reason for this increase is not completely clear but has been attributed to changes in climate, nutritional habits and possibly other environ-mental factors. Although less frequent than adult stone disease, urolithiasis in the pediatric age group is also related to significant morbidity, particularly since stones tend to recur, and, thus, should not be underestimated. Most children with idiopathic stone disease have an underlying metabolic abnormality substantiating the importance of metabolic evaluation already following initial diagnosis of urolithiasis. Identification of the metabolic abnormality allows for more specifc prescription of non pharmacological and pharmacological interventions aimed at preventing recurrent stone formation. A better understanding of the causes of kidney stone disease will provide better strategies for stone prevention in children.展开更多
文摘Backgound Bartter's syndrome(BS)is a rare group of salt losing tubulopathies due to the impairment of transport mecha-nisms at the thick ascending limb of the Henle's loop.Data sources Literature reviews and original research articles were collected from database,including PubMed and Scopus.Results According to the time of onset and symptoms,BS can be classified into antenatal and classic BS.Molecular studies have identified different subtypes of BS.BS types Ⅰ,Ⅱ and Ⅲ are caused by mutations on genes encoding the luminal Na^(+)-K^(+)-2Cl^(-) co-transporter,the luminal K+ channel ROMK,and the basolateral chloride channel ClC-Kb(CLCNKB),respectively.Loss-of-function mutations of Barttin CLCNK type accessory beta subunit cause BS type Ⅳa.Simultaneous mutations of CLCNKB and CLCNKA cause BS type Ⅳb.BS type Ⅴ consists in a novel transient form characterized by antenatal presentation due to mutations in the MAGE family member D2.Severe gain-of-function mutations of the extracellular calcium sensing receptor gene can result in an autosomal dominant condition of BS.Main clinical and biochemical alterations in BS include polyuria,dehydration,hypokalemia,hypochloremic metabolic alka-losis,hyperreninemia,high levels of prostaglandins,normal or low blood pressure,hypercalciuria and failure to thrive.Treatment focuses mainly at correcting dehydration and electrolyte disturbances and in measures to reduce polyuria,including the use of nonsteroidal anti-inflammatory medications to control excessive renal prostaglandin E2 production.Conclusions Early diagnosis and treatment of BS may prevent long-term consequences such as growth failure,nephrocal-cinosis and end-stage renal disease.
文摘The expression of calcium epithelium TRPV5, alcium binding protein Calbindin-D28k and Na＋/Ca2＋ exchanger NCX1 was detected in renal distal convoluted tubule, and their effects on urine calcium reabsorption and the possible pathogenic mechanism in idiopathic hypercalciuria （IH） were investigated. Genetic hypercalciuric stone-forming （GHS） rats were chosen as animal models to study urine calcium reabsorption and IH. The cognate female and male rats that had maximal urine calcium were matched to breed next generation. Twelve GHS rats and 12 normal control （NC） SD rats were selected. Western blot and real time quantitative PCR were used to detect the protein and gene expression of TRPV5, Calbindin-D28k and NCX1 respectively. The expression levels of TRPV5 protein and mRNA in GHS rats were significantly lower than in NC rats （P〈0.05）. Western blot revealed that the expression levels of Calbindin-D28k in GHS rats and NC rats were 0.49±0.02 and 0.20±0.01 respectively, with the difference being significant between them （P〈0.05）. By using real time quantitative PCR, it was found that there was no significant difference in Calbindin-28k mRNA expression levels between GHS rats and NC rats （P〉0.05）. There was no significant differ- ence in the NCX1 expression between GHS rats and NC rats （P〉0.05）. It was suggested that TRPV5 and Calbindin-D28k might play an important role in urine calcium reabsorption and IH, but they dif- ferently contributed to the pathogenesis： The down-regulation of TRPV5 decreases urine calcium reabsorption, directly leading to loss of the urine calcium and resulting in hypercalciuria, and the increased Calbindin-D28k expression could relieve, neutralize and decrease intracellular Ca2＋ concentration to maintain calcium balance. NCX1 is not the key protein in urine calcium reabsorption.
文摘Over 1%-15% of the population worldwide is affected by nephrolithiasis,which remains the most common and costly disease that urologists manage today.Identification of atrisk individuals remains a theoretical and technological challenge.The search for monogenic causes of stone disease has been largely unfruitful and a technological challenge;however,several candidate genes have been implicated in the development of nephrolithiasis.In this review,we will review current data on the genetic inheritance of stone disease,as well as investigate the evolving role of genetic analysis and counseling in the management of nephrolithiasis.
