Renal Hyperparathyroidism

A class of allosteric activators of the Ca2+-sensing receptor that sensitizes the receptor to extracellular calcium and acts only in the presence but not in the absence of calcium. Calcimimetics can be used to treat various forms of hyperparathyroidism, although they are only approved for use in patients with end stage renal disease receiving dialysis treatment. 

Primary hyperparathyroidism occurs as a result of hyperplasia or the occurrence of adenoma. Secondary hyperparathyroidism may result from renal failure because of the associated phosphate retention, resistance to the metabolic actions of PTH, or impaired vitamin D metabolism. The last-mentioned factor is primarily responsible for the development of osteomalacia. Muscle symptoms are much more common in patients with osteomalacia than in primary hyperparathyroidism. Muscle biopsy has revealed disseminated atrophy, sometimes confined to type 2 fibers, but in other cases involving both fiber types. Clinical features of osteomalacic myopathy are proximal limb weakness and associated bone pain the condition responds well to treatment with vitamin D. 

FIGURE 23-5. Pathogenesis of secondary hyperparathyroidism and renal osteodystrophy in patients with CKD. 

Clinical Presentation of Secondary Hyperparathyroidism and Renal Osteodystrophy ... 

Renal osteodystrophy Altered bone turnover that results from sustained metabolic conditions that occur in chronic kidney disease, including secondary hyperparathyroidism, hyperphosphatemia, hypocalcemia, and vitamin D deficiency. 

Secondary hyperparathyroidism Increased secretion of parathyroid hormone from the parathyroid glands caused by hyperphosphatemia, hypocalcemia, and vitamin D deficiency that result from decreased kidney function. It can lead to bone disease (renal osteodystrophy). 

Parathyroid hormone (PTH) produces CNS effects in normal subjects and neuropsychiatric symptoms are frequently encountered in patients with primary hyperparathyroidism, where EEG changes resemble those described in acute renal failure. Circulating PTH is not removed by hemodialysis. In uremic patients both EEG changes and neuropsychiatric symptoms are improved by either parathyroidectomy or medical suppression of PTH. The mechanism whereby PTH causes disturbances of CNS function is not well understood, but it has been suggested that increased PTH might facilitate the entry of Ca2+ into the cell resulting in cell death. 

Glucocorticoids decrease bone formation through decreased proliferation and differentiation, and enhanced apoptosis of osteoblasts. They also increase bone resorption, decrease calcium absorption, increase renal calcium excretion, and result in secondary hyperparathyroidism. 

FIGURE 76-7. Pathogenesis of secondary hyperparathyroidism and renal osteodystrophy in patients with chronic kidney disease. These adaptations are lost as renal failure progresses. (Ca, calcium, P04 phosphate PTH, parathyroid hormone.)... 

Cancer and hyperparathyroidism are the most common causes of hypercalcemia. The primary mechanisms are increased bone resorption, increased GI absorption, and decreased renal elimination. 

Chronic hypercalcemia (i.e., hyperparathyroidism) is associated with metastatic calcification, nephrolithiasis, and chronic renal insufficiency. 

High phosphate diets cause decreased Ca absorption, secondary hyperparathyroidism, accelerated bone resorption and soft tissue calcification in some animals, but not in normal humans. Although phosphates may decrease Ca absorption in man at very high (> 2000 mg/day) Ca intakes, they do not do so at more moderate Ca levels and enhance Ca absorption at very low levels (< 500 mg/day). Phosphates increase renal tubular reabsorption and net retention of Ca. At low Ca intakes, phosphates stimulate parathyroid hormone (PTH) secretion without causing net bone resorption. 

Patients with advanced renal insufficiency (Ccr less than 30 mL/min) exhibit phosphate retention and some degree of hyperphosphatemia. The retention of phosphate plays a role in causing secondary hyperparathyroidism associated with osteodystrophy and soft-tissue calcification. Calcium acetate, when taken with meals, combines with dietary phosphate to form insoluble calcium phosphate, which is excreted in the feces. 

Renal osteodystrophy is a complex disorder with several pathogenic factors. Histological evidence of bone disease is common in early renal failure and deficits in calcitriol synthesis seems to be an important factor in the pathogenesis of secondary hyperparathyroidism in early CRF. The most common component is osteitis fibrosa manifested as subperiosteal resorption of bone. This is due to decreased excretion as well as increased secretion of parathyroid hormone. In CRF small increments of serum phosphorus cause small decreases in serum calcium. 

Patients with chronic renal failure develop hyperphosphatemia, hypocalcemia, secondary hyperparathyroidism, and severe metabolic bone disease. The secondary hyperparathyroidism is thought to be due to hyperphosphatemia and decreased 1, 25-(OH)2 formation. Oral or intravenous l,25-(OH)2D3 (calcitriol) therapy along with oral phosphate-binding agents and calcium supplementation is effective in reducing the effects of renal osteodystrophy. 

Contraindications Primary or secondary hyperparathyroidism, including hypercalci-uria (renal calcium leak), hypomagnesemic states (serum magnesium less than 1.5 mg/dl), bone disease (osteoporosis, osteomalacia, osteitis), hypocalcemic states (e.g., hypoparathyroidism, intestinal malabsorption), normal or low intestinal absorption and renal excretion of calcium, enteric hyperoxaluria, and patients with high fasting urinary calcium or hypophosphatemia. 

It is indicated in osteoporosis, hypoparathyroidism, hyperparathyroidism (with bone disease), renal osteodystrophy, nutritional and malabsorptive rickets, hypophosphataemic vitamin D resistant rickets and osteomalacia. 

Three adolescent boys with chronic renal insufficiency, treated with somatropin during the pubertal growth spurt, developed severe hyperparathyroidism (35). It is unclear whether this was coincidental or whether growth hormone and sex steroid hormones had a synergistic effect. 

Exacerbation of secondary hyperparathyroidism occurred in a 20-year-old renal transplant patient who also developed psoriasis during interferon alfa treatment (527). Both disorders resolved after withdrawal. 

In the last case the authors concluded that the hypercalcemia was due to long-term lithium treatment and cited studies showing that hyperparathyroidism occurs in 5—40% of patients taking long-term lithium, compared with a population frequency of less than 4%. The patient s chief complaint included nausea when he was exposed to food and water, and he therefore refused food and water for 2-3 days before admission. He also had acute renal insufficiency, which was thought to be due to... 

The major problems of chronic renal failure that impact on bone mineral homeostasis are the loss of l,25(OH)2D and 24,25(OH)2D production, the retention of phosphate that reduces ionized calcium levels, and the secondary hyperparathyroidism that results. With the loss of l,25(OH)2D production, less calcium is absorbed from the intestine and less bone is resorbed under the influence of PTH. As a result hypocalcemia usually develops, furthering the development of hyperparathyroidism. The bones show a mixture of osteomalacia and osteitis fibrosa. 

In contrast to the hypocalcemia that is more often associated with chronic renal failure, some patients may become hypercalcemic from two causes (in addition to overzealous treatment with calcium). The most common cause of hypercalcemia is the development of severe secondary (sometimes referred to as tertiary) hyperparathyroidism. In such cases, the PTH level in blood is very high. Serum alkaline phosphatase levels also tend to be high. Treatment often requires parathy roi dectomy. 

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