|
1
|
Heilberg IP, Carvalho AB, Denburg MR. Between a Rock and a Short Place-The Impact of Nephrolithiasis on Skeletal Growth and Development Across the Lifespan. Curr Osteoporos Rep 2024; 22:576-589. [PMID: 39356465 DOI: 10.1007/s11914-024-00888-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/10/2024] [Indexed: 10/03/2024]
Abstract
PURPOSE OF REVIEW The impact of nephrolithiasis on skeletal growth and bone health across the life span of kidney stone formers is reviewed. MAIN FINDINGS Bone disease is an early event among kidney stone formers (SF), with distinct phenotypes according to each age, sex, menopausal status, dietary, hormonal and genetic factors. Nephrolithiasis-associated bone disorder is characterized by reduced bone mineral density (BMD) and histologically discloses low bone formation, high bone resorption and abnormal mineralization. Although hypercalciuria has been presumed to be pathogenic for bone loss in SF, the association of BMD with urinary calcium is not uniform in all studies. Hypocitraturia, metabolic disturbances, cytokines and receptors, growth factors and acid-base status may all influence skeletal outcomes. The potential link of bone disease with vascular calcification and cardiovascular disease among SF is discussed. The unique vulnerability of the younger skeleton to the effects of nephrolithiasis on attainment of peak bone mass and strength is highlighted and the association of bone loss with kidney stone formation early in life indicate the opportunity for intervention to reduce the risk of future bone fractures.
Collapse
Affiliation(s)
- Ita Pfeferman Heilberg
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, Rua Botucatu 740 - Vila Clementino, São Paulo, 04023-900, Brazil.
| | - Aluizio Barbosa Carvalho
- Nephrology Division, Department of Medicine, Universidade Federal de São Paulo, Rua Botucatu 740 - Vila Clementino, São Paulo, 04023-900, Brazil
| | - Michelle R Denburg
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, USA
- Division of Pediatric Nephrology, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
| |
Collapse
|
|
2
|
Hilma RF, Widaty S, Marissa M, Ilyas M. Association between serum level of vitamin D (25-hydroxyvitamin D) and plasma level of vitamin D receptor with bacteriological index in leprosy patients. Dermatol Reports 2023; 15:9705. [PMID: 38327594 PMCID: PMC10848641 DOI: 10.4081/dr.2023.9705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 04/23/2023] [Indexed: 02/09/2024] Open
Abstract
Macrophages respond against Mycobacterium leprae infection through interacting with vitamin D and vitamin D receptor (VDR). There has been no study analyzing the association between vitamin D and VDR with bacteriological index (BI) in leprosy patients in Indonesia. To analyze the serum level of 25- hydroxyvitamin D (25(OH)D) and plasma level of VDR as well as their association with BI in leprosy patients in Indonesia. This is a cross-sectional study. Serum level of 25(OH)D was assessed with in vitro chemiluminescent immunoassay. Plasma level of VDR was assessed with enzyme linked immunosorbent assay method. Median serum level of 25(OH)D was 12.68 ng/mL. There was no correlation between serum level of 25(OH)D and BI (r=0.033; p=0.869). Median plasma level of VDR was 1.36 ng/mL. There was no correlation between plasma level of VDR and BI (r=- 0.063; p=0.749) and no significant association between BI and serum level of 25(OH) and plasma level of VDR (R2=0.055). There was no association between serum level of 25(OH)D and plasma level of VDR with BI in leprosy patients.
Collapse
Affiliation(s)
- Rizka Farah Hilma
- Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo National Hospital, Jakarta
| | - Sandra Widaty
- Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo National Hospital, Jakarta
| | - Melani Marissa
- Department of Dermatology and Venereology, Faculty of Medicine Universitas Indonesia, Dr. Cipto Mangunkusumo National Hospital, Jakarta
| | - Muhammad Ilyas
- Department of Community Medical Science, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
| |
Collapse
|
|
3
|
Penido MGMG, Tavares MDS. Beyond kidney stones: Why pediatricians should worry about hypercalciuria. World J Clin Pediatr 2021; 10:137-150. [PMID: 34868890 PMCID: PMC8603641 DOI: 10.5409/wjcp.v10.i6.137] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 08/08/2021] [Accepted: 10/31/2021] [Indexed: 02/06/2023] Open
Abstract
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.
Collapse
Affiliation(s)
- Maria Goretti Moreira Guimarães Penido
- Pediatric Nephrology Unit, Nephrology Center, Santa Casa de Belo Horizonte Hospital, CEP 30150320, Belo Horizonte, Minas Gerais, Brazil
- Pediatric Nephrology Unit, Pediatric Department, Clinics Hospital, Universidade Federal de Minas Gerais, CEP 30130100, Belo Horizonte, Minas Gerais, Brazil
| | - Marcelo de Sousa Tavares
- Pediatric Nephrology Unit, Nephrology Center, Santa Casa de Belo Horizonte Hospital, CEP 30150320, Belo Horizonte, Minas Gerais, Brazil
| |
Collapse
|
|
4
|
Chamsuwan S, Angkanaporn K, Dissayabutra T, Chuaypen N, Buranakarl C. The association between single nucleotide polymorphism in vitamin D receptor and calcium oxalate urolithiasis in dogs. J Vet Intern Med 2021; 35:2263-2270. [PMID: 34322901 PMCID: PMC8478019 DOI: 10.1111/jvim.16225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 07/06/2021] [Accepted: 07/14/2021] [Indexed: 11/28/2022] Open
Abstract
Background Polymorphisms of the vitamin D receptor (VDR) are associated with calcium oxalate (CaOx) nephrolithiasis in humans. Objectives To investigate the association between VDR polymorphisms and susceptibility to CaOx urolithiasis in dogs. Animals Thirty‐five dogs with CaOx urolithiasis were compared with 40 stone‐free dogs. Methods This was a case‐control study. Two VDR gene polymorphisms (rs851998024 and rs852900542) were detected by specific TaqMan real‐time polymerase chain reaction assay, and their relationship with serum 1,25‐dihydroxyvitamin D, serum and urinary electrolyte concentrations was evaluated. Results The distribution of the rs852900542 polymorphism was significantly different between the case and the control dogs (x2 = 6.369, P = .04). Dogs with a CC or CT genotype had an increased risk of CaOx stones than those with the TT genotype (odds ratio = 3.82, 95% confidence interval 1.04‐13.98). The CaOx dogs with the TT genotype had a significantly lower urinary calcium‐to‐creatinine ratio than the CT+CC genotypes. 1,25‐(OH)2D concentrations did not differ between the cases and the controls (308.7 ± 217.4 vs 286.7 ± 185.1 pg/mL, P = .45). Conclusions and Clinical Importance This finding suggests that vitamin D metabolism might play a role in CaOx stone formation in dogs.
Collapse
Affiliation(s)
- Sumonwan Chamsuwan
- Department of Physiology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - Kris Angkanaporn
- Department of Physiology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| | - Thasinas Dissayabutra
- STAR unit of Renal Biochemistry and Stone Disease, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Natthaya Chuaypen
- Center of Excellence in Hepatitis and Liver Cancer, Department of Biochemistry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Chollada Buranakarl
- Department of Physiology, Faculty of Veterinary Science, Chulalongkorn University, Bangkok, Thailand
| |
Collapse
|
|
5
|
Daryanto B, Purnomo BB, Gunawan A, Mayasari ED, Kusumaningrum AG, Tamara F, Hutama SA, Fajar JK. The association between vitamin D receptor gene polymorphisms and the risk of nephrolithiasis: A meta-analysis. Meta Gene 2020. [DOI: 10.1016/j.mgene.2019.100628] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
|
|
6
|
Pérez Suárez G, Serrano A, Magallanes MV, Arango Sancho P, Luis Yanes MI, García Nieto VM. Longitudinal study of kidney water management in patients diagnosed with idiopathic hypercalciuria in childhood. Nefrologia 2019; 40:190-196. [PMID: 31806292 DOI: 10.1016/j.nefro.2019.07.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Revised: 06/24/2019] [Accepted: 07/15/2019] [Indexed: 10/25/2022] Open
Abstract
INTRODUCTION There is much debate about whether idiopathic hypercalciuria (IH) affects kidney water management. For the first time in the literature, we carried out a longitudinal study of kidney water management (KWM) in patients diagnosed with IH in childhood and followed-up until adulthood (mean follow-up 17.7±1.4 years). METHODS Twenty-nine patients (7 M, 22 F) over the age of 24 years (mean 28.2±2.9 years, range: 24.1-35.9) who were diagnosed with IH in childhood (mean 7.6±3.2 years, range: 1-14) were included. Maximum urine osmolality (UO) and/or urine volume adjusted for 100ml of glomerular filtration rate (V/GFR) in both age groups (paediatric and adult) were determined. Moreover, whenever possible, in both age groups plasma creatinine levels, plasma sodium levels, uric acid levels, the citrate/creatinine ratio and the calcium/citrate ratio were recorded and a renal and bladder ultrasound was performed. RESULTS In the paediatric age group, KWM was altered in 9/29 cases (31%) (4 with reduced maximum UO and 5 with elevated V/GFR). In adulthood, KWM was found to be affected in 7/29 cases (24.1%) (6 with reduced UO and one with elevated V/GFR). Compared to the paediatric age group, adult patients had lower V/GFR, calcium/creatinine and citrate/creatinine values, as well as higher plasma creatinine, uric acid and calcium/citrate. There were no differences in the maximum UO in both age groups. However, UO in adulthood was significantly lower in subjects who had renal colic compared to those who did not (P=.04). CONCLUSIONS KWM was affected in approximately one third of patients with IH, which persisted 20 years after diagnosis. We think that these results may be due to adherence to the recommended protective diet and to the pharmacological treatment administered at the diagnosis of IH during childhood.
Collapse
Affiliation(s)
- Germán Pérez Suárez
- Servicio de Nefrología, Hospital Insular de Las Palmas de Gran Canaria, Las Palmas, España.
| | - Alma Serrano
- Servicio de Nefrología Pediátrica, Centro Médico Nacional La Raza, México DF, México
| | | | - Pedro Arango Sancho
- Servicio de Nefrología Pediátrica, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - María Isabel Luis Yanes
- Servicio de Nefrología Pediátrica, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - Víctor M García Nieto
- Servicio de Nefrología Pediátrica, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| |
Collapse
|
|
7
|
Expression of vitamin D receptor, CYP27B1 and CYP24A1 hydroxylases and 1,25-dihydroxyvitamin D3 levels in stone formers. Urolithiasis 2019; 48:19-26. [DOI: 10.1007/s00240-019-01163-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Accepted: 09/16/2019] [Indexed: 01/16/2023]
|
|
8
|
García Nieto VM, Luis Yanes MI, Tejera Carreño P, Perez Suarez G, Moraleda Mesa T. The idiopathic hypercalciuria reviewed. Metabolic abnormality or disease? Nefrologia 2019; 39:592-602. [PMID: 31160051 DOI: 10.1016/j.nefro.2019.02.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Revised: 02/02/2019] [Accepted: 02/20/2019] [Indexed: 02/08/2023] Open
Abstract
Idiopathic hypercalciuria (IH) is defined as that clinical situation in which an increase in urinary calcium excretion is observed, in the absence of hypercalcemia and other known causes of hypercalciuria. In recent years, its diagnosis in pediatric age has been more frequent because it has been known that it can debut with very different symptoms, in the absence of kidney stone formation. The discovery of genetic hypercalciuric stone-forming rats has allowed us to glimpse the pathophysiological mechanism of IH since they show many data in common with humans with IH as normal levels of blood calcium, intestinal calcium hyperabsorption, increased bone resorption and a defect in the renal tubular calcium reabsorption. In 1993, it was shown that in these animals there is an increase in the number of vitamin D receptors (VDR) in the intestine, which favors an increase in the functional capacity of calcitriol-VDR complexes that explains the increase in intestinal transport of calcium. The same happens at the bone level producing a greater resorption. In our opinion, IH is a 'metabolic anomaly' or, better, an inheritable constitutive metabolic characteristic. In this sense, what patients with IH would inherit is the availability of having a greater number of VDRs in their cells than those with normal urinary calcium excretion. IH cannot be considered a sensu stricto disease, so pharmacological treatment must be individualized.
Collapse
Affiliation(s)
- Víctor M García Nieto
- Sección de Nefrología Pediátrica, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España.
| | - María Isabel Luis Yanes
- Sección de Nefrología Pediátrica, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - Patricia Tejera Carreño
- Sección de Nefrología Pediátrica, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| | - German Perez Suarez
- Servicio de Nefrología, Hospital Universitario Insular de Gran Canaria, Las Palmas de Gran Canaria, España
| | - Teresa Moraleda Mesa
- Sección de Nefrología Pediátrica, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, España
| |
Collapse
|
|
9
|
Vitamin D, Hypercalciuria and Kidney Stones. Nutrients 2018; 10:nu10030366. [PMID: 29562593 PMCID: PMC5872784 DOI: 10.3390/nu10030366] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Revised: 03/13/2018] [Accepted: 03/14/2018] [Indexed: 01/30/2023] Open
Abstract
The estimated lifetime risk of nephrolithiasis is growing nowadays, and the formation of kidney stones is frequently promoted by hypercalciuria. Vitamin D, and especially its active metabolite calcitriol, increase digestive calcium absorption—as urinary calcium excretion is directly correlated with digestive calcium absorption, vitamin D metabolites could theoretically increase calciuria and promote urinary stone formation. Nevertheless, there was, until recently, low evidence that 25-hydroxyvitamin D serum levels would be correlated with kidney stone formation, even if high calcitriol concentrations are frequently observed in hypercalciuric stone formers. Low 25-hydroxyvitamin D serum levels have been associated with a broad spectrum of diseases, leading to a huge increase in vitamin D prescription in the general population. In parallel, an increased frequency of kidney stone episodes has been observed in prospective studies evaluating vitamin D alone or in association with calcium supplements, and epidemiological studies have identified an association between high 25-hydroxyvitamin D serum levels and kidney stone formation in some groups of patients. Moreover, urinary calcium excretion has been shown to increase in response to vitamin D supplements, at least in some groups of kidney stone formers. It seems likely that predisposed individuals may develop hypercalciuria and kidney stones in response to vitamin D supplements.
Collapse
|
|
10
|
Role of FGF23 in Pediatric Hypercalciuria. BIOMED RESEARCH INTERNATIONAL 2018; 2017:3781525. [PMID: 29457024 PMCID: PMC5804327 DOI: 10.1155/2017/3781525] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 09/26/2017] [Accepted: 10/22/2017] [Indexed: 01/29/2023]
Abstract
Background This study explored the possible role of FGF23 in pediatric hypercalciuria. Methods Plasma FGF23 was measured in 29 controls and 58 children and adolescents with hypercalciuria: 24 before treatment (Pre-Treated) and 34 after 6 months of treatment (Treated). Hypercalciuric patients also measured serum PTH hormone, 25(OH)vitD, phosphate, calcium, creatinine, and 24 h urine calcium, phosphate, and creatinine. Results There were no differences in age, gender, ethnicity, or body mass index either between controls and patients, or between Pre-Treated and Treated patients. Median plasma FGF23 in controls was 72 compared with all patients, 58 RU/mL (p = 0.0019). However, whereas FGF23 in Pre-Treated patients, 73 RU/mL, was not different from controls, in Treated patients it was 50 RU/mL, significantly lower than in both controls (p < 0.0001) and Pre-Treated patients (p = 0.02). In all patients, there was a correlation between FGF23 and urinary calcium (r = 0.325; p = 0.0014). Treated patients had significantly lower urinary calcium (p < 0.0001), higher TP/GFR (p < 0.001), and higher serum phosphate (p = 0.007) versus Pre-Treated patients. Conclusions Pharmacological treatment of hypercalciuric patients resulted in significantly lower urinary calcium excretion, lower serum FGF23, and elevated TP/GFR and serum phosphate concentration, without significant changes in PTH. Further studies are indicated. This trial is registered with Clinical Registration Number RBR 8W27X5.
Collapse
|
|
11
|
Relationship between Urinary Calcium and Bone Mineral Density in Patients with Calcium Nephrolithiasis. J Urol 2017; 197:1472-1477. [PMID: 28063842 DOI: 10.1016/j.juro.2017.01.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/25/2016] [Indexed: 11/23/2022]
Abstract
PURPOSE Calcium nephrolithiasis is associated with an increased risk of osteoporosis and fracture. Hypercalciuria has been assumed to be pathogenic for bone loss in kidney stone formers, although this association was shown in small cross-sectional studies. We explored the association of urine calcium with bone mineral density in kidney stone formers. MATERIALS AND METHODS We retrospectively studied bone mineral density in kidney stone formers. Excluded were subjects with hypercalcemia, chronic bowel disease, primary hyperparathyroidism, distal renal tubular acidosis or endogenous creatinine clearance less than 40 ml per minute. We included 250 males and 182 females subdivided into 145 who were estrogen treated and postmenopausal, and 37 who were nonestrogen treated and postmenopausal. We assessed the association of lumbar spine and femoral neck bone mineral density with 24-hour urine calcium on random and restricted diets, and while fasting using univariable and multivariable models adjusting for body mass index, urine sodium and sulfate. RESULTS On multivariable analysis no significant association was found between urine calcium on a random or a restricted diet, or during fasting conditions and femoral neck or lumbar spine bone mineral density in men and estrogen treated women. In estrogen untreated women lumbar spine bone mineral density inversely correlated with urine calcium on the restricted diet (r = -0.38, p = 0.04 and adjusted r = -0.45, p = 0.02) and in the fasting state (r = -0.42, p = 0.05). CONCLUSIONS Unlike in previous small cross-sectional studies we found no significant relationship between urine calcium and bone mineral density in a large group of calcium kidney stone formers. However, a significant inverse relationship was found in estrogen untreated kidney stone formers only. This study suggests that mechanism(s) other than hypercalciuria explain the lower bone mineral density and the higher fracture risk in patients who are kidney stone formers. It also highlights the role of estrogen on bone integrity.
Collapse
|
|
12
|
Unilateral renal agenesis. New arguments about the genetic relationship between kidney malformations and urolithiasis. An Pediatr (Barc) 2016. [DOI: 10.1016/j.anpede.2015.09.025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
|
|
13
|
Garcia Nieto V, Huertes Díaz B, Escribano Subias J, Alarcón Alacio MT, Gonzalez Rodríguez JD, Cabrera Sevilla JE, Peralta Aros C, Luis Yanes MI. [Unilateral renal agenesis. New arguments about the genetic relationship between kidney malformations and urolithiasis]. An Pediatr (Barc) 2016; 85:240-246. [PMID: 26669685 DOI: 10.1016/j.anpedi.2015.09.023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2015] [Revised: 08/12/2015] [Accepted: 09/07/2015] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND In few previous works, it has been reported that hypercalciuria is associated with some types of CAKUT, namely ureteropelvic junction obstruction, vesicoureteral reflux or simple renal cysts. In addition, one higher prevalence of hypercalciuria and/or urolithiasis has been described in their family members compared to the general population. This study was carried out to find out whether children with unilateral renal agenesis (URA) have these features previously described in other CAKUT types. METHODS In a descriptive and multicenter study we studied the prevalence of hypercalciuria, hypocitraturia and urolithiasis in 67 children (43 males and 24 females) with URA and their families. RESULTS The two metabolic anomalies that promote stone formation were observed in 26 children (38.8%), distributed as follows: hypercalciuria in 16, hypocitraturia in 9, and both hypercalciuria and hypocitraturia in 1. Eight children (11.9%) suffered renal colic during follow-up. Familial history of urolithiasis was found in 42/67 children (62.7%): in 12 of the first-degree relatives, in 15 of the second degree relatives and in 15 patients both in the first-degree as in their second degree relatives. In contrast, in historic control group, only in 28.1% of families at least one member had urolithiasis. CONCLUSION Our results show that the prevalence of hypercalciuria and/or hypocitraturia is greater in pediatric patients with URA than in the general population. Likewise, the prevalence of urolithiasis in the families of these children is also higher than that in the general population.
