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Haffner D, Emma F, Seefried L, Högler W, Javaid KM, Bockenhauer D, Bacchetta J, Eastwood D, Biosse Duplan M, Schnabel D, Wicart P, Ariceta G, Levtchenko E, Harvengt P, Kirchhoff M, Gardiner O, Di Rocco F, Chaussain C, Brandi ML, Savendahl L, Briot K, Kamenický P, Rejnmark L, Linglart A. Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia. Nat Rev Nephrol 2025; 21:330-354. [PMID: 39814982 DOI: 10.1038/s41581-024-00926-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/12/2024] [Indexed: 01/18/2025]
Abstract
X-linked hypophosphataemia (XLH) is a rare metabolic bone disorder caused by pathogenic variants in the PHEX gene, which is predominantly expressed in osteoblasts, osteocytes and odontoblasts. XLH is characterized by increased synthesis of the bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23), which results in renal phosphate wasting with consecutive hypophosphataemia, rickets, osteomalacia, disproportionate short stature, oral manifestations, pseudofractures, craniosynostosis, enthesopathies and osteoarthritis. Patients with XLH should be provided with multidisciplinary care organized by a metabolic bone expert. Historically, these patients were treated with frequent doses of oral phosphate supplements and active vitamin D, which was of limited efficiency and associated with adverse effects. However, the management of XLH has evolved in the past few years owing to the availability of burosumab, a fully humanized monoclonal antibody that neutralizes circulating FGF23. Here, we provide updated clinical practice recommendations for the diagnosis and management of XLH to improve outcomes and quality of life in these patients.
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Affiliation(s)
- Dieter Haffner
- Department of Paediatric Kidney, Liver, Metabolic and Neurological Diseases, Hannover Medical, School, Hannover, Germany.
- Center for Congenital Kidney Diseases, Center for Rare Diseases, Hannover Medical School, Hannover, Germany.
| | - Francesco Emma
- Division of Nephrology, Children's Hospital Bambino Gesù, IRCCs, Rome, Italy
| | - Lothar Seefried
- Clinical Trial Unit, Orthopedic Institute, Koenig-Ludwig-Haus, University of Würzburg, Würzburg, Germany
| | - Wolfgang Högler
- Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria
| | - Kassim M Javaid
- Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, UK
| | - Detlef Bockenhauer
- University College London, Department of Renal Medicine and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
- Department of Paediatric Nephrology, University Hospitals Leuven, Katholic University of Leuven, Leuven, Belgium
| | - Justine Bacchetta
- Paediatric Nephrology Rheumatology and Dermatology Unit, Hospices Civils de Lyon, INSERM1033 Research Unit, Lyon, France
| | - Deborah Eastwood
- Department of Orthopaedics, Great Ormond Street Hospital for Children, London, UK
- The Catterall Unit, Royal National Orthopaedic Hospital NHS Trust, Stanmore, UK
| | - Martin Biosse Duplan
- Université Paris Cité, Dental School, Montrouge, France
- APHP, Department of Odontology, Bretonneau Hospital, Paris, France
- APHP, Reference Center for Rare Diseases of Calcium and Phosphate Metabolism, and Filière OSCAR, endo ERN and ERN BOND, Paris, France
| | - Dirk Schnabel
- Center for Chronic Sick Children, Paediatric Endocrinology, Charité-University Medicine, Berlin, Germany
| | - Philippe Wicart
- APHP, Reference Center for Rare Diseases of Calcium and Phosphate Metabolism, and Filière OSCAR, endo ERN and ERN BOND, Paris, France
- APHP, Department of Paediatric Orthopedic Surgery, Necker - Enfants Malades University Hospital, Paris, France
- Université Paris Cité, Paris, France
| | - Gema Ariceta
- Department of Paediatric Nephrology, University Hospital Vall d'Hebron, Autonomous University of Barcelona, Barcelona, Spain
| | | | - Pol Harvengt
- International XLH Alliance, London, United Kingdom
| | - Martha Kirchhoff
- Phosphatdiabetes e.V., German Patient Association for XLH, Lippstadt, Germany
| | | | - Federico Di Rocco
- Paediatric Neurosurgery, Hôpital Femme Mère Enfant, Centre de Référence Craniosténoses, Université de Lyon, INSERM 1033, Lyon, France
| | - Catherine Chaussain
- Université Paris Cité, Dental School, Montrouge, France
- APHP, Department of Odontology, Bretonneau Hospital, Paris, France
- APHP, Reference Center for Rare Diseases of Calcium and Phosphate Metabolism, and Filière OSCAR, endo ERN and ERN BOND, Paris, France
| | | | - Lars Savendahl
- Paediatric Endocrinology Unit, Karolinska University Hospital, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Karine Briot
- APHP, Reference Center for Rare Diseases of Calcium and Phosphate Metabolism, and Filière OSCAR, endo ERN and ERN BOND, Paris, France
- Université Paris Cité, Paris, France
- APHP, Department of Rheumatology, Cochin Hospital, Paris, France
- INSERM UMR-1153, Paris, France
| | - Peter Kamenický
- APHP, Reference Center for Rare Diseases of Calcium and Phosphate Metabolism, and Filière OSCAR, endo ERN and ERN BOND, Paris, France
- Université Paris Saclay, Inserm, AP-HP, Physiologie et Physiopathologie Endocriniennes, Service d'Endocrinologie et des Maladies de la Reproduction, Hôpital Bicêtre Paris Saclay, Le Kremlin Bicêtre, France
| | - Lars Rejnmark
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Agnès Linglart
- APHP, Reference Center for Rare Diseases of Calcium and Phosphate Metabolism, and Filière OSCAR, endo ERN and ERN BOND, Paris, France
- Université Paris Saclay, Inserm, AP-HP, Physiologie et Physiopathologie Endocriniennes, Service Endocrinologie et diabète de l'enfant, Hôpital Bicêtre Paris Saclay, Le Kremlin-Bicêtre, France
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Cabezas L, Letourneau P, De Mul A, Bacchetta J, Chardon L, Derain Dubourg L, Lemoine S. Improving the diagnostic of absorptive hypercalciuria: a comparative analysis of calcium load tests at 2-hour and 4-hour intervals. Clin Kidney J 2025; 18:sfae399. [PMID: 39917537 PMCID: PMC11799772 DOI: 10.1093/ckj/sfae399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Indexed: 02/09/2025] Open
Abstract
Introduction The calcium load test (CLT) was developed by Pak et al. in 1974 to better discriminate hypercalciuria. Absorptive hypercalciuria (AH) is defined by an increase of the difference between urinary calcium/creatinine ratio (ΔUCa/Cr) of more than 0.5 mmol/mmol with a 4-hour CLT. In clinical practice and more recent studies, CLT is a 2-hour test. We hypothesized that the 4 h timepoint is more efficient in AH diagnosis. Methods We report a single-centre retrospective study including all patients who underwent CLT because of hypercalciuria or hyperparathyroidism. After a 3-day low-calcium diet and a 12-hour fast, 24-hour urines were collected. Blood and urinary samples were done at arrival and after 2 h and 4 h of oral ingestion of 1 g of calcium. AH was diagnosed by ΔUCa/Cr between baseline and 2 h or 4 h of more than 0.05 mmol/mmol. Results We included 328 patients. Baseline UCa/Cr ratio was 0.3 ± 0.2 mmol/mmol and increased significantly after 2 h and 4 h (0.6 ± 0.3 and 0.8 ± 0.4 mmol/mmol, P < 0.001). ΔUCa/Cr was significantly different between baseline and 2 h or 4 h (0.2 ± 0.2 versus 0.5 ± 0.4, P < 0.001). AH was diagnosed in 35 (10.7%) patients after 2 h, 84 (25.6%) more were diagnosed at 4 h (P < 0.001). Conclusions The 4 h CLT improves the diagnosis of AH with more than 50% of AH diagnosed within 4 h of calcium ingestion. It seems that there are cases of AH of later diagnosis with a similar clinical and biological profile depending on enteral absorption.
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Affiliation(s)
- Lara Cabezas
- Service de Néphrologie, HTA, dialyse et explorations fonctionnelles rénales, Hopital Edouard Herriot, Hospices civils de Lyon, Lyon, France
- Nephrology, Hemodialysis, Apheresis and Kidney Transplantation Department, University Hospital Grenoble, Grenoble, France
| | - Pierre Letourneau
- Service de Néphrologie, HTA, dialyse et explorations fonctionnelles rénales, Hopital Edouard Herriot, Hospices civils de Lyon, Lyon, France
| | - Aurélie De Mul
- Service de Néphrologie, HTA, dialyse et explorations fonctionnelles rénales, Hopital Edouard Herriot, Hospices civils de Lyon, Lyon, France
- INSERM 1060-CARMEN, Université de Lyon, Université Lyon 1, Lyon, France
| | - Justine Bacchetta
- Centre de Référence des Maladies Rénales Rares, Centre de Référence des Maladies Rares du Calcium et du Phosphore, HFME, Bron, France
| | - Laurence Chardon
- Hospices civils de Lyon, Groupement hospitalier Est, Service de biochimie, Lyon, France
| | - Laurence Derain Dubourg
- Service de Néphrologie, HTA, dialyse et explorations fonctionnelles rénales, Hopital Edouard Herriot, Hospices civils de Lyon, Lyon, France
- Centre de Référence des Maladies Rénales Rares, Centre de Référence des Maladies Rares du Calcium et du Phosphore, HFME, Bron, France
| | - Sandrine Lemoine
- Service de Néphrologie, HTA, dialyse et explorations fonctionnelles rénales, Hopital Edouard Herriot, Hospices civils de Lyon, Lyon, France
- INSERM 1060-CARMEN, Université de Lyon, Université Lyon 1, Lyon, France
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Bisikirska B, Labella R, Cuesta-Dominguez A, Luo N, De Angelis J, Mosialou I, Lin CS, Beck D, Lata S, Shyu PT, McMahon DJ, Guo E, Hagen J, Chung WK, Shane E, Cohen A, Kousteni S. Melatonin receptor 1A variants as genetic cause of idiopathic osteoporosis. Sci Transl Med 2024; 16:eadj0085. [PMID: 39413162 DOI: 10.1126/scitranslmed.adj0085] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 03/19/2024] [Accepted: 09/23/2024] [Indexed: 10/18/2024]
Abstract
Idiopathic osteoporosis (IOP) is a rare form of early-onset osteoporosis diagnosed in patients with no known metabolic or hormonal cause of bone loss and unknown pathogenesis. Patients with IOP commonly report both childhood fractures and family history of osteoporosis, raising the possibility of genetic etiologies of IOP. Whole-exome sequencing analyses of different IOP cohorts identified multiple variants in melatonin receptor 1A (MTNR1A) with a potential pathogenic outcome. A rare MTNR1A variant (rs374152717) was found in members of an Ashkenazi Jewish family with IOP, and an MTNR1A variant (rs28383653) was found in a nonrelated female IOP cohort (4%). Both variants occur at a substantially higher frequency in Ashkenazi Jewish individuals than in the general population. We investigated consequences of the heterozygous (rs374152717) variant [MTNR1Ac.184+1G>T (MTNR1Ac.184+1G>T)] on bone physiology. A mouse model of the human rs374152717 variant reproduced the low bone mass (BM) phenotype of young-adult patients with IOP. Low BM occurred because of induction of senescence in mutant osteoblasts followed by compromised differentiation and function. In human cells, introduction of rs374152717 led to translation of a nonfunctional protein and subsequent dysregulation of melatonin signaling. These studies provide evidence that MTNR1A mutations entail a genetic etiology of IOP and establish the rs374152717 variant as a loss-of-function allele that impairs bone turnover by inducing senescence in osteoblasts. The higher prevalence of the MTNR1A variants identified in IOP cohorts versus the general population indicates a greater risk of IOP in those carrying these variants, especially Ashkenazi Jewish individuals bearing the rs374152717 variant.
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Affiliation(s)
- Brygida Bisikirska
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA
| | - Rossella Labella
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA
| | - Alvaro Cuesta-Dominguez
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA
| | - Na Luo
- Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA
| | - Jessica De Angelis
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA
| | - Ioanna Mosialou
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA
| | - Chyuan-Sheng Lin
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA
| | - David Beck
- New York University Grossman School of Medicine, New York, NY 10012, USA
| | - Sneh Lata
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Peter Timothy Shyu
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Donald J McMahon
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Edward Guo
- Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA
| | - Jacob Hagen
- Department of Pediatrics and Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Wendy K Chung
- Department of Pediatrics and Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Elizabeth Shane
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Adi Cohen
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA
| | - Stavroula Kousteni
- Department of Physiology and Cellular Biophysics, Columbia University Medical Center, New York, NY 10032, USA
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García Pascual L, Simó-Servat A, Puig-Jové C, García-González L. Normocalcemic hyperparathyroidism after successful parathyroidectomy for single parathyroid adenoma: Prevalence, etiological factors, predictive markers, treatment and evolution. ENDOCRINOL DIAB NUTR 2023; 70:640-648. [PMID: 38000970 DOI: 10.1016/j.endien.2023.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Accepted: 09/14/2023] [Indexed: 11/26/2023]
Abstract
BACKGROUND AND OBJECTIVE Postparathyroidectomy normocalcemic hyperparathyroidism (PPNCHPPT) is a frequent situation for which we have no information in our country. The objective is to know our prevalence of PPNCHPPT, the associated etiological factors, the predictive markers, the treatment administered and the evolution. PATIENTS AND METHOD Retrospective observational cross-sectional study on 42 patients. Twelve patients with PPNCHPPT and 30 without PPNCHPPT are compared. RESULTS HPPTNCPP prevalence: 28.6%. Etiological factors: vitamin D deficiency: 75%; bone remineralization: 16.7%; renal failure: 16.7%; hypercalciruria: 8.3%. No change in the set point of calcium-mediated parathormone (PTH) secretion was observed, but an increase in the preoperative PTH/albumin-corrected calcium (ACC) ratio was observed. Predictive markers: PTH/ACC ratio (AUC 0.947; sensitivity 100%, specificity 78.9%) and PTH (AUC 0.914; sensitivity 100%, specificity 73.7%) one week postparathyroidectomy. EVOLUTION follow-up 30 ± 16.3 months: 50% normalized PTH and 8.3% had recurrence of hyperparathyroidism. Patients with PPNCHPPT less frequently received preoperative treatment with bisphosphonates and postoperative treatment with calcium salts. CONCLUSIONS This is the first study in our country that demonstrates a mean prevalence of PPNCHPPT, mainly related to a vitamin D deficiency and a probable resistance to the action of PTH, which can be predicted by the PTH/ACC ratio and PTH a week post-intervention and often evolves normalizing the PTH. We disagree with the etiological effect of hypercalciuria and the change in the PTH/calcemia regulation set point, and we acknowledge the scant treatment administered with calcium salts in the postoperative period.
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Affiliation(s)
- Luis García Pascual
- Servei d'Endocrinologia, Hospital Universitari Mútua de Terrasa, Terrassa, Spain.
| | - Andreu Simó-Servat
- Servei d'Endocrinologia, Hospital Universitari Mútua de Terrasa, Terrassa, Spain
| | - Carlos Puig-Jové
- Servei d'Endocrinologia, Hospital Universitari Mútua de Terrasa, Terrassa, Spain
| | - Lluís García-González
- Servei de Cirurgia General i Aparell Digestiu, Hospital Universitari Arnau de Vilanova, Lleida, Spain
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TOPUZ E, TÜZÜN D, ÖZBAY ÜN, ŞAHİN M, KARA İ. A case of normocalcemic primary hyperparathyroidism presenting with a mass in the oral cavity and accompanying incidental papillary thyroid carcinoma. CUKUROVA MEDICAL JOURNAL 2022. [DOI: 10.17826/cumj.1184876] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Hyperparathyroidism (HPT) is an endocrine disorder characterized by high secretion of parathyroid hormone. Brown tumor is one of the skeletal manifestations of HPT. Its overall prevalence is low (about 0.1%). Involvement of facial bones is extremely rare. The mandible is involved in 4.5% of cases. Primary HPT (PHPT)with vitamin D deficiency worsens the clinical course. Parathyroid adenoma is detected in ectopic places with a rate of 8.5%. 0.2% is intrathyroidal, 2% is located in different neck regions, 4.1% is in the upper mediastinum, and 2.2% is in the lower mediastinum. The prevalence of papillary thyroid cancer (PTC) in PHPT patients has been reported to range from 2% to 15%. In the literature, incidentally detected papillary thyroid cancer in patients with hyperparathyroidism was detected in patients who underwent total thyroidectomy associated with intrathyroidal parathyroid adenoma.
In this article, we present a case of incidental papillary thyroid carcinoma with ectopic parathyroid adenoma accompanied by severe vitamin D, and diagnosed during accompanying surgery following a brown tumor was considered after primary hyperparathyroidism was detected. However, the patient was admitted with a mass in the oral cavity, diagnosed before as a pyogenic granuloma with a delayed diagnosis without considering brown tumor because it was normocalcemic. It is the first case in the literature of papillary thyroid carcinoma detected incidentally with ectopic parathyroid adenoma in the thyrothymic region.
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Affiliation(s)
- Emek TOPUZ
- Kahramanmaraş Sütçü İmam Tıp Fakültesi Endokrinoloji ve Metabolizma B.D
| | - Dilek TÜZÜN
- Kahramanmaraş Sütçü İmam Tıp Fakültesi Endokrinoloji ve Metabolizma B.D
| | - Ümit Nur ÖZBAY
- Kahramanmaraş Sütçü İmam Tıp Fakültesi Endokrinoloji ve Metabolizma B.D
| | - Murat ŞAHİN
- Kahramanmaraş Sütçü İmam Tıp Fakültesi Endokrinoloji ve Metabolizma B.D
| | - İrfan KARA
- Kahramanmaraş Sütçü İmam Tıp Fakültesi Kulak Burun Boğaz A.B.D
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Bal SK, Sorensen MJ, Crawford AR. A Diagnosis of Normocalcemic Primary Hyperparathyroidism Prompted by “Salt and Pepper” Lesions of the Calvarium. AACE Clin Case Rep 2022; 8:37-40. [PMID: 35097201 PMCID: PMC8784707 DOI: 10.1016/j.aace.2021.07.004] [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: 02/04/2021] [Revised: 05/04/2021] [Accepted: 07/26/2021] [Indexed: 11/25/2022] Open
Abstract
Background We report a case of normocalcemic primary hyperparathyroidism, a diagnosis prompted by radiographic “salt and pepper” calvarial lesions, typically described in hypercalcemic primary hyperparathyroidism or secondary hyperparathyroidism. Case Report A 60-year-old woman noticed indentations of her scalp and presented to her primary care provider. Radiography of the calvarium demonstrated granular “salt and pepper” lesions, prompting investigation. The patient was found to have an elevated parathyroid hormone (PTH) level of 79 pg/mL (reference range, 14-54 pg/mL) and a normal albumin-corrected calcium level of 9.8 mg/dL (reference range, 8.6-10.4 mg/dL). She was referred to our endocrine clinic and described having bone aches, fevers, leg cramps, and a remote history of nephrolithiasis. Her physical examination revealed hypertension. Repeat laboratory evaluation confirmed elevated PTH and normal albumin-corrected calcium. Secondary causes of hyperparathyroidism were ruled out. Her 25-hydroxyvitamin D level was 35 ng/mL (reference range, 30-100 ng/mL), with a normal creatinine level (0.73 mg/dL; reference range, 0.5-0.99 mg/dL). The patient underwent ultrasound and sestamibi scintigraphy, with uptake in the right inferior thyroid pole. She was found to have a 6-mm parathyroid adenoma and underwent a targeted parathyroidectomy, with normalization of serum PTH. Discussion Many cases of normocalcemic primary hyperparathyroidism are diagnosed in asymptomatic patients presenting with low bone mass; however, imaging prompted this patient's evaluation. Ultimately, the calvarial lesions were thought secondary to bone resorption from increased osteoclast activity. Conclusion This case highlights an atypical presentation of normocalcemic primary hyperparathyroidism in that the evaluation was precipitated by unexpected radiographic evidence of metabolic bone disease, rather than by symptoms or biochemical studies.
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Haffner D, Leifheit-Nestler M, Grund A, Schnabel D. Rickets guidance: part I-diagnostic workup. Pediatr Nephrol 2022; 37:2013-2036. [PMID: 34910242 PMCID: PMC9307538 DOI: 10.1007/s00467-021-05328-w] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 09/30/2021] [Accepted: 10/01/2021] [Indexed: 01/22/2023]
Abstract
Rickets is a disease of the growing child arising from alterations in calcium and phosphate homeostasis resulting in impaired apoptosis of hypertrophic chondrocytes in the growth plate. Its symptoms depend on the patients' age, duration of disease, and underlying disorder. Common features include thickened wrists and ankles due to widened metaphyses, growth failure, bone pain, muscle weakness, waddling gait, and leg bowing. Affected infants often show delayed closure of the fontanelles, frontal bossing, and craniotabes. The diagnosis of rickets is based on the presence of these typical clinical symptoms and radiological findings on X-rays of the wrist or knee, showing metaphyseal fraying and widening of growth plates, in conjunction with elevated serum levels of alkaline phosphatase. Nutritional rickets due to vitamin D deficiency and/or dietary calcium deficiency is the most common cause of rickets. Currently, more than 20 acquired or hereditary causes of rickets are known. The latter are due to mutations in genes involved in vitamin D metabolism or action, renal phosphate reabsorption, or synthesis, or degradation of the phosphaturic hormone fibroblast growth factor 23 (FGF23). There is a substantial overlap in the clinical features between the various entities, requiring a thorough workup using biochemical analyses and, if necessary, genetic tests. Part I of this review focuses on the etiology, pathophysiology and clinical findings of rickets followed by the presentation of a diagnostic approach for correct diagnosis. Part II focuses on the management of rickets, including new therapeutic approaches based on recent clinical practice guidelines.
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Affiliation(s)
- Dieter Haffner
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany. .,Hannover Medical School, Pediatric Research Center, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
| | - Maren Leifheit-Nestler
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany ,Hannover Medical School, Pediatric Research Center, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Andrea Grund
- Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany ,Hannover Medical School, Pediatric Research Center, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
| | - Dirk Schnabel
- Center for Chronically Sick Children, Pediatric Endocrinology, University Medicine, Charitè Berlin, Germany
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8
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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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Abstract
After the initial description of extrarenal synthesis of 1,25-dihydroxyvitamin D (1,25-(OH)2D) three decades ago, extensive progress has been made in unraveling the immunomodulatory roles of vitamin D in the pathogenesis of granulomatous disorders, including sarcoidosis. It has been shown that 1,25-(OH)2D has dual effects on the immune system, including upregulating innate immunity as well as downregulating the autoimmune response. The latter mechanism plays an important role in the pathogenesis and treatment of sarcoidosis. Vitamin D supplementation in patients with sarcoidosis has been hampered owing to concerns about the development of hypercalcemia and hypercalciuria given that extrarenal 1-α hydroxylase is substrate dependent. Recently, a few studies have cast doubt over the mechanisms underlying the development of hypercalcemia in this population. These studies demonstrated an inverse relationship between the level of vitamin D and severity of sarcoidosis. Consequently, clinical interest has been piqued in the use of vitamin D to attenuate the autoimmune response in this disorder. However, the development of hypercalcemia and the attendant detrimental effects are real possibilities. Although the average serum calcium concentration did not change following vitamin D supplementation, in two recent studies, hypercalciuria occurred in one out of 13 and two out of 16 patients. This review is a concise summary of the literature, outlining past work and newer developments in the use of vitamin D in sarcoidosis. We feel that larger-scale placebo-controlled randomized studies are needed in this population. Since the current first-line treatment of sarcoidosis is glucocorticoids, which confer many systemic adverse effects, and steroid-sparing immunosuppressant treatment options carry additional risks of adverse effects, adjunct management with vitamin D in combination with potent anti-osteoporotic medications could minimize the risk of glucocorticoid-induced osteoporosis and modulate the immune system to attenuate disease activity in sarcoidosis.
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Affiliation(s)
- Fabiola Gianella
- Pulmonary and Critical Care Medicine Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Connie CW Hsia
- Pulmonary and Critical Care Medicine Division, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Khashayar Sakhaee
- Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, 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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The interest of oral calcium loads test in the diagnosis and management of pediatric nephrolithiasis with hypercalciuria: Experience from a tertiary pediatric centre. J Pediatr Urol 2020; 16:489.e1-489.e9. [PMID: 32593617 DOI: 10.1016/j.jpurol.2020.05.160] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 04/30/2020] [Accepted: 05/22/2020] [Indexed: 11/20/2022]
Abstract
INTRODUCTION The use of calcium load has been forgotten in pediatrics until recently whereas it is of utmost importance to have a practical approach to guide management of hypercalciuric nephrolithiasis. OBJECTIVE The purpose of this study was to evaluate the practical interest of oral calcium loads to improve the overall management of nephrolithiasis in children. METHODS We retrospectively studied all pediatric patients having undergone an oral calcium load in our pediatric nephrology unit between September 2015 and April 2017. RESULTS A total of 16 patients were included, at a median age of 12.0 (5.5-17.5) years. The indications of oral calcium load were: presence of an active urolithiasis without any obvious explanation after ruling out the "classical" biological abnormalities, or presence of hypercalciuria with stones composed of weddellite or carbapatite crystals. Among the 16 patients, 6 (38%) patients displayed absorptive hypercalciuria, 2 (12%) renal leak, 3 (19%) "unclassified" inadapted PTH, and 5 (31%) a normal calcium load test. The result of oral calcium load modified the clinical management in 14 (88%) patients, mainly based on the type of hypercalciuria. It allowed us to individualize nutritional advice: in patients with absorptive hypercalciuria, we proposed calcium intake within the lower normal range for age with dairy products not enriched with vitamin D, with the advice to avoid salt and calcium loads during evenings. Conversely, in patients with resorptive hypercalciuria, we proposed normal calcium intake for age. Showing the results of the calcium load is meaningful to patients and parents, and can be considered as an "educational" tool. DISCUSSION To the best of our knowledge, this study is the first to evaluate the interest of calcium load in children with nephrolithiasis in an era of routine PTH and 1-25-D assessment. Here, we demonstrate the feasibility and safety of oral calcium load in children, its interest to understand the underlying mechanisms of hypercalciuria, and its major interest as an "educational tool" for patients to explain them the underlying mechanisms and thus guide the therapeutic management using an individualized dietary approach. This study did not include many patients, but to the best of our knowledge, this is the first study evaluating and validating the feasibility of a safe and non-expensive diagnosis tool in pediatric hypercalciuria. CONCLUSION Oral calcium load is helpful to guide therapeutic adaptation in pediatrics using an individualized dietary approach.
