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Whittamore JM, Hatch M. Oxalate Flux Across the Intestine: Contributions from Membrane Transporters. Compr Physiol 2021; 12:2835-2875. [PMID: 34964122 DOI: 10.1002/cphy.c210013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Epithelial oxalate transport is fundamental to the role occupied by the gastrointestinal (GI) tract in oxalate homeostasis. The absorption of dietary oxalate, together with its secretion into the intestine, and degradation by the gut microbiota, can all influence the excretion of this nonfunctional terminal metabolite in the urine. Knowledge of the transport mechanisms is relevant to understanding the pathophysiology of hyperoxaluria, a risk factor in kidney stone formation, for which the intestine also offers a potential means of treatment. The following discussion presents an expansive review of intestinal oxalate transport. We begin with an overview of the fate of oxalate, focusing on the sources, rates, and locations of absorption and secretion along the GI tract. We then consider the mechanisms and pathways of transport across the epithelial barrier, discussing the transcellular, and paracellular components. There is an emphasis on the membrane-bound anion transporters, in particular, those belonging to the large multifunctional Slc26 gene family, many of which are expressed throughout the GI tract, and we summarize what is currently known about their participation in oxalate transport. In the final section, we examine the physiological stimuli proposed to be involved in regulating some of these pathways, encompassing intestinal adaptations in response to chronic kidney disease, metabolic acid-base disorders, obesity, and following gastric bypass surgery. There is also an update on research into the probiotic, Oxalobacter formigenes, and the basis of its unique interaction with the gut epithelium. © 2021 American Physiological Society. Compr Physiol 11:1-41, 2021.
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Affiliation(s)
- Jonathan M Whittamore
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Marguerite Hatch
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, USA
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2
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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.
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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
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3
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Khan A, Bashir S, Khan SR. Antiurolithic effects of medicinal plants: results of in vivo studies in rat models of calcium oxalate nephrolithiasis-a systematic review. Urolithiasis 2021; 49:95-122. [PMID: 33484322 DOI: 10.1007/s00240-020-01236-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Accepted: 12/17/2020] [Indexed: 11/25/2022]
Abstract
Urolithiasis is one of the oldest diseases affecting humans, while plants are one of our oldest companions providing food, shelter, and medicine. In spite of substantial progress in understanding the pathophysiological mechanisms, treatment options are still limited, often expensive for common people in most parts of the world. As a result, there is a great interest in herbal remedies for the treatment of urinary stone disease as an alternative or adjunct therapy. Numerous in vivo and in vitro studies have been carried out to understand the efficacy of herbs in reducing stone formation. We adopted PRISMA guidelines and systematically reviewed PubMed/Medline for the literature, reporting results of various herbal products on in vivo models of nephrolithiasis/urolithiasis. The Medical Subject Heading Terms (Mesh term) "Urolithiasis" was used with Boolean operator "AND" and other related Mesh Unique terms to search all the available records (July 2019). A total of 163 original articles on in vivo experiments were retrieved from PubMed indexed with the (MeshTerm) "Urolithiasis" AND "Complementary Therapies/Alternative Medicine, "Urolithiasis" AND "Plant Extracts" and "Urolithiasis" AND "Traditional Medicine". Most of the studies used ethylene glycol (EG) to induce hyperoxaluria and nephrolithiasis in rats. A variety of extraction methods including aqueous, alcoholic, hydro-alcoholic of various plant parts ranging from root bark to fruits and seeds, or a combination thereof, were utilized. All the investigations did not study all aspects of nephrolithiasis making it difficult to compare the efficacy of various treatments. Changes in the lithogenic factors and a reduction in calcium oxalate (CaOx) crystal deposition in the kidneys were, however, considered favorable outcomes of the various treatments. Less than 10% of the studies examined antioxidant and diuretic activities of the herbal treatments and concluded that their antiurolithic activities were a result of antioxidant, anti-inflammatory, and/or diuretic effects of the treatments.
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Affiliation(s)
- Aslam Khan
- College of Science and Health Professions, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.,King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Jeddah, Saudi Arabia
| | - Samra Bashir
- Department of Pharmacy, Faculty of Health and Life Sciences, Capital University of Science and Technology, Islamabad, Pakistan
| | - Saeed R Khan
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL, USA.
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Guo S, Chia W, Wang H, Bushinsky DA, Zhong B, Favus MJ. Vitamin D receptor (VDR) contributes to the development of hypercalciuria by sensitizing VDR target genes to vitamin D in a genetic hypercalciuric stone-forming (GHS) rat model. Genes Dis 2020; 9:797-806. [PMID: 35782986 PMCID: PMC9243318 DOI: 10.1016/j.gendis.2020.09.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2020] [Revised: 09/08/2020] [Accepted: 09/09/2020] [Indexed: 12/03/2022] Open
Abstract
Human idiopathic hypercalciuria (IH) is the most common cause of calcium oxalate nephrolithiasis with perturbed calcium metabolism with increased bone resorption and decreased renal calcium reabsorption, which can be phenotype-copied in the genetic hypercalciuric stone-forming (GHS) rat model. We previously demonstrated that high VDR expression plays important roles in the development of hypercalciuria in the GHS rats. However, the underlying mechanism through which VDR impact hypercalciuria development remains to be fully understood. Here, we sought to determine how VDR regulated its target genes that are implicated in calcium homeostasis and potentially hypercalciuria. We found that VDR expression in the GHS rats was elevated in the calcium transporting tissues, as well as in the thymus and prostate, but not in lung, brain, heart, liver and spleen, when compared with control SD rats. Snail expression in the GHS rats was significantly downregulated in kidney, intestine, thymus and testis. Intraperitoneal injection of 1,25(OH)2D3 significantly upregulated the expression of renal calcium sensing receptor (CaSR), intestinal calcium transporters transient receptor potential vanilloid type 6 (TRPV6), and VDR in GHS rats, compared with that in control SD rats. ChIP assays revealed that VDR specifically bound to the proximal promoters of target genes, followed by histone H3 hyperacetylation or hypermethylation. Collectively, our results suggest that elevated VDR expression may contribute to the development of hypercalciuria by sensitizing VDR target genes to 1,25(OH)2D3 through histone modifications at their promoter regions in a genetic hypercalciuric stone-forming (GHS) rat model.
