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The Role Of FGF23, Klotho, And Sclerostin In Kidney Stone Formers

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ClinicalTrials.gov Identifier: NCT01526304
Recruitment Status : Unknown
Verified January 2012 by University of Zurich.
Recruitment status was:  Recruiting
First Posted : February 3, 2012
Last Update Posted : February 3, 2012
Sponsor:
Information provided by (Responsible Party):
University of Zurich

Brief Summary:
Kidney stones are very common in industrialized countries and the lifetime risk is about 10 to 15% in this population. Kidney stones are composed of inorganic and organic components. Calcium containing stones are the most common stone type accounting for more than 80% of kidney stones. Many factors predispose or contribute to the development of kidney stones, including genetic variants or mutations, diet, environmental factors, and behavior. To date, little is known on fibroblast growth factor (FGF23) levels in patients with calcium nephrolithiasis. FGF23 is crucial for phosphate homeostasis including physiological and pathophysiological conditions such as X-linked hypophosphatemic rickets and it seems that FGF23 is probably the most important regulator of serum phosphate and calcitriol (1,25(OH)2D3) levels in addition to parathyroid hormone (PTH) produced by the parathyroid gland. Novel factors such as Klotho and Sclerostin, which are involved in the bone-kidney-parathyroid endocrine axis, have been identified recently. Klotho is a putative aging suppressor gene and its deficiency results in osteopenia, hyperphosphaturia, and calcification. Klotho is mainly expressed in the kidney but also in the parathyroid gland and acts as a FGF23 specific co-receptor mediating FGF23 participation in the bone-kidney-parathyroid endocrine axis as described above. Sclerostin is a protein secreted by osteocytes that inhibits bone formation by osteoblasts. However, the potential role of FGF23, Klotho, and Sclerostin in nephrolithiasis is still poorly under-stood or even unexplored. The aim of this study is to test if levels of FGF23, Klotho, and Sclerostin are differentially regulated in kidney stone formers.

Condition or disease Intervention/treatment
Kidney Stones Other: no intervention

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Detailed Description:

Kidney stones are very common in industrialized countries and the lifetime risk is about 10 to 15% in this population. Men are more affected than women and the mean age of the patients is be-tween the fourth and sixth decade of life. Notably, a considerable percentage of patients experience recurrent kidney stones with a relapse rate of 50% in 5-10 years complicated by pain and urinary tract infections and potential loss of functional renal parenchyma with development of chronic renal failure in the long term. Kidney stones are composed of inorganic and organic components. Calcium containing stones are the most common stone type accounting for more than 80% of kidney stones. Many factors predispose or contribute to the development of kidney stones, including genetic variants or mutations, diet, environmental factors, and behavior. Among all factors, abnormal urinary pH and calcium excretion are predominant findings in stone formers and seem to play a major role in the pathogenesis of stone formation (1-5). Moreover, a significant percentage of patients with calcium nephrolithiasis and normal parathyroid function show hypophosphatemia and reduced renal phosphate reabsorption i.e. a renal phosphate leak (6-8) with resulting hyperphosphaturia. To date, little is known on fibroblast growth factor (FGF23) levels in patients with calcium nephrolithiasis (6). The authors demonstrated that FGF23 was increased in stone formers with renal phosphate leak when compared to controls. Also serum FGF23 concentration was strongly inversely associated with serum phosphate levels and rate of tubular phosphate re-absorption, respectively. This study suggests a role of FGF23 in the pathogenesis of calcium nephrolithiasis, however, more studies are necessary to confirm these findings. More, the influence of other novel factors involved in hyperphosphaturia has not been identified yet, such as Klotho.

