Recent advances in understanding and managing secondary hyperparathyroidism in chronic kidney disease

Introduction

Mineral homeostasis is a tightly regulated process in which kidneys play an essential role. The development and progression of chronic kidney disease (CKD) cause serious disturbances in the maintenance of calcium (Ca) and phosphorus (P) metabolism. The term chronic kidney disease–mineral and bone disorder (CKD-MBD) summarizes all the alterations derived from the onset of CKD (that is, biochemical alterations, renal osteodystrophy, and extraosseous calcifications).

Parathyroid glands have a central role in mineral homeostasis. Under normal circumstances, small variations in serum Ca levels are detected by the Ca-sensing receptor (CaSR), located in the surface of parathyroid cells, which respond by secreting appropriate levels of parathyroid hormone (PTH). PTH stimulates bone resorption, releasing Ca and P ions into the extracellular space. At the renal level, PTH stimulates renal calcitriol (1,25D₃) synthesis, which in turn promotes Ca and P absorption by the intestine. PTH, by stimulating tubular reabsorption, reduces renal excretion of Ca while exerting a phosphaturic action. All together, these actions are mainly intended to maintain appropriate concentrations of Ca. The concentration of P is regulated predominantly by fibroblast growth factor 23 (FGF23), which reduces tubular reabsorption of P. The parathyroid function is inhibited by high levels of Ca, 1,25D₃, and FGF23. Derangements in the levels of these elements constitute potent stimuli for the onset and progression of secondary hyperparathyroidism (SHPT)^1,2. Here, we will briefly review the latest advances regarding the pathophysiology and certain aspects of the management of SHPT.

Novel insights into the pathogenesis of secondary hyperparathyroidism in patients with chronic kidney disease

The development of SHPT occurs in response to the impairment of renal function, being frequently diagnosed at advanced stages of CKD. SHPT is characterized by elevated rates of PTH synthesis and secretion accompanied by parathyroid cell hyperplasia. Classically, three main factors present in CKD have been considered responsible for the onset and progression of SHPT: hypocalcemia, hyperphosphatemia, and low 1,25D₃ levels. Nowadays, FGF23 is also recognized as an element that is intimately involved in the pathophysiology of SHPT³.

The aforementioned factors are responsible for the progression of hyperparathyroidism from diffuse to nodular by different mechanisms: hypocalcemia and hyperphosphatemia stimulates PTH production and secretion^4–6 and promotes cell proliferation. Hypocalcemia increases the expression of proliferating cell nuclear antigen^7–9. The absent or reduced antiproliferative action of 1,25D₃⁹ and the impaired regulation of p21 and αKlotho/FGFR signaling by FGF23^10,11 also contribute to the development of parathyroid hyperplasia. The progression from diffuse to nodular hyperplasia is characterized by a progressive reduction in the expression of parathyroid receptors. This is known as tertiary hyperparathyroidism and at this point the gland is refractory to the action of its natural inhibitors.

In early CKD, several factors contribute to the onset of SHPT. Since early CKD, there is an increase in the renal load of P. The increase in serum PTH and FGF23 prevents the accumulation of P, but the excess of FGF23 reduces the serum concentration of 1,25D₃, which results in a stimulus for PTH production. This effect is direct at the parathyroid level and indirect through the reduction in extracellular Ca. The increase in the tubular load of P and the progressive reduction in the glomerular filtration rate cause a reduction in the renal expression of Klotho, which generates resistance to the action of FGF23¹². Thus, FGF23 production has to increase, 1,25D₃ levels decrease further, and hyperparathyroidism is then established. With CKD stage 4, the number of nephrons is reduced to the point that the increases in PTH and FGF23 are not able to augment P excretion and hyperphosphatemia, together with hypocalcemia, develops. In animals with normal renal function, the elevation in FGF23 causes a reduction in PTH production, but as parathyroid hyperplasia develops, there is a lower expression of parathyroid FGFR and Klotho receptors, which prevent any inhibitory effect of FGF23¹⁰.

In patients on dialysis, hyperphosphatemia directly stimulates PTH secretion and maintains a persistent stimulus for parathyroid hyperplasia. Recent studies have demonstrated that high P prevents the activation of the CaSR¹³, a mechanism whereby P stimulates PTH secretion despite normal serum Ca levels. Another important effect of P is the generation of skeletal resistance to the calcemic effect of PTH¹⁴, which contributes to hypocalcemia with the subsequent stimulus for parathyroid hyperplasia. In the absence of kidney function, the production of 1,25D₃ is very low and the consequences are hypocalcemia and parathyroid hyperplasia.

Although the mechanisms underlying the pathophysiology of SHPT are largely known, recent work has shed light on our knowledge of this pathology. Klotho serves as a co-receptor for FGF23¹⁵. However, the use of genetic approaches has revealed that there is an interaction between Klotho and the CaSR and that Klotho has a key role in suppressing PTH synthesis and parathyroid proliferation¹⁶.