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Krieger NS, Chen L, Becker J, DeBoyace S, Wang H, Favus MJ, Bushinsky DA. Increased Osteoclast and Decreased Osteoblast Activity Causes Reduced Bone Mineral Density and Quality in Genetic Hypercalciuric Stone-Forming Rats. JBMR Plus 2020; 4:e10350. [PMID: 32258968 PMCID: PMC7117851 DOI: 10.1002/jbm4.10350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Accepted: 02/09/2020] [Indexed: 11/16/2022] Open
Abstract
To study human idiopathic hypercalciuria (IH), we developed an animal model, genetic hypercalciuric stone-forming (GHS) rats, whose pathophysiology parallels that in IH. All GHS rats form kidney stones and have decreased BMD and bone quality compared with the founder Sprague-Dawley (SD) rats. To understand the bone defect, we characterized osteoclast and osteoblast activity in the GHS compared with SD rats. Bone marrow cells were isolated from femurs of GHS and SD rats and cultured to optimize differentiation into osteoclasts or osteoblasts. Osteoclasts were stained for TRAcP (tartrate resistant acid phosphatase), cultured to assess resorptive activity, and analyzed for specific gene expression. Marrow stromal cells or primary neonatal calvarial cells were differentiated to osteoblasts, and osteoblastic gene expression as well as mineralization was analyzed. There was increased osteoclastogenesis and increased resorption pit formation in GHS compared with SD cultures. Osteoclasts had increased expression of cathepsin K, Tracp, and MMP9 in cells from GHS compared with SD rats. Osteoblastic gene expression and mineralization was significantly decreased. Thus, alterations in baseline activity of both osteoclasts and osteoblasts in GHS rats, led to decreased BMD and bone quality, perhaps because of their known increase in vitamin D receptors. Better understanding of the role of GHS bone cells in decreased BMD and quality may provide new strategies to mitigate the low BMD and increased fracture risk found in patients with IH. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Nancy S Krieger
- Division of NephrologyUniversity of Rochester School of MedicineRochesterNYUSA
| | - Luojing Chen
- Division of NephrologyUniversity of Rochester School of MedicineRochesterNYUSA
| | - Jennifer Becker
- Division of NephrologyUniversity of Rochester School of MedicineRochesterNYUSA
| | - Sean DeBoyace
- Division of NephrologyUniversity of Rochester School of MedicineRochesterNYUSA
| | - Hongwei Wang
- Section of EndocrinologyUniversity of Chicago Pritzker School of MedicineChicagoILUSA
| | - Murray J Favus
- Section of EndocrinologyUniversity of Chicago Pritzker School of MedicineChicagoILUSA
| | - David A Bushinsky
- Division of NephrologyUniversity of Rochester School of MedicineRochesterNYUSA
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Abstract
Current understanding of the mechanisms underlying renal disease in humans is incomplete. Consequently, our ability to prevent the occurrence of renal disease or treat established kidney disease is limited. Investigating kidney disease directly in humans poses objective difficulties, which has led investigators to seek experimental animal models that simulate renal disease in humans. Animal models have thus become a tool of major importance in the study of renal physiology and have been crucial in shedding light on the complex mechanisms involved in kidney function and in our current understanding of the pathophysiology of renal disease. Among animal models, the rat has been the preferred and most commonly used species for the investigation of renal disease. This chapter reviews what has been achieved over the years, using the rat as a tool for the investigation of renal disease in humans, focusing on the contribution of rat genetics and genomics to the elucidation of the mechanisms underlying the pathophysiology of the major types of renal disease, including primary and secondary renal diseases.
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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.
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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
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Krieger NS, Grynpas M, VandenEynde A, Asplin JR, Frick KK, Kim MH, Ramos FM, Granja I, Bushinsky DA. Low Sodium Diet Decreases Stone Formation in Genetic Hypercalciuric Stone-Forming Rats. Nephron Clin Pract 2019; 142:147-158. [PMID: 30726853 DOI: 10.1159/000497117] [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: 11/26/2018] [Accepted: 01/20/2019] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Urine (u) calcium (Ca) excretion is directly dependent on dietary sodium (Na) intake leading to the recommendation for Na restriction in hypercalciuric kidney stone formers. However, there is no direct evidence that limiting Na intake will reduce recurrent stone formation. MATERIALS AND METHODS We used genetic hypercalciuric stone-forming (GHS) rats, which universally form Ca phosphate (P) kidney stones, fed either a low Na (LNa, 0.05%) or normal Na (NNa, 0.4%) Na diet (D) for 18 weeks. Urine was collected at 6-week intervals. Radiographic analysis for stone formation and bone analyses were done at the conclusion of the study. RESULTS Mean uCa was lower with LNaD than NNaD as was uP and LNaD decreased mean uNa and uChloride. There were no differences in urine supersaturation (SS) with respect to calcium phosphate (CaP) or Ca oxalate (CaOx). However, stone formation was markedly decreased with LNaD by radiographic analysis. The LNaD group had significantly lower femoral anterior-posterior diameter and volumetric bone mineral density (vBMD), but no change in vertebral trabecular vBMD. There were no differences in the bone formation rate or osteoclastic bone resorption between groups. The LNaD group had significantly lower femoral stiffness; however, the ultimate load and energy to fail was not different. CONCLUSION Thus, a low Na diet reduced uCa and stone formation in GHS rats, even though SS with respect to CaP and CaOx was unchanged and effects on bone were modest. These data, if confirmed in humans, support dietary Na restriction to prevent recurrent Ca nephrolithiasis.
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Affiliation(s)
- Nancy S Krieger
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA,
| | - Marc Grynpas
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Amy VandenEynde
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - John R Asplin
- Litholink Corporation, Laboratory Corporation of America® Holdings, Chicago, Illinois, USA
| | - Kevin K Frick
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Min Ho Kim
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Felix M Ramos
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Ignacio Granja
- Litholink Corporation, Laboratory Corporation of America® Holdings, Chicago, Illinois, USA
| | - David A Bushinsky
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
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9
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Abstract
Preclinical animal research has greatly contributed and will continue to contribute in our understanding of various disease states and provided methods for more understanding of disease states and designs to test novel pharmaco-therapeutic interventions against these diseases. For urolithiasis, scientists have developed numerous in vitro and in vivo models that attempt to replicate human urolithiasis. In this review, I have explained in vitro and in vivo models that are more common, affordable, and easy to replicate. In the in vitro models, I have focused on the CaOx crystallization models and in the in vivo models, hyperoxaluric rat model has been explained along with other available option such as Knockout (KO) mice and fly models. Each model has been explained stepwise along with its pros and cons.
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Affiliation(s)
- Aslam Khan
- Basic Sciences Department, College of Science and Health Professions, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Jeddah, Saudi Arabia
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10
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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.
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11
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Tzou DT, Taguchi K, Chi T, Stoller ML. Animal models of urinary stone disease. Int J Surg 2016; 36:596-606. [PMID: 27840313 DOI: 10.1016/j.ijsu.2016.11.018] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2016] [Revised: 11/04/2016] [Accepted: 11/07/2016] [Indexed: 01/29/2023]
Abstract
The etiology of stone disease remains unknown despite the major technological advances in the treatment of urinary calculi. Clinically, urologists have relied on 24-h urine collections for the last 30-40 years to help direct medical therapy in hopes of reducing stone recurrence; yet little progress has been made in preventing stone disease. As such, there is an urgent need to develop reliable animal models to study the pathogenesis of stone formation and to assess novel interventions. A variety of vertebrate and invertebrate models have been used to help understand stone pathogenesis. Genetic knockout and exogenous induction models are described. Surrogates for an endpoint of stone formation have been urinary crystals on histologic examination and/or urinalyses. Other models are able to actually develop true stones. It is through these animal models that real breakthroughs in the management of urinary stone disease will become a reality.
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Affiliation(s)
- David T Tzou
- Department of Urology, University of California, San Francisco, 400 Parnassus Avenue, Suite Box 0738, San Francisco, CA 94143, USA.
| | - Kazumi Taguchi
- Department of Urology, University of California, San Francisco, 400 Parnassus Avenue, Suite Box 0738, San Francisco, CA 94143, USA; Department of Nephro-urology, Nagoya City University Graduate School of Medical Sciences, Japan.
| | - Thomas Chi
- Department of Urology, University of California, San Francisco, 400 Parnassus Avenue, Suite Box 0738, San Francisco, CA 94143, USA.
| | - Marshall L Stoller
- Department of Urology, University of California, San Francisco, 400 Parnassus Avenue, Suite Box 0738, San Francisco, CA 94143, USA.
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Letavernier E, Verrier C, Goussard F, Perez J, Huguet L, Haymann JP, Baud L, Bazin D, Daudon M. Calcium and vitamin D have a synergistic role in a rat model of kidney stone disease. Kidney Int 2016; 90:809-17. [DOI: 10.1016/j.kint.2016.05.027] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 05/25/2016] [Accepted: 05/26/2016] [Indexed: 10/21/2022]
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13
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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.