文摘Background: Renal stone (RS) is a highly prevalent disease in our societies and is mostly secondary to lifestyle habits. HIV<sub>1</sub> patients often experience RS, although specific risk factors are not known. Despite other priorities, comprehensive work-up should be offered to avoid recurrences (50% risk in 5 years). Purpose and Methods: The aim of the study is to describe how to handle RS in persons living with HIV<sub>1</sub> and to suggest how the understanding of mechanisms involved in stone composition helps customize therapy and prevent recurrences. We prospectively performed a complete work-up in a cohort of 23 prevalent HIV<sub>1</sub> patients referred to our highly-specialized center by HIV physicians. Results: Inclusion was secondary to a colic episode with spontaneous elimination of the stone (74%), bilateral (67%), not obstructive (67%);53% underwent urologic interventions. Mean age was 34 ± 16 years old and BMI was 22.5 ± 3 (one-third with metabolic syndrome). History of RS showed only one episode (22%), >one (74%) or >4 (4%). Estimated GFR was 78 ± 24 ml/min/1.73m<sup>2</sup> (mean Cr 101 ± 24 μmol/L), and 5 were classified CKD stage 3. Stone analysis was only available for 7 patients and in 6/7 patients, and calcium metabolism was fully explored (2 absorptive hypercalciuria, 4 renal primitive hypercalciuria). Retained mechanism for RS was uric acid dependent for one, oxalic acid dependent for three and calcium dependent for three. Very few patients were exposed to known environmental risk factors for RS, 3 were/had been exposed to darunavir and 3 to atazanavir, 1 to efavirenz, 1 to acetazolamide, 2 to allopurinol. Conclusion: RS in HIV<sub>1</sub> patients is mostly not related to ARV. Understanding of renal stone composition is critical to prevent recurrences by offering specific dietetic counselling and therapy. The role of HIV physicians is important due to the high prevalence of RS in the context of HIV disease.
文摘特发性高钙尿症(idiopathic hypercalciuria,IH)是病因未明的尿钙增多而血清钙正常的钙代谢异常,是尿路结石形成的重要危险因素。患者肠道钙吸收增加、骨再吸收增加及肾尿钙再吸收减少而导致高钙尿。目前利用动物模型对该病发病机制进行了较深入的研究,发现维生素D受体(Vitamin D receptor,VDR)基因多态性、VDR表达增加及其调控蛋白的异常在IH基本的发病机制中起重要作用。
基金National Institute of Diabetes and Digestive and Kidney Diseases(No.DK102043)funding to B.C.B supported this study.
文摘Proximal tubule(PT)transports most of the renal Ca^(2+),which was usually described as paracellular(passive).We found a regulated Ca^(2+)entry pathway in PT cells via the apical transient receptor potential canonical 3(TRPC3)channel,which initiates transcellular Ca^(2+)transport.Although TRPC3 knockout(−/−)mice were mildly hypercalciuric and displayed luminal calcium phosphate(CaP)crystals at Loop of Henle(LOH),no CaP+calcium oxalate(CaOx)mixed urine crystals were spotted,which are mostly found in calcium nephrolithiasis(CaNL).Thus,we used oral calcium gluconate(CaG;2%)to raise the PT luminal[Ca^(2+)]o further in TRPC3−/−mice for developing such mixed stones to understand the mechanistic role of PT-Ca^(2+)signaling in CaNL.Expectedly,CaG-treated mice urine samples presented with numerous mixed crystals with remains of PT cells,which were pronounced in TRPC3−/−mice,indicating PT cell damage.Notably,PT cells from CaG-treated groups switched their mode of Ca^(2+)entry from receptor-operated to store-operated pathway with a sustained rise in intracellular[Ca^(2+)]([Ca^(2+)]i),indicating the stagnation in PT Ca^(2+)transport.Moreover,those PT cells from CaG-treated groups demonstrated an upregulation of calcification,inflammation,fibrotic,oxidative stress,and apoptotic genes;effects of which were more robust in TRPC3 ablated condition.Furthermore,kidneys from CaG-treated groups exhibited fibrosis,tubular injury and calcifications with significant reactive oxygen species generation in the urine,thus,indicating in vivo CaNL.Taken together,excess PT luminal Ca^(2+)due to escalation of hypercalciuria in TRPC3 ablated mice induced surplus CaP crystal formation and caused stagnation of PT[Ca^(2+)]i,invoking PT cell injury,hence mixed stone formation.
文摘In the past few decades pediatric urolithiasis has become more frequent. The reason for this increase is not completely clear but has been attributed to changes in climate, nutritional habits and possibly other environ-mental factors. Although less frequent than adult stone disease, urolithiasis in the pediatric age group is also related to significant morbidity, particularly since stones tend to recur, and, thus, should not be underestimated. Most children with idiopathic stone disease have an underlying metabolic abnormality substantiating the importance of metabolic evaluation already following initial diagnosis of urolithiasis. Identification of the metabolic abnormality allows for more specifc prescription of non pharmacological and pharmacological interventions aimed at preventing recurrent stone formation. A better understanding of the causes of kidney stone disease will provide better strategies for stone prevention in children.
