Renal disease phosphate disorders

Patients with end-stage renal disease hyperphosphatemia ineffectively filter excess phosphate that enters the body in the normal diet.278 Elevated phosphate produces the bone disorder renal osteodystrophy. Skeletal deformity may occur, possibly associated with cardiovascular disease. Calcium deposits may further build up around the body and in blood vessels creating further health risks. The use of lanthanum carbonate is being promoted as an alternative to aluminum-based therapies.279,280 Systemic absorption, and cost have produced a clinical candidate, Fosrenol (AnorMED), an intriguing use of a lanthanide compound in therapy. 

Laboratory findings in rickets and osteomalacia include an increased serum ALP, with other alterations in bone and mineral metabolism dependent on the cause and severity of the disorder. ALP is usually increased because of the increased osteoblastic activity associated with producing unmineralized osteoid. Calcium may be low-normal or low in vitamin D deficiency depending on the severity of the disease. Phosphate may be normal or low, but falls with the development of secondary hyperparathyroidism. The serum calcium and PTH concentrations are usually normal in renal tubular defects of phosphate transport. Vitamin D nutrition may be assessed by the determination of serum 25(OH)D. Renal phosphate defects can be best assessed by determination of the renal phosphate threshold. 

Osteitis fibrosa (hyperparathyroid bone disease) is the most common high-turnover bone disease. This disorder is caused by the high concentrations of serum PTH in secondary hyperparathyroidism. Secondary hyperparathyroidism is a consequence of the hypocalcemia associated with hyperphosphatemia and l,25(OH)2D deficiency. Hyperphosphatemia is a result of the kidneys inability to excrete phosphate. l,25(OH)2D deficiency results from the inability of the kidneys to synthesize l,25(OH)2 because of decreased renal mass and suppression of 25(OH)D-la-hydroxylase activity by high concentrations of phosphate. Deficiency of l,25(OH)2D leads to reduced intestinal absorption of calcium and reduced inhibition of PTH secretion by l,25(OH)2D. Skeletal resistance to PTH also contributes to the hypocalcemia and secondary hyperparathyroidism. 

In addition to an increase in serum urea and creatinine levels, uric acid and inorganic phosphate levels also increase in chronic renal failure. The increase in serum inorganic phosphate leads to deposition of calcium phosphate in bones, causing hypocalcemia. In the early stages of chronic renal failure, calcium levels are restored by the stimulation of parathyroid hormone. However, as the renal disease progresses, the ability of the kidney to hydroxylate vitamin D and thus convert it to the active form decreases, thereby affecting the uptake of calcium by the gut and thus perpetuating hypocalcemia. Serum alkaline phosphatase levels increase due to disordered bone metabolism. Loss of bicarbonate is seen in some patients with increased parathyroid hormone activity. 

The most common cause of hypercalcemia in outpatients is primary hyperparathyroidism, due either to a single adenoma or diffuse hyperplasia. Primary hyperparathyroidism is often associated with significant hypophosphatemia due to PTH effects on renal phosphate reabsorption. The diagnosis is generally apparent from the elevated serum CcP associated with an inappropriately high PTH level. In contrast, secondary hyperparathyroidism is a disorder in which PTH levels are elevated in response to persistent threats to norrruil calcium homeostasis such as hyperphosphatemia from chronic renal disease. 

Calciphylaxis is a rare life-threatening disorder characterized hy progressive vascular calcification and ischemic tissue loss in patients with end-stage renal disease (Wood et al. 1997 Hafner et al. 1998 Karpman et al. 2003 Guvel et al. 2004). The pathogenesis is poorly understood it is likely the result of a multiplicity of co-morbid factors or events. Disorders that are most often implicated include chronic renal failure, hypercalcemia, hyperphosphatemia, an elevated calcium-phosphate product and secondary hyperparathyroidism. Very rare cases of calciphylaxis not associated with chronic renal failure have been reported with breast cancer, hyperparathyroidism and alcoholic cirrhosis. 

Vascular calcification is a process that involves accumulation of calcium deposits in vessel walls, resulting in increased arterial wall stiffness. Extra-osseous calcification occurs in areas of chronic inflammation, as in atherosclerotic lesions, in which oxidized lipids are the inflammatory stimulus. However, nonatherosclerotic calcification can occur in metabolic disorders like end-stage renal disease, diabetes, hyperparathyroidism, and vitamin K deficiency. This involves a complex interplay of various factors such as serum calcium and phosphate levels, activity of calcification promoters and inhibitors. Vascular calcification is associated with increased morbidity and mortality, predominantly from cardiovascular causes. ... 

Disorders of the calcium-phosphate metabolism are additional risk factors for renal disease progression. Several factors related to disturbed calcium-phosphorus metabolism, such as hyperphosphatemia, hyperparathyroidism, lack of... 

