The prevalence of chronic kidney disease (CKD) in the adult population is estimated to 10%. CKD increases risk of bone fractures, cardiovascular disease and death. The main role of parathyroid hormone (PTH) is to regulate mineral metabolism, including the calcium and phosphate homeostasis. PTH increases as the kidney function declines, and at end stage kidney disease almost all patients have disturbances in the mineral metabolism. Decreasing bone mineral density is associated with risk of fracture, both in background population and in patients with CKD. For decades, treatment with activated vitamin D, phosphate binders, and calcium supplements has been used for patients with chronic kidney disease and elevated parathyroid hormone, but treatment targets have varied greatly over the years, reflecting the lack of randomized clinical trials with clinical important end points. The purpose of The REPAIR-CKD trial is to determine if treatment of hyperparathyroidism improves the bone mineral density in patients with chronic kidney disease. During this trial it will also be evaluated if it is feasible to obtain a difference in PTH levels when targeting two different levels of PTH. Further this trial will explore if a difference in PTH influences on arterial stiffness, muscle mass, muscle function, bone histology and health related quality of life.
The prevalence of chronic kidney disease (CKD) is estimated to afflict 10 % of the adult population, and it is increasing world-wide. CKD is a devastating disease due to the risk of kidney failure and thereby the need for dialysis or transplantation, but also because the presence of CKD increases the risk of bone fracture, cardiovascular disease and mortality. Parathyroid hormone (PTH) is a peptide hormone produced by the parathyroid glands(5). The main function of PTH is to regulate mineral metabolism, including the calcium and phosphate homeostasis. PTH increases as the kidney function declines, and at end stage kidney disease almost all patients have disturbances in the mineral metabolism. Treatment with activated vitamin D, phosphate binder and calcium supplementation has been used for more than 30 years to suppress hyperparathyroidism and keep calcium and phosphate within the normal range. Later calcimetics has been introduced as a treatment for secondary hyperparathyroidism. The risk of bone fracture is increased in patients with CKD and the risk increases as the kidney function declines. A bone fracture leads to a direct burden on the individual. In addition, the risk of complications after a bone fracture is higher in the CKD population compared to the general population. A fracture also constitutes a significant cost for the society. The increased risk of fracture in patients with CKD is associated to the presence of hyperparathyroidism. Bone mineral density (BMD) assessed by dual energy x-ray (DXA) scan is a highly used modality to diagnose osteoporosis and future fracture risk in the general population. Bone mineral density associates with the risk of future fracture in patients with CKD. In patients with CKD there is an association between decreasing eGFR and both low BMD and future fracture risk. It is unknown how elevated PTH associates with BMD and its changes at different stages of CKD, and it is unknown if treatment of hyperparathyroidism influence on BMD and fracture risk in patients with CKD. The risk of cardiovascular mortality, coronary heart disease, heart failure, stroke and peripheral arterial disease increase as the kidney function declines. Elevated PTH associates with an increased risk of cardiovascular disease. However, hyperparathyroidism is tightly connected to the general disturbances in the mineral metabolism in CKD, i.e. hyperphosphatemia and elevated FGF-23, which associate with an increased risk of cardiovascular disease and mortality. Therefore, it is questioned if PTH is directly involved in the pathogenesis of cardiovascular disease, or if the increased risk of cardiovascular disease could be caused by other factors involved in the mineral metabolism. One way to approach precursors of vascular disease is measuring vascular stiffness with pulse wave velocity which is associated with cardiovascular outcomes in patients with CKD. The active circulating form of vitamin D is 1,25 dihydroxy vitamin D (calcitriol). The level of calcitriol is regulated by the activity of the 1α hydroxylase enzyme located in the kidney. The 1α hydroxylase enzyme hydroxylate 25-hydroxy vitamin D at the 1-position. As kidney function declines the activity of 1α hydroxylase is reduced and thereby the circulating level of calcitriol is reduced. The reduced level of calcitriol, together with hypocalcaemia and hyperphosphatemia, leads to secondary hyperparathyroidism. Activated vitamin D is given to patients with hyperparathyroidism to try lowering PTH. In a randomized placebo-controlled trial with 36 patients with CKD G3-5 the intervention group were treated with active vitamin D, which resulted in a difference in BMD by +4.2% in the spine compared to controls after 18 months (P\< 0.05). No clinical trials have aimed to explore the influence of targeting different levels of PTH and