Parathyroidectomy

The Development of Secondary Hyperparathyroidism in Chronic Kidney Disease Patients

Mineral homeostasis requires precise regulation, and the kidney plays a crucial role. Deterioration of renal function causes an alteration in the regulation of calcium (Ca) and phosphate (P). There are a number of hormonal changes aiming to correct Ca and P disturbances. The term “chronic kidney disease-metabolic bone disease” (CKD-MBD) includes all abnormalities of mineral metabolism in CKD, that is, biochemical alterations, renal osteodystrophy, and extraosseous calcifications.

The parathyroid hormone (PTH) plays a central role in mineral homeostasis; small changes in serum Ca concentration levels are detected by parathyroid cells that are equipped with G-coupled Ca sensing receptor (CaSR). The activation of the CaSR by an increase in serum Ca reduces PTH secretion, and vice versa, a reduction in Ca stimulates PTH secretion. Intracellular signaling triggered by the CaSR will modify not only PTH secretion but also PTH synthesis and parathyroid cell proliferation. The increase in PTH corrects serum Ca levels by stimulating bone resorption with the consequent release of Ca and P to the extracellular space. In addition, PTH increases the synthesis of 1,25(OH) ₂ D3 (calcitriol) by the kidney, which augments the intestinal absorption of Ca and P. PTH reduces calciuria through the stimulation of tubular reabsorption of Ca and also increases phosphaturia by reducing tubular reabsorption of P.

The parathyroid function is inhibited by high levels of Ca, 1,25D3, and FGF-23. Derangements in the levels of these elements constitute potent stimuli for the onset and progression of secondary hyperparathyroidism (SHPT). One key factor in the development of SHPT is the accumulation of P due to the reduction of glomerular filtration. In CKD stage 3 and even 4, serum phosphate concentration is not increased because the increased P load stimulates the production of fibroblast growth factor 23 (FGF-23). FGF-23 is produced by mature osteoblasts and osteocytes. It acts on the receptor FGFR1–Klotho complex, reducing the proximal reabsorption of P and also reducing calcitriol production by the kidneys. Therefore the P balance is maintained by the increased distal delivery of P, which is finally excreted in the urine. It has been shown that the increase in fractional excretion of phosphate reduces the expression of Klotho, causing resistance to the action of FGF-23; thus, more FGF-23 has to be produced to maintain P excretion, and the demand for FGF-23 will continue unless oral P load is reduced. FGF-23 is found to be increased since the very early stages of CKD ; the progressive increase in FGF-23 produces a gradual decrease in calcitriol synthesis, which not only contributes to hypocalcemia but also deprives the parathyroid cell of the inhibitory effect of calcitriol. With CKD stage 4, the number of nephrons is reduced to the point that the increases in PTH and FGF-23 are not able to augment P excretion, then hyperphosphatemia, together with hypocalcemia, develops.

SHPT develops progressively in parallel with the continuous deterioration of renal function. It is characterized by elevated rates of PTH synthesis and secretion accompanied by parathyroid cell hyperplasia. Factors involved in the development of SHPT are hypocalcemia, hyperphosphatemia, and low 1,25D3 and FGF-23. Hypocalcemia and hyperphosphatemia stimulate PTH production and secretion and promote cell proliferation. An important effect of P is the generation of skeletal resistance to the calcemic effect of PTH, which contributes to hypocalcemia with the subsequent stimulus for parathyroid hyperplasia. Hypocalcemia increases the expression of proliferating cell nuclear antigen. A direct stimulatory effect of P on PTH secretion was demonstrated 25 years ago. Recent work by Centeno et al. 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. A recent study by Kan et al. examined signaling mechanisms involved in the development of parathyroid hyperplasia; low vitamin D levels activate nuclear factor kappa B (NFκB) in parathyroid glands. The absent or reduced antiproliferative action of 1,25D3 and the impaired regulation of p21 and αKlotho/FGF receptor (FGFR) signaling by FGF-23 contribute to the development of parathyroid hyperplasia. In animals with normal renal function, the elevation in FGF-23 causes a reduction in PTH production and cell proliferation, but as parathyroid hyperplasia develops, there is a lower expression of parathyroid FGFR and Klotho receptors, which prevents any inhibitory effect of FGF-23. In addition, there is a direct interaction between Klotho and CaSR that results in suppression of PTH synthesis and parathyroid proliferation.