Several studies have shown that FGF23 suppresses PTH production by acting on the specific parathyroid receptor FGFR1 (FGF23 receptor 1)-Klotho. However, with the development of parathyroid hyperplasia, Klotho expression is reduced and the high FGF23 is not able to inhibit PTH production and parathyroid cell proliferation^10,11. Clinical studies have demonstrated that FGF23 starts to rise at very early stages of CKD in an attempt to prevent accumulation of P. The increase in FGF23 is observed before the elevation in PTH¹⁷. High FGF23 levels reduce the renal production of 1,25D₃, which in turn promotes parathyroid hyperplasia. Phosphorus load, the main stimulus for FGF23 production, causes renal damage and a more rapid deterioration of renal function¹⁸ and P restriction prevents the elevation in FGF23^19–21. Thus, the early control of the factors influencing FGF23 also slows down the development of SHPT.

Although evidence of a direct stimulatory effect of P on PTH secretion was demonstrated more than 20 years ago, recent work by Centeno et al.¹³ shows that high P concentrations act on specific elements of the CaSR to stimulate PTH secretion. Therefore, it is very difficult to manage SHPT without controlling serum P levels. Furthermore, high serum P inhibits the calcemic response to PTH. Thus, in the presence of hyperphosphatemia, more PTH is required to maintain serum Ca levels^14,22.

In regard to the signaling mechanisms involved in the development of parathyroid hyperplasia, a recent study by Kan et al. reported that vitamin D deficiency promotes activation of nuclear factor kappa B (NFκB) both in parathyroid glands from patients on hemodialysis and in experimental models of uremia²³. Given that vitamin D also inhibits NFκB in other tissues²⁴, this might represent an additional benefit of vitamin D supplementation in the management of SHPT.

It is widely known that hyperplastic glands are characterized by reduced expression of parathyroid vitamin D receptor (VDR), CaSR, and FGFR1 and its co-receptor Klotho. In this regard, a very interesting study has investigated the transcriptomic signature in hyperplastic parathyroid glands, performing comparative analyses with parathyroid adenomas and healthy tissue²⁵. In addition to the repeatedly reported down-regulation of the VDR and CaSR genes, marked reductions in NFIL3 and RET were found when hyperplastic and normal tissues were compared²⁵. In addition, there is increasing awareness about the involvement of microRNAs (miRNAs) in the pathophysiology of parathyroid hyperplasia. miRNAs are small non-coding RNA molecules that modulate the expression of RNA. The miRNA profile in healthy and pathological parathyroid tissue is not well known. This matter was deeply investigated by Shilo et al., who found high expression of members of let-7, miR-30, and miR-141/200 miRNA families in parathyroid samples from humans, mice, and rats²⁶. In experimental hyperparathyroidism, the authors reported up-regulation of miR-29, miR-21, miR-148, miR-30, and miR-141 and down-regulation of miR-10, miR-125, and miR-25²⁶. Taken together, these results may help unravel novel mechanisms underlying the development of SHPT as well as design strategies to prevent parathyroid hyperplasia and manage PTH secretion.

Recent advances in the management of secondary hyperparathyroidism

Parathyroidectomy

Parathyroidectomy (PTx) is the surgical resection of the parathyroid glands and is considered in patients with hyperparathyroidism refractory to conservative medical therapy. Owing to the availability of new molecules for medical therapy, the indications for PTx could be reduced to the following: (1) hyperparathyroidism resistant to calcimimetic administration, (2) severe refractory hyperphosphatemia, (3) severe hyperparathyroidism in dialysis without response to medical treatment, (4) cases of calciphylaxis with PTH levels above 500 pg/mL that do not rapidly respond to calcimimetics, (5) complications derived from SHPT, and (6) primary hyperparathyroidism in patients with CKD⁵⁹. There are different modalities of PTx: subtotal PTx, total PTx with autotransplantation, and total PTx without autografting. The choice of one or another technique will depend on the clinical characteristics of the patient and the availability of a surgeon with the skills needed to perform the procedure⁵⁹.

The use of PTx in patients with CKD is associated with improvements in biochemical parameters of mineral and bone metabolism^60–62, cardiovascular health⁶³, and mortality^64,65. However, this technique is not free of complications, such as persistent hyperparathyroidism, often due to the existence of supernumerary or abnormally located parathyroid glands⁶⁶, or the development of hungry bone syndrome due to PTH oversuppression⁶⁷.

The surgical removal of parathyroid glands is a useful resource mainly in cases of hyperparathyroidism refractory to medical treatment. However, it should be taken into account that, despite the post-surgical benefits, PTx is not free of complications, and the risks and benefits should be considered in each particular case.

Conclusions

The management of SHPT is essential to control CKD-MBD. Thus, the appropriate prevention and treatment of SHPT may derive in lower occurrence of metabolic bone disease, vascular calcifications, and mortality. The management of SHPT is based on avoiding hyperphosphatemia and decreasing PTH levels by administrating calcimimetics and, when needed, VDR activators. PTx is required in only a small proportion of patients.