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Affiliation(s)
- Kevin K Frick
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
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14
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Krieger NS, Asplin JR, Frick KK, Granja I, Culbertson CD, Ng A, Grynpas MD, Bushinsky DA. Effect of Potassium Citrate on Calcium Phosphate Stones in a Model of Hypercalciuria. J Am Soc Nephrol 2015; 26:3001-8. [PMID: 25855777 DOI: 10.1681/asn.2014121223] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 02/02/2015] [Indexed: 01/24/2023] Open
Abstract
Potassium citrate is prescribed to decrease stone recurrence in patients with calcium nephrolithiasis. Citrate binds intestinal and urine calcium and increases urine pH. Citrate, metabolized to bicarbonate, should decrease calcium excretion by reducing bone resorption and increasing renal calcium reabsorption. However, citrate binding to intestinal calcium may increase absorption and renal excretion of both phosphate and oxalate. Thus, the effect of potassium citrate on urine calcium oxalate and calcium phosphate supersaturation and stone formation is complex and difficult to predict. To study the effects of potassium citrate on urine supersaturation and stone formation, we utilized 95th-generation inbred genetic hypercalciuric stone-forming rats. Rats were fed a fixed amount of a normal calcium (1.2%) diet supplemented with potassium citrate or potassium chloride (each 4 mmol/d) for 18 weeks. Urine was collected at 6, 12, and 18 weeks. At 18 weeks, stone formation was visualized by radiography. Urine citrate, phosphate, oxalate, and pH levels were higher and urine calcium level was lower in rats fed potassium citrate. Furthermore, calcium oxalate and calcium phosphate supersaturation were higher with potassium citrate; however, uric acid supersaturation was lower. Both groups had similar numbers of exclusively calcium phosphate stones. Thus, potassium citrate effectively raises urine citrate levels and lowers urine calcium levels; however, the increases in urine pH, oxalate, and phosphate levels lead to increased calcium oxalate and calcium phosphate supersaturation. Potassium citrate induces complex changes in urine chemistries and resultant supersaturation, which may not be beneficial in preventing calcium phosphate stone formation.
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Affiliation(s)
- Nancy S Krieger
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York;
| | - John R Asplin
- Litholink Corporation, Laboratory Corporation of America Holdings, Chicago, Illinois; and
| | - Kevin K Frick
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
| | - Ignacio Granja
- Litholink Corporation, Laboratory Corporation of America Holdings, Chicago, Illinois; and
| | - Christopher D Culbertson
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
| | - Adeline Ng
- Laboratory Medicine and Pathobiology Department, University of Toronto, Toronto, Ontario, Canada
| | - Marc D Grynpas
- Laboratory Medicine and Pathobiology Department, University of Toronto, Toronto, Ontario, Canada
| | - David A Bushinsky
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York
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15
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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.
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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
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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.
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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.
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Pathophysiology. Urolithiasis 2014. [DOI: 10.1007/978-1-4614-8196-6_25] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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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.
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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,
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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.
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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.
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Fu B, Wang H, Wang J, Barouhas I, Liu W, Shuboy A, Bushinsky DA, Zhou D, Favus MJ. Epigenetic regulation of BMP2 by 1,25-dihydroxyvitamin D3 through DNA methylation and histone modification. PLoS One 2013; 8:e61423. [PMID: 23620751 PMCID: PMC3631216 DOI: 10.1371/journal.pone.0061423] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2012] [Accepted: 03/08/2013] [Indexed: 12/13/2022] Open
Abstract
Genetic hypercalciuric stone-forming (GHS) rats have increased intestinal Ca absorption, decreased renal tubule Ca reabsorption and low bone mass, all of which are mediated at least in part by elevated tissue levels of the vitamin D receptor (VDR). Both 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and bone morphogenetic protein 2 (BMP2) are critical for normal maintenance of bone metabolism and bone formation, respectively. The complex nature of bone cell regulation suggests a potential interaction of these two important regulators in GHS rats. In the present study, BMP2 expression is suppressed by the VDR-1,25(OH)2D3 complex in Bone Marrow Stromal Cells (BMSCs) from GHS and SD rat and in UMR-106 cell line. We used chromatin immunoprecipitation (ChIP) assays to identify VDR binding to only one of several potential binding sites within the BMP2 promoter regions. This negative region also mediates suppressor reporter gene activity. The molecular mechanisms underlying the down-regulation of BMP2 by 1,25(OH)2D3 were studied in vitro in BMSCs and UMR-106 cells using the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (DAC) and the histone deacetylase inhibitor trichostatin A (TSA). Both DAC and TSA activate BMP2 expression in combination with 1,25(OH)2D3. Bisulfite DNA pyrosequencing reveals 1,25(OH)2D3 to completely hypermethylate a single CpG site in the same BMP2 promoter region identified by the ChIP and reporter gene assays. ChIP assays also show that 1,25(OH)2D3 can increase the repressive histone mark H3K9me2 and reduce the acetylation of histone H3 at the same BMP2 promoter region. Taken together, our results indicate that 1,25(OH)2D3 binding to VDR down-regulates BMP2 gene expression in BMSCs and osteoblast-like UMR-106 cells by binding to the BMP2 promoter region. The mechanism of this 1,25(OH)2D3-induced transcriptional repression of BMP2 involves DNA methylation and histone modification. The study provides novel evidence that 1,25(OH)2D3 represses bone formation through down-regulating BMP2 expression both in vivo and in vitro.
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Affiliation(s)
- Baisheng Fu
- Department of Orthopedic Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
| | - Hongwei Wang
- Section of Endocrinology, University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States of America
| | - Jinhua Wang
- Section of Endocrinology, University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States of America
| | - Ivana Barouhas
- Section of Endocrinology, University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States of America
| | - Wanqing Liu
- Department of Medicinal Chemistry & Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, Indiana, United States of America
| | - Adam Shuboy
- Section of Endocrinology, University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States of America
| | - David A. Bushinsky
- Division of Nephrology, University of Rochester School of Medicine and Dentistry, Rochester, New York, United States of America
| | - Dongsheng Zhou
- Department of Orthopedic Surgery, Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, People’s Republic of China
- * E-mail: (DZ); (MJF)
| | - Murray J. Favus
- Section of Endocrinology, University of Chicago Pritzker School of Medicine, Chicago, Illinois, United States of America
- * E-mail: (DZ); (MJF)
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22
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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.
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Affiliation(s)
- Kevin K Frick
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
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23
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Abstract
Calcium is an important participant in many physiologic processes including coagulation, cell membrane transfer, hormone release, neuromuscular activation, and myocardial contraction. The body cooperates in a sophisticated web of hormonally mediated interactions to maintain stable extracellular calcium levels. Calcium is vital for skeletal mineralization, and perturbations in extracellular calcium may be corrected at the expense of bone strength and integrity. The aim of this review is to delineate our current understanding of idiopathic hypercalciuria in the context of bone health, specifically its definition, etiology, epidemiology, laboratory evaluation, and potential therapeutic management.
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Affiliation(s)
- Laura E Ryan
- Center for Women's Health, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, 43210, USA.
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24
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Perry GML, Nehrke KW, Bushinsky DA, Reid R, Lewandowski KL, Hueber P, Scheinman SJ. Sex modifies genetic effects on residual variance in urinary calcium excretion in rat (Rattus norvegicus). Genetics 2012; 191:1003-13. [PMID: 22554889 PMCID: PMC3389963 DOI: 10.1534/genetics.112.138909] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2012] [Accepted: 04/23/2012] [Indexed: 01/03/2023] Open
Abstract
Conventional genetics assumes common variance among alleles or genetic groups. However, evidence from vertebrate and invertebrate models suggests that residual genotypic variance may itself be under partial genetic control. Such a phenomenon would have great significance: high-variability alleles might confound the detection of "classically" acting genes or scatter predicted evolutionary outcomes among unpredicted trajectories. Of the few works on this phenomenon, many implicate sex in some aspect of its control. We found that female genetic hypercalciuric stone-forming (GHS) rats (Rattus norvegicus) had higher coefficients of variation (CVs) for urinary calcium (CV = 0.14) than GHS males (CV = 0.06), and the reverse in normocalciuric Wistar-Kyoto rats (WKY) (CV(♂) = 0.14; CV(♀) = 0.09), suggesting sex-by-genotype interaction on residual variance. We therefore investigated the effect of sex on absolute-transformed residuals in urinary calcium in an F(2) GHS × WKY mapping cohort. Absolute residuals were associated with genotype at two microsatellites, D3Rat46 (RNO3, 33.9 Mb) and D4Mgh1 (RNO4, 84.8 MB) at Bonferroni thresholds across the entire cohort, and with the microsatellites D3Rat46, D9Mgh2 (RNO9, 84.4 Mb), and D12Rat25 (RNO12, 40.4 Mb) in females (P < 0.05) but not males. In GHS chromosome 1 congenic lines bred onto a WKY genomic background, we found that congenic males had significantly (P < 0.0001) higher CVs for urinary calcium (CV = 0.25) than females (CV = 0.15), supporting the hypothesis of the inheritance of sex-by-genotype interaction on this effect. Our findings suggest that genetic effects on residual variance are sex linked; heritable, sex-specific residuals might have great potential implications for evolution, adaptation, and genetic analysis.