the influence on bone mineral density or bone fracture in patients with CKD. Two randomized placebo-controlled trials aimed to address effect of 1 year of active vitamin D treatment on the left ventricular mass, a surrogate endpoint for development of heart failure. No difference between the treatment groups was found in any of the trials. Cohort studies in dialysis patients have found increased survival in patients treated with active vitamin D, but the result could be biased having the design in mind. One Japanese randomized controlled trial compared alfacalcidol with placebo in 976 patients on dialysis. Of importance, not all the included participants did have hyperparathyroidism. No difference was found in fatal and non-fatal cardiovascular events, additionally no difference was found in risk of fracture during the study. If this finding would have differed in patients with hyperparathyroidism or in patients with earlier stages of kidney disease and thereby preventable progression of vascular calcification, remains to be determined. Treatment with active vitamin D, phosphate binders and calcimetics has been used for patients with CKD for decades. Recommendations regarding the appropriate dose and PTH target for different stages of CKD has varied during years and between guidelines, reflecting the lack of randomized clinical trials with clinical important end points. In patients with CKD G3b-5, it is currently recommended to monitor the PTH every 3-6 month. As more than 50 % of the patients have elevated PTH already at CKD G3b, it is an everyday consideration for the clinician if the patients should be treated to reduce PTH. This is both time- and cost consuming. At present, there is no evidence to advise if secondary hyperparathyroidism should be treated in patients with CKD. To improve knowledge about when secondary hyperparathyroidism should be treated, investigators want to conduct a randomized clinical trial with one group of patients being treated if PTH is elevated versus a second group of patients not being treated if PTH is elevated. The investigators hypothesize that suppression of initially elevated PTH will improve BMD, arterial stiffness, muscle mass and muscle strength in patients with CKD. Subjects will be recruited from the patient population in the outpatient clinic at the Department of Nephrology at Herlev and Gentofte Hospital, Herlev, Denmark.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
70
Participants will receive treatment from a "toolbox" depending on the situation to reach the PTH target. Available medication is mirroring what is used in the outpatient clinic setting already (native vitamin D, activated vitamin D, phosphate binders, calcimetics).
Department of Nephrology, outpatient clinic, Herlev Hospital
Herlev, Capital Region, Denmark
RECRUITINGDifference in percent change in bone mineral density (BMD) between the treatment groups.
Measured with DEXA-scan
Time frame: From baseline to final follow-up at 18 months
Difference in follow-up BMD between treatment groups
Measured with DEXA-scan
Time frame: From baseline to final follow-up at 18 months
Difference in follow-up arterial stiffness between the treatment groups
Measured as pulse wave velocity by applanation tonometry with Sphygmocor
Time frame: From baseline to final follow-up at 18 months
Difference in follow-up muscle mass between the treatment groups
Measured as appendicular lean body mass (DEXA-scan) as an approximation of muscle mass
Time frame: From baseline to final follow-up at 18 months
Difference in follow-up hand grip strenght between the treatment groups
Muscle function will be assessed by different measures including hand grip strenght.
Time frame: From baseline to final follow-up at 18 months
Difference in follow-up 10 meter walk test between the treatment groups
Muscle function will be assessed by different measures including 10 meter walk test.
Time frame: From baseline to final follow-up at 18 months
Difference in follow-up sit-to-stand test between the treatment groups
Muscle function will be assessed by different measures including sit-to-stand test.
Time frame: From baseline to final follow-up at 18 months
Differences in bone histology between the treatment groups
Tetracycline labelled bone biopsy is performed by a trained physician experienced in performing bone biopsies from the iliac crest after a standardised procedure. At randomisation, we will start with a single labelling of the bone with tetracycline, for us to be able to tell how the bone was at the time of randomisation. Before the biopsy procedure the bone is again labelled with tetracycline
Time frame: Labelling at baseline and repeated labelling and biopsy at 18 months
Differences in follow-up health-related quality of life between the treatment groups
Health related quality of life will be evaluated through questionnaire "Kidney Disease and Quality of Life" (KDQOL-SF1.3, Danish version).
Time frame: From baseline to final follow-up at 18 months
Differences in number of spinal fractures between the treatment groups
Evaluated with DEXA-scan
Time frame: From baseline to final follow-up at 18 months
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