Collapse
Affiliation(s)
- Victor Garcia Nieto
- Sección de Nefrología Pediátrica, Hospital Universitario Nuestra Señora de Candelaria Santa Cruz de Tenerife, España.
| | | | | | | | | | | | | | - Maria Isabel Luis Yanes
- Sección de Nefrología Pediátrica, Hospital Universitario Nuestra Señora de Candelaria Santa Cruz de Tenerife, España
| |
Collapse
|
|
14
|
Mirza F, Canalis E. Management of endocrine disease: Secondary osteoporosis: pathophysiology and management. Eur J Endocrinol 2015; 173:R131-51. [PMID: 25971649 PMCID: PMC4534332 DOI: 10.1530/eje-15-0118] [Citation(s) in RCA: 202] [Impact Index Per Article: 20.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2015] [Accepted: 05/12/2015] [Indexed: 12/14/2022]
Abstract
Osteoporosis is a skeletal disorder characterized by decreased mass and compromised bone strength predisposing to an increased risk of fractures. Although idiopathic osteoporosis is the most common form of osteoporosis, secondary factors may contribute to the bone loss and increased fracture risk in patients presenting with fragility fractures or osteoporosis. Several medical conditions and medications significantly increase the risk for bone loss and skeletal fragility. This review focuses on some of the common causes of osteoporosis, addressing the underlying mechanisms, diagnostic approach and treatment of low bone mass in the presence of these conditions.
Collapse
Affiliation(s)
- Faryal Mirza
- Division of Endocrinology and MetabolismDepartments of MedicineOrthopaedic SurgeryUConn Musculoskeletal Institute, UConn Health, 263 Farmington Avenue, Farmington, Connecticut 06030-5456, USA
| | - Ernesto Canalis
- Division of Endocrinology and MetabolismDepartments of MedicineOrthopaedic SurgeryUConn Musculoskeletal Institute, UConn Health, 263 Farmington Avenue, Farmington, Connecticut 06030-5456, USA Division of Endocrinology and MetabolismDepartments of MedicineOrthopaedic SurgeryUConn Musculoskeletal Institute, UConn Health, 263 Farmington Avenue, Farmington, Connecticut 06030-5456, USA
| |
Collapse
|
|
15
|
Jia Z, Wang S, He D, Cui L, Lu Y, Hu H, Qin B, Zhao Z. Role of calcium in the regulation of bone morphogenetic protein 2, runt-related transcription factor 2 and Osterix in primary renal tubular epithelial cells by the vitamin D receptor. Mol Med Rep 2015; 12:2082-2088. [PMID: 25823394 DOI: 10.3892/mmr.2015.3568] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 02/20/2015] [Indexed: 11/05/2022] Open
Abstract
The aim of the present study was to investigate the effect of 1,25(OH)2D3/vitamin D receptor (VDR) and calcium on the expression levels of osteogenic factors in primary renal tubular epithelial cells (RTECs) using genetic hypercalciuric rats. The basal levels of osteogenic factors were detected in Sprague Dawley and genetic hypercalciuric rats. The gene and protein levels of bone morphogenetic protein 2 (BMP2), runt-related transcription factor 2 (Runx2) and osterix were detected in the RTECs transduced with Lenti-VDR-sh and were incubated with calcium. Using the o-cresolphthalein complexone method, the calcium levels of the primary RTECs cultured with Lenti-VDR-sh and with 1,25(OH)2D3 were assessed. The basal levels of BMP2, Runx2 and Osterix in the cells were significantly higher in the genetic hypercalciuric rats compared with the control rats. VDR knockdown in the RTECs reduced the expression levels of BMP2, Runx2 and Osterix. The calcium depositions in the primary RTECs were also decreased following exposure to Lenti-VDR-sh, but increased following treatment with 1,25(OH)2D3. The expression levels of BMP2, Runx2 and Osterix were markedly increased in the cells incubated with calcium compared with the cells treated with normal saline and the untreated cells. These findings indicated that osteogenic factors, including BMP2, Runx2 and Osterix may be important in renal stone formation in idiopathic hypercalciuria. VDR may mediate the increased expression levels of BMP2, Runx2 and Osterix by positively regulating calcium levels in primary RTECs.
Collapse
Affiliation(s)
- Zhaohui Jia
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Shaogang Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Deng He
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Lei Cui
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Yuchao Lu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Henglong Hu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Baolong Qin
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Zhenyu Zhao
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| |
Collapse
|
|
16
|
Frick KK, Krieger NS, Bushinsky DA. Modeling hypercalciuria in the genetic hypercalciuric stone-forming rat. Curr Opin Nephrol Hypertens 2015; 24:336-44. [PMID: 26050120 PMCID: PMC4495578 DOI: 10.1097/mnh.0000000000000130] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PURPOSE OF REVIEW In this review, we discuss how the genetic hypercalciuric stone-forming (GHS) rats, which closely model idiopathic hypercalciuria and stone formation in humans, provide insights into the pathophysiology and consequences of clinical hypercalciuria. RECENT FINDINGS Hypercalciuria in the GHS rats is due to a systemic dysregulation of calcium transport, as manifest by increased intestinal calcium absorption, increased bone resorption and decreased renal tubule calcium reabsorption. Increased levels of vitamin D receptor in intestine, bone and kidney appear to mediate these changes. The excess receptors are biologically active and increase tissue sensitivity to exogenous vitamin D. Bones of GHS rats have decreased bone mineral density (BMD) as compared with Sprague-Dawley rats, and exogenous 1,25(OH)2D3 exacerbates the loss of BMD. Thiazide diuretics improve the BMD in GHS rats. SUMMARY Studying GHS rats allows direct investigation of the effects of alterations in diet and utilization of pharmacologic therapy on hypercalciuria, urine supersaturation, stone formation and bone quality in ways that are not possible in humans.
Collapse
Affiliation(s)
- Kevin K Frick
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | | | | |
Collapse
|
|
17
|
A Single Nucleotide Polymorphism (rs4236480) in TRPV5 Calcium Channel Gene Is Associated with Stone Multiplicity in Calcium Nephrolithiasis Patients. Mediators Inflamm 2015; 2015:375427. [PMID: 26089600 PMCID: PMC4452106 DOI: 10.1155/2015/375427] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 03/31/2015] [Accepted: 04/17/2015] [Indexed: 12/11/2022] Open
Abstract
Nephrolithiasis is characterized by calcification of stones in the kidneys from an unknown cause. Animal models demonstrated the functional roles of the transient receptor potential vanilloid member 5 (TRPV5) gene in calcium renal reabsorption and hypercalciuria. Therefore, TRPV5 was suggested to be involved in calcium homeostasis. However, whether genetic polymorphisms of TRPV5 are associated with kidney stone multiplicity or recurrence is unclear. In this study, 365 Taiwanese kidney-stone patients were recruited. Both biochemical data and DNA samples were collected. Genotyping was performed by a TaqMan allelic discrimination assay. We found that a TRPV5 polymorphism (rs4236480) was observed to be associated with stone multiplicity of calcium nephrolithiasis, as the risk of stone multiplicity was higher in patients with the TT+CT genotype than in patients with the CC genotype (p = 0.0271). In summary, despite the complexity of nephrolithiasis and the potential association of numerous calcium homeostatic absorption/reabsorption factors, TRPV5 plays an important role in the pathogenesis of calcium nephrolithiasis.
Collapse
|
|
18
|
Letavernier E, Vandermeersch S, Traxer O, Tligui M, Baud L, Ronco P, Haymann JP, Daudon M. Demographics and characterization of 10,282 Randall plaque-related kidney stones: a new epidemic? Medicine (Baltimore) 2015; 94:e566. [PMID: 25761176 PMCID: PMC4602465 DOI: 10.1097/md.0000000000000566] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Renal stone incidence has progressively increased in industrialized countries, but the implication of Randall plaque in this epidemic remains unknown. Our objectives were to determine whether the prevalence of Randall plaque-related stones increased during the past decades after having analyzed 30,149 intact stones containing mainly calcium oxalate since 1989 (cross-sectional study), and to identify determinants associated with Randall plaque-related stones in patients (case-control study). The proportion of Randall plaque-related stones was assessed over 3 time periods: 1989-1991, 1999-2001, and 2009-2011. Moreover, we analyzed clinical and biochemical parameters of 105 patients affected by calcium oxalate stones, with or without plaque. Of 30,149 calcium oxalate stones, 10,282 harbored Randall plaque residues (34.1%). The prevalence of Randall plaque-related stones increased dramatically during the past years. In young women, 17% of calcium oxalate stones were associated with Randall plaque during the 1989-1991 period, but the proportion rose to 59% 20 years later (P < 0.001). Patients with plaques experienced their first stone-related event earlier in life as compared with those without plaque (median age 26 vs 34 years, P = 0.02), had increased ionized serum calcium levels (P = 0.04), and increased serum osteocalcin (P = 0.001) but similar 25-hydroxyvitamin D levels. The logistic regression analysis showed that age (odds ratio [OR] 0.96, confidence interval [CI] 0.926-0.994, P = 0.02), weight (OR 0.97, CI 0.934-0.997, P = 0.03), and osteocalcin serum levels (OR 1.12, CI 1.020-1.234, P = 0.02) were independently associated with Randall plaque. The prevalence of the FokI f vitamin D receptor polymorphism was higher in patients with plaque (P = 0.047). In conclusion, these findings point to an epidemic of Randall plaque-associated renal stones in young patients, and suggest a possible implication of altered vitamin D response.
