From the Guidelines
Serum calcium levels remain normal in CKD despite elevated PTH levels due to the body's compensatory mechanisms, which include increased calcium reabsorption in the renal tubules, stimulated bone resorption, and enhanced production of active vitamin D. As kidney function declines, phosphorus retention occurs due to decreased renal excretion, triggering increased PTH secretion, which is a compensatory response to maintain calcium homeostasis 1. The pathogenesis of secondary hyperparathyroidism (SHPT) is complex and driven by several factors, including vitamin D deficiency, hypocalcemia, and hyperphosphatemia, with high phosphate intake being an additional modifiable risk factor for SHPT 1. Key actions of PTH include:
- Increasing calcium reabsorption in the renal tubules
- Stimulating bone resorption to release calcium into the bloodstream
- Enhancing the production of active vitamin D (calcitriol) which increases intestinal calcium absorption These combined actions effectively counterbalance the tendency toward hypocalcemia that would otherwise occur in CKD, but prolonged elevation of PTH leads to bone disease 1. In adult patients with CKD G3a to G5 not on dialysis, it is suggested that calcitriol and vitamin D analogues not be routinely used, but rather reserved for patients with CKD G4 to G5 with severe and progressive hyperparathyroidism 1. Prevention and treatment of SHPT are important because imbalances in mineral metabolism are associated with CKD–MBD, and higher PTH levels are associated with increased morbidity and mortality in patients with CKD 1. Treatments such as phosphate binders, vitamin D analogs, or calcimimetics may be required to manage mineral metabolism disturbances while preventing hypercalcemia in patients with CKD 1.
From the Research
Serum Calcium Levels in CKD
- Serum calcium levels remain normal in CKD despite elevated PTH levels due to hyperphosphatemia, as phosphate homeostatic mechanisms maintain normal phosphorus levels until late-stage CKD 2.
- The management of mineral and bone disorders (MBD) in CKD is a huge clinical challenge, and serum calcium and phosphate remain normal until the late stages of CKD at the expense of elevated fibroblast growth factor-23 (FGF-23) and reduced 1,25-dihydroxy-vitamin D (1,25[OH]2D) 3.
Phosphate Retention and Hyperphosphatemia
- Phosphate retention is thought to be the initial cause of CKD-MBD, and hyperphosphatemia is a key contributor to CKD-MBD 2, 3.
- Hyperphosphatemia develops in later CKD stages and worsens with disease progression, leading to elevated serum PTH levels 4.
Parathyroid Hormone (PTH) Levels
- Elevated PTH levels are noted in later CKD stages and worsen with disease progression 4.
- The intermittent administration of PTH at the early stages of CKD could prevent FGF-23 increases, the drop of 1,25(OH)2D, and the development of renal osteodystrophy, including secondary hyperparathyroidism (HPT) and its catabolic effects on the skeleton 3.
Treatment and Management
- Early phosphate control may help reduce the early clinical consequences of CKD-MBD, and achieving normal phosphorus levels is associated with distinct clinical benefits 2.
- Cinacalcet hydrochloride is an effective treatment for secondary hyperparathyroidism in patients with CKD not receiving dialysis, and it can decrease iPTH concentrations without affecting serum calcium and phosphorus levels 5.
- Vitamin D supplementation can improve vitamin D deficiency and PTH levels, but it may worsen phosphate retention and increase FGF-23 levels, requiring concomitant phosphate binder therapy 2, 6.