Chronic Kidney Disease–Mineral and Bone Disorder

Introduction

Patients with CKD often have disturbances in divalent ion metabolism, including the dysregulation of calcium and phosphorus, bone disease, and extraosseous calcification. These disturbances were previously referred to as renal osteodystrophy. However, the term renal osteodystrophy is primarily a description of altered bone morphology in patients with CKD. In 2006, the Kidney Disease: Improving Global Outcomes (KDIGO) proposed a new term called CKD-MBD. CKD-MBD is defined as a systemic disorder of mineral and bone metabolism due to CKD and is manifested by either one or a combination of the following: (1) abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; (2) abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and (3) vascular or other soft-tissue calcification.

Pathophysiology of Chronic Kidney Disease–Mineral Bone Disorder

Chronic kidney disease (CKD)–mineral bone disorder (MBD) is a complex disorder that involves physiologic feedback loops among kidneys, intestine, bone, and vasculature. It is characterized by phosphate retention and secondary hyperparathyroidism. Before discussing the pathophysiology of secondary hyperparathyroidism, we briefly review the regulation and action of the hormones that are involved in mineral metabolism: parathyroid hormone (PTH), vitamin D, and fibroblast growth factor-23 (FGF23).

Development of Secondary Hyperparathyroidism in Chronic Kidney Disease

Phosphate excretion decreases as renal function declines. With a constant dietary intake of phosphorus and the majority of phosphorus being absorbed, phosphate is retained. Phosphate retention reduces ionized calcium by directly binding with calcium, as well as stimulating FGF23 release from osteocytes and decreasing calcitriol synthesis. The reduced level of ionized calcium leads to an increase in PTH. The decreased calcitriol concentration in CKD appears to be secondary to a combination of an increase in FGF23 concentration, loss of functional renal mass, and phosphate retention. The pathophysiology of secondary hyperparathyroidism in patients with CKD is illustrated in Fig. 39.1 .

If elevated PTH is a normal physiologic response to low ionized calcium, why is secondary hyperparathyroidism a disorder? In the 1970s, Bricker and Slatopolsky proposed the “trade-off” hypothesis for the development of secondary hyperparathyroidism. The idea of the “trade-off” hypothesis is that the body pays a biological “price” (i.e., PTH excess) in order to maintain normal levels of calcium and phosphorus. At some increased levels of PTH, this response appears to be maladaptive because although PTH is phosphaturic, it increases serum phosphorus by increasing bone resorption. As renal function deteriorates, the effect of PTH on urinary phosphate excretion diminishes, and the excess PTH exacerbates hyperphosphatemia by increasing bone resorption and leading to significant bone disease.

The temporal sequence of disordered phosphorus metabolism in progressive CKD is demonstrated in Fig. 39.2 . The prevalence of hyperphosphatemia is elevated FGF23, and PTH levels increase progressively with worsening kidney function. Alterations in FGF23, PTH, and calcitriol are physiologic responses to prevent the increase in serum phosphorus. An increase in FGF23 is detected first, well before the development of CKD stage 3. Elevated FGF23 levels lead to a decreased production of calcitriol and, subsequently, development of secondary hyperparathyroidism. The serum level of phosphorus begins to increase when the estimated glomerular filtrate rate (eGFR) falls below approximately 60 mL/min/1.73 m ² but remains in a relatively normal range until eGFR is less than approximately 30 mL/min/1.73 m ² . Serum phosphate, FGF23, and PTH levels continue to rise as renal function declines.

Disordered Mineral Metabolism and Mortality

Increased FGF23 levels appear to be independently associated with mortality in patients with advanced CKD. In a study with patients who were beginning hemodialysis treatment, increasing FGF23 levels were associated with a monotonically increased risk of death in a year and compared to hemodialysis patients with FGF23 levels in the first quartile, the odds of dying were 4 to 5 times higher for those with FGF23 in the third or fourth quartile.

The relationships of serum calcium, phosphorus, and PTH with mortality are U shaped, with very low and very high levels associated with increased mortality. According to the data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) 1996–2007, the lowest mortality risk was observed with serum calcium between 8.6 and 10.0 mg/dL (albumin-corrected calcium between 7.6 and 9.5 mg/dL), phosphorus between 3.6 and 5.0 mg/dL, and PTH between 101 and 300 pg/mL. Mortality was the highest when serum calcium was > 10.0 mg/dL, phosphorus > 7.0 mg/dL, and PTH > 600 pg/mL.

In the dialysis population, both hypocalcemia and hypercalcemia are associated with high all-cause mortality, and hypercalcemia is closely associated with cardiovascular mortality. The prevalence of hypocalcemia, defined as serum calcium < 8.5 mg/dL, is ~ 11% in patients on dialysis. Patients on dialysis develop hypocalcemia due to phosphate retention and reduced levels of calcitriol. The prevalence of hypercalcemia, defined as serum calcium > 10.2 mg/dL, is slightly lower at ~ 5%. The causes of hypercalcemia in patients on dialysis include the use of calcium- containing phosphate binders, vitamin D analogs, high dialysate calcium concentration, and development of tertiary hyperparathyroidism.

Hyperphosphatemia is a late manifestation of CKD with a prevalence of more than 50% when eGFR is < 20 mL/min/1.73 m ² . In an observational cohort using the data of prevalent and incident patients on maintenance dialysis (both hemodialysis and peritoneal dialysis [PD]), participants with serum phosphorus ≥ 6.4 mg/dL had an increased risk of all-cause and cause-specific mortality: comparing participants with serum phosphorous level ≥ 6.4 mg/dL with those with normal serum phosphorous level (i.e., 4.5 to < 5.4 mg/dL), the adjusted hazard ratio of all-cause mortality was 1.50 (95% confidence interval [CI], 1.47–1.54) for patients on hemodialysis and 1.48 (95% CI, 1.34–1.63) for patients on PD.

Similarly, both hypoparathyroidism and hyperparathyroidism in patients on dialysis are associated with higher mortality. According to the DOPPS data, compared to PTH between 101 to 300 pg/mL, PTH ≤ 100 pg/mL was associated with significantly greater cardiovascular mortality, and PTH > 600 pg/mL was associated with both higher all-cause and cardiovascular mortality.

Bone Disease