FGF23 is crucial for phosphate homeostasis including physiological and pathophysiological conditions such as X-linked hypophosphatemic rickets and it seems that FGF23 is probably the most important regulator of serum phosphate and calcitriol (1,25(OH)2D3) levels in addition to parathyroid hormone (PTH) produced by the parathyroid gland (9-13). FGF23 is produced by osteocytes and osteoblasts, secreted in response to phosphate, and 1,25(OH)2D3, binds to the FGF receptor (FGFR)/Klotho complex, and acts as a phosphaturic hormone by reducing the expression of both sodium dependent phosphate cotransporters, namely NaPi2a and NaPi2c in renal proximal tubule cells (14). There is some evidence of PTH induced expression and secretion of FGF23 and on the other hand FGF23 decreases 1,25(OH)2D3 production and thus stimulates PTH production. In chronic kidney disease (CKD) patients, FGF23 is involved in CKD-related mineral and bone disorder (CKD-MBD) and has been shown to be an independent and probably more critical cardiovascular risk factor than phosphate (14).

Novel factors such as Klotho and Sclerostin, which are involved in the bone-kidney-parathyroid endocrine axis, have been identified recently. Klotho is a putative aging suppressor gene and its deficiency results in osteopenia, hyperphosphaturia, and calcification. Klotho is mainly expressed in the kidney but also in the parathyroid gland and acts as a FGF23 specific co-receptor mediating FGF23 participation in the bone-kidney-parathyroid endocrine axis as described above. Interestingly, secreted Klotho is also able to induce phosphaturia independently of FGF23 (15).

Sclerostin is a protein secreted by osteocytes that inhibits bone formation by osteoblasts. Deficiency of Sclerostin causes van Buchem disease and sclerosteosis, both rare sclerosing bone disorders, respectively. Interestingly, in humans, Sclerostin mRNA is expressed in several tissues, with high levels in the kidney whereas Sclerostin protein is only restricted to osteocytes. The exclusive effect of Sclerostin on bone formation and its deficiency causing bone disorders suggest a potential role of this molecule also in other diseases where bone homeostasis may be disarranged such as nephrolithiasis (16-18).

However, the potential role of FGF23, Klotho, and Sclerostin in nephrolithiasis is still poorly under-stood or even unexplored. The aim of this study is to test if levels of FGF23, Klotho, and Sclerostin are differentially regulated in kidney stone formers. Given the large number of kidney stone patients worldwide, the better understanding of the pathogenesis of kidney disease may provide the basis for the design of more individualized and specifically targeted therapeutics for this patient cohort.


Study Type : Observational
Estimated Enrollment : 150 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: A Cross-Sectional Study To Investigate The Role Of FGF23, Klotho, And Sclerostin In Kidney Stone Formers
Study Start Date : January 2012
Estimated Study Completion Date : January 2014

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Kidney Stones


Intervention Details:
  • Other: no intervention
    No intervention, only observational study


Biospecimen Retention:   Samples Without DNA
Whole Blood


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
All stoneformer patients at the first outpatient stone clinic consultation
Criteria

Inclusion criteria:

- stoneformer patients with signed informed consent


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01526304


Contacts
Contact: Marian Struker, Study Coordinator +41 (0)44 255 35 45 marian.struker@usz.ch
Contact: Nilufar Mohebbi, MD nilufar.mohebbi@usz.ch

Locations
Switzerland
University Hospital Zurich, Nephrology Recruiting
Zurich, ZH, Switzerland, 8091
Sponsors and Collaborators
University of Zurich
Investigators
Principal Investigator: Nilufar Mohebbi, MD University Hospital Zurich, Division of Nephrology

Responsible Party: University of Zurich
ClinicalTrials.gov Identifier: NCT01526304     History of Changes
Other Study ID Numbers: SFS
First Posted: February 3, 2012    Key Record Dates
Last Update Posted: February 3, 2012
Last Verified: January 2012

Additional relevant MeSH terms:
Kidney Calculi
Nephrolithiasis
Kidney Diseases
Urologic Diseases
Urolithiasis
Urinary Calculi
Calculi
Pathological Conditions, Anatomical