Collapse
Affiliation(s)
- Emmanuel Letavernier
- From the Sorbonne universités-UPMC Univ Paris 06 (EL, SV, OT, LB, PR, J-PH, MD); INSERM UMR S 1155 (EL, SV, LB, PR, J-PH, MD); AP-HP (EL, LB, J-PH, MD), Hôpital Tenon, Explorations fonctionnelles multidisciplinaires and Cristal Laboratory; AP-HP (OT, MT), Hôpital Tenon, Service d'Urologie; and AP-HP (PR), Hôpital Tenon, Service de Nephrologie, Paris, France
| | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Abstract
Osteoporosis is a skeletal disease characterized by decreased bone mass and microarchitectural changes in bone tissue that increase the susceptibility to fracture. Secondary osteoporosis is loosely defined as low bone mineral density or increased risk of fragility fracture caused by any factor other than aging or postmenopausal status. The purpose of this review is to discuss the current understanding of the pathophysiology and contribution to fracture risk of many of the more common causes of secondary osteoporosis, as well as diagnostic considerations, outlined by organ system. While not comprehensive, included are a wide array of diseases, conditions, and medications that have been associated with bone loss and susceptibility to fractures. The hope is to highlight the importance to the general clinician of screening for and treating the osteoporosis in these patients, so to limit the resultant increased morbidity associated with fractures.
Collapse
Affiliation(s)
- Gregory R Emkey
- Pennsylvania Regional Center for Arthritis & Osteoporosis Research, 1200 Broadcasting Road, Suite 200, Wyomissing, PA 19610, USA.
| | - Sol Epstein
- Mt Sinai School of Medicine, I Gustave Levy Place New York, New York, NY, USA
| |
Collapse
|
|
20
|
Urinary excretion of calcium, magnesium, phosphate, citrate, oxalate, and uric acid by healthy schoolchildren using a 12-h collection protocol. Pediatr Nephrol 2014; 29:1201-8. [PMID: 24519097 DOI: 10.1007/s00467-014-2755-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 12/10/2013] [Accepted: 01/03/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND Improving knowledge about normal urine composition in children is important for early prevention of lithiasis. We describe urinary excretion values of calcium (Ca), magnesium (Mg), phosphate (P), citrate (Cit), uric acid (Ur), and oxalate (Ox) in healthy children with and without a family history of lithiasis, using a 12-h urine collection protocol. METHODS Urine samples were obtained from 184 children (5-12 years): a spot sample collected in the afternoon, and a 12-h overnight sample. Solute/creatinine (Cr) and 12-h solute excretion was calculated. RESULTS Urinary excretion values of the studied solutes are presented as percentile values, separately for each type of sample. Due to age-related differences in the solute/creatinine ratios, except for Ca and Cit, results are described according to the child's age. The presence of excretion values related to an increased risk of lithiasis was more common in children with a family history. CONCLUSIONS We report data from urine samples collected by using a simplified collection protocol. The observed differences between children with and without a family history of lithiasis could justify that in population studies aimed at setting reference values, the former are excluded.
Collapse
|
|
21
|
Ng AH, Frick KK, Krieger NS, Asplin JR, Cohen-McFarlane M, Culbertson CD, Kyker-Snowman K, Grynpas MD, Bushinsky DA. 1,25(OH)₂D₃ induces a mineralization defect and loss of bone mineral density in genetic hypercalciuric stone-forming rats. Calcif Tissue Int 2014; 94:531-43. [PMID: 24481706 PMCID: PMC4276134 DOI: 10.1007/s00223-014-9838-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 01/07/2014] [Indexed: 11/29/2022]
Abstract
Genetic hypercalciuric stone-forming (GHS) rats, bred to maximize urine (u) calcium (Ca) excretion, demonstrate increased intestinal Ca absorption, increased bone Ca resorption, and reduced renal Ca reabsorption, all leading to elevated uCa compared to the parental Sprague-Dawley (SD) rats. GHS rats have increased numbers of vitamin D receptors (VDRs) at each site, with normal levels of 1,25(OH)₂D₃ (1,25D), suggesting their VDR is undersaturated with 1,25D. We have shown that 1,25D induces a greater increase in uCa in GHS than SD rats. To examine the effect of the increased VDR on the osseous response to 1,25D, we fed GHS and SD rats an ample Ca diet and injected either 1,25D [low dose (LD) 12.5 or high dose (HD) 25 ng/100 g body weight/day] or vehicle (veh) daily for 16 days. Femoral areal bone mineral density (aBMD, by DEXA) was decreased in GHS+LD and GHS+HD relative to GHS+veh, while there was no effect on SD. Vertebral aBMD was lower in GHS compared to SD and further decreased in GHS+HD. Both femoral and L6 vertebral volumetric BMD (by μCT) were lower in GHS and further reduced by HD. Histomorphometry indicated a decreased osteoclast number in GHS+HD compared to GHS+veh or SD+HD. In tibiae, GHS+HD trabecular thickness and number increased, with a 12-fold increase in osteoid volume but only a threefold increase in bone volume. Bone formation rate was decreased in GHS+HD relative to GHS+veh, confirming the mineralization defect. The loss of BMD and the mineralization defect in GHS rats contribute to increased hypercalciuria; if these effects persist, they would result in decreased bone strength, making these bones more fracture-prone. The enhanced effect of 1,25D in GHS rats indicates that the increased VDRs are biologically active.
Collapse
Affiliation(s)
- Adeline H. Ng
- Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada
| | - Kevin K. Frick
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Nancy S. Krieger
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | | | | | - Christopher D. Culbertson
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Kelly Kyker-Snowman
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| | - Marc D. Grynpas
- Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada
| | - David A. Bushinsky
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA
| |
Collapse
|
|
22
|
Menon VB, Moysés RMA, Gomes SA, de Carvalho AB, Jorgetti V, Heilberg IP. Expression of fibroblast growth factor 23, vitamin D receptor, and sclerostin in bone tissue from hypercalciuric stone formers. Clin J Am Soc Nephrol 2014; 9:1263-70. [PMID: 24763863 DOI: 10.2215/cjn.10030913] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Increased bone resorption, low bone formation, and abnormal mineralization have been described in stone formers with idiopathic hypercalciuria. It has been previously shown that the receptor activator of NF-κB ligand mediates bone resorption in idiopathic hypercalciuria (IH). The present study aimed to determine the expression of fibroblast growth factor 23 (FGF-23), vitamin D receptor (VDR), and sclerostin in bone tissue from IH stone formers. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Immunohistochemical analysis was performed in undecalcified bone samples previously obtained for histomorphometry from 30 transiliac bone biopsies of idiopathic hypercalciuria stone-forming patients between 1992 and 2002 and 33 healthy individuals (controls). Serum parameters were obtained from their medical records. RESULTS Histomorphometry disclosed 21 IH patients with high and 9 IH patients with normal bone resorption. Importantly, eroded surfaces (ES/BS) from IH patients but not controls were significantly correlated with VDR immunostaining in osteoblasts (r=0.51; P=0.004), sclerostin immunostaining in osteocytes (r=0.41; P=0.02), and serum 1,25-dihydroxyvitamin D (r=0.55; P<0.01). Of note, both VDR and sclerostin immunostaining were significantly correlated with serum 1,25-dihydroxyvitamin D in IH patients (r=0.52; P=0.01 and r=0.53; P=0.02, respectively), although VDR and sclerostin expression did not differ between IH and controls. IH patients with high bone resorption exhibited a significantly stronger sclerostin immunostaining than IH patients with normal bone resorption. FGF-23 expression in osteocytes from IH patients did not differ from controls and was not correlated with any histomorphometric parameter. CONCLUSIONS These findings suggest the contribution of VDR and sclerostin, as well as 1,25-dihydroxyvitamin D, to increase bone resorption in idiopathic hypercalciuria but do not implicate FGF-23 in the bone alterations seen in these patients.
Collapse
Affiliation(s)
| | | | - Samirah Abreu Gomes
- Nephrology Division, Federal University of São Paulo, São Paulo, Brazil; and
| | | | - Vanda Jorgetti
- Nephrology Division, University of São Paulo, São Paulo, Brazil
| | | |
Collapse
|
|
23
|
Frick KK, Asplin JR, Culbertson CD, Granja I, Krieger NS, Bushinsky DA. Persistence of 1,25D-induced hypercalciuria in alendronate-treated genetic hypercalciuric stone-forming rats fed a low-calcium diet. Am J Physiol Renal Physiol 2014; 306:F1081-7. [PMID: 24573387 DOI: 10.1152/ajprenal.00680.2013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Genetic hypercalciuric stone-forming (GHS) rats demonstrate increased intestinal Ca absorption, increased bone resorption, and reduced renal tubular Ca reabsorption leading to hypercalciuria and all form kidney stones. GHS have increased vitamin D receptors (VDR) at these sites of Ca transport. Injection of 1,25(OH)2D3 (1,25D) leads to a greater increase in urine (u)Ca in GHS than in control Sprague-Dawley (SD), possibly due to the additional VDR. In GHS the increased uCa persists on a low-Ca diet (LCD) suggesting enhanced bone resorption. We tested the hypothesis that LCD, coupled to inhibition of bone resorption by alendronate (alen), would eliminate the enhanced 1,25D-induced hypercalciuria in GHS. SD and GHS were fed LCD and half were injected daily with 1,25D. After 8 days all were also given alen until euthanasia at day 16. At 8 days, 1,25D increased uCa in SD and to a greater extent in GHS. At 16 days, alen eliminated the 1,25D-induced increase in uCa in SD. However, in GHS alen decreased, but did not eliminate, the 1,25D-induced hypercalciuria, suggesting maximal alen cannot completely prevent the 1,25D-induced bone resorption in GHS, perhaps due to increased VDR. There was no consistent effect on mRNA expression of renal transcellular or paracellular Ca transporters. Urine CaP and CaOx supersaturation (SS) increased with 1,25D alone in both SD and GHS. Alen eliminated the increase in CaP SS in SD but not in GHS. If these results are confirmed in humans with IH, the use of bisphosphonates, such as alen, may not prevent the decreased bone density observed in these patients.
