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
Idiopathic hypercalciuria （IH） is the leading metabolic risk factor for urolithiasis and affects all age groups without gender or race predominance. IH has a high morbidity with or without lithiasis and reduced bone...Idiopathic hypercalciuria （IH） is the leading metabolic risk factor for urolithiasis and affects all age groups without gender or race predominance. IH has a high morbidity with or without lithiasis and reduced bone mineral density （BMD）, as described previously in pe-diatric patients as well as in adults. The pathogenesis of IH is complex and not completely understood, given that urinary excretion of calcium is the end result of an interplay between three organs （gut, bone and kidney）, which is further orchestrated by hormones, such as 1,25 dihydroxyvitamin D, parathyroid hormone, calcitonin and fosfatonins （i.e., fbroblast growth-factor-23）. Usu-ally, a primary defect in one organ induces compensa-tory mechanisms in the remaining two organs, such as increased absorption of calcium in the gut secondary toa primary renal loss. Thus, IH is a systemic abnormality of calcium homeostasis with changes in cellular trans-port of this ion in intestines, kidneys and bones. Re-duced BMD has been demonstrated in pediatric patients diagnosed with IH. However, the precise mechanisms of bone loss or failure of adequate bone mass gain are still unknown. The largest accumulation of bone mass occurs during childhood and adolescence, peaking atthe end of the second decade of life. This accumulation should occur without interference to achieve the peak of optimal bone mass. Any interference may be a risk factor for the reduction of bone mass with increased risk of fractures in adulthood. This review will address the pathogenesis of IH and its consequence in bone mass.展开更多
BACKGROUND Hypercalciuria is the most common metabolic risk factor for calcium urolithiasis and is associated with bone loss in adult patients.Reduced bone mineral density(BMD)was already described in idiopathic hyper...BACKGROUND Hypercalciuria is the most common metabolic risk factor for calcium urolithiasis and is associated with bone loss in adult patients.Reduced bone mineral density(BMD)was already described in idiopathic hypercalciuria(IH)children,but the precise mechanisms of bone loss or inadequate bone mass gain remain unknown.Life-long hypercalciuria might be considered a risk to change bone structure and determine low bone mass throughout life.The peak of bone mass should occur without interferences.A beneficial effect of citrate formulations and thiazides on bone mass in adult and pediatric patients with IH have been shown.AIM To evaluate whether pharmacological therapy has a beneficial effect on bone mass in children and adolescents with IH.METHODS This retrospective cohort study evaluated 40 hypercalciuric children nonresponsive to lifestyle and diet changes.After a 2-mo run-in period of citrate formulation(Kcitrate)usage,the first bone densitometry(DXA)was ordered.In patients with sustained hypercalciuria,a thiazide diuretic was prescribed.The second DXA was performed after 12 mo.Bone densitometry was performed by DXA at lumbar spine(L2-L4).A 24-h urine(calcium,citrate,creatinine)and blood samples(urea,creatinine,uric acid,calcium,phosphorus,magnesium,chloride,hemoglobin)were obtained.Clinical data included age,gender,weight,height and body mass index.RESULTS Forty IH children;median age 10.5 year and median time follow-up 6.0 year were evaluated.Nine patients were treated with Kcitrate(G1)and 31 with Kcitrate+thiazide(G2).There were no differences in age,gender,body mass index z-score and biochemical parameters between G1 and G2.There were no increases in total cholesterol,kalemia and magnesemia.Calciuria decreased in both groups after treatment.Lumbar spine BMD z-score increased after thiazide treatment in G2.There was no improvement in G1.CONCLUSION Results point to a beneficial effect of thiazide on lumbar spine BMD z-score in children with IH.Further studies are necessary to confirm the results of the present study.展开更多
The incidence of urolithiasis(UL)is increasing,and it has become more common in children and adolescents over the past few decades.Hypercalciuria is the leading metabolic risk factor of pediatric UL,and it has high mo...The incidence of urolithiasis(UL)is increasing,and it has become more common in children and adolescents over the past few decades.Hypercalciuria is the leading metabolic risk factor of pediatric UL,and it has high morbidity,with or without lithiasis as hematuria and impairment of bone mass.The reduction in bone mineral density has already been described in pediatric idiopathic hypercalciuria(IH),and the precise mechanisms of bone loss or failure to achieve adequate bone mass gain remain unknown.A current understanding is that hypercalciuria throughout life can be considered a risk of change in bone structure and low bone mass throughout life.However,it is still not entirely known whether hypercalciuria throughout life can compromise the quality of the mass.The peak bone mass is achieved by late adolescence,peaking at the end of the second decade of life.This accumulation should occur without interference in order to achieve the peak of optimal bone mass.The bone mass acquired during childhood and adolescence is a major determinant of adult bone health,and its accumulation should occur without interference.This raises the critical question of whether adult osteoporosis and the risk of fractures are initiated during childhood.Pediatricians should be aware of this pediatric problem and investigate their patients.They should have the knowledge and ability to diagnose and initially manage patients with IH,with or without UL.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