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Irzyniec T, Boryń M, Kasztalska J, Nowak-Kapusta Z, Maciejewska-Paszek I, Grochowska-Niedworok E. The effect of an oral sodium phosphate load on parathyroid hormone and fibroblast growth factor 23 secretion in normo- and hypercalciuric stone-forming patients. Clin Nutr 2020; 39:3804-3812. [PMID: 32386861 DOI: 10.1016/j.clnu.2020.04.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2020] [Revised: 04/13/2020] [Accepted: 04/15/2020] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS Abnormalities of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) secretion may cause calcium-phosphate (Ca-P) metabolism disorders in nephrolithiasis. Post-phosphate-load alterations in serum Ca, P and PTH, phosphaturia and calciuria enable monitoring hormonal regulation of Ca-P homeostasis. Our study aimed to determine differences in: 1.selected Ca-P metabolism parameters between healthy and kidney-stone-forming individuals, 2.PTH and FGF23 secretion induced by sodium-phosphate-load(NaP-load) in patients with/without hypercalciuria, 3.secretion of Ca-P related hormones in patients with low and normal/high serum concentrations of 25-hydroxyvitamin D3 (25OHD3). METHODS Sodium phosphates NaH2PO4/Na2HPO4-100mmol were administered orally for five days in 19 hypercalciuric [urinary Ca(U-Ca) 6.5 ± 1.7 mmol/d]-HSF, 35 normocalciuric (2.5±1 mmol/d)-NSF stone-forming patients and 19 controls (U-Ca 2.5 ± 1.4 mmol/d)-CG. On days 1 and 5 PTH-,FGF23-,Ca-,P were determined before and after NaP-load. The areas under PTH, FGF23 curves (AUC) were calculated. U-Ca, urinary phosphate (U-P) and sodium (U-Na) were also determined. RESULTS Following NaP-load, patients and controls exhibited expected alterations in Ca-P homeostasis. Despite changes in phosphate and PTH, no differences in FGF23 concentrations were observed. Patients differed from controls in having higher AUCPTH, calciuria and natriuresis, taking longer for PTH and P to normalize and lack of correlation between AUCPTH and phosphaturia. Post-NaP-load hypocalciuric effect of PTH secretion in NSF was less pronounced than in CG. In the HSFs, the hypocalciuric effect was more pronounced than in NSFs, but insufficient to correct hypercalciuria. In all stone-formers with low 25OHD3 concentrations, the AUCFGF23 was significantly increased on first (1215 ± 605vs766 ± 315 p = 0.0457) and fifth days (1211 ± 641vs777 ± 299 p = 0.041) of NaP-load, compared to normal/high 25OHD3-patients. Hypercalciuric patients with low 25OHD3 concentrations had greater AUCPTH5 than those with normal/high 25OHD3 (1005 ± 401vs835 ± 220 p = 0.0341). CONCLUSIONS Compared to controls, kidney-stone-forming patients exhibited enhanced PTH secretion after NaP-load. The HSFs showed a more pronounced hypocalciuric effect than NSFs, but insufficient to correct hypercalciuria. In hypercalciuric stone-formers with low 25OHD3, FGF23 engagement in hyperphosphatemia reduction increased.
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Affiliation(s)
- Tomasz Irzyniec
- Department of Nephrology/ENDO, Hospital of the Ministry of the Interior and Administration, Ul. Głowackiego 10, 40-052, Katowice, Poland; Department of Health Promotion and Community Nursing, Faculty of Health Sciences, Medical University of Silesia, Ul. Medyków 12, 40-752, Katowice, Poland.
| | - Monika Boryń
- Department of Nephrology/ENDO, Hospital of the Ministry of the Interior and Administration, Ul. Głowackiego 10, 40-052, Katowice, Poland.
| | - Joanna Kasztalska
- Department of Nephrology/ENDO, Hospital of the Ministry of the Interior and Administration, Ul. Głowackiego 10, 40-052, Katowice, Poland.
| | - Zofia Nowak-Kapusta
- Department of Health Promotion and Community Nursing, Faculty of Health Sciences, Medical University of Silesia, Ul. Medyków 12, 40-752, Katowice, Poland.
| | - Izabela Maciejewska-Paszek
- Department of Health Promotion and Community Nursing, Faculty of Health Sciences, Medical University of Silesia, Ul. Medyków 12, 40-752, Katowice, Poland.
| | - Elżbieta Grochowska-Niedworok
- Department of Dietetics, School of Public Health in Bytom, Medical University of Silesia, Ul. Piekarska 19, 41-902, Bytom, Poland.
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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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A randomised controlled trial comparing the efficacy of micellised and fat-soluble vitamin D3 supplementation in healthy adults. Br J Nutr 2019; 121:859-865. [PMID: 30898175 DOI: 10.1017/s0007114518003215] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Nanoemulsion formulation of vitamin D3 have been shown to have better bioavailability than the coarse emulsion preparation in vitro and in vivo animal studies. In the absence of randomised trial in humans, comparing the efficacy of nanotechnology-based miscellised vitamin D3 over conventional vitamin D3, we undertook this study. A total of 180 healthy adults were randomised to receive either micellised (DePura, group A) or conventional vitamin D3 (Calcirol, group B) at a monthly dose of 60 000 IU (1500μg) for 6 months. The outcome parameters were serum 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH), Ca, phosphate, alkaline phosphatase and urinary Ca:creatinine ratio. A total of eighty-nine subjects in group A and seventy-seven in group B completed the trial. Subjects in both the groups had a significant increase in their serum 25(OH)D levels following supplementation (group A: 21·5 (sd 10·9) to 76·7 (sd 18·8) nmol/l (P<0·001); group B: 22·8 (sd 10·4) to 57·8 (sd 16·0) nmol/l (P<0·001)). Participants in micellised group had an additional increase of 20·2 (95 % CI 14·0, 26·4) nmol/l in serum 25(OH)D levels (P<0·001). The difference between the groups was 17·5 (95 % CI 11·8, 23·1) nmol/l, which remained statistically significant (P<0·001) even after adjustment for age and sex. Significant decline in mean serum PTH was observed in both the groups. No hypercalcaemia or hypercalciuria was noted. Although supplementation with both the preparations resulted in a significant rise in serum 25(OH)D levels, micellised vitamin D3 appeared to be more efficacious in achieving higher levels of serum 25(OH)D.
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Martin CT, Niewoehner CB, Burmeister LA. Significant Loss of Areal Bone Mineral Density Following Prolonged Bed Rest During Treatment With Teriparatide. J Endocr Soc 2017; 1:609-614. [PMID: 29264514 PMCID: PMC5686584 DOI: 10.1210/js.2017-00049] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2017] [Accepted: 04/19/2017] [Indexed: 11/19/2022] Open
Abstract
We present of a case of severe osteoporosis with thoracic myelopathy secondary to nontraumatic T8 compression fracture managed nonsurgically with 3.5 months of bed rest. Despite treatment with teriparatide starting at initial presentation, 1-year follow-up dual energy x-ray absorptiometry scan revealed a significantly greater than expected 19% reduction in lumbar spine bone mineral density (BMD) and a 6% reduction in total hip density. Daily alcohol consumption, severe osteoporosis at baseline, and immobilization secondary to transient myelopathy treated with strict bed rest all likely contributed to unexpected BMD findings.
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Affiliation(s)
- Christopher T. Martin
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455
| | - Catherine B. Niewoehner
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455
| | - Lynn A. Burmeister
- Department of Medicine, Division of Diabetes, Endocrinology and Metabolism, University of Minnesota Twin Cities, Minneapolis, Minnesota 55455
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Vezzoli G, Macrina L, Rubinacci A, Spotti D, Arcidiacono T. Intestinal Calcium Absorption among Hypercalciuric Patients with or without Calcium Kidney Stones. Clin J Am Soc Nephrol 2016; 11:1450-1455. [PMID: 27284011 PMCID: PMC4974885 DOI: 10.2215/cjn.10360915] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2015] [Accepted: 04/06/2016] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND OBJECTIVES Idiopathic hypercalciuria is a frequent defect in calcium kidney stone formers that is associated with high intestinal calcium absorption and osteopenia. Characteristics distinguishing hypercalciuric stone formers from hypercalciuric patients without kidney stone history (HNSFs) are unknown and were explored in our study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We compared 172 hypercalciuric stone formers with 36 HNSFs retrospectively selected from patients referred to outpatient clinics of the San Raffaele Hospital in Milan from 1998 to 2003. Calcium metabolism and lumbar bone mineral density were analyzed in these patients. A strontium oral load test was performed: strontium was measured in 240-minute urine and serum 30, 60, and 240 minutes after strontium ingestion; serum strontium concentration-time curve and renal strontium clearance were evaluated to estimate absorption and excretion of divalent cations. RESULTS Serum strontium concentration-time curve (P<0.001) and strontium clearance (4.9±1.3 versus 3.5±2.7 ml/min; P<0.001) were higher in hypercalciuric stone formers than HNSFs, respectively. The serum strontium-time curve was also higher in hypercalciuric stone formers with low bone mineral density (n=42) than in hypercalciuric stone formers with normal bone mineral density (n=130; P=0.03) and HNSFs with low (n=22; P=0.01) or normal bone mineral density (n=14; P=0.02). Strontium clearance was greater in hypercalciuric stone formers with normal bone mineral density (5.3±3.4 ml/min) than in hypercalciuric stone formers and HNSFs with low bone mineral density (3.6±2.5 and 3.1±2.5 ml/min, respectively; P=0.03). Multivariate regression analyses displayed that strontium absorption at 30 minutes was positively associated calcium excretion (P=0.03) and negatively associated with lumbar bone mineral density z score (P=0.001) in hypercalciuric stone formers; furthermore, hypercalciuric patients in the highest quartile of strontium absorption had increased stone production risk (odds ratio, 5.06; 95% confidence interval, 1.2 to 20.9; P=0.03). CONCLUSIONS High calcium absorption in duodenum and jejunum may expose hypercalciuric patients to the risk of stones because of increased postprandial calcium concentrations in urine and tubular fluid. High calcium absorption may identify patients at risk of bone loss among stone formers.