Collapse
Affiliation(s)
- Kevin K Frick
- Research Assistant Professor of Medicine, Univ. of Rochester School of Medicine and Dentistry, Division of Nephrology, Dept. of Medicine, 601 Elmwood Ave., Box 675, Rochester, NY 14642.
| | | | | | | | | | | |
Collapse
|
|
24
|
Jia Z, Wang S, Tang J, He D, Cui L, Liu Z, Guo B, Huang L, Lu Y, Hu H. Does crystal deposition in genetic hypercalciuric rat kidney tissue share similarities with bone formation? Urology 2014; 83:509.e7-14. [PMID: 24468523 DOI: 10.1016/j.urology.2013.11.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2013] [Revised: 10/20/2013] [Accepted: 11/04/2013] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To address the effect of bone-related factors and 1,25(OH)2D3/vitamin D receptor (VDR) on renal stone formation in idiopathic hypercalciuria using genetic hypercalciuric rats. METHODS The basal levels of bone-related factors were detected in Sprague-Dawley and genetic hypercalciuric rats. In VDR silenced kidneys, the expression levels of bone morphogenetic protein 2 (BMP2), runt-related transcription factor 2 (Runx2), Osterix, and osteopontin (OPN) were measured, respectively. Tubular calcium phosphate deposits in kidneys and renal tubular epithelial cells (RTECs) were assessed using von Kossa stain. Kidneys were stained with immunohistochemical staining for OPN expression. Gene and protein expression levels of BMP2, Runx2, and Osterix were examined in RTECs incubated with 1,25(OH)2D3. RESULTS The basal levels of BMP2, Runx2, Osterix, and OPN were significantly increased in genetic hypercalciuric rats, whereas there were no differences in the expression levels of msh homeobox homolog 2 and alkaline phosphatase between the genetic hypercalciuric and normal control rats. VDR knockdown in genetic hypercalciuric rats reduced the expression levels of BMP2, Runx2, Osterix, and OPN. Tubular calcium phosphate deposits were also decreased in VDR silenced kidneys. Immunohistochemical staining showed that there was a reduction in OPN expression in RTECs along with reduction in calcification. Gene and protein expression levels of BMP2, Runx2, and Osterix were upregulated in RTECs incubated with 1,25(OH)2D3. The calcium phosphate deposits in RTECs were also increased by elevated 1,25(OH)2D3. CONCLUSION Our findings indicate that BMP2, Runx2, Osterix, and OPN might play an important role in renal stone formation in idiopathic hypercalciuria, and 1,25(OH)2D3/VDR might be the significant regulator in this process.
Collapse
Affiliation(s)
- Zhaohui Jia
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Shaogang Wang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
| | - Jinhui Tang
- Department of Paediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China.
| | - Deng He
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Lei Cui
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Zhenyu Liu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Bingtao Guo
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Lei Huang
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Yuchao Lu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| | - Henglong Hu
- Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People's Republic of China
| |
Collapse
|
|
25
|
Zhang P, Nie W, Jiang H. Effects of vitamin D receptor polymorphisms on urolithiasis risk: a meta-analysis. BMC MEDICAL GENETICS 2013; 14:104. [PMID: 24093218 PMCID: PMC3850980 DOI: 10.1186/1471-2350-14-104] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/14/2013] [Accepted: 09/24/2013] [Indexed: 11/24/2022]
Abstract
Background Several studies analyzed the associations of Vitamin D receptor (VDR) polymorphisms with urolithiasis risk in different ethnic groups. However, the results were inconclusive. To evaluate a more precise estimation of the relationship, a meta-analysis was performed. Methods Pubmed, EMBASE, Wanfang Database, China National Knowledge Infrastructure (CNKI) and Weipu Database were searched. Data were extracted independently by two investigators. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of associations. Results Twenty-three case–control studies were included in this meta-analysis. Significant associations between ApaI, BsmI, FokI, and TaqI polymorphisms and urolithiasis risk were observed. However, sensitivity analyses for BsmI and FokI polymorphisms indicated that the results were not reliable and credible. In addition, there was a significant association of the ApaI-TaqI haplotype with urolithiasis risk. Conclusions This meta-analysis suggested that ApaI and TaqI polymorphisms in VDR gene were associated with urolithiasis risk.
Collapse
Affiliation(s)
- Pan Zhang
- Department of Nephrology, the First People's Hospital of Jingzhou City, the First Hospital of Yangtze University, Jingzhou, Hubei Province 434000, China.
| | | | | |
Collapse
|
|
26
|
Abstract
Hypercalciuria is the most common metabolic abnormality found in patients with calcium-containing kidney stones. Patients with hypercalciuria often excrete more calcium than they absorb, indicating a net loss of total-body calcium. The source of this additional urinary calcium is almost certainly the skeleton, the largest repository of calcium in the body. Hypercalciuric stone formers exhibit decreased bone mineral density (BMD), which is correlated with the increase in urine calcium excretion. The decreased BMD also correlates with an increase in markers of bone turnover as well as increased fractures. In humans, it is difficult to determine the cause of the decreased BMD in hypercalciuric stone formers. To study the effect of hypercalciuria on bone, we utilized our genetic hypercalciuric stone-forming (GHS) rats, which were developed through successive inbreeding of the most hypercalciuric Sprague-Dawley rats. GHS rats excrete significantly more urinary calcium than similarly fed controls, and all the GHS rats form kidney stones while control rats do not. The hypercalciuria is due to a systemic dysregulation of calcium homeostasis, with increased intestinal calcium absorption, enhanced bone mineral resorption, and decreased renal tubule calcium reabsorption associated with an increase in vitamin D receptors in all these target tissues. We recently found that GHS rats fed an ample calcium diet have reduced BMD and that their bones are more fracture-prone, indicating an intrinsic disorder of bone not secondary to diet. Using this model, we should better understand the pathogenesis of hypercalciuria and stone formation in humans to ultimately improve the bone health of patients with kidney stones.
Collapse
Affiliation(s)
- Nancy S Krieger
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine, 601 Elmwood Ave., Box 675, Rochester, NY, 14642, USA,
| | | |
Collapse
|
|
27
|
Frick KK, Asplin JR, Krieger NS, Culbertson CD, Asplin DM, Bushinsky DA. 1,25(OH)₂D₃-enhanced hypercalciuria in genetic hypercalciuric stone-forming rats fed a low-calcium diet. Am J Physiol Renal Physiol 2013; 305:F1132-8. [PMID: 23926184 DOI: 10.1152/ajprenal.00296.2013] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
The inbred genetic hypercalciuric stone-forming (GHS) rats exhibit many features of human idiopathic hypercalciuria and have elevated levels of vitamin D receptors (VDR) in calcium (Ca)-transporting organs. On a normal-Ca diet, 1,25(OH)2D3 (1,25D) increases urine (U) Ca to a greater extent in GHS than in controls [Sprague-Dawley (SD)]. The additional UCa may result from an increase in intestinal Ca absorption and/or bone resorption. To determine the source, we asked whether 1,25D would increase UCa in GHS fed a low-Ca (0.02%) diet (LCD). With 1,25D, UCa in SD increased from 1.2 ± 0.1 to 9.3 ± 0.9 mg/day and increased more in GHS from 4.7 ± 0.3 to 21.5 ± 0.9 mg/day (P < 0.001). In GHS rats on LCD with or without 1,25D, UCa far exceeded daily Ca intake (2.6 mg/day). While the greater excess in UCa in GHS rats must be derived from bone mineral, there may also be a 1,25D-mediated decrease in renal tubular Ca reabsorption. RNA expression of the components of renal Ca transport indicated that 1,25D administration results in a suppression of klotho, an activator of the renal Ca reabsorption channel TRPV5, in both SD and GHS rats. This fall in klotho would decrease tubular reabsorption of the 1,25D-induced bone Ca release. Thus, the greater increase in UCa with 1,25D in GHS fed LCD strongly suggests that the additional UCa results from an increase in bone resorption, likely due to the increased number of VDR in the GHS rat bone cells, with a possible component of decreased renal tubular calcium reabsorption.
Collapse
Affiliation(s)
- Kevin K Frick
- Univ. of Rochester School of Medicine and Dentistry, Div. of Nephrology, Dept. of Medicine, 601 Elmwood Ave., Box 675, Rochester, NY 14642.
| | | | | | | | | | | |
Collapse
|
|
28
|
|
|
29
|
Frick KK, Asplin JR, Favus MJ, Culbertson C, Krieger NS, Bushinsky DA. Increased biological response to 1,25(OH)(2)D(3) in genetic hypercalciuric stone-forming rats. Am J Physiol Renal Physiol 2013; 304:F718-26. [PMID: 23344574 DOI: 10.1152/ajprenal.00645.2012] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Genetic hypercalciuric stone-forming (GHS) rats, bred to maximize urine (U) calcium (Ca) excretion, have increased intestinal Ca absorption and bone Ca resorption and reduced renal Ca reabsorption, leading to increased UCa compared with the Sprague-Dawley (SD) rats. GHS rats have increased vitamin D receptors (VDR) at each of these sites, with normal levels of 1,25(OH)(2)D(3) (1,25D), indicating that their VDR is undersaturated with 1,25D. We tested the hypothesis that 1,25D would induce a greater increase in UCa in GHS rats by feeding both strains ample Ca and injecting 1,25D (25 ng · 100 g body wt(-1) · day(-1)) or vehicle for 16 days. With 1,25D, UCa in SD increased from 1.7 ± 0.3 mg/day to 24.4 ± 1.2 (Δ = 22.4 ± 1.5) and increased more in GHS from 10.5 ± 0.7 to 41.9 ± 0.7 (Δ = 29.8 ± 1.8; P = 0.003). To determine the mechanism of the greater increase in UCa in GHS rats, we measured kidney RNA expression of components of renal Ca transport. Expression of transient receptor potential vanilloid (TRPV)5 and calbindin D(28K) were increased similarly in SD + 1,25D and GHS + 1,25D. The Na(+)/Ca(2+) exchanger (NCX1) was increased in GHS + 1,25D. Klotho was decreased in SD + 1,25D and GHS + 1,25D. TRPV6 was increased in SD + 1,25D and increased further in GHS + 1,25D. Claudin 14, 16, and 19, Na/K/2Cl transporter (NKCC2), and secretory K channel (ROMK) did not differ between SD + 1,25D and GHS + 1,25D. Increased UCa with 1,25D in GHS exceeded that of SD, indicating that the increased VDR in GHS induces a greater biological response. This increase in UCa, which must come from the intestine and/or bone, must exceed any effect of 1,25D on TRPV6 or NCX1-mediated renal Ca reabsorption.
