The treatment of hyperparathyroidism secondary to renal failure is a complex clinical dilemma. No simple optimal approach to patient selection and stratification for surgical intervention is available at this time. The goals of this publication are to review the pathophysiology of parathyroid gland function in patients with impaired renal function, make recommendations for how to proceed with a parathyroidectomy in these patients, and to provide some guidelines for preoperative and postoperative management.
Many patients with renal failure present with symptoms associated with chronically elevated levels of phosphate. In particular, the high parathyroid hormone (PTH) levels in patients with renal failure can be a management challenge. Given the unique physiologic state of these patients, their hyperparathyroidism (HPT) warrants special considerations for selecting appropriate medical and surgical management.
Secondary HPT is caused by any condition associated with a chronic depression in the serum calcium level because low serum calcium leads to compensatory overactivity of the parathyroid glands. Renal failure is, by far, the most common cause of secondary HPT, although other diseases, including inadequate dietary calcium intake, steatorrhea, and vitamin D deficiency can also cause this condition. Chronic renal insufficiency is associated with impaired phosphate excretion, which leads to hyperphosphatemia. Elevated serum phosphate directly depresses serum calcium levels and thereby stimulates parathyroid gland activity.
In contrast, tertiary HPT is observed in patients with renal failure that have undergone renal transplantation but still overproduce PTH. This condition is typically observed after successful renal transplantation when asymptomatic elevated calcium levels are observed. Laboratory studies in these patients are similar to patients with primary HPT, namely elevated PTH secondary to over activity of the parathyroid glands.
In renal HPT, the hypercalcemia is observed with elevated synthesis of calcitriol. The persistent hyperphosphatemia, bone resistance, and change in the PTH set point lead to the diffuse hyperplasia of the parathyroid glands. These changes are not limited to a single gland, but affect all of the glands.
It has been reported that 1% to 28% of patients who have hemodialysis develop significant secondary HPT. For patients with renal transplant, failure of the resolution of the calcium and phosphate metabolism leading to tertiary HPT has been estimated to occur in 1% to 10%.
Calcium metabolism
Plasma calcium exists in ionized and protein bound phases. Normally about 1gm of calcium in the inorganic form is absorbed daily in the proximal small intestine. Extracellular calcium is constantly being exchanged with that in the bone, intracellular fluid, and glomerular filtrate. Normal kidney can reabsorb 99% of the calcium that is present in the filtrate. Bone is an enormous reservoir of calcium.
The serum calcium level is controlled by the interaction of PTH, calcitonin, and Vitamin D. Vitamin D is not one molecule but a mix of sterols. Active form of Vitamin D results from activity of renal 1a-hydroxylase conversion of 25-Vitamin D to 1,2-dihydroxycholecalciferol, which is the active form of the Vitamin D. The role of the Vitamin D activity in calcium homeostasis is directed at increased intestinal absorption and increased bone resorption. As the glomerular filtration rate decreases, renal production of 1,2-dihydroxycholecalciferol decreases, leading to decreased intestinal calcium absorption to create a negative calcium balance. A compensatory increase in PTH secretion keeps the serum calcium level near normal by mobilizing calcium from bone.
Renal insufficiency with continued decrease in kidney function abrogates Vitamin D effects. Furthermore, chronic elevation of phosphate in renal failure affects parathyroid gland function. With elevated serum phosphate and low active vitamin D levels, serum calcium is low, which triggers development of secondary HPT–hypertrophy of the parathyroid glands. In contrast to what is observed in primary and tertiary HPT, patients with secondary HPT have low serum calcium levels, which lead to elevated levels of PTH.
Parathyroid hormone
Parathyroid hormone is a single-chain polypeptide consisting of 84 amino acids. PTH is synthesized by chief cells of the parathyroid gland. The principal actions of parathyroid hormone include an increase in
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Serum calcium and decrease in serum phosphorus levels
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Bone osteoclast and osteoblast activity
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Gastrointestinal absorption of calcium
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Renal bicarbonate excretion
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Renal hydroxylation of 25-hydroxy Vitamin D3.
The level of serum calcium in humans is under a sensitive feedback-control mechanism. Hypercalcemia reduces parathyroid hormone secretion and the formation of 1,25-dihydroxy vitamin D3 in normal healthy individuals. In cases of secondary HPT, elevated levels of phosphate lead to suppression of the calcium levels and elevation of the PTH in response to low calcium levels.
Parathyroid hormone
Parathyroid hormone is a single-chain polypeptide consisting of 84 amino acids. PTH is synthesized by chief cells of the parathyroid gland. The principal actions of parathyroid hormone include an increase in
- •
Serum calcium and decrease in serum phosphorus levels
- •
Bone osteoclast and osteoblast activity
- •
Gastrointestinal absorption of calcium
- •
Renal bicarbonate excretion
- •
Renal hydroxylation of 25-hydroxy Vitamin D3.
The level of serum calcium in humans is under a sensitive feedback-control mechanism. Hypercalcemia reduces parathyroid hormone secretion and the formation of 1,25-dihydroxy vitamin D3 in normal healthy individuals. In cases of secondary HPT, elevated levels of phosphate lead to suppression of the calcium levels and elevation of the PTH in response to low calcium levels.
Medical treatment goals
Given that the underlying cause for secondary HPT is overstimulation of the parathyroid glands, medical management is focused on decreasing that stimulation. One of the methods to control serum hyperphosphatemia may be achieved with phosphate binders in conjunction with dietary limits on the phosphate intake. In addition, supplemental calcium and Vitamin D may assist in achieving these goals. Calcium may also be added to patients’ dialysate on a regular basis. Despite the best management of hyperphosphatemia, a significant number of patients may develop prominent osteodystrophy. Osteodystrophy is especially common in patients that are on chronic hemodialysis because aluminum accumulates in the bones contributing to osteomalacia. Furthermore, patients may also develop ectopic calcification.
Surgical indications in secondary and tertiary HPT
The secondary HPT in the majority of renal patients on hemodialysis may not warrant surgical intervention. Thus, medical management should always be undertaken first. The symptoms that favor surgical intervention are persistent hypercalcemia, uncontrolled hyperphosphatemia, elevated alkaline phosphatase levels, and evidence of significant bone erosion on imaging or development of osteitis fibrosa cystica (OFC). The clinical finding associated with OFC may manifest as worsening bone pain and fractures. Significant discomfort is reported from persistent pruritus and development of the soft tissue calcifications. Several additional clinical findings should be taken into consideration, such as erythropoietin resistant anemia, poorly controlled hypertension, impaired myocardial perfusion, and peripheral neuropathies. Development of significant calciphylaxis (deposition of calcium in skin) should also be taken into consideration when making a decision for surgical intervention. However, elevation of the PTH alone does not warrant surgical intervention.
Table 1 summarizes some of the critical considerations in determining indications for surgery in renal failure. Although many different factors can be examined in deciding whether to operate on patients, calcium levels, alkaline phosphatase levels, and the presence of subperiosteal bone resorption are all important. As patients progress from Stage I to Stage II, they develop relative and then an absolute indication for surgery. Certainly, any patient with a diagnosis of calciphylaxis has an absolute indication for surgery.