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Affiliation(s)
- Giuseppe Vezzoli
- Nephrology and Dialysis Unit, San Raffaele Scientific Institute and Postgraduate School of Nephrology, Vita Salute University, Milan, Italy; and
| | - Lorenza Macrina
- Nephrology and Dialysis Unit, San Raffaele Scientific Institute and Postgraduate School of Nephrology, Vita Salute University, Milan, Italy; and
| | | | - Donatella Spotti
- Nephrology and Dialysis Unit, San Raffaele Scientific Institute and Postgraduate School of Nephrology, Vita Salute University, Milan, Italy; and
| | - Teresa Arcidiacono
- Nephrology and Dialysis Unit, San Raffaele Scientific Institute and Postgraduate School of Nephrology, Vita Salute University, Milan, Italy; and
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Urinary calcium excretion in postmenopausal African American women. Clin Nephrol 2016; 84:130-7. [PMID: 26226948 PMCID: PMC4928031 DOI: 10.5414/cn108548] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/18/2015] [Indexed: 11/30/2022] Open
Abstract
Aim: The objective of this study was to develop a reference range for urine calcium excretion (both 24-hour and fasting) for African American women compared to White women. In addition, the variables that determine urine calcium excretion were identified. Material: Data were analyzed for baseline studies of healthy postmenopausal volunteers who participated in seven separate studies conducted at one site. Methods: Some studies included fasting urine Ca/Cr and others 24-hour urine calcium excretion. 24-hour urine calcium was considered with and without correction for urinary creatinine excretion. Calcium was measured initially by atomic absorption spectrophotometry and more recently by an automated method (ADVIA 2400 Chemistry System). Results: Participants were considered healthy based on history and physical and routine laboratory studies. Those screened who had a history of nephrolithiasis were excluded. A reference range for 24-hour urine calcium and fasting urine calcium/creatinine was developed. Reference intervals of 11 – 197 mg/24-hour urine calcium excretion and of 0.007 – 0.222 of fasting Ca/Cr were found for African American women compared to 21 – 221 mg/24 hours and 0.019 – 0.264 in White women, respectively. Urine creatinine excretion was higher in African Americans consistent with their higher muscle mass. Conclusion: Urine calcium excretion is lower in postmenopausal African American than White women. The reference range developed should be considered in the diagnosis of hypocalciuric states and may also be useful in the diagnosis of hypercalciuria.
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Abstract
Calcium homeostasis is a complicated and incompletely understood process that is primarily regulated through an interaction between the intestines, kidneys, and bones. Intestinal calcium absorption is determined by many factors including the amount of regular calcium intake, as well as vitamin D and parathyroid hormone levels. Intestinal calcium absorption is likely different between stone formers and non-stone formers, with higher levels of calcium absorption in those with a history of stones independent of their calcium intake. We no longer recommend dietary calcium restriction as this may lead to bone demineralization and an increase in stone formation. Practitioners need to continue to educate patients to maintain moderate dietary calcium intake. The effect of calcium supplementation on stone formation is currently controversial. It is likely that large doses of supplemental calcium, especially if taken separate from a meal, may lead to stone formation. When necessary, stone forming patients should be encouraged to take their calcium supplements with a meal and their stone disease should be monitored.
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Affiliation(s)
- Mathew D Sorensen
- Department of Urology, Urological Research Outcomes Collaboration, University of Washington School of Medicine, Seattle, Washington, USA
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Ketha H, Singh RJ, Grebe SK, Bergstralh EJ, Rule AD, Lieske JC, Kumar R. Altered Calcium and Vitamin D Homeostasis in First-Time Calcium Kidney Stone-Formers. PLoS One 2015; 10:e0137350. [PMID: 26332888 PMCID: PMC4558059 DOI: 10.1371/journal.pone.0137350] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Accepted: 08/15/2015] [Indexed: 11/30/2022] Open
Abstract
Background Elevated serum 1,25-dihydroxyvitamin D (1,25(OH)2D) concentrations have been reported among cohorts of recurrent calcium (Ca) kidney stone-formers and implicated in the pathogenesis of hypercalciuria. Variations in Ca and vitamin D metabolism, and excretion of urinary solutes among first-time male and female Ca stone-formers in the community, however, have not been defined. Methods In a 4-year community-based study we measured serum Ca, phosphorus (P), 25-hydroxyvitamin D (25(OH)D), 1,25(OH)2D, 24,25-dihydroxyvitamin D (24,25(OH)2D), parathyroid hormone (PTH), and fibroblast growth factor-23 (FGF-23) concentrations in first-time Ca stone-formers and age- and gender frequency-matched controls. Results Serum Ca and 1,25(OH)2D were increased in Ca stone-formers compared to controls (P = 0.01 and P = 0.001). Stone-formers had a lower serum 24,25(OH)2D/25(OH)D ratio compared to controls (P = 0.008). Serum PTH and FGF-23 concentrations were similar in the groups. Urine Ca excretion was similar in the two groups (P = 0.82). In controls, positive associations between serum 25(OH)D and 24,25(OH)2D, FGF-23 and fractional phosphate excretion, and negative associations between serum Ca and PTH, and FGF-23 and 1,25(OH)2D were observed. In SF associations between FGF-23 and fractional phosphate excretion, and FGF-23 and 1,25(OH)2D, were not observed. 1,25(OH)2D concentrations associated more weakly with FGF-23 in SF compared with C (P <0.05). Conclusions Quantitative differences in serum Ca and 1,25(OH)2D and reductions in 24-hydroxylation of vitamin D metabolites are present in first-time SF and might contribute to first-time stone risk.
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Affiliation(s)
- Hemamalini Ketha
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, United States of America
- Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Ravinder J. Singh
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Stefan K. Grebe
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Eric J. Bergstralh
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Andrew D. Rule
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, United States of America
- Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, United States of America
| | - John C. Lieske
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, United States of America
- Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, United States of America
| | - Rajiv Kumar
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, United States of America
- Department of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America
- * E-mail:
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Ou SM, Chen YT, Shih CJ, Tarng DC. Increased risk of bone fracture among patients with urinary calculi: a nationwide longitudinal population-based study. Osteoporos Int 2015; 26:1261-9. [PMID: 25524022 DOI: 10.1007/s00198-014-2998-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Accepted: 12/08/2014] [Indexed: 12/18/2022]
Abstract
UNLABELLED Urinary calculi were associated with higher risk of vertebral and upper limb fracture. Therefore, patients with urinary calculi should be evaluated carefully because they may have a higher risk of subsequent fracture later in life. INTRODUCTION The contribution of urinary calculi to reduced bone mineral density has been recognized. However, the association of urinary calculi with the risk of fracture remains inconclusive. The aim of the study was to determine the risk of overall fracture and fractures at different anatomic sites in patients with urinary calculi. METHODS The records of inpatients and outpatients with urinary calculi were retrieved from the Taiwan National Health Insurance Database from 2000 to 2010. Among patients with urinary calculi at the cohort entry, controls were matched using propensity scores on a 1:1 ratio. All subjects were followed up from the date of enrollment until fracture occurrence, death, or December 31, 2010. There were 46,243 Medicare beneficiaries with a diagnosis of urinary calculi and 46,243 controls without calculi enrolled. RESULTS Among these patients, 6005 patients with a diagnosis of urinary calculi and 5339 controls developed fractures during a median follow-up period of 5.3 years. Patients with urinary calculi had a higher incidence of fracture compared with controls (23.9 versus 22.1 per 1000 person-years) and a greater risk of overall fractures (adjusted hazard ratio [aHR] 1.08, 95 % confidence interval [CI], 1.04-1.12), mainly located at the vertebrae (aHR 1.15, 95 % CI, 1.06-1.25) and upper limb (aHR 1.07, 95 % CI, 1.01-1.14), but the risk for hip fracture was not increased (aHR 1.09, 95 % CI, 0.96-1.22). CONCLUSIONS Urinary calculus is independently associated with higher risk of subsequent fracture. Patients with urinary calculi should pay attention to the future vertebral and upper limb fractures.
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Affiliation(s)
- S-M Ou
- School of Medicine, National Yang-Ming University, No. 201, Section 2, Shih-Pai Road, Taipei, 11217, Taiwan
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Moran ME. Modern Stone Science. Urolithiasis 2014. [DOI: 10.1007/978-1-4614-8196-6_29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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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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Bianchi G, Giusti A, Pioli G, Barone A, Palummeri E, Girasole G. Bisphosphonates in the management of idiopathic hypercalciuria associated with osteoporosis: a new trick from an old drug. Ther Adv Musculoskelet Dis 2012; 2:29-35. [PMID: 22870435 DOI: 10.1177/1759720x09356399] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Idiopathic hypercalciuria (IHC) is defined as a 24-hour urinary calcium excretion that exceeds 4 mg/kg/day, regardless of gender and in absence of systemic diseases or pharmacological treatments that may cause normocalcemic hypercalciuria (eg sarcoidosis, normocalcemic primary hyperparathyroidism, vitamin D intoxication, hyperthyroidism). Patients with IHC and nephrolithiasis often present increased bone turnover, decreased bone mineral density (BMD) and increased susceptibility to fragility fractures. Although the pathogenesis of IHC seems complex and multifactorial, recent evidences suggest that cells involved in bone resorption may play a critical role in the chain of events leading to the excessive urinary calcium excretion. Therefore, it has been proposed that bisphosphonates, potent inhibitors of bone resorption, may have beneficial effects in hypercalciuric patients with low BMD. This manuscript reports recent findings regarding the role of bone tissue in the pathogenesis of IHC, and supports the use of bisphosphonates in such conditions. It also reviews the literature on the effects of bisphosphonates in subjects with osteoporosis-associated IHC.