Collapse
Affiliation(s)
- Kevin K Frick
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
| | | | | | | | | | | |
Collapse
|
|
30
|
Sakhaee K, Maalouf NM, Sinnott B. Clinical review. Kidney stones 2012: pathogenesis, diagnosis, and management. J Clin Endocrinol Metab 2012; 97:1847-60. [PMID: 22466339 PMCID: PMC3387413 DOI: 10.1210/jc.2011-3492] [Citation(s) in RCA: 157] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
CONTEXT The pathogenetic mechanisms of kidney stone formation are complex and involve both metabolic and environmental risk factors. Over the past decade, major advances have been made in the understanding of the pathogenesis, diagnosis, and treatment of kidney stone disease. EVIDENCE ACQUISITION AND SYNTHESIS Both original and review articles were found via PubMed search reporting on pathophysiology, diagnosis, and management of kidney stones. These resources were integrated with the authors' knowledge of the field. CONCLUSION Nephrolithiasis remains a major economic and health burden worldwide. Nephrolithiasis is considered a systemic disorder associated with chronic kidney disease, bone loss and fractures, increased risk of coronary artery disease, hypertension, type 2 diabetes mellitus, and the metabolic syndrome. Further understanding of the pathophysiological link between nephrolithiasis and these systemic disorders is necessary for the development of new therapeutic options.
Collapse
Affiliation(s)
- Khashayar Sakhaee
- Department of Internal Medicine, Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
| | | | | |
Collapse
|
|
31
|
Moreira Guimarães Penido MG, de Sousa Tavares M. Bone disease in pediatric idiopathic hypercalciuria. World J Nephrol 2012; 1:54-62. [PMID: 24175242 PMCID: PMC3782196 DOI: 10.5527/wjn.v1.i2.54] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2011] [Revised: 11/11/2011] [Accepted: 02/10/2012] [Indexed: 02/06/2023] Open
Abstract
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 pediatric 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., fibroblast growth-factor-23). Usually, a primary defect in one organ induces compensatory mechanisms in the remaining two organs, such as increased absorption of calcium in the gut secondary to a primary renal loss. Thus, IH is a systemic abnormality of calcium homeostasis with changes in cellular transport of this ion in intestines, kidneys and bones. Reduced 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 at the 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.
Collapse
Affiliation(s)
- Maria Goretti Moreira Guimarães Penido
- Maria Goretti Moreira Guimarães Penido, Marcelo de Sousa Tavares, Department of Pediatrics, Pediatric Nephrology Unit, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Belo Horizonte, CEP 30130100, Minas Gerais, Brazil
| | | |
Collapse
|
|
32
|
Where is the vitamin D receptor? Arch Biochem Biophys 2012; 523:123-33. [PMID: 22503810 DOI: 10.1016/j.abb.2012.04.001] [Citation(s) in RCA: 446] [Impact Index Per Article: 34.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2012] [Revised: 03/30/2012] [Accepted: 04/01/2012] [Indexed: 02/08/2023]
Abstract
The vitamin D receptor (VDR) is a member of the nuclear receptor superfamily and plays a central role in the biological actions of vitamin D. VDR regulates the expression of numerous genes involved in calcium/phosphate homeostasis, cellular proliferation and differentiation, and immune response, largely in a ligand-dependent manner. To understand the global function of the vitamin D system in physiopathological processes, great effort has been devoted to the detection of VDR in various tissues and cells, many of which have been identified as vitamin D targets. This review focuses on the tissue- and cell type-specific distribution of VDR throughout the body.
Collapse
|
|
33
|
Metabolic Stone Disease in Children. Urolithiasis 2012. [DOI: 10.1007/978-1-4471-4387-1_78] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
|
|
34
|
Abstract
Urolithiasis affects approximately 10% of individuals in Western societies by the seventh decade of life. The most common form, idiopathic calcium oxalate urolithiasis, results from the interaction of multiple genes and their interplay with dietary and environmental factors. To date, considerable progress has been made in identifying the metabolic risk factors that predispose to this complex trait, among which hypercalciuria predominates. The specific genetic and epigenetic factors involved in urolithiasis have remained less clear, partly owing to the candidate gene and linkage methods that have been available until now, being inherently low in their power of resolution and in assessing modest effects in complex traits. However, together with investigations of rare, Mendelian forms of urolithiasis associated with various metabolic risk factors, these methods have afforded insights into biological pathways that seem to underlie the development of stones in the urinary tract. Monogenic diseases account for a greater proportion of stone formers in children and adolescents than in adults. Early diagnosis of monogenic forms of urolithiasis is of importance owing to associated renal injury and other potentially treatable disease manifestations, but diagnosis is often delayed because of a lack of familiarity with these rare disorders. In this Review, we will discuss advances in the understanding of the genetics underlying polygenic and monogenic forms of urolithiasis.
Collapse
Affiliation(s)
- Carla G Monico
- Division of Nephrology and Hypertension, Department of Internal Medicine, Mayo Clinic Hyperoxaluria Center, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
| | | |
Collapse
|
|
35
|
Xi QL, Wang SG, Ye ZQ, Zhu ZW, Li C, Bai J, Yu X, Liu JH. Effect of Silencing VDR Gene in Kidney on Renal Epithelial Calcium Transporter Proteins and Urinary Calcium Excretion in Genetic Hypercalciuric Stone-forming Rats. Urology 2011; 78:1442.e1-7. [DOI: 10.1016/j.urology.2011.08.051] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2011] [Revised: 08/26/2011] [Accepted: 08/26/2011] [Indexed: 11/25/2022]
|
|
36
|
Xi Q, Wang S, Ye Z, Liu J, Yu X, Zhu Z, Su S, Bai J, Li C. Adenovirus-delivered microRNA targeting the vitamin D receptor reduces intracellular Ca²⁺ concentrations by regulating the expression of Ca²⁺-transport proteins in renal epithelial cells. BJU Int 2011; 107:1314-9. [PMID: 20553254 DOI: 10.1111/j.1464-410x.2010.09444.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
UNLABELLED What’s known on the subject? and What does the study add? Experimental data have shown that VDR overexpression in the duodenum and kidney cortex is a biological characteristic of genetic hypercalciuric stone-forming rats (GHS rat), and a link between idiopathic calcium stone formation and the microstatellite marker D12S339 (near the VDR locus) has been proven in humans. Our study shows that VDR can positively regulate the mRNA and protein expression of TRPV5, calbindin-D28k and PMCA1b in NRK cell lines. VDR knockdown results in a decrease in intracellular Ca²⁺ concentration in NRK cell lines. The effect of the elevated VDR level in the kidney on hypercalciuria and the underlying mechanisms need to be further addressed. OBJECTIVE • To determine the effects of vitamin D receptor (VDR) on hypercalciuria and the mechanisms underlying such effects. MATERIALS AND METHODS • The adenovirus vector-delivered microRNA targeting rat VDR was constructed. We infected the normal rat kidney epithelial cell line NRK (Cellbank, China) with the adenovirus and then collected the cells at 0, 48, 72, 96, 120 h after infection. The mRNA and protein levels of VDR and VDR-dependent epithelial Ca2+ transport proteins were detected using real-time polymerase chain reaction and Western blot assays, respectively. • Fluorescent Ca²⁺ indicator Fluo-4 NW (Fluo-4 NW calcium assay kit, Molecular Probes, Invitrogen, USA) and laser scanning confocal microscope (Olympus, FV500-IX71, Japan) were used to detect the cytosolic free Ca²⁺ concentration at different time points after infection. RESULTS • The mRNA and protein level of VDR, transient receptor potential vanilloid receptor subtype 5 (TRPV5), calbindin-D28k and plasma membrane Ca²⁺-ATPase (PMCA1b) in infected NRK cells was significantly lower at 72 and 96 h after infection than that in control cells. • There was no significant difference between the two groups in the mRNA and protein level of TRPV6 and the Na⁺/Ca²⁺-exchanger (NCX1). • Furthermore, VDR knockdown results in a decrease in intracellular Ca²⁺ concentration ([Ca²⁺]i) in NRK cell lines. CONCLUSIONS • Our study shows that VDR can positively regulate the mRNA and protein expression of TRPV5, calbindin-D28k and PMCA1b, but not of TRPV6 or NCX1, in NRK cell lines. VDR knockdown results in a decrease in [Ca²⁺]i in NRK cell lines. • The effect of the elevated VDR level in the kidney on hypercalciuria and the mechanisms underlying need to be further addressed.
Collapse
Affiliation(s)
- Qilin Xi
- Department of Urology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, HuBei, China
| | | | | | | | | | | | | | | | | |
Collapse
|
|
37
|
Abstract
Nephrolithiasis remains a formidable health problem in the United States and worldwide. A very important but underaddressed area in nephrolithiasis is the accompanying bone disease. Epidemiologic studies have shown that osteoporotic fractures occur more frequently in patients with nephrolithiasis than in the general population. Decreased bone mineral density and defects in bone remodeling are commonly encountered in patients with calcium nephrolithiasis. The pathophysiologic connection of bone defects to kidney stones is unknown. Hypercalciuria and hypocitraturia are two important risk factors for stone disease, and treatments with thiazide diuretics and alkali, respectively, have been shown to be useful in preventing stone recurrence in small prospective trials. However, no studies have examined the efficacy of these agents or other therapies in preventing continued bone loss in calcium stone formers. This manuscript reviews the epidemiology, pathophysiology, and potential treatments of bone disease in patients with nephrolithiasis.
