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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| PTH intensive target | Experimental | Intensive parathyroid hormone target (within interval of lower and upper normal limits = 2,0 - 8,5 µmol/L). In the intensive PTH target group, treatment will be initiated as soon as the PTH rise above the upper limit of normal. Participants in this group will receive treatment to lower PTH level (activated vitamin D, phosphate binder, native vitamin D and calcimetics). PTH will be measured as intact PTH with Atellica IM PTH assay at Herlev Hospital laboratory (normal range 2,0 - 8,5 µmol/L). |
|
| PTH liberal target | Experimental | Liberal parathyroid hormone target (< 5 x upper normal limit = 42,5 µmol/L). In the liberal PTH target group, treatment will not be initiated until PTH rise above five times the upper limit of normal. This is expected to be a small part of the participants. The cut-off for the liberal PTH target (<5 x upper normal limit) was discussed in the national CKD-MBD group. It is chosen to allow the clinician initiate treatment if PTH reaches unusually high levels, no studies have focussed on PTH-targets before, consequently the cut-off is chosen as part of the pragmatic design. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Treat to target | Other | 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). |
| Measure | Description | Time Frame |
|---|---|---|
| Difference in percent change in bone mineral density (BMD) between the treatment groups. | Measured with DEXA-scan | From baseline to final follow-up at 18 months |
| Measure | Description | Time Frame |
|---|---|---|
| Difference in follow-up BMD between treatment groups | Measured with DEXA-scan | From baseline to final follow-up at 18 months |
| Difference in follow-up arterial stiffness between the treatment groups |
| Measure | Description | Time Frame |
|---|---|---|
| The feasibility to obtain a differential PTH level of at least 0.5 times the upper limit of normal between the two groups will be determined | 18 months |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Freja S Hassager, Medical doctor | Contact | 0045+22554707 | freja.staehr.hassager.01@regionh.dk |
| Name | Affiliation | Role |
|---|---|---|
| Ditte Hansen, Medical doctor, professor | Department of Nephrology, Herlev Hospital | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Nephrology, outpatient clinic, Herlev Hospital | Recruiting | Herlev | Capital Region | 2730 | Denmark |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 7287505 | Background | Rao SD, Matkovic V, Duncan H. Transiliac bone biopsy. Complications and diagnostic value. Henry Ford Hosp Med J. 1980;28(2-3):112-5. No abstract available. | |
| 16376161 | Background | Blake GM, Naeem M, Boutros M. Comparison of effective dose to children and adults from dual X-ray absorptiometry examinations. Bone. 2006 Jun;38(6):935-42. doi: 10.1016/j.bone.2005.11.007. Epub 2005 Dec 22. |
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We do not plan to share IPD as the trial will be conducted according to local legislation (Databeskyttelsesloven, Databeskyttelsesforordningen and Sundhedsloven), which does not allow sharing data.
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jul 17, 2025 | Sep 9, 2025 |
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Intervention in both treatment groups is used to reach a target of PTH (different levels in different groups, no pre-defined treatment)
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Investigators will be blinded to the primary endpoint (DEXA-scan and the analysis of this)
|
Measured as pulse wave velocity by applanation tonometry with Sphygmocor
| 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 | 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. | 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. | 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. | 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 | 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). | From baseline to final follow-up at 18 months |
| Differences in number of spinal fractures between the treatment groups | Evaluated with DEXA-scan | From baseline to final follow-up at 18 months |
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| Background | https://www.kidney.org/sites/default/files/02-10-4899_GB_SHPT-PTH_v8.pdf |
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| Prot_000.pdf |
| ID | Term |
|---|---|
| D012080 | Chronic Kidney Disease-Mineral and Bone Disorder |
| D051436 | Renal Insufficiency, Chronic |
| ID | Term |
|---|---|
| D012279 | Rickets |
| D001851 | Bone Diseases, Metabolic |
| D001847 | Bone Diseases |
| D009140 | Musculoskeletal Diseases |
| D007674 | Kidney Diseases |
| D014570 | Urologic Diseases |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D002128 | Calcium Metabolism Disorders |
| D014808 | Vitamin D Deficiency |
| D001361 | Avitaminosis |
| D003677 | Deficiency Diseases |
| D044342 | Malnutrition |
| D009748 | Nutrition Disorders |
| D006962 | Hyperparathyroidism, Secondary |
| D006961 | Hyperparathyroidism |
| D010279 | Parathyroid Diseases |
| D004700 | Endocrine System Diseases |
| D002908 | Chronic Disease |
| D020969 | Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D051437 | Renal Insufficiency |
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