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Affiliation(s)
- Gerolamo Bianchi
- Department of Gerontology and Musculoskeletal Sciences Galliera Hospital, Genoa, Italy
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Sakhaee K, Maalouf NM, Sinnott B. Clinical review. Kidney stones 2012: pathogenesis, diagnosis, and management. J Clin Endocrinol Metab 2012; 97:1847-60. [PMID: 22466339 PMCID: PMC3387413 DOI: 10.1210/jc.2011-3492] [Citation(s) in RCA: 157] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
CONTEXT The pathogenetic mechanisms of kidney stone formation are complex and involve both metabolic and environmental risk factors. Over the past decade, major advances have been made in the understanding of the pathogenesis, diagnosis, and treatment of kidney stone disease. EVIDENCE ACQUISITION AND SYNTHESIS Both original and review articles were found via PubMed search reporting on pathophysiology, diagnosis, and management of kidney stones. These resources were integrated with the authors' knowledge of the field. CONCLUSION Nephrolithiasis remains a major economic and health burden worldwide. Nephrolithiasis is considered a systemic disorder associated with chronic kidney disease, bone loss and fractures, increased risk of coronary artery disease, hypertension, type 2 diabetes mellitus, and the metabolic syndrome. Further understanding of the pathophysiological link between nephrolithiasis and these systemic disorders is necessary for the development of new therapeutic options.
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Affiliation(s)
- Khashayar Sakhaee
- Department of Internal Medicine, Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
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Effect of thiazides on bone mineral density in children with idiopathic hypercalciuria. Pediatr Nephrol 2012; 27:261-8. [PMID: 21874585 DOI: 10.1007/s00467-011-1987-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2010] [Revised: 07/20/2011] [Accepted: 08/01/2011] [Indexed: 02/07/2023]
Abstract
To determine the effect of thiazide treatment on bone mineral density (BMD) in children with idiopathic hypercalciuria (IH) and osteopenia, we reviewed the case notes of 22 children aged 11.7 ± 2.7 years diagnosed with IH and osteopenia who had received thiazides for 2.4 years. The data on this group were compared with those of 32 IH children with osteopenia aged 11.2 ± 2.7 years who had not received thiazide treatment. By the end of the follow-up period, the z-BMD had improved spontaneously in 23 of the 32 control children (72%) and in 12 of the 22 patients on thiazides (54%). Although treated patients had a higher body mass index (BMI) and a higher BMD following treatment, the differences became statistically negligible when these parameters were expressed as z-BMD or as bone mineral apparent density (BMAD). In contrast, within the control group, there were significant differences in BMAD and z-BMD at the end of the follow-up. Patients who had an improved z-BMD at the end of the treatment also showed an increase in their BMI. Based on these results, we conclude that thiazide treatment does not improve the z-BMD in children with IH. More than half of the children suffering from IH enrolled in our study showed a spontaneous improvement in their z-BMD, which was more evident when the initial BMAD was not low and when their BMI increased during the follow-up period.
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Caudarella R. Orthophosphates. Urolithiasis 2012. [DOI: 10.1007/978-1-4471-4387-1_91] [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
The classic definition of hypercalciuria, an upper normal limit of 200 mg/day, is based on a constant diet restricted in calcium, sodium, and animal protein; however, random diet data challenge this. Here our retrospective study determined the validity of the classic definition of hypercalciuria by comparing data from 39 publications analyzing urinary calcium excretion on a constant restricted diet and testing whether hypercalciuria could be defined when extraneous dietary influences were controlled. These papers encompassed 300 non-stone-forming patients, 208 patients with absorptive hypercalciuria type I (presumed due to high intestinal calcium absorption), and 234 stone formers without absorptive hypercalciuria; all evaluated on a constant restricted diet. In non-stone formers, the mean urinary calcium was well below 200 mg/day, and the mean for all patients was 127±46 mg/day with an upper limit of 219 mg/day. In absorptive hypercalciuria type I, the mean urinary calcium significantly exceeded 200 mg/day in all studies with a combined mean of 259±55 mg/day. Receiver operating characteristic curve analysis showed the optimal cutoff point for urinary calcium excretion was 172 mg/day on a restricted diet, a value that approximates the traditional limit of 200 mg/day. Thus, on a restricted diet, a clear demarcation was seen between urinary calcium excretion of kidney stone formers with absorptive hypercalciuria type I and normal individuals. When dietary variables are controlled, the classic definition of hypercalciuria of nephrolithiasis appears valid.
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Pak CYC, Pearle MS, Sakhaee K. Evidence for metabolic origin of absorptive hypercalciuria Type II. UROLOGICAL RESEARCH 2011; 39:147-52. [PMID: 21063699 DOI: 10.1007/s00240-010-0315-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2010] [Accepted: 09/25/2010] [Indexed: 10/18/2022]
Abstract
The objective of this retrospective data analysis was to test the hypothesis that absorptive hypercalciuria Type II (AH-II) is a less severe variant of absorptive hypercalciuria Type I (AH-I), a common cause of calcareous stones. 24-h urinary calcium obtained on constant metabolic diets was retrieved from several data sources, including those of the authors and another group. On a low calcium diet (10 mmol calcium), 35 patients with AH-II were compared with 70 non-stone formers (NSF) and 76 patients with AH-I. On a high calcium diet (25 mmol calcium/day), 10 patients with AH-II were compared with 35 NSF and 32 with AH-I. On a low calcium diet for all participants, 24-h urinary calcium in AH-II (4.13 ± 0.63 mmol/day) was significantly higher than in NSF (3.06 ± 1.17 mmol/day), but significantly lower than in AH-I (6.11 ± 1.14 mmol/day) (p < 0.001). In a smaller subset, fractional intestinal calcium absorption in AH-II (65.0 ± 11.1%) was intermediate between NSF (50.0 ± 6.4%) and AH-I (71.0 ± 6.7%) (p < 0.001 between AH-II and other groups). On a high calcium diet, the rise in urinary calcium in AH-II was significantly higher than in NSF, but not as marked as in AH-I. Estimated calcium balance in AH-II was similar to NSF, but significantly more positive than AH-I. In conclusion, AH-II shares with AH-I the same metabolic disturbance(s) stimulating intestinal absorption and renal excretion of calcium but to a lesser degree. Bone might be spared in AH-II.
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Affiliation(s)
- Charles Y C Pak
- Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-8885, USA.
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Detection of Absorptive Hypercalciuria Type I Without the Oral Calcium Load Test. J Urol 2011; 185:915-9. [DOI: 10.1016/j.juro.2010.10.067] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2010] [Indexed: 11/18/2022]
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Taylor EN, Stampfer MJ, Mount DB, Curhan GC. DASH-style diet and 24-hour urine composition. Clin J Am Soc Nephrol 2010; 5:2315-22. [PMID: 20847091 DOI: 10.2215/cjn.04420510] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES We previously observed associations between a Dietary Approaches to Stop Hypertension (DASH)-style diet and large reductions in kidney stone risk. This study examined associations between a DASH-style diet and 24-hour excretions of urinary lithogenic factors. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We studied 3426 participants with and without nephrolithiasis in the Health Professionals Follow-up Study (HPFS) and the Nurses' Health Studies (NHS) I and II. A dietary DASH score was based on seven components: high intake of fruits, vegetables, nuts and legumes, dairy products, and whole grains and low intake of sweetened beverages and red and processed meats. We used analysis of covariance to adjust for age, stone history, body size, and other factors. RESULTS Comparing participants in the highest to lowest quintiles of DASH score, multivariate-adjusted urinary calcium excretion was 3% greater in HPFS (P trend 0.12), 10% greater in NHS I (P trend <0.01), and 12% greater in NHS II (P trend 0.05). Urinary oxalate was 4% to 18% greater (P trend all ≤0.03), urinary citrate was 11% to 16% greater (P trend all <0.01), and urinary volume was 16% to 32% greater (P trend all <0.001). Higher DASH score was associated with higher urine potassium, magnesium, phosphate, and pH, and lower relative supersaturations (RSS) of calcium oxalate (women only) and uric acid. CONCLUSIONS A DASH-style diet may reduce stone risk by increasing urinary citrate and volume. The small associations between higher DASH score and lower RSS suggest unidentified stone inhibitors in dairy products and/or plants.