Collapse
|
|
38
|
Bai S, Wang H, Shen J, Zhou R, Bushinsky DA, Favus MJ. Elevated vitamin D receptor levels in genetic hypercalciuric stone-forming rats are associated with downregulation of Snail. J Bone Miner Res 2010; 25:830-40. [PMID: 19929616 PMCID: PMC3153334 DOI: 10.1359/jbmr.091010] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2009] [Revised: 09/21/2009] [Accepted: 10/09/2009] [Indexed: 11/18/2022]
Abstract
Patients with idiopathic hypercalciuria (IH) and genetic hypercalciuric stone-forming (GHS) rats, an animal model of IH, are both characterized by normal serum Ca, hypercalciuria, Ca nephrolithiasis, reduced renal Ca reabsorption, and increased bone resorption. Serum 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels are elevated or normal in IH and are normal in GHS rats. In GHS rats, vitamin D receptor (VDR) protein levels are elevated in intestinal, kidney, and bone cells, and in IH, peripheral blood monocyte VDR levels are high. The high VDR is thought to amplify the target-tissue actions of normal circulating 1,25(OH)(2)D levels to increase Ca transport. The aim of this study was to elucidate the molecular mechanisms whereby Snail may contribute to the high VDR levels in GHS rats. In the study, Snail gene expression and protein levels were lower in GHS rat tissues and inversely correlated with VDR gene expression and protein levels in intestine and kidney cells. In human kidney and colon cell lines, ChIP assays revealed endogenous Snail binding close to specific E-box sequences within the human VDR promoter region, whereas only one E-box specifically bound Snail in the rat promoter. Snail binding to rat VDR promoter E-box regions was reduced in GHS compared with normal control intestine and was accompanied by hyperacetylation of histone H(3). These results provide evidence that elevated VDR in GHS rats likely occurs because of derepression resulting from reduced Snail binding to the VDR promoter and hyperacetylation of histone H(3).
Collapse
Affiliation(s)
- Shaochun Bai
- Section of Endocrinology and Metabolism, The University of Chicago Pritzker School of MedicineChicago, IL, USA
| | - Hongwei Wang
- Section of Endocrinology and Metabolism, The University of Chicago Pritzker School of MedicineChicago, IL, USA
| | - Jikun Shen
- Section of Endocrinology and Metabolism, The University of Chicago Pritzker School of MedicineChicago, IL, USA
| | - Randal Zhou
- Section of Endocrinology and Metabolism, The University of Chicago Pritzker School of MedicineChicago, IL, USA
| | - David A Bushinsky
- Department of Medicine, University of Rochester School of MedicineRochester, New York, USA
| | - Murray J Favus
- Section of Endocrinology and Metabolism, The University of Chicago Pritzker School of MedicineChicago, IL, USA
| |
Collapse
|
|
39
|
Zerwekh JE. Bone disease and hypercalciuria in children. Pediatr Nephrol 2010; 25:395-401. [PMID: 19885683 DOI: 10.1007/s00467-009-1338-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2009] [Revised: 10/05/2009] [Accepted: 10/05/2009] [Indexed: 10/20/2022]
Abstract
There have been relatively few studies of bone mass in children with idiopathic hypercalciuria (IH). When performed, bone mineral density (BMD) measurements have consistently disclosed decreased Z-scores for children with IH at the lumbar spine and, to a lesser extent, at the femoral neck. Few investigations have delineated the nature of the mechanism(s) that may contribute to the bone loss in these children. Some studies have been consistent, showing increased bone resorption as the probable mechanism of bone loss. To date, there have been no reports regarding the assessment of biochemical markers specific for bone formation in children with IH. However, since most of the children with IH in these reports had demonstrated normal longitudinal growth, it seems less likely that there is an alteration in bone formation. The causes for increased bone resorption also are not firmly established, but genetics, dietary indiscretions, and altered cytokine production have been proposed as being contributory to the decreased BMD observed in these children with IH. Optimal bone mineral accretion during childhood and adolescence is important in attaining peak bone mass and may serve to prevent the development of osteoporosis in adulthood. Thus, a better understanding of bone loss in children with IH is warranted.
Collapse
Affiliation(s)
- Joseph E Zerwekh
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390-8885, USA.
| |
Collapse
|
|
40
|
Hamilton DC, Grover VK, Smith CA, Cole DEC. Heterogeneous Disease Modeling for Hardy-Weinberg Disequilibrium in Case-Control Studies: Application to Renal Stones and Calcium-Sensing Receptor Polymorphisms. Ann Hum Genet 2009; 73:176-83. [DOI: 10.1111/j.1469-1809.2008.00492.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
|
|
41
|
Stechman MJ, Loh NY, Thakker RV. Genetic causes of hypercalciuric nephrolithiasis. Pediatr Nephrol 2009; 24:2321-32. [PMID: 18446382 PMCID: PMC2770137 DOI: 10.1007/s00467-008-0807-0] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2007] [Revised: 02/15/2008] [Accepted: 02/25/2008] [Indexed: 12/19/2022]
Abstract
Renal stone disease (nephrolithiasis) affects 3-5% of the population and is often associated with hypercalciuria. Hypercalciuric nephrolithiasis is a familial disorder in over 35% of patients and may occur as a monogenic disorder that is more likely to manifest itself in childhood. Studies of these monogenic forms of hypercalciuric nephrolithiasis in humans, e.g. Bartter syndrome, Dent's disease, autosomal dominant hypocalcemic hypercalciuria (ADHH), hypercalciuric nephrolithiasis with hypophosphatemia, and familial hypomagnesemia with hypercalciuria have helped to identify a number of transporters, channels and receptors that are involved in regulating the renal tubular reabsorption of calcium. Thus, Bartter syndrome, an autosomal disease, is caused by mutations of the bumetanide-sensitive Na-K-Cl (NKCC2) co-transporter, the renal outer-medullary potassium (ROMK) channel, the voltage-gated chloride channel, CLC-Kb, the CLC-Kb beta subunit, barttin, or the calcium-sensing receptor (CaSR). Dent's disease, an X-linked disorder characterized by low molecular weight proteinuria, hypercalciuria and nephrolithiasis, is due to mutations of the chloride/proton antiporter 5, CLC-5; ADHH is associated with activating mutations of the CaSR, which is a G-protein-coupled receptor; hypophosphatemic hypercalciuric nephrolithiasis associated with rickets is due to mutations in the type 2c sodium-phosphate co-transporter (NPT2c); and familial hypomagnesemia with hypercalciuria is due to mutations of paracellin-1, which is a member of the claudin family of membrane proteins that form the intercellular tight junction barrier in a variety of epithelia. These studies have provided valuable insights into the renal tubular pathways that regulate calcium reabsorption and predispose to hypercalciuria and nephrolithiasis.
Collapse
Affiliation(s)
- Michael J. Stechman
- Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, OX3 7LJ UK
| | - Nellie Y. Loh
- Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, OX3 7LJ UK
| | - Rajesh V. Thakker
- Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism (OCDEM), University of Oxford, Oxford, OX3 7LJ UK
| |
Collapse
|
|
42
|
Bevilacqua M, Dominguez LJ, Gandolini G, Valdes V, Vago T, Righini V, Barrella M, Barbagallo M. Vitamin D substrate-product relationship in idiopathic hypercalciuria. J Steroid Biochem Mol Biol 2009; 113:3-8. [PMID: 19013526 DOI: 10.1016/j.jsbmb.2008.08.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2007] [Accepted: 08/06/2008] [Indexed: 11/16/2022]
Abstract
Absorptive hypercalciuria (AH) is associated with elevated levels of 1,25-dihydroxyvitamin D (1,25(OH)(2)D). While no increase of 1,25(OH)(2)D after oral administration of 25-hydroxyvitamin D (25OHD) at high doses has been claimed in normal subjects, a substrate-product relationship has been reported in normal children, young people after UV irradiation, older persons, postmenopausal women, primary hyperparathyroidism, renal failure, osteomalacia, and sarcoidosis. No data of this relationship in AH is available. To investigate 25OHD-1,25(OH)(2)D substrate-product relationship in AH, 161 AH patients (mean age 60.9+/-11.7 years) and 110 age- and sex-matched controls (mean age 61.5+/-12.4 years) were studied. In 57 controls and 52 AH subjects 25OHD-1,25(OH)(2)D relationship in basal conditions and after 2-week oral 25OHD (25 microg/day) administration were evaluated. In basal conditions 25OHD and 1,25(OH)(2)D were correlated in both, controls and AH; 25OHD treatment was followed by an increase in serum 25OHD and 1,25(OH)(2)D in both groups. However, delta responses of 25OHD and 1,25(OH)(2)D to 25OHD were higher in AH suggesting an enhanced activity of 1 alpha-hydroxylase. In conclusion, the higher response of 1,25(OH)(2)D after oral 25OHD in AH patients suggests a differential capacity between both groups in handling the increases in 1,25(OH)(2)D.
Collapse
Affiliation(s)
- Maurizio Bevilacqua
- Endocrinology and Diabetes Unit, Department of Medicine, Luigi Sacco Hospital (Vialba), University of Milan, Italy
| | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Bone Disease and Idiopathic Hypercalciuria. Clin Rev Bone Miner Metab 2008. [DOI: 10.1007/s12018-008-9023-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
|
|
44
|
Abstract
Idiopathic hypercalciuria (IH) is the most common metabolic abnormality in patients with calcium kidney stones. It is characterized by normocalcemia, absence of diseases that cause increased urine calcium, and calcium excretion that is greater than 250 mg/d in women and 300 mg/d in men. Subjects with IH have a generalized increase in calcium turnover, which includes increased gut calcium absorption, decreased renal calcium reabsorption, and a tendency to lose calcium from bone. Despite the increase in intestinal calcium absorption, a negative calcium balance is seen commonly in balance studies, especially on a low-calcium diet. The mediator of decreased renal calcium reabsorption is not clear; it is not associated with either an increase in filtered load of calcium or altered parathyroid hormone levels. There is an increased incidence of hypercalciuria in first-degree relatives of those with IH, but IH appears to be a complex polygenic trait with a large contribution from diet to expression of increased calcium excretion. Increased tissue vitamin D response may be responsible for the manifestations of IH in at least some patients.