Substitution therapy for deficiency states acute or chronic adrenal insufficiency, congenital adrenal hyperplasia, and adrenal insufficiency secondary to pituitary insufficiency, nonendocrine disorders arthritis rheumatic carditis allergic, collagen, intestinal tract, liver, ocular, renal, shin diseases bronchial asthma cerebral edema malignancies PO 5-60 mg/day in divided doses. Intra-articular, Intralesional (acetate) 4-100 mg, repeated as needed. Intra-articular, Intralesional (sodium phosphate) 2-30 mg, repeated at 3-day to 3-week intervals, as needed. IM (acetate, sodium phosphate) 4-60 mg a day. 

A number of gastrointestinal and hepatic diseases result in disordered calcium and phosphate homeostasis that ultimately leads to bone disease. The bones in such patients show a combination of osteoporosis and osteomalacia. Osteitis fibrosa does not occur (as it does in renal osteodystrophy). The common features that appear to be important in this group of diseases are malabsorption of calcium and vitamin D. Liver disease may, in addition, reduce the production of 25(OH)D from vitamin D, though the importance of this in all but patients with terminal liver failure remains in dispute. The malabsorption of vitamin D is probably not limited to exogenous vitamin D. The liver secretes into bile a substantial number of vitamin D metabolites and conjugates that are reabsorbed in (presumably) the distal jejunum and ileum. Interference with this process could deplete the body of endogenous vitamin D metabolites as well as limit absorption of dietary vitamin D. 

Kidneys Dysfunction of the proximal tubule may occur as a late manifestation of Wilson s disease. Epithelial flattening, a loss of the brush-border membrane, mitochondrial anomalies and fatty cellular changes can be observed. These findings are, in turn, responsible for proteinuria with a predominance of hyperaminoaciduria (L. UzMAN et al., 1948). Enhanced calciuria and phosphat-uria may cause osteomalacia as well as hypoparathyroidism. (329, 344) Glucosuria and uricosuria, if present, are without clinical relevance. Due to decreased bicarbonate resorption, tubular acidosis may occur, with a tendency towards osteomalacia as well as the development of nephrocalcinosis and renal stones (in some 15% of cases). (344, 356, 392) The intensity of the copper deposits in the kidneys correlates closely with the cellular changes and functional disorders. The glomerular function is not compromised, with the result that substances normally excreted in the urine are not retained. 

Other chronic disorders cause osteomalacia. " " Phosphate depletion from low dietary intake, phosphate-binding antacids, and oncogenic osteomalacia (potentially phosphaturic effect) can cause osteomalacia. Hypophosphatasia is an inborn error of metabolism in which deficient activity of alkaline phosphatase causes impaired mineralization of bone matrix. Acidosis from renal dysfunction, distal renal tubular acidosis, hypergammaglobulinemic states (e.g., multiple myeloma), and drugs (e.g., chemotherapy) compromises bone mineralization. Renal tubular disorders secondary to Fanconi s syndrome, hereditary diseases (e.g., Wilson s disease, a defect in copper metabolism), acquired disease (e.g., myeloma), and toxins (e.g., lead) cause osteomalacia to varying degrees. Chronic wastage of phosphorus and/or calcium limits mineralization, which may be further compromised by acidosis and secondary hyperparathyroidism. 

The combination of hypophosphatemia, vitamin D resistance, osteomalacia, and rickets is seen in a number of syndromes (W24). These include (a) familial hypophosphatemic vitamin D-resistant rickets, a sex-linked, dominant disorder (P3), (b) familial vitamin D dependency, an autosomal recessive disorder due to la-hydroxylase deficiency (F19), and (c) nonfamilial hypophosphatemic osteomalacia (D9), considered by some workers (P3) to be a separate disease entity because of its late onset, its severity, and its lack of response to therapy. In addition, there are many inherited and acquired disorders which are associated with impairment of renal tubular reabsorption of phosphate, and these may be accompanied by hypophosphatemia, rickets, and relative vitamin D resistance. Serum alkaline phosphatase values in these disorders correlate poorly with the severity of the disease (A14) and with the response to therapy (E4, MclO, P7, S50). 

While alcohol abuse may be associated with a variety of electrolyte and acid-base disorders, the role of the kidneys in this process has only recently been fully defined [164]. Renal functional abnormalities have now been related to chronic alcoholism in patients without liver disease and these defects have reverted to normal with abstinence from alcohol abuse. These abnor-mahties include decreases in the maximal reabsorptive abihty and threshold for glucose, a decrease in the threshold for phosphate excretion, and increases in the fractional excretion of P2-microglobulin, uric acid, calcium, magnesium, and amino acids. Defective tubular acidification and impaired renal concentrating ability... 

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