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Affiliation(s)
- Eric N Taylor
- Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, 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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Taylor EN, Curhan GC. Demographic, dietary, and urinary factors and 24-h urinary calcium excretion. Clin J Am Soc Nephrol 2009; 4:1980-7. [PMID: 19820135 DOI: 10.2215/cjn.02620409] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Higher urinary calcium is a risk factor for nephrolithiasis. This study delineated associations between demographic, dietary, and urinary factors and 24-h urinary calcium. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Cross-sectional studies were conducted of 2201 stone formers (SF) and 1167 nonstone formers (NSF) in the Health Professionals Follow-up Study (men) and Nurses' Health Studies I and II (older and younger women). RESULTS Median urinary calcium was 182 mg/d in men, 182 mg/d in older women, and 192 mg/d in younger women. Compared with NSF, urinary calcium as a fraction of calcium intake was 33 to 38% higher in SF (P values < or =0.01). In regression analyses, participants were combined because associations with urinary calcium were similar in each cohort and in SF and NSF. After multivariate adjustment, participants in the highest quartile of calcium intake excreted 18 mg/d more urinary calcium than those in the lowest (P trend =0.01). Caffeine and family history of nephrolithiasis were positively associated, whereas urinary potassium, thiazides, gout, and age were inversely associated, with urinary calcium. After multivariate adjustment, participants in the highest quartiles of urinary magnesium, sodium, sulfate, citrate, phosphorus, and volume excreted 71 mg/d, 37 mg/d, 44 mg/d, 61 mg/d, 37 mg/d, and 24 mg/d more urinary calcium, respectively, than participants in the lowest (P values trend < or =0.01). CONCLUSIONS Intestinal calcium absorption and/or negative calcium balance is greater in SF than NSF. Higher calcium intakes at levels typically observed in free-living individuals are associated with only small increases in urinary calcium.
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Affiliation(s)
- Eric N Taylor
- Renal Division and Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
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Cioppi F, Taddei L, Brandi ML, Croppi E. Idiopathic hypercalciuria and calcium renal stone disease: our cases. CLINICAL CASES IN MINERAL AND BONE METABOLISM : THE OFFICIAL JOURNAL OF THE ITALIAN SOCIETY OF OSTEOPOROSIS, MINERAL METABOLISM, AND SKELETAL DISEASES 2009; 6:251-253. [PMID: 22461254 PMCID: PMC2811358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Renal idiopathic stone disease affects about 8% of the Italian population. The most common form in western countries (70- 80% of the cases) is calcium nephrolithiasis, with stones formed mainly by calcium oxalate and phosphate. One of the main metabolic anomalies that is often associated with calcium nephrolithiasis is hypercalciuria. Primary hypercalciuria is a metabolic defect characterized by an increased renal calcium excretion. This metabolic alteration is present in the general population with a frequency of 5-10%, but can reach 45-50% in subjects affected by nephrolithiasis. We studied 149 patients affected by idiopathic calcium nephrolithiasis.The aim of the present study was to evaluate the association between familiarity for nephrolithiasis and hypercalciuria in this population of patients.
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Affiliation(s)
- Federica Cioppi
- S.O.D. Mineral and Bone Metabolism Diseases, D.A.I. Ortopedia, AOU Careggi, Florence
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Bone Disease in Patients With Primary Hypercalciuria and Calcium Nephrolithiasis. Urology 2009; 74:22-7. [DOI: 10.1016/j.urology.2008.11.014] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2008] [Revised: 10/22/2008] [Accepted: 11/04/2008] [Indexed: 11/21/2022]
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Abstract
The transient receptor potential (TRP) superfamily consists, in mammals, of six protein subfamilies, TRPC, TRPM, TRPV, TRPA, TRPML and TRPP. TRPs are cation channels involved in many physiological processes and in the pathogenesis of various disorders. In the kidney, TRP channels are expressed along the nephron, and a role for some of these channels in renal function has been proposed. TRPC3 is thought to facilitate calcium ion influx into the principal cells of the collecting duct in response to vasopressin. TRPM3 and TRPV4 might be osmosensors, whereas the TRPP1/TRPP2 complex could function as a mechanosensor in the cilia of renal epithelial cells. A number of kidney diseases have also been linked to dysfunctional activity of TRPs. TRPC6 dysfunction has been associated with the onset of focal segmental glomerosclerosis; TRPP2 dysfunction is linked to autosomal-dominant polycystic kidney disease, TRPM6 mutations underlie hypomagnesemia with secondary hypocalcemia, and TRPV1 dysfunction is implicated in renal hypertension. A link between TRPC1 dysfunction and diabetic nephropathy has also been suggested in an animal model. Animal studies have implicated a role for TRPV5 in idiopathic hypercalciuria and vitamin D-dependent rickets, although these observations have not been confirmed in patients. This Review focuses on the role of renal TRP channels in health and disease.
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Renal Phosphate Control as a Reliable Predictive Factor of Stone Recurrence. J Urol 2009; 181:2566-72; discussion 2572. [DOI: 10.1016/j.juro.2009.01.101] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2008] [Indexed: 11/22/2022]
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Israelsson B, Lindgärde F, Malmquist J. Urinary cyclic AMP: relation to calcium balance and comparison of assay methods. ACTA MEDICA SCANDINAVICA 2009; 202:43-5. [PMID: 197798 DOI: 10.1111/j.0954-6820.1977.tb16780.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Urinary adenosine 3',5'-monophosphate (cyclic AMP, cAMP) has been determined in 84 males. Two protein-binding assays were used: the method of Gilman and the Amersham assay kit. The results were in close agreement. The excretion of cAMP was nor correlated to urinary calcium or to estimated calcium intake.
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Weaver S, Doherty DB, Jimenez C, Perrier ND. Peer-Reviewed, Evidence-Based Analysis of Vitamin D and Primary Hyperparathyroidism. World J Surg 2009; 33:2292-302. [DOI: 10.1007/s00268-009-9966-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Giusti A, Barone A, Pioli G, Girasole G, Siccardi V, Palummeri E, Bianchi G. Alendronate and indapamide alone or in combination in the management of hypercalciuria associated with osteoporosis: a randomized controlled trial of two drugs and three treatments. Nephrol Dial Transplant 2008; 24:1472-7. [PMID: 19075192 DOI: 10.1093/ndt/gfn690] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The role of bisphosphonates (BPs) in the management of patients with hypercalciuria (HC) associated with osteoporosis is still uncertain. The aim of the study was to evaluate the effect of alendronate and indapamide alone or in combination on bone mineral density (BMD) and 24-h urinary calcium excretion (24-CaU) in post-menopausal women with HC and low BMD. METHODS A total of 77 post-menopausal women with HC (24-CaU > 4 mg/kg/day) and low BMD [T-score < -2.0 at lumbar spine (LS), femoral neck (FN) or total hip (TH)] from two centres of Northern Italy were randomized to receive indapamide 2.5 mg daily alone (24 patients, IND group), alendronate 70 mg weekly alone (27 patients, ALN group) or the combination therapy (26 patients, ALN + IND group). Throughout the study, all subjects received daily calcium supplements, depending on their dietary intake, to maintain a daily input of 1000 mg. Patients were instructed to increase water intake up to 2000 mL daily. The percentage and absolute changes of BMD at LS, FN and TH, and the variation of 24-CaU from baseline at 1 year were the primary outcomes. Serum calcium, phosphate, parathyroid hormone and bone alkaline phosphatase were also measured. RESULTS Overall 67 women completed the study and were included in the final analysis. Patients in the three groups were similar with regard to baseline characteristics. BMD did not significantly change from baseline after 1 year of treatment with indapamide (LS: +1 +/- 3.1%; FN: -0.3 +/- 3.5%; TH: -0.4 +/- 3.1%), while it showed a significant increase from baseline in the other two groups (ALN; LS: +5.8 +/- 4.2%, P < 0.001; FN: +3.9 +/- 7.9%, P = 0.018; TH: +2 +/- 3.6%, P = 0.006) (ALN + IND; LS: +8.2 +/- 5.3%, P < 0.001; FN: +4.9 +/- 6.7%, P = 0.007; TH: +2.9 +/- 4.2%, P = 0.004). Patients in the combination group showed a significantly higher increase of BMD at LS compared to ALN (P = 0.04). After 1 year, 24-CaU values significantly decreased from baseline in all groups (IND, 239 +/- 78 versus 364 +/- 44, P < 0.001) (ALN, 279 +/- 68 versus 379 +/- 79, P < 0.001) (ALN + IND, 191 +/- 68 versus 390 +/- 55, P < 0.001). The mean percentage decrease of 24-CaU in ALN + IND group (-50%) was significantly greater compared to ALN (-24%, P < 0.001) and IND (-35%, P = 0.012). CONCLUSIONS These results show a benefit, in terms of BMD improvement and 24-CaU reduction, associated with BPs' therapy in combination with indapamide in HC associated with osteoporosis. The combination therapy demonstrated a reduction of 24-CaU and an increase in LS BMD superior to that observed with alendronate alone. Our results support a new potential approach with BPs associated with thiazide diuretics or indapamide in the management of post-menopausal women with HC and associated bone loss. Studies on the larger sample size are needed to demonstrate the efficacy on the fracture outcome.
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Affiliation(s)
- Andrea Giusti
- E.O. Galliera Hospital, Department of Gerontology and Musculoskeletal Sciences, Corso Mentana 10, Genoa 16128, Italy.