In hyperplastic glands, the expressions of vitamin D receptor (VDR), CaSR, FGFR1, and its coreceptor Klotho are markedly reduced. In addition, parathyroid adenomas show marked reductions in NFIL3 (nuclear factor, interleukin 3) and RET (rearranged during transfection). Changes in microRNAs (miRNAs) are also involved in the pathophysiology of parathyroid hyperplasia, as shown by Shilo et al., who found high expressions of members of let-7, miR-30, and miR-141/200 miRNA families in parathyroid samples from humans, mice, and rats. In experimental hyperparathyroidism, the authors reported upregulation of miR-29, miR-21, miR-148, miR-30, and miR-141 and downregulation of miR-10, miR-125, and miR-25. This information may help to understand the development of SHPT better and may help in designing strategies to prevent parathyroid hyperplasia.

Refractory Hyperparathyroidism

Parathyroid hyperplasia may progress from diffuse to nodular hyperplasia, which is characterized by a reduction in the expression of parathyroid receptors: CaSR, VDR, FGFR1, and Klotho. This is known as tertiary hyperparathyroidism, and at this point, the gland may be refractory to the medical treatment. Several research groups have reported that there is a decrease in CaSR in nodular areas. Fig. 42.1 shows the in vitro PTH secretion in glands from patients with refractory SHPT (secondary hyperparathyroidism) incubated in normal calcium concentration; for the same ambient calcium, the PTH secretion is inversely proportional to the abundance of CaSR. This explains the poor response to calcimimetics or the increase in Ca induced by 1,25D3 administration. Likewise, Fig. 42.2 shows the reduction of receptor FGFR1 in parathyroid glands with nodular hyperplasia. The marked reduction in VDR density in nodular hyperplasia also contributes to the refractoriness to 1,25D3 treatment. Studies performed in vitro using parathyroid gland tissue from parathyroidectomies performed in uremic patients demonstrate that there is an abnormal response to both Ca and 1,25D3 in nodular hyperplasia.

Indications for Parathyroidectomy

Parathyroidectomy (PTX) should be considered if medical therapy is ineffective in controlling PTH. Nowadays, with the introduction of new alternatives for medical treatment, mainly oral and intravenous (IV) calcimimetics, the indications could be reduced to:

• hyperparathyroidism refractory to treatment with calcimimetics

• severe refractory hyperphosphatemia

• severe SHPT (PTH > 800–1000 pg/mL without hypocalcemia) in dialysis without response to combined medical treatment (association of cinacalcet, P binders, and vitamin D derivates) for more than 12 months

• patients with calciphylaxis and PTH greater than 500 pg/mL who do not respond rapidly to treatment with calcimimetics

• complications associated with SHPT, such as tendinous rupture, severe bone pain, or refractory anemia

• primary hyperparathyroidism (non-iatrogenic hypercalcemia with nonsuppressed PTH) in patients with CKD (especially young patients)

• kidney transplanted patients with uncontrolled hypercalcemia with high PTH and poor response to calcimimetics

Important consequences of prolonged untreated SHPT are hip fracture and vascular calcification. Hip fracture is more than 85 times higher among dialysis patients younger than 45 years than in healthy persons of the same age. This cannot be ascribed solely to PTH, but its role is clearly contributory and, importantly, amenable to therapy. The prevalence of vascular calcifications is extremely high in end-stage renal disease. Excessive elevation of PTH accentuates hyperphosphatemia, which produces osteogenic transdifferentiation of vascular smooth muscle cells. In these cases, PTX may be an effective therapy that increases survival rates and patient quality of life.

Surgical Management of Secondary Hyperparathyroidism

In the 1990s, Ca-containing P binders and calcitriol were increasingly used in the management of SHPT in dialysis patients in the United States. The PTX rate decreased from 11.6/1000 patient-years in 1992 to 6.8/1000 patients-years in 1998. From 1998 to 2002, with the advent of synthetic active vitamin D analogs and non-Ca-containing P binders, the use of calcitriol declined in favor of paricalcitol. However, the PTX rate increased to 11.8/1000 patients-years in 2002. In 2004, cinacalcet was introduced in the United States. In 2011 the rate of PTX was 4.9/1000 patients-years.

Nowadays, technological advances allow performing surgeries efficiently with a very short hospital stay, less pain, and minimal scars. Inhospital mortality rates after PTX for SHPT have steadily declined to < 1% in recent years.