Collapse
Affiliation(s)
- Elaine M Worcester
- Nephrology Section, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
| | | |
Collapse
|
|
45
|
Abstract
Observational and epidemiologic studies alike have shown that idiopathic hypercalciuric (IH) stone-forming patients typically show bone mineral density scores that are significantly lower than those observed for age- and sex-matched normal subjects or those for nonhypercalciuric stone-forming patients. Most of these studies have relied on changes in bone mineral density and have not explored the mechanism(s) involved. There have been a small number of studies that have relied on dynamic bone histomorphometry to ascertain the nature of the bone defect in IH patients. When performed, these studies clearly have shown increased bone resorption and high bone turnover in patients with fasting hypercalciuria whereas suppressed bone formation indices are the most consistent finding in patients with the absorptive variant of IH. The causes of this apparent difference in bone remodeling between the 2 variants of IH still is uncertain. Available evidence suggests that potential mechanisms may be dependent in large part to genetic, metabolic, and nutritional causes of hypercalciuria and bone loss in patients with IH.
Collapse
Affiliation(s)
- Joseph E Zerwekh
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8885, USA.
| |
Collapse
|
|
46
|
Gomes SA, dos Reis LM, Noronha IL, Jorgetti V, Heilberg IP. RANKL is a mediator of bone resorption in idiopathic hypercalciuria. Clin J Am Soc Nephrol 2008; 3:1446-52. [PMID: 18480302 DOI: 10.2215/cjn.00240108] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND OBJECTIVES This study aimed to determine the expression of osteoprotegerin, receptor activator of nuclear factor kappaB ligand, interleukin-1alpha, transforming growth factor-beta, and basic fibroblast growth factor in stone-forming patients with idiopathic hypercalciuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Immunohistochemical analysis was performed in undecalcified bone samples previously obtained from 36 transiliac bone biopsies of patients who had idiopathic hypercalciuria and whose histomorphometry had shown lower bone volume, increased bone resorption, and prolonged mineralization lag time. RESULTS Bone expression of receptor activator of nuclear factor kappaB ligand and osteoprotegerin was significantly higher in patients with idiopathic hypercalciuria versus control subjects. Transforming growth factor-beta immunostaining was lower in patients with idiopathic hypercalciuria than in control subjects and correlated directly with mineralization surface. Interleukin-1alpha and basic fibroblast growth factor staining did not differ between groups. Receptor activator of nuclear factor kappaB ligand bone expression was significantly higher in patients who had idiopathic hypercalciuria and exhibited higher versus normal bone resorption. CONCLUSION A higher expression of receptor activator of nuclear factor kappaB ligand in bone tissue suggests that increased bone resorption in patients with idiopathic hypercalciuria is mediated by receptor activator of nuclear factor kappaB ligand. Osteoprotegerin bone expression might have been secondarily increased in an attempt to counteract the actions of receptor activator of nuclear factor kappaB ligand. The low bone expression of transforming growth factor-beta could contribute to the delayed mineralization found in such patients.
Collapse
|
|
47
|
Abstract
Hypercalcuria is the most common metabolic disorder found in patients with nephrolithiasis. As the prevalence of kidney stones rises in industrialized nations, understanding the pathogenesis and treatment of hypercalciuria becomes increasingly important. Idiopathic hypercalciuria (IH), defined as an excess urine calcium excretion without an apparent underlying etiology, is the most frequent cause of hypercalciuria and will be the focus of this paper. Calcium homeostasis is tightly controlled and slight disturbances in transport at the level of the intestine, bone, and/or kidney can lead to excessive urine calcium excretion and promote stone formation. IH is a systemic disorder with dysregulation of calcium transport at a combination of these calcium regulatory sites. The goal of treatment is to prevent stone formation and relies on a combination of dietary and pharmaceutical interventions. Dietary management includes increasing fluid intake, salt restriction, animal protein restriction, and maintaining a normal calcium intake. Thiazide diuretics have proven effective in preventing calcium stone formation by reducing the urinary excretion of calcium. It is important to note that while decreasing urinary calcium excretion is important the clinician should focus primarily on reducing the supersaturation of calcium oxalate as this determines the true tendency for stone formation.
Collapse
Affiliation(s)
- Scott E Liebman
- University of Rochester School of Medicine and Dentistry, Nephrology Division, Strong Memorial Hospital, 601 Elmwood Avenue, Box 675, Rochester, NY 14642, USA.
| | | | | |
Collapse
|
|
48
|
Heller HJ, Zerwekh JE, Gottschalk FA, Pak CYC. Reduced bone formation and relatively increased bone resorption in absorptive hypercalciuria. Kidney Int 2007; 71:808-15. [PMID: 17311067 DOI: 10.1038/sj.ki.5002181] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Absorptive hypercalciuria (AH), a common stone-forming condition characterized biochemically by intestinal hyperabsorption of calcium and hypercalciuria may be associated with bone loss. In AH type I (AH-1), hypercalciuria persists despite restriction in dietary calcium intake. We therefore hypothesized that the skeleton may contribute to the hypercalciuria in this subgroup of patients. Histomorphometric analysis of iliac crest biopsies were performed on nine stone-formers with AH-1 and on nine matched normal subjects. After stabilization on a stone-prevention diet, calcium homeostasis in the stone formers was then evaluated on inpatient constant metabolic diet before and after short-term blockade of bone resorption by alendronate (10 mg daily, 17 days total). Compared with controls, the stone-formers had lower indices of bone formation (osteoblast surface/bone surface 1.8+/-2.1 vs 3.0+/-1.5%, P=0.04; wall thickness 35.8+/-6.9 vs 47.2+/-7.6%, P=0.001) and relatively higher bone resorption (osteoclast surface/bone surface 0.4+/-0.2 vs 0.2+/-0.2%, P=0.05). In the stone-formers, a short-term course of alendronate treatment corrected fasting urinary calcium (0.14+/-0.06 to 0.06+/-0.04 mg Ca/mg Cr, P=0.001) and marginally reduced 24-h urinary calcium by 48 mg/day (P=0.06). Increased intestinal calcium absorption and hypercalciuria persisted, but estimated calcium balance improved (P=0.007). Our results suggest that the hypercalciuria of AH-1 originates primarily from intestinal hyperabsorption of calcium, but bone resorption in excess of bone formation may contribute.
Collapse
Affiliation(s)
- H J Heller
- Department of Internal Medicine, UT Southwestern Medical Center at Dallas, Center for Mineral Metabolism and Clinical Research, Dallas, Texas, USA
| | | | | | | |
Collapse
|
|
49
|
Srivastava T, Alon US. Pathophysiology of hypercalciuria in children. Pediatr Nephrol 2007; 22:1659-73. [PMID: 17464515 PMCID: PMC6904412 DOI: 10.1007/s00467-007-0482-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2007] [Revised: 03/11/2007] [Accepted: 03/12/2007] [Indexed: 12/17/2022]
Abstract
Urinary excretion of calcium is the result of a complex interplay between three organs-namely, the gastrointestinal tract, bone, and kidney-which is finely orchestrated by multiple hormones. Hypercalciuria is believed to be a polygenic trait and is influenced significantly by diet. This paper briefly reviews calcium handling by the renal tubule in normal and in hereditary disorders as it relates to the pathophysiology of hypercalciuria. The effects of dietary sodium, potassium, protein, calcium, and phosphate on calcium excretion, and the association of hypercalciuria with bone homeostasis is discussed, leading to recommendations on means to address excessive urinary calcium excretion.
Collapse
Affiliation(s)
- Tarak Srivastava
- Section of Nephrology, Bone and Mineral Disorder Clinic, The Children’s Mercy Hospital and Clinics, University of Missouri, 2401 Gillham Road, Kansas City, MO 64108 USA
| | - Uri S. Alon
- Section of Nephrology, Bone and Mineral Disorder Clinic, The Children’s Mercy Hospital and Clinics, University of Missouri, 2401 Gillham Road, Kansas City, MO 64108 USA
| |
Collapse
|
|
50
|
Abstract
PURPOSE OF REVIEW We will describe the pathophysiology of hypercalciuria and the mechanism of the resultant stone formation in a rat model and draw parallels to human hypercalciuria and stone formation. RECENT FINDINGS Through inbreeding we have established a strain of rats that excrete 8-10 times more urinary calcium than control rats. These genetic hypercalciuric rats absorb more dietary calcium at lower 1,25-dihydroxyvitamin D3 levels. Elevated urinary calcium excretion on a low-calcium diet indicated a defect in renal calcium reabsorption and/or an increase in bone resorption. Bone from hypercalciuric rats released more calcium when exposed to 1,25-dihydroxyvitamin D3. Bisphosphonate significantly reduced urinary calcium excretion in rats fed a low-calcium diet. Clearance studies showed a primary defect in renal calcium reabsorption. The intestine, bone and kidneys of the hypercalciuric rats had increased numbers of vitamin D receptors. When hydroxyproline is added to their diet they form calcium oxalate stones, the most common stone type in humans. Increased numbers of vitamin D receptors may cause hypercalciuria in these rats and humans. SUMMARY Understanding the mechanism of hypercalciuria and stone formation in this animal model will help clinicians devise effective treatment strategies for preventing recurrent stone formation in humans.
Collapse
Affiliation(s)
- David A Bushinsky
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642, USA.
| | | | | |
Collapse
|