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
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
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Idiopathic hypercalciuria （IH） is the leading metabolic risk factor for urolithiasis and affects all age groups without gender or race predominance. IH has a high morbidity with or without lithiasis and reduced bone mineral density （BMD）, as described previously in pe-diatric patients as well as in adults. The pathogenesis of IH is complex and not completely understood, given that urinary excretion of calcium is the end result of an interplay between three organs （gut, bone and kidney）, which is further orchestrated by hormones, such as 1,25 dihydroxyvitamin D, parathyroid hormone, calcitonin and fosfatonins （i.e., fbroblast growth-factor-23）. Usu-ally, a primary defect in one organ induces compensa-tory mechanisms in the remaining two organs, such as increased absorption of calcium in the gut secondary toa primary renal loss. Thus, IH is a systemic abnormality of calcium homeostasis with changes in cellular trans-port of this ion in intestines, kidneys and bones. Re-duced BMD has been demonstrated in pediatric patients diagnosed with IH. However, the precise mechanisms of bone loss or failure of adequate bone mass gain are still unknown. The largest accumulation of bone mass occurs during childhood and adolescence, peaking atthe end of the second decade of life. This accumulation should occur without interference to achieve the peak of optimal bone mass. Any interference may be a risk factor for the reduction of bone mass with increased risk of fractures in adulthood. This review will address the pathogenesis of IH and its consequence in bone mass.
文摘BACKGROUND Hypercalciuria is the most common metabolic risk factor for calcium urolithiasis and is associated with bone loss in adult patients.Reduced bone mineral density(BMD)was already described in idiopathic hypercalciuria(IH)children,but the precise mechanisms of bone loss or inadequate bone mass gain remain unknown.Life-long hypercalciuria might be considered a risk to change bone structure and determine low bone mass throughout life.The peak of bone mass should occur without interferences.A beneficial effect of citrate formulations and thiazides on bone mass in adult and pediatric patients with IH have been shown.AIM To evaluate whether pharmacological therapy has a beneficial effect on bone mass in children and adolescents with IH.METHODS This retrospective cohort study evaluated 40 hypercalciuric children nonresponsive to lifestyle and diet changes.After a 2-mo run-in period of citrate formulation(Kcitrate)usage,the first bone densitometry(DXA)was ordered.In patients with sustained hypercalciuria,a thiazide diuretic was prescribed.The second DXA was performed after 12 mo.Bone densitometry was performed by DXA at lumbar spine(L2-L4).A 24-h urine(calcium,citrate,creatinine)and blood samples(urea,creatinine,uric acid,calcium,phosphorus,magnesium,chloride,hemoglobin)were obtained.Clinical data included age,gender,weight,height and body mass index.RESULTS Forty IH children;median age 10.5 year and median time follow-up 6.0 year were evaluated.Nine patients were treated with Kcitrate(G1)and 31 with Kcitrate+thiazide(G2).There were no differences in age,gender,body mass index z-score and biochemical parameters between G1 and G2.There were no increases in total cholesterol,kalemia and magnesemia.Calciuria decreased in both groups after treatment.Lumbar spine BMD z-score increased after thiazide treatment in G2.There was no improvement in G1.CONCLUSION Results point to a beneficial effect of thiazide on lumbar spine BMD z-score in children with IH.Further studies are necessary to confirm the results of the present study.
文摘The incidence of urolithiasis(UL)is increasing,and it has become more common in children and adolescents over the past few decades.Hypercalciuria is the leading metabolic risk factor of pediatric UL,and it has high morbidity,with or without lithiasis as hematuria and impairment of bone mass.The reduction in bone mineral density has already been described in pediatric idiopathic hypercalciuria(IH),and the precise mechanisms of bone loss or failure to achieve adequate bone mass gain remain unknown.A current understanding is that hypercalciuria throughout life can be considered a risk of change in bone structure and low bone mass throughout life.However,it is still not entirely known whether hypercalciuria throughout life can compromise the quality of the mass.The peak bone mass is achieved by late adolescence,peaking at the end of the second decade of life.This accumulation should occur without interference in order to achieve the peak of optimal bone mass.The bone mass acquired during childhood and adolescence is a major determinant of adult bone health,and its accumulation should occur without interference.This raises the critical question of whether adult osteoporosis and the risk of fractures are initiated during childhood.Pediatricians should be aware of this pediatric problem and investigate their patients.They should have the knowledge and ability to diagnose and initially manage patients with IH,with or without UL.
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。
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.
