Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease-mineral and bone disorder (CKD-MBD). Both hormones increase as ...kidney function declines, presumably as a response to maintain normal phosphate balance, but when patients reach kidney failure, PTH and FGF23 fail to exert their phosphaturic effects, leading to hyperphosphatemia and further elevations in PTH and FGF23. In patients with kidney failure, the major target organ for PTH is the bone, but elevated PTH is also associated with mortality presumably through skeletal and nonskeletal mechanisms. Indeed, accumulated evidence suggests improved survival with PTH-lowering therapies, and a more recent study comparing parathyroidectomy and calcimimetic treatment further suggests a notion of “the lower, the better” for PTH control. Emerging data suggest that the link between SHPT and mortality could in part be explained by the action of PTH to induce adipose tissue browning and wasting. In the absence of a functioning kidney, the classical target organ for FGF23 is the parathyroid gland, but FGF23 loses its hormonal effect to suppress PTH secretion owing to the depressed expression of parathyroid Klotho. In this setting, experimental data suggest that FGF23 exerts adverse nontarget effects, but it remains to be confirmed whether FGF23 directly contributes to multiple organ injury in patients with kidney failure and whether targeting FGF23 can improve patient outcomes. Further efforts should be made to determine whether intensive control of SHPT improves clinical outcomes and whether nephrologists should aim at controlling FGF23 levels just as with PTH levels.
Over the past few years there have been considerable advances in our understanding of the physiological regulation of mineral homeostasis. One of the most important breakthroughs is the ...identification of fibroblastic growth factor 23 (FGF23) and its role as a key regulator of phosphate and 1,25-dihydroxyvitamin D metabolism. FGF23 exerts its biological functions by binding to its cognate receptor in the presence of Klotho as a cofactor. FGF23 principally acts on the kidney to induce urinary phosphate excretion and suppresses 1,25-dihydroxyvitamin D synthesis, thereby indirectly modulating parathyroid hormone secretion. FGF23 also acts directly on the parathyroid to decrease parathyroid hormone synthesis and secretion. In patients with chronic kidney disease, FGF23 levels increase progressively to compensate for phosphate retention, but these elevated FGF23 levels fail to suppress the secretion of parathyroid hormone, particularly in the setting of uremia. Recent data suggest that this parathyroid resistance to FGF23 may be caused by decreased expression of Klotho–FGFR1 complex in hyperplastic parathyroid glands. This review summarizes recent insights into the role of FGF23 in mineral homeostasis and discusses the involvement of its direct and indirect interaction with the parathyroid gland, particularly focusing on the pathophysiology of secondary hyperparathyroidism in chronic kidney disease.
Anemia is a common complication of chronic kidney disease (CKD). There are various causes of renal anemia such as decreased production of erythropoietin, resistance to erythropoietin, shortened ...survival of red blood cells, and bone marrow fibrosis. Secondary hyperparathyroidism (SHPT) is a less recognized, but potentially significant cause of renal anemia in CKD patients. Parathyroid hormone (PTH) has been regarded as a uremic toxin that has multiple adverse effects, and its elevated levels have been associated with renal anemia in hemodialysis patients. Moreover, recent clinical studies have shown that the treatment of SHPT using either vitamin D receptor activators, calcimimetics, or parathyroidectomy leads to improvement of anemia, supporting the role of PTH in renal anemia. Emerging data have also indicated the involvement of bone‐derived fibroblast growth factor 23 in renal anemia. This review summarizes recent insights into the role of PTH in renal anemia and discusses the importance of treating SHPT in improving the control of renal anemia in hemodialysis patients.
Disturbances in mineral and bone metabolism are common in patients with chronic kidney disease (CKD), especially those undergoing dialysis. Renal osteodystrophy, which describes an alteration of bone ...morphology, is an important component of this systemic disorder and may explain the elevated risk of fracture which adversely affects morbidity and mortality. The most common form of renal osteodystrophy is high-turnover bone disease (osteitis fibrosa), which is induced by secondary hyperparathyroidism (SHPT). During the past decade, there has been considerable advances in the management of SHPT, with the introduction of the calcimimetic agents, the optimized use of nutritional and active vitamin D, and the accumulated experience with surgical parathyroidectomy. Studies supported that these advances could translate into improvement of renal bone disease and fracture prevention, as well as decreasing the risk of cardiovascular events and mortality. In this review, we summarize the available clinical evidence on the effect of old and new drugs on bone disorders in patients with CKD.
Parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) each play a central role in the pathogenesis of chronic kidney disease (CKD)-mineral and bone disorder. Levels of both hormones ...increase progressively in advanced CKD and can lead to damage in multiple organs. Secondary hyperparathyroidism (SHPT), characterized by parathyroid hyperplasia with increased PTH secretion, is associated with fractures and mortality. Emerging evidence suggests that these associations may be partially explained by PTH-induced browning of adipose tissue and increased energy expenditure. Observational studies suggest a survival benefit of PTHlowering therapy, and a recent study comparing parathyroidectomy and calcimimetics further suggests the importance of intensive PTH control. The mechanisms underlying the regulation of FGF23 secretion by osteocytes in response to phosphate load have been unclear, but recent experimental studies have identified glycerol-3-phosphate, a byproduct of glycolysis released by the kidney, as a key regulator of FGF23 production. Elevated FGF23 levels have been shown to be associated with mortality, and experimental data suggest off-target adverse effects of FGF23. However, the causal role of FGF23 in adverse outcomes in CKD patients remains to be established. Further studies are needed to determine whether intensive SHPT control improves clinical outcomes and whether treatment targeting FGF23 can improve patient outcomes.
Protein‐energy wasting (PEW), a syndrome involving adverse changes in nutrition and body composition, is a serious problem associated with morbidity and mortality in patients with end‐stage renal ...disease (ESRD). The pathogenesis of PEW is multifactorial, and the underlying mechanisms are not fully understood. However, recent translational work has provided compelling evidence for a causal role of parathyroid hormone (PTH) in the pathogenesis of adipose tissue browning and increased energy expenditure, a critical component of PEW in ESRD. These results provide a biological explanation for the clinical association between secondary hyperparathyroidism (SHPT) and PEW in hemodialysis patients and may serve as an additional rationale for treating SHPT. Large‐scale clinical and epidemiological studies should determine the clinical significance of SHPT as a contributor to PEW and establish the optimal management of SHPT to ameliorate PEW.
Parathyroidectomy (PTx) and cinacalcet are both effective treatments for secondary hyperparathyroidism in hemodialysis patients, but limited data exist comparing the long-term outcomes of these ...interventions.
We aimed to compare the risk of mortality among hemodialysis patients who underwent PTx and those who started treatment with cinacalcet.
In this prospective cohort study, comprising patients from the Japanese Society for Dialysis Therapy Renal Data Registry, patients who had intact parathyroid hormone (PTH) levels ≥ 300 pg/mL in late 2007 and underwent PTx or started treatment with cinacalcet in 2008 to 2009 were matched by propensity score at 1:3. PTx and cinacalcet were compared for all-cause mortality within 6 years.
Among eligible patients, 894 patients who underwent PTx were matched with 2682 patients who started treatment with cinacalcet. The median baseline intact PTH levels were 588 pg/mL and 566 pg/mL in the PTx and cinacalcet groups, respectively. PTx resulted in greater reductions in intact PTH, calcium, and phosphorus levels compared with cinacalcet. During the 6-year follow-up period, 201 patients (22.5%) in the PTx group and 736 patients (27.4%) in the cinacalcet group died. PTx was associated with a lower risk of mortality compared with cinacalcet (hazard ratio, 0.78 95% CI, 0.67-0.91; P = 0.002). This association was more pronounced in patients with intact PTH levels ≥ 500 pg/mL and in patients with serum calcium levels ≥ 10.0 mg/dL (both P for interaction < 0.001).
PTx compared with cinacalcet is associated with a lower risk of mortality, particularly among patients with severe secondary hyperparathyroidism.
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