Persons with chronic kidney disease (CKD) have a 3-fold increased risk of bone fracture and a 10-fold increased risk of cardiovascular disease than the general population. These increased risks are related to the disturbances in the mineral metabolism, and this clinical entity is termed Chronic Kidney Disease - Mineral and Bone Disorder (CKD-MBD).

The overall aim of the present project is to explore factors that may predict or associate with the development of bone and cardiovascular disease in patients with CKD and hopefully provide insight into underlying mechanisms and pathophysiological pathways for future treatment and prevention.

In a sub study investigators aim to explore the calcium and phosphate balance in patients with CKD and describe how these associate with each other as well as with kidney function (eGFR).

Chronic kidney disease (CKD) is a chronic condition where the excretory kidney function (estimated glomerular filtration rate (eGFR)) is reduced and/or markers of kidney damage is present (often presented as albuminuria). CKD is classified into stages CKD G1-5 according the severity of the reduction in eGFR.

The prevalence of CKD is increasing world-wide, partly explained by the increase in the ageing population and prevalence of diabetes3. In Denmark, the prevalence of CKD in the population is 4-8% depending on the applied algorithm. CKD is a devastating disease both 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.

Disturbances in the mineral metabolism, including hyperphosphatemia and hyperparathyroidism develops as kidney function declines. These disturbances are closely related to the increased risk of bone and cardiovascular disease, and this relation has been gathered since 2009 in the clinical entity named Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD).

The bone pathology in patients with CKD, named renal osteodystrophy, can be classified by the TMV classification. The TMV classification describes the bone Turnover, the bone Mineralization and the bone Volume, which may all be disturbed in renal osteodystrophy.

Per see, disturbances in the bone pathology, especially in the bone turnover is considered harmful to the bone strength. However, no studies have addressed if disturbances in the bone turnover increases the risk of bone fracture. This is the primary aim of the present study.

The golden standard for description of bone turnover is a bone biopsy. However, bone turnover markers may describe the bone turnover with a reasonable validity, and will be used in the present study to describe the turnover, as bone biopsy is not considered feasible in 1000 patients.

Especially, the low bone turnover has been a frightened condition as former studies have found an association between low bone turnover and progression of vascular calcification. However, these were executed when treatment with active vitamin D and calcium were more aggressive than today. Treatments that may also affect the vascular calcification. Therefore, it is uncertain if low bone turnover predicts cardiovascular disease. This will also be explored in the present study.

Bone and cardiovascular disease often co-occur in patients with CKD. Preclinical and clinical studies has suggested a bone vascular tissue crosstalk in CKD that may be a mediator of the high risk of fracture and cardiovascular events in patients with CKD. In the present study, it will be possible to explore how these factors, including sclerostin, Dkk-1, and Activin A, associate with changes in bone mineral density (BMD) and future fracture and cardiovascular disease.

Sarcopenia is an age-related disease characterized by a progressive decline in muscle function and mass. Sarcopenia is associated with numerous adverse health outcomes in the general population, including increased risk of falls, fractures, and mortality. Low BMD predicts an increased risk of fracture in the general population as well as in patients with CKD. A few studies have found an association between osteoporosis and sarcopenia in patients with CKD. This association between bone fragility and sarcopenia may be due to common risk factors such as age, sex, and malnutrition, but increasing evidence points towards an interaction between muscles and bone, giving rise to the uniting term osteosarcopenia. The present study will explore if sarcopenia predicts decline in BMD and future fracture.

Patients with CKD are often put on a strict diet to reduce their intake of phosphorous, potassium, sodium and protein. In theory, these dietary restrictions may in turn cause malnutrition, sarcopenia and increased risk of fall and fracture. Especially, the reduced calcium intake due to phosphorous restriction have been speculated to impact on the bone quality. This study will determine the habitual dietary intake of phosphate and calcium in patients with CKD4-5 and explore the association with bone quantity and sarcopenia.

A novel urine acid/base-score (calculated on the basis of urine pH and urine ammonium) assesses the renal tubular capacity for acid excretion and the degree of subclinical acid retention. This disease marker has been found to be largely independent of traditional kidney disease markers and robustly associated with CKD progression and incident ESKD in CKD stage 3-4 patients. This study will determine the association between the subclinical acid retention and clinical outcomes.

The study will include 1000 patients with chronic kidney disease. The patients will be recruited from the outpatient clinic at the Department of Nephrology at Herlev Hospital. The sub study focused on calcium and phosphate balance will include 50 patients with chronic kidney disease.

Inclusion Criteria:

• Age ≥18 years
• CKD stage 4-5nonD (eGFR ≤ 29 ml/min) according to KDIGO (Kidney Disease Improving Global Outcome) definition

Exclusion Criteria:

• None

Participants will be recruited from the outpatient clinic, Department of Nephrology at Herlev Hospital. The outpatient clinic has approximately 1500 patients with CKD4-5nonD.

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.