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Bone Disease and Idiopathic Hypercalciuria. Clin Rev Bone Miner Metab 2008. [DOI: 10.1007/s12018-008-9023-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Intestinal hyperabsorption of calcium and low bone turnover in hypercalciuric postmenopausal osteoporosis. ACTA ACUST UNITED AC 2008; 36:233-9. [PMID: 18633606 DOI: 10.1007/s00240-008-0146-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2008] [Accepted: 06/27/2008] [Indexed: 10/21/2022]
Abstract
Hypercalciuria of intestinal origin has been linked with bone loss in calcium nephrolithiasis and idiopathic osteoporosis. This retrospective data analysis was performed to explore potential pathogenetic link between intestinal hyperabsorption of calcium and postmenopausal osteoporosis. Data were retrieved from postmenopausal women who were evaluated for osteoporosis or osteopenia at the Mineral Metabolism Clinic of UT Southwestern Medical Center. A total of 319 patients underwent the test of calciuric response to oral calcium load to obtain an indirect measure of intestinal calcium absorption. Serum and urinary biochemistry and L2-L4 bone mineral density (BMD) were compared between five quintiles of calciuric response. There was a statistically significant trend toward a rise in 24-h urinary calcium and a decrease in urinary deoxypyridinoline (DPD) and BMD, with increasing order of quintiles. The presentation of those in the 1st quintile was consistent with vitamin D insufficiency or deficiency, with impaired calcium absorption, secondary hyperparathyroidism, and stimulated bone turnover (high normal urinary DPD). In contrast, patients in the 5th quintile displayed a picture of absorptive hypercalciuria of stone disease, with intestinal hyperabsorption of calcium, high or high normal urinary calcium and suppressed bone turnover (low or low normal urinary DPD). Thus, the assessment of intestinal calcium absorption in a seemingly homogeneous group of postmenopausal women with osteoporosis or osteopenia revealed a spectrum of calciuric response whose extremes may represent two physiologically distinct subtypes that have important diagnostic and therapeutic implications.
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Abstract
Idiopathic hypercalciuria (IH) is the most common metabolic abnormality in patients with calcium kidney stones. It is characterized by normocalcemia, absence of diseases that cause increased urine calcium, and calcium excretion that is greater than 250 mg/d in women and 300 mg/d in men. Subjects with IH have a generalized increase in calcium turnover, which includes increased gut calcium absorption, decreased renal calcium reabsorption, and a tendency to lose calcium from bone. Despite the increase in intestinal calcium absorption, a negative calcium balance is seen commonly in balance studies, especially on a low-calcium diet. The mediator of decreased renal calcium reabsorption is not clear; it is not associated with either an increase in filtered load of calcium or altered parathyroid hormone levels. There is an increased incidence of hypercalciuria in first-degree relatives of those with IH, but IH appears to be a complex polygenic trait with a large contribution from diet to expression of increased calcium excretion. Increased tissue vitamin D response may be responsible for the manifestations of IH in at least some patients.
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Affiliation(s)
- Elaine M Worcester
- Nephrology Section, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
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Sella S, Cattelan C, Realdi G, Giannini S. Bone disease in primary hypercalciuria. CLINICAL CASES IN MINERAL AND BONE METABOLISM : THE OFFICIAL JOURNAL OF THE ITALIAN SOCIETY OF OSTEOPOROSIS, MINERAL METABOLISM, AND SKELETAL DISEASES 2008; 5:118-26. [PMID: 22460993 PMCID: PMC2781204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Primary Hypercalciuria (PH) is very often accompanied with some degrees of bone demineralization. The most frequent clinical condition in which this association has been observed is calcium nephrolithiasis. In patients affected by this disorder bone density is very frequently low and increased susceptibility to fragility fractures is reported. The very poor definition of this bone disease from a histomorphometric point of view is a crucial aspect. At present, the most common finding seems to be a low bone turnover condition. Many factors are involved in the complex relationships between bone loss and PH. Since bone loss was mainly reported in patients with fasting hypercalciuria, a primary alteration in bone metabolism was proposed as a cause of both hypercalciuria and bone demineralization. This hypothesis was strengthened by the observation that some bone resorbing-cytokines, such as IL-1, IL-6, and TNF-α are high in hypercalciuric patients. The effect of an excessive response to the acid load induced by dietary protein intake seems an additional factor explaining a primitive alteration of bone. The intestine plays a major role in the clinical course of bone disease in PH. Patients with absorptive hypercalciuria less frequently show bone disease and a reduction in dietary calcium greatly increases the probability of bone loss in PH subjects. It has recently been reported that greater bone loss is associated with a larger increase in intestinal calcium absorption in PH patients. Considering the absence of PTH alterations, it was proposed that this is not a compensatory phenomenon, but probably the marker of disturbed cell calcium transport, involving both intestinal and bone tissues. While renal hypercalciuria is rather uncommon, the kidney still seems to play a role in the pathogenesis of bone loss of PH patients, possibly via the effect of mild to moderate urinary phosphate loss with secondary hypophosphatemia. In conclusion, bone loss is very common in PH patients. Even if most of the factors involved in this process have been identified, many aspects of this intriguing clinical condition remain to be elucidated.
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Affiliation(s)
- Stefania Sella
- Department of Medical and Surgical Sciences, University of Padua, Padua, Italy
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Vezzoli G, Soldati L, Gambaro G. Update on primary hypercalciuria from a genetic perspective. J Urol 2008; 179:1676-82. [PMID: 18343451 DOI: 10.1016/j.juro.2008.01.011] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2007] [Indexed: 10/22/2022]
Abstract
PURPOSE This review provides a brief update on genetic studies of primary hypercalciuria. We consider their possible implications for the pathogenesis and complications of primary hypercalciuria. MATERIALS AND METHODS Using the PubMed, MEDLINE and Scopus databases we reviewed the literature on pathogenesis and the complications of hypercalciuria, giving particular attention to genetic studies in humans. RESULTS Primary hypercalciuria is a defect occurring in 5% to 10% of the general population and it is most commonly detected in patients with calcium kidney stones or osteoporosis. In children it is associated with hematuria, renal stones or nocturnal enuresis. Although high penetrance, autosomal dominant inheritance cannot be ruled out, hypercalciuria is probably a polygenic disorder. A number of genes have been suggested as candidates in the pathogenesis of common idiopathic calcium nephrolithiasis and hypercalciuria, ie soluble adenylate cyclase, calcium sensing receptor, vitamin D receptor, chloride channel-5, sodium-phosphate cotransporter-2 and claudin-16. These genes may also have a role in complications of hypercalciuria. CONCLUSIONS The classic distinction among absorptive, renal and resorptive hypercalciuria seems insufficient to explain the many cellular and tissue modifications observed in patients with primary hypercalciuria. The condition seems to be a separate disorder, characterized by altered calcium transport in the intestine, kidney and bone, and caused by various combinations of multiple genetic and dietary changes.
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Affiliation(s)
- Giuseppe Vezzoli
- Nephrology Unit, San Raffaele Scientific Institute, Milan, Italy.
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Abstract
Nephrolithiasis is a common disorder that accounts for significant cost, morbidity, and loss of work. There is a one in eight lifetime chance of being diagnosed with urinary stones. Calcium is the most common component of renal stones in individuals in industrialized nations. Calcium stones form as a result of a variety of environmental and metabolic abnormalities that change the urinary environment and increase supersaturation of stone-forming salts. Understanding the pathophysiology of stone disease can help direct treatment toward correction of the underlying abnormalities. Current medical and dietary therapeutic regimens have been shown to significantly reduce the risk of recurrent stone formation.
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Affiliation(s)
- Sangtae Park
- Department of Urology, University of Washington Medical Center, Box 356510, 1959 NE Pacific, Seattle, WA 98195, USA
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Heller HJ, Zerwekh JE, Gottschalk FA, Pak CYC. Reduced bone formation and relatively increased bone resorption in absorptive hypercalciuria. Kidney Int 2007; 71:808-15. [PMID: 17311067 DOI: 10.1038/sj.ki.5002181] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Absorptive hypercalciuria (AH), a common stone-forming condition characterized biochemically by intestinal hyperabsorption of calcium and hypercalciuria may be associated with bone loss. In AH type I (AH-1), hypercalciuria persists despite restriction in dietary calcium intake. We therefore hypothesized that the skeleton may contribute to the hypercalciuria in this subgroup of patients. Histomorphometric analysis of iliac crest biopsies were performed on nine stone-formers with AH-1 and on nine matched normal subjects. After stabilization on a stone-prevention diet, calcium homeostasis in the stone formers was then evaluated on inpatient constant metabolic diet before and after short-term blockade of bone resorption by alendronate (10 mg daily, 17 days total). Compared with controls, the stone-formers had lower indices of bone formation (osteoblast surface/bone surface 1.8+/-2.1 vs 3.0+/-1.5%, P=0.04; wall thickness 35.8+/-6.9 vs 47.2+/-7.6%, P=0.001) and relatively higher bone resorption (osteoclast surface/bone surface 0.4+/-0.2 vs 0.2+/-0.2%, P=0.05). In the stone-formers, a short-term course of alendronate treatment corrected fasting urinary calcium (0.14+/-0.06 to 0.06+/-0.04 mg Ca/mg Cr, P=0.001) and marginally reduced 24-h urinary calcium by 48 mg/day (P=0.06). Increased intestinal calcium absorption and hypercalciuria persisted, but estimated calcium balance improved (P=0.007). Our results suggest that the hypercalciuria of AH-1 originates primarily from intestinal hyperabsorption of calcium, but bone resorption in excess of bone formation may contribute.
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Affiliation(s)
- H J Heller
- Department of Internal Medicine, UT Southwestern Medical Center at Dallas, Center for Mineral Metabolism and Clinical Research, Dallas, Texas, USA
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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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