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Affiliation(s)
- Guy M L Perry
- Department of Medicine, SUNY Upstate Medical University, Syracuse, NY 13210, USA.
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Bushinsky DA, Willett T, Asplin JR, Culbertson C, Che SPY, Grynpas M. Chlorthalidone improves vertebral bone quality in genetic hypercalciuric stone-forming rats. J Bone Miner Res 2011; 26:1904-12. [PMID: 21351146 PMCID: PMC4493760 DOI: 10.1002/jbmr.374] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
We have bred a strain of rats to maximize urine (u) calcium (Ca) excretion and model hypercalciuric nephrolithiasis. These genetic hypercalciuric stone-forming (GHS) rats excrete more uCa than control Sprague-Dawley rats, uniformly form kidney stones, and similar to patients, demonstrate lower bone mineral density. Clinically, thiazide diuretics reduce uCa and prevent stone formation; however, whether they benefit bone is not clear. We used GHS rats to test the hypothesis that the thiazide diuretic chlorthalidone (CTD) would have a favorable effect on bone density and quality. Twenty GHS rats received a fixed amount of a 1.2% Ca diet, and half also were fed CTD (4 to 5 mg/kg/d). Rats fed CTD had a marked reduction in uCa. The axial and appendicular skeletons were studied. An increase in trabecular mineralization was observed with CTD compared with controls. CTD also improved the architecture of trabecular bone. Using micro-computed tomography (µCT), trabecular bone volume (BV/TV), trabecular thickness, and trabecular number were increased with CTD. A significant increase in trabecular thickness with CTD was confirmed by static histomorphometry. CTD also improved the connectivity of trabecular bone. Significant improvements in vertebral strength and stiffness were measured by vertebral compression. Conversely, a slight loss of bending strength was detected in the femoral diaphysis with CTD. Thus results obtained in hypercalciuric rats suggest that CTD can favorably influence vertebral fracture risk. CTD did not alter formation parameters, suggesting that the improved vertebral bone strength was due to decreased bone resorption and retention of bone structure.
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Affiliation(s)
- David A Bushinsky
- Nephrology Division, Department of Medicine, University of Rochester School of Medicine, Rochester, NY 14642, USA.
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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).
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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
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Abstract
Current understanding of the mechanisms underlying renal disease in humans is incomplete. Consequently, our ability to prevent the occurrence of renal disease or treat kidney disease once it develops is limited. There are objective difficulties in investigating kidney disease directly in humans, leading investigators to resort to experimental animal models that simulate renal disease in humans. Animal models have thus been a tool of major importance in the study of normal renal physiology and have been crucial in shedding light on the complex mechanisms involved in normal kidney function and in our current understanding of and ability to treat renal disease. Among the animal models, rat has been the preferred and most commonly used species for the investigation of renal disease. This chapter reviews what has been achieved over the years, using rat as a tool for the investigation of renal disease in humans, focusing on the contribution of rat genetics and genomics to the elucidation of the mechanisms underlying the pathophysiology of the major types of renal disease, including primary and secondary renal diseases.
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Abstract
Kidney stone patients often have a decrease in BMD. It is unclear if reduced BMD is caused by a primary disorder of bone or dietary factors. To study the independent effects of hypercalciuria on bone, we used genetic hypercalciuric stone-forming (GHS) rats. GHS and control (Ctl) rats were fed a low Ca (0.02% Ca, LCD) or a high Ca (1.2% Ca, HCD) diet for 6 wk in metabolic cages. All comparisons are to Ctl rats. Urine Ca was greater in the GHS rats on both diets. GHS fed HCD had reduced cortical (humerus) and trabecular (L(1)-L(5) vertebrae) BMD, whereas GHS rats fed LCD had a reduction in BMD similar to Ctl. GHS rats fed HCD had a decrease in trabecular volume and thickness, whereas LCD led to a approximately 20-fold increase in both osteoid surface and volume. GHS rats fed HCD had no change in vertebral strength (failure stress), ductibility (failure strain), stiffness (modulus), or toughness, whereas in the humerus, there was reduced ductibility and toughness and an increase in modulus, indicating that the defect in mechanical properties is mainly manifested in cortical, rather than trabecular, bone. GHS rat cortical bone is more mineralized than trabecular bone and LCD led to a decrease in the mineralization profile. Thus, the GHS rats, fed an ample Ca diet, have reduced BMD with reduced trabecular volume, mineralized volume, and thickness, and their bones are more brittle and fracture prone, indicating that GHS rats have an intrinsic disorder of bone that is not secondary to diet.
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Asplin JR, Donahue SE, Lindeman C, Michalenka A, Strutz KL, Bushinsky DA. Thiosulfate reduces calcium phosphate nephrolithiasis. J Am Soc Nephrol 2009; 20:1246-53. [PMID: 19369406 DOI: 10.1681/asn.2008070754] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
An uncontrolled trial reported that sodium thiosulfate reduces formation of calcium kidney stones in humans, but this has not been established in a controlled human study or animal model. Using the genetic hypercalciuric rat, an animal model of calcium phosphate stone formation, we studied the effect of sodium thiosulfate on urine chemistries and stone formation. We fed genetic hypercalciuric rats normal food with or without sodium thiosulfate for 18 wk and measured urine chemistries, supersaturation, and the upper limit of metastability of urine. Eleven of 12 untreated rats formed stones compared with only three of 12 thiosulfate-treated rats (P < 0.002). Urine calcium and phosphorus were higher and urine citrate and volume were lower in the thiosulfate-treated rats, changes that would increase calcium phosphate supersaturation. Thiosulfate treatment lowered urine pH, which would lower calcium phosphate supersaturation. Overall, there were no statistically significant differences in calcium phosphate supersaturation or upper limit of metastability between thiosulfate-treated and control rats. In vitro, thiosulfate only minimally affected ionized calcium, suggesting a mechanism of action other than calcium chelation. In summary, sodium thiosulfate reduces calcium phosphate stone formation in the genetic hypercalciuric rat. Controlled trials testing the efficacy and safety of sodium thiosulfate for recurrent kidney stones in humans are needed.
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Affiliation(s)
- John R Asplin
- Litholink Corp., 2250 W. Campbell Park Drive, Chicago, IL 60612, USA.
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Abstract
Kidney stone disease remains a major health and economic burden on the nation. It has been increasingly recognized that nephrolithiasis can be both a chronic or systemic illness. There have been major limitations in the development of new drugs for the prevention and management of this disease, largely due to our lack of understanding of the complex pathophysiologic mechanisms involving the interaction of three major target organs: the kidney, bone, and intestine. We also do not yet understand the molecular genetic basis of this polygenic disorder. These limitations are coupled with the incorrect perception that kidney stone disease is solely an acute illness, and the lack of reliable tests to assess outcome measures. All of these factors combined have diminished the willingness of the pharmaceutical industry to engage in the development of novel drugs.
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Vezzoli G, Arcidiacono T, Paloschi V, Terranegra A, Biasion R, Soldati L. Update on the genetics of nephrolithiasis. CLINICAL CASES IN MINERAL AND BONE METABOLISM : THE OFFICIAL JOURNAL OF THE ITALIAN SOCIETY OF OSTEOPOROSIS, MINERAL METABOLISM, AND SKELETAL DISEASES 2008; 5:110-113. [PMID: 22460991 PMCID: PMC2781208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Genetic studies of calcium kidney stones evidenced the possible involvement of calcium-sensing receptor gene, vitamin D receptor gene and bicarbonate-sensitive adenylate cyclase gene, but it is uncertain which specific polymorphisms could be responsible. Thus, further studies are required to better assess the involvement of these or other genes and the interactions between different genes and between genes and environment. In addition to research in humans, the study of different strains of knock-out mice let us include the gene of phosphate reabsorption carrier NPT2, caveolin-1, protein NHERF-1, osteopontin and Tamm-Horsfall protein among the possible determinants. Further steps in the knowledge of calcium stone causes may be done using the instruments that the modern biotechnology and bioinformatics have made available to the researchers.
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Affiliation(s)
- Giuseppe Vezzoli
- Nephrology and Dialysis Unit, San Raffaele Scientific Institute, Vita Salute University, Milan, Italy
| | - Teresa Arcidiacono
- Nephrology and Dialysis Unit, San Raffaele Scientific Institute, Vita Salute University, Milan, Italy
| | - Vera Paloschi
- Nephrology and Dialysis Unit, San Raffaele Scientific Institute, Vita Salute University, Milan, Italy
| | - Annalisa Terranegra
- Department of Sciences and Biomedical Technologies, Nephrology Section, University of Milan, Milan, Italy
| | - Rita Biasion
- Department of Sciences and Biomedical Technologies, Nephrology Section, University of Milan, Milan, Italy
| | - Laura Soldati
- Department of Sciences and Biomedical Technologies, Nephrology Section, University of Milan, Milan, Italy
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Effect of bolus and divided feeding on urine ions and supersaturation in genetic hypercalciuric stone-forming rats. Kidney Int 2007; 73:423-9. [PMID: 18046318 DOI: 10.1038/sj.ki.5002699] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Because urine ion excretion varies throughout the day, clinicians monitor 24 h urine samples to measure ion excretion and supersaturation in kidney stone patients. However, these results are averages and may not reflect maximal supersaturation which drives stone formation. We measured ion excretion and saturation in genetic hypercalciuric stone-forming rats on both a normal or low calcium diet over 0-3, 3-6 and 6-24 h using two feeding protocols, where the daily food allotment was fed either as a bolus or divided into three portions. With a normal calcium diet, urine calcium, oxalate, volume, and calcium oxalate supersaturation were significantly greater on the bolus compared to the divided feeds in the prandial and postprandial periods. Bolus eaters also excreted more calcium and oxalate and had increased volume over 24 h. Maximal calcium oxalate supersaturation was greater during the initial time periods than during the entire 24 h, regardless of the feeding schedule. With the low calcium diet, the effect of bolus feeding was reduced. Thus, urine ion excretion and supersaturation vary with the type of feeding. If these results are confirmed in man, it suggests that eating as a bolus may result in greater prandial and postprandial calcium oxalate supersaturation. This may increase growth on Randall's plaques and promote stone disease.
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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.
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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.
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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.
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Affiliation(s)
- David A Bushinsky
- Division of Nephrology, Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642, USA.
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Abstract
PURPOSE OF REVIEW In idiopathic hypercalciuria, patients have increased intestinal Ca absorption and decreased renal Ca reabsorption, with either elevated or normal serum levels of 1,25-dihydroxyvitamin D. As 1,25-dihydroxyvitamin D exerts its biologic effects through interactions with the vitamin D receptor, we examine the actions of this receptor and 1,25-dihydroxyvitamin D in animals with genetic hypercalciuria. RECENT FINDINGS In genetic hypercalciuric stone-forming rats intestinal calcium transport is increased and renal calcium reabsorption is reduced, yet serum 1,25-dihydroxyvitamin D levels are normal. Elevated intestinal and kidney vitamin D receptors suggest that increased tissue 1,25-dihydroxyvitamin D-vitamin D receptor complexes enhance 1,25-dihydroxyvitamin D actions on intestine and kidney, and vitamin D-dependent over-expression of renal calcium-sensing receptor alone can decrease tubule calcium reabsorption. In TRPV5-knockout mice, ablation of the renal calcium-influx channel decreases tubular calcium reabsorption, and secondary elevations in 1,25-dihydroxyvitamin D increase intestinal calcium transport. SUMMARY 1,25-Dihydroxyvitamin D or vitamin D receptor may change intestinal and renal epithelial calcium transport simultaneously or calcium-transport changes across renal epithelia may be primary with a vitamin D-mediated secondary increase in intestinal transport. The extent of homology between the animal models and human idiopathic hypercalciuria remains to be determined.
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Affiliation(s)
- Shaochun Bai
- Section of Endocrinology, University of Chicago Pritzker School of Medicine, Chicago, Illinois 60637, USA
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Bushinsky DA, Laplante K, Asplin JR. Effect of cinacalcet on urine calcium excretion and supersaturation in genetic hypercalciuric stone-forming rats. Kidney Int 2006; 69:1586-92. [PMID: 16557225 DOI: 10.1038/sj.ki.5000324] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Idiopathic hypercalciuria is the most common metabolic abnormality in patients with nephrolithiasis. Through successive inbreeding, we have developed a strain of rats whose urine calcium (UCa) excretion is approximately 8-10-fold greater than that of control rats and who spontaneously form kidney stones. We have termed these rats genetic hypercalciuric stone-forming (GHS) rats. The physiology of the hypercalciuria in the GHS rats closely parallels that of man. We have recently shown that the GHS rat kidneys have an increased number of receptors for calcium (CaR) compared to Sprague-Dawley rats, the strain of rats originally bred to develop the GHS rats. Calcimimetics, such as cinacalcet (Cin), increase the sensitivity of the CaR to Ca. The effects of Cin on UCa are complex and difficult to predict. We tested the hypothesis that Cin would alter urinary (U) Ca and supersaturation with respect to calcium hydrogen phosphate (CaHPO(4)) and calcium oxalate (CaOx). GHS or control rats were fed a normal Ca diet (0.6% Ca) for 28 days with Cin (30 mg/kg/24 h) added to the diet of half of each group for the last 14 days. The protocol was then repeated while the rats were fed a low Ca (0.02% Ca) diet. We found that Cin led to a marked reduction in circulating parathyroid hormone and a modest reduction in serum Ca. Cin did not alter UCa when the GHS rats were fed the normal Ca diet but lowered UCa when they were fed the low Ca diet. However, Cin did not alter U supersaturation with respect to either CaOx or CaHPO(4) on either diet. If these findings in GHS rats can be confirmed in man, it suggests that Cin would not be an effective agent in the treatment of human idiopathic hypercalciuria and resultant stone formation.
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Affiliation(s)
- D A Bushinsky
- Nephrology Division, Department of Medicine, University of Rochester School of Medicine, Rochester, New York, USA.
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Hoopes RR, Middleton FA, Sen S, Hueber PA, Reid R, Bushinsky DA, Scheinman SJ. Isolation and confirmation of a calcium excretion quantitative trait locus on chromosome 1 in genetic hypercalciuric stone-forming congenic rats. J Am Soc Nephrol 2006; 17:1292-304. [PMID: 16611718 DOI: 10.1681/asn.2005080828] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Hypercalciuria is the most common risk factor for kidney stones and has a substantial genetic component. The genetic hypercalciuric stone-forming (GHS) rat model displays complex changes in physiology involving intestine, bone, and kidney and overexpression of the vitamin D receptor, thereby reproducing the human phenotype of idiopathic hypercalciuria. Through quantitative trait locus (QTL) mapping of rats that were bred from GHS female rats and normocalciuric Wistar Kyoto (WKY) male rats, loci that are linked to hypercalciuria and account for a 6 to eight-fold phenotypic difference between the GHS and WKY progenitors were mapped. GHS x WKY rats were backcrossed to breed for congenic rats with the chromosome 1 QTL HC1 on a normocalciuric WKY background. Ten generations of backcrosses produced N10F1 rats, which were intercrossed to produce rats that were homozygous for GHS loci in the HC1 region between markers D1Mit2 and D1Mit32. On a high-calcium diet (1.2% calcium), significantly different levels of calcium excretion were found between male congenic (1.67 +/- 0.71 mg/24 h) and male WKY control rats (0.78 +/- 0.19 mg/24 h) and between female congenic (3.11 +/- 0.90 mg/24 h) and female WKY controls (2.11 +/- 0.50 mg/24 h); the congenics preserve the calcium excretion phenotype of the GHS parent strain. Microarray expression analyses of the congenic rats, compared with WKY rats, showed that of the top 100 most changed genes, twice as many as were statistically expected mapped to chromosome 1. Of these, there is a clear bias in gene expression change for genes in the region of the HC1. Of >1100 gene groups analyzed, one third of the 50 most differentially expressed gene groups have direct or secondary action on calcium metabolism or transport. This is the first QTL for hypercalciuria to be isolated in a congenic animal.
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Affiliation(s)
- Richard R Hoopes
- Department of Medicine, SUNY Upstate Medical University, 750 E. Adams Street, Syracuse, NY 13210, USA.
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Gambaro G, Vezzoli G, Casari G, Rampoldi L, D'Angelo A, Borghi L. Genetics of hypercalciuria and calcium nephrolithiasis: from the rare monogenic to the common polygenic forms. Am J Kidney Dis 2005; 44:963-86. [PMID: 15558518 DOI: 10.1053/j.ajkd.2004.06.030] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Idiopathic calcium nephrolithiasis is a multifactorial disease with a pathogenesis that involves a complex interaction of environmental and individual factors. This review discusses what is known about monogenic renal calcium stone-related disorders, provides an update on genetic research in calcium nephrolithiasis and such intermediate phenotypes as idiopathic hypercalciuria, discusses the problems that these conditions pose to clinicians and geneticists interested in their pathogenesis, and proposes some method tools potentially useful in this research frame of reference.
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Affiliation(s)
- Giovanni Gambaro
- Department of Biomedical and Surgical Sciences, Division of Nephrology, University of Verona, Verona, Italy.
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Yao JJ, Bai S, Karnauskas AJ, Bushinsky DA, Favus MJ. Regulation of renal calcium receptor gene expression by 1,25-dihydroxyvitamin D3 in genetic hypercalciuric stone-forming rats. J Am Soc Nephrol 2005; 16:1300-8. [PMID: 15788476 DOI: 10.1681/asn.2004110991] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Hypercalciuria in inbred genetic hypercalciuric stone-forming (GHS) rats is due, in part, to a decrease in renal tubule Ca reabsorption. Activation of the renal Ca receptor (CaR) may decrease renal tubule Ca reabsorption and cause hypercalciuria through suppression of Ca-sensitive potassium channel activity. Because the rat renal CaR gene is regulated by extracellular calcium and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and GHS rats have increased renal vitamin D receptor content, the current study was undertaken to determine the level of CaR gene expression in GHS rat kidney and whether CaR gene expression is regulated by 1,25(OH)2D3. Male GHS and normal control (NC) rats were fed a Ca-sufficient diet (0.6% Ca). Western blotting revealed a four-fold increase in CaR protein in GHS rat renal tissue, and 1,25(OH)2D3 administration increased renal CaR in both GHS and NC rats. Northern blot analysis of extracts of renal cortical tissue from GHS and NC rats revealed a major 7-kb transcript of CaR and a more modest 4-kb transcript, both of which were readily detectable. Both Northern blotting and real-time reverse transcription-PCR revealed increased basal CaR mRNA expression levels in GHS rat kidney. 1,25(OH)2D3 administration increased renal CaR mRNA levels 2.0- and 3.3-fold in GHS and NC rats, respectively. Despite the greater incremental increase by 1,25(OH)2D3 in NC rats, CaR mRNA levels remained higher in GHS rat kidney, and the elevation was more sustained. 1,25(OH)2D3 increased CaR mRNA through both elevated CaR gene expression and prolonged tissue half-life. These results demonstrate that GHS rats have high levels of CaR gene expression and CaR protein that may contribute to the hypercalciuria and calcium nephrolithiasis.
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Affiliation(s)
- Jim J Yao
- The University of Chicago, Pritzker School of Medicine, 5841 S. Maryland Avenue, MC 1027, Chicago, Illinois 60637, USA
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Karnauskas AJ, van Leeuwen JPTM, van den Bemd GJCM, Kathpalia PP, DeLuca HF, Bushinsky DA, Favus MJ. Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric stone-forming rats. J Bone Miner Res 2005; 20:447-54. [PMID: 15746989 DOI: 10.1359/jbmr.041120] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2004] [Revised: 07/15/2004] [Accepted: 10/15/2004] [Indexed: 11/18/2022]
Abstract
UNLABELLED The functional status and mechanism of increased VDR in GHS rats were investigated. Basal VDR and calbindins were increased in GHS rats. 1,25(OH)(2)D(3) increased VDR and calbindins in controls but not GHS rats. VDR half-life was prolonged in GHS rats. This study supports the mechanism and functional status of elevated VDR in GHS rats. INTRODUCTION Genetic hypercalciuric stone-forming (GHS) rats form calcium kidney stones from hypercalciuria arising from increased intestinal calcium absorption and bone resorption and decreased renal calcium reabsorption. Normal serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels and increased vitamin D receptor (VDR) protein suggest that high rates of expression of vitamin D-responsive genes may mediate the hypercalciuria. The mechanism of elevated VDR and state of receptor function are not known. MATERIALS AND METHODS GHS and non-stone-forming control (NC) male rats (mean, 249 g), fed a normal calcium diet, were injected intraperitoneally with 1,25(OH)2D3 (30 ng/100 g BW) or vehicle 24 h before cycloheximide (6 mg/100 g, IP) and were killed 0-8 h afterward. Duodenal VDR was measured by ELISA and Western blot, and duodenal and kidney calbindins (9 and 28 kDa) were measured by Western blots. RESULTS AND CONCLUSIONS Duodenal VDR protein by Western blot was increased 2-fold in GHS versus NC rats (633 +/- 62 versus 388 +/- 48 fmol/mg protein, n = 4, p < 0.02), and 1,25(OH)2D3 increased VDR and calbindins (9 and 28 kDa) further in NC but not GHS rats. Duodenal VDR half-life was prolonged in GHS rats (2.59 +/- 0.2 versus 1.81 +/- 0.2 h, p < 0.001). 1,25(OH)2D3 prolonged duodenal VDR half-life in NC rats to that of untreated GHS rats (2.59 +/- 0.2 versus 2.83 +/- 0.3 h, not significant). This study supports the hypothesis that prolongation of VDR half-life increases VDR tissue levels and mediates increased VDR-regulated genes that result in hypercalciuria through actions on vitamin D-regulated calcium transport in intestine, bone, and kidney.
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Affiliation(s)
- Alexander J Karnauskas
- Department of Medicine, University of Chicago Pritzker School of Medicine, Chicago, Illinois 60637, USA
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41
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Abstract
Hypercalciuria is an important, identifiable, and reversible risk factor in stone formation. The foremost and most fundamental step in dissecting the genetics of hypercalciuria is understanding its pathophysiology. Hypercalciuria is a complex trait. This article outlines the various factors that compromise the attempt to dissect the genetics of hypercalciuria, summarizes the clinical and experimental monogenic causes of hypercalciuria, and outlines the initial results from attempts in studying polygenic hypercalciuria. Finally, the problem is set in perspective of the current database, technologic advances and limitations are highlighted, and prospects of further advances in the field are speculated upon.
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Affiliation(s)
- Orson W Moe
- Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8855, USA.
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Bushinsky DA, Asplin JR. Thiazides Reduce Brushite, but not Calcium Oxalate, Supersaturation, and Stone Formation in Genetic Hypercalciuric Stone–Forming Rats. J Am Soc Nephrol 2005; 16:417-24. [PMID: 15647340 DOI: 10.1681/asn.2004070543] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Over 59 generations, a strain of rats has been inbred to maximize urine calcium excretion. The rats now excrete eight to 10 times as much calcium as controls. These rats uniformly form calcium phosphate (apatite) kidney stones and have been termed genetic hypercalciuric stone-forming (GHS) rats. The addition of a common amino acid and oxalate precursor, hydroxyproline, to the diet of the GHS rats leads to formation of calcium oxalate (CaOx) kidney stones. Hydroxyproline-supplemented GHS rats were used to test the hypothesis that the thiazide diuretic chlorthalidone would decrease urine calcium excretion, supersaturation, and perhaps stone formation. All GHS rats received a fixed amount of a standard 1.2% calcium diet with 5% trans-4-hydroxy-l-proline (hydroxyproline) so that the rats would exclusively form CaOx stones. Half of the rats had chlorthalidone (Thz; 4 to 5 mg/kg per d) added to their diets. Urine was collected weekly, and at the conclusion of the study, the kidneys, ureters, and bladders were radiographed for the presence of stones. Compared with control, the addition of Thz led to a significant reduction of urine calcium and phosphorus excretion, whereas urine oxalate excretion increased. Supersaturation with respect to the calcium hydrogen phosphate fell, whereas supersaturation with respect to CaOx was unchanged. Rats that were fed Thz had fewer stones. As calcium phosphate seems to be the preferred initial solid phase in patients with CaOx kidney stones, the reduction in supersaturation with respect to the calcium phosphate solid phase may be the mechanism by which thiazides reduce CaOx stone formation.
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Affiliation(s)
- David A Bushinsky
- Department of Medicine, University of Rochester School of Medicine and Dentistry, Strong Memorial Hospital, 601 Elmwood Avenue, Box 675, Rochester, NY 14642, USA.
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Evan AP, Bledsoe SB, Smith SB, Bushinsky DA. Calcium oxalate crystal localization and osteopontin immunostaining in genetic hypercalciuric stone-forming rats. Kidney Int 2004; 65:154-61. [PMID: 14675046 DOI: 10.1111/j.1523-1755.2004.00396.x] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
BACKGROUND The inbred genetic hypercalciuric stone-forming (GHS) rats develop calcium phosphate (apatite) stones when fed a normal 1.2% calcium diet. The addition of 1% hydroxyproline to this diet does not alter the type of stone formed, while rats fed this diet with 3% hydroxyproline form mixed apatite and calcium oxalate stones and those with 5% hydroxyproline added form only calcium oxalate stones. The present study was designed to determine the localization of stone formation and if this solid phase resulted in pathologic changes to the kidneys. METHODS GHS rats were fed 15 g of the standard diet or the diet supplemented with 1%, 3%, or 5% hydroxyproline for 18 weeks. A separate group of Sprague-Dawley rats (the parental strain of the GHS rats), fed the standard diet for a similar duration, served as an additional control. At 18 weeks, all kidneys were perfusion-fixed for structural analysis, detection of crystal deposits using the Yasue silver substitution method, and osteopontin immunostaining. RESULTS There were no crystal deposits found in the kidneys of Sprague-Dawley rats. Crystal deposits were found in the kidneys of all GHS rats and this Yasue-stained material was detected only in the urinary space. No crystal deposits were noted within the cortical or medullary segments of the nephron and there was no evidence for tubular damage in any group. The only pathologic changes occurred in 3% and 5% hydroxyproline groups with the 5% group showing the most severe changes. In these rats, which form only calcium oxalate stones, focal sites along the urothelial lining of the papilla and fornix of the urinary space demonstrated a proliferative response characterized by increased density of urothelial cells that surrounded the crystal deposits. At the fornix, some crystals were lodged within the interstitium, deep to the proliferative urothelium. There was increased osteopontin immunostaining in the proliferating urothelium. CONCLUSION Thus in the GHS rat, the initial stone formation occurred solely in the urinary space. Tubular damage was not observed with either apatite or calcium oxalate stones. The apatite stones do not appear to cause any pathological change while those rats forming calcium oxalate stones have a proliferative response of the urothelium, with increased osteopontin immunostaining, around the crystal deposits in the fornix.
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Affiliation(s)
- Andrew P Evan
- Anatomy Department, Indiana University School of Medicine, Indianapolis, Indiana, USA
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Hoopes RR, Reid R, Sen S, Szpirer C, Dixon P, Pannett AAJ, Thakker RV, Bushinsky DA, Scheinman SJ. Quantitative trait loci for hypercalciuria in a rat model of kidney stone disease. J Am Soc Nephrol 2003; 14:1844-50. [PMID: 12819244 DOI: 10.1097/01.asn.0000073920.43848.a3] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Hypercalciuria is the most common risk factor for kidney stones and has a recognized familial component. The genetic hypercalciuric stone-forming (GHS) rat is an animal model that closely resembles human idiopathic hypercalciuria, with excessive intestinal calcium absorption, increased bone resorption, and impaired renal calcium reabsorption; overexpression of the vitamin D receptor (VDR) in target tissues; and calcium nephrolithiasis. For identifying genetic loci that contribute to hypercalciuria in the GHS rat, an F2 generation of 156 rats bred from GHS female rats and normocalciuric WKY male rats was studied. The calcium excretion was six- to eightfold higher in the GHS female than in the WKY male progenitors. Selective genotyping of those F2 rats with the highest 30% and lowest 30% rates of calcium excretion was performed, scoring 98 markers with a mean interval of 23 cM across all 20 autosomes and the X chromosome. With the use of strict criteria for significance, significant linkage was found between hypercalciuria and a region of chromosome 1 at D1Rat169 (LOD, 2.91). Suggestive linkage to regions of chromosomes 4, 7, 10, and 14 was found. The proportion of phenotypic variance contributed by the region on chromosome 1, with appropriate adjustments, was estimated to be 7%. Candidate genes encoding the VDR and the calcium-sensing receptor were localized to regions on rat chromosomes 7 and 11, respectively, but the suggestive quantitative trait locus on chromosome 7 was not in the region of the VDR gene locus. Identification of genes that contribute to hypercalciuria in this animal model should prove valuable in understanding idiopathic hypercalciuria and kidney stone disease in humans.
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Affiliation(s)
- Richard R Hoopes
- Department of Medicine, State University of New York Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210, USA
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Affiliation(s)
- Kevin K Frick
- Department of Medicine, Nephrology Unit, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA.
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46
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Abstract
The major contribution of hypercalciuria in raising urinary state of saturation with respect to calcium salts and subsequent risk of nephrolithiasis is appreciated. Derangements in the physiological mechanisms that regulate calcium homeostasis and contribute to hypercalciuria have also been identified. New avenues of research are beginning to explore the specific defects that may contribute to hypercalciuria. From such studies, an understanding of the role of certain dietary excesses as contributors to the development of hypercalciuria and, in some cases, attendant bone loss, is beginning. The contribution of genetics to hypercalciuria has provided a powerful means of identifying genes that contribute to the hypercalciuric phenotype in a number of hypercalciuric conditions. Such studies have disclosed that hypercalciuria is probably polygenic in nature and will require a concerted effort to better understand the defects while attempting to develop gene-specific countermeasures.
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Affiliation(s)
- Joseph E Zerwekh
- Department of Internal Medicine, Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390-8885, USA.
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Bushinsky DA, Asplin JR, Grynpas MD, Evan AP, Parker WR, Alexander KM, Coe FL. Calcium oxalate stone formation in genetic hypercalciuric stone-forming rats. Kidney Int 2002; 61:975-87. [PMID: 11849452 DOI: 10.1046/j.1523-1755.2002.00190.x] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Over 54 generations, we have successfully bred a strain of rats that maximizes urinary calcium excretion. The rats now consistently excrete 8 to 10 times as much calcium as controls, uniformly form poorly crystalline calcium phosphate kidney stones, and are termed genetic hypercalciuric stone-forming (GHS) rats. These rats were used to test the hypothesis that increasing urinary oxalate excretion would not only increase the supersaturation with respect to the calcium oxalate solid phase, but also would increase the ratio of calcium oxalate-to-calcium phosphate supersaturation and result in calcium oxalate stone formation. METHODS To increase urine oxalate excretion an oxalate precursor, hydroxyproline, was added to the diet of male GHS rats. The GHS rats were fed a standard 1.2% calcium diet alone or with 1%, 3% or 5% trans-4-hydroxy-l-proline (hydroxyproline). RESULTS The addition of 1% hydroxyproline to the diet of GHS rats led to an increase in urinary oxalate excretion, which did not increase further with the provision of additional hydroxyproline. The addition of 1% and 3% hydroxyproline did not alter calcium excretion while the provision of 5% hydroxyproline led to a decrease in urine calcium excretion. The addition of 1% hydroxyproline led to an increase in urinary calcium oxalate supersaturation, which did not further increase with additional hydroxyproline. The addition of 1% and 3% hydroxyproline did not alter urinary supersaturation with respect to calcium hydrogen phosphate while the addition of 5% hydroxyproline tended to lower this supersaturation. Compared to rats fed the control and the 3% hydroxyproline diet the addition of 5% hydroxyproline increased the ratio of calcium oxalate supersaturation to calcium phosphate supersaturation. Virtually all rats formed stones. In the control and 1% hydroxyproline group, all of the stones were composed of calcium and phosphate (apatite), in the 3% hydroxyproline group the stones were a mixture of apatite and calcium oxalate, while in the 5% hydroxyproline group all of the stones were calcium oxalate. CONCLUSIONS The provision of additional dietary hydroxyproline to GHS rats increases urinary oxalate excretion, calcium oxalate supersaturation and the ratio of calcium oxalate-to-calcium phosphate supersaturation, resulting in the formation of calcium oxalate kidney stones. Thus, with the addition of a common amino acid, the GHS rats now not only model the most common metabolic abnormality found in patients with nephrolithiasis, hypercalciuria, but form the most common type of kidney stone, calcium oxalate.
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Affiliation(s)
- David A Bushinsky
- Department of Medicine, Nephrology Unit, University of Rochester School of Medicine, Strong Memorial Hospital, 601 Elmwood Avenue, Rochester, NY 14642, USA.
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Tessier J, Petrucci M, Trouvé ML, Valiquette L, Guay G, Ouimet D, Bonnardeaux A. A family-based study of metabolic phenotypes in calcium urolithiasis. Kidney Int 2001; 60:1141-7. [PMID: 11532110 DOI: 10.1046/j.1523-1755.2001.0600031141.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND A family history increases the risk of kidney stone passage independent of dietary risk factors. However, the metabolic basis for familial aggregation of urolithiasis is unknown. METHODS We evaluated metabolic risk factors in families with at least two sibs with a history of calcium stones. Sibs underwent outpatient evaluations simultaneously, including 24-hour urine collection and oral calcium loading. Phenotypes were compared between affected and unaffected sibs from the same sibship. RESULTS Eighty-three sibships comprising 388 sibs (212 affected sibs, 114 males and 98 females, and 176 unaffected sibs, 68 males and 108 females) from 71 families were analyzed. Daily urine calcium excretion was higher in affected compared with unaffected sibs (0.64 +/- 0.33 vs. 0.50 +/- 0.22 mmol Ca(2+)/mmol creatinine, respectively, P < 10(-5)). This corresponded to absolute values of 7.4 +/- 3.9 and 5.1 +/- 2.3 mmol Ca(2+)/day, respectively, for affected and unaffected males, and 5.4 +/- 2.6 and 4.2 +/- 1.9 mmol Ca(2+)/day, respectively, for affected and unaffected female sibs. When analyzed by tertile of onset age of stone passage, the differences in urine calcium were only significant in the first two tertiles (with onset age of stone passage <35 years). The fasting urine Ca(2+)/creatinine ratio was significantly higher in stone formers compared with control sibs (0.46 +/- 0.27 vs. 0.40 +/- 0.27, P = 0.04), as was the postcalcium load Ca(2+)/creatinine ratio (0.57 +/- 0.46 vs. 0.43 +/- 0.41, respectively, P = 0.02). Body mass index was marginally significantly higher in stone forming sibs (P = 0.04). Other urine phenotypes, including oxalate, phosphate, magnesium, citrate, urate, sodium, ammonium, and volume, were not associated with stone passage. CONCLUSION Increased urine calcium excretion is the only phenotype associated with a kidney stone formation in these French-Canadian families.
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Affiliation(s)
- J Tessier
- Centre de Recherche Guy Bernier, Hôpital Maisonneuve-Rosemont, Montréal, Québec, Canada
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Bushinsky DA, Grynpas MD, Asplin JR. Effect of acidosis on urine supersaturation and stone formation in genetic hypercalciuric stone-forming rats. Kidney Int 2001; 59:1415-23. [PMID: 11260403 DOI: 10.1046/j.1523-1755.2001.0590041415.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND We have successively inbred over 45 generations a strain of rats to maximize urine calcium excretion. The rats now consistently excrete 8 to 10 times as much calcium as controls and uniformly form poorly crystalline calcium phosphate kidney stones. In humans with calcium nephrolithiasis, consumption of a diet high in acid precursors is often cited as a risk factor for the development of calcium-based kidney stones; however, the effect of this diet on urinary supersaturation with respect to the common solid phases found in kidney stones has not been determined. METHODS To determine the effect of the addition of an acid precursor on urine ion excretion, supersaturation, and stone formation, we fed these genetic hypercalciuric stone-forming (GHS) rats 13 g/day of a 1.2% calcium diet with 0.0, 0.5, 1.0, or 1.5% NH4Cl in the drinking water for 14 weeks (N = 8 for each). Urine was collected and analyzed every two weeks. RESULTS As expected, the addition of dietary NH4Cl led to a progressive fall in urine pH and urine citrate, while urine ammonium increased. Urine calcium and phosphorus increased, while urine oxalate fell. Increasing dietary NH4Cl led to a fall in supersaturation with respect to CaHPO4 (brushite) and CaOx and a rise in supersaturation with respect to uric acid. In spite of differences in supersaturation, most rats in each group formed stones that contained calcium phosphate and not calcium oxalate. CONCLUSIONS Thus, while the provision of additional dietary acids alters urinary ion excretion and lowers supersaturation with respect to CaHPO4 and CaOx, it does not change the character or rate of stone formation in the GHS rats.
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Affiliation(s)
- D A Bushinsky
- Nephrology Unit, University of Rochester School of Medicine, Rochester, New York 14642, USA.
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Bushinsky DA. Bench to bedside: lessons from the genetic hypercalciuric stone-forming rat. Am J Kidney Dis 2000; 36:LXI-LXIV. [PMID: 10977815 DOI: 10.1053/ajkd.2000.18014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- D A Bushinsky
- University of Rochester Medical Center, Nephrology Unit, Rochester, NY, USA
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