Gene/Protein Disease Symptom Drug Enzyme Compound
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Phosphorus is the sixth most abundant element in the body after oxygen, hydrogen, carbon, nitrogen, and calcium. It comprises about 1% of the total body weight of humans. Eighty-five percent of it is stored in the bone in the form of hydroxyapatite crystal; 14% is in the soft tissues in the form of energy-storing bonds with nucleotides (ATP, GTP), nucleic acids in chromosomes and ribosomes, 2,3-DPG in the red blood cells, and phospholipids in the cells' membranes. Less than 1% is in the extracellular fluids. Phosphate balance is maintained by multiple systems. The gut is responsible for the absorption of two thirds of the 4-30 mg/kg/day of phosphate intake. Absorption sites are all along the gut; in humans the most active site is the jejunum. The kidney filters 90% of the plasma phosphate and reabsorbs it in the tubuli. In states of hypophosphatemia the kidney can reabsorb the filtered phosphates very efficiently, reducing the amount excreted in the urine virtually to zero. The healthy kidney can excrete high loads of phosphate and rid the body of phosphate overload. Through the vitamin D-PTH axis the endocrine system regulates the phosphate balance by influencing the kidney, gut, and bone. Other hormones, including thyroid, insulin, glucagon, glucocorticosteroid, and thyrocalcitonin, play a lesser role in regulation of phosphate metabolism. Because of the complex control of phosphate homeostasis, various clinical conditions may lead to hypophosphatemia. These include nutritional repletion, gastrointestinal malabsorption, use of phosphate binders, starvation, diabetes mellitus, and increased urinary losses due to tubular dysfunction. The clinical picture of phosphate depletion is manifested in different organs and is due mainly to the fall in intracellular levels of ATP and decreased availability of oxygen to the tissues, secondary to 2,3-DPG depletion. The various manifestations of phosphate depletion are listed in Table 2. The treatment of hypophosphatemia consists of administering enteral or parenteral phosphate salts. An important aspect of dealing with the potentially serious effects of phosphate depletion is to prevent the depletion from happening in the first place. Hyperphosphatemia can occur in renal failure, hemolysis, tumor lysis syndrome, and rhabdomyolysis. The treatment of hyperphosphatemia usually consists of fluid administration (in the absence of kidney failure). In chronic hyperphosphatemia, phosphate binders such as aluminum and magnesium salts can reduce the phosphate load. The use of these phosphate binders is limited by their potential side effects.
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PMID:Consequences of phosphate imbalance. 306 Jan 61

Cunninghamella bertholletiae, an uncommon cause of human infection, has been reported with increasing frequency in recent years. C. bertholletiae belongs to the order Mucorales and produces infections similar to those produced by the other agents of mucormycosis. Infections with this group of organisms have typically been seen either in patients with diabetes mellitus or in those receiving chemotherapy. Recent reports of mucormycosis in dialysis patients receiving deferoxamine for iron or aluminum overload have raised the possibility that deferoxamine therapy is a risk factor for mucormycosis. A case of C. bertholletiae infection in a patient receiving deferoxamine for iron overload unrelated to hemodialysis was investigated in detail, and possible explanations for this patient's infection were assessed.
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PMID:Cunninghamella bertholletiae infection associated with deferoxamine therapy. 306 Sep 47

Aluminum has been proposed as the causative agent in dialysis encephalopathy syndrome. We prospectively assessed whether other, less severe, neuropsychologic abnormalities were also associated with aluminum. A total of 16 patients receiving chronic dialytic therapy were studied. The deferoxamine infusion test (DIT) was used to assess total body aluminum burden. Neurologic function was evaluated by quantitative measures of asterixis, myoclonus, motor strength, and sensation. Cognitive function was assessed by measures of dementia, memory, language, and depression. There were four patients with a positive DIT (greater than 125 micrograms/L increment in serum aluminum) that was associated with an increase in the number of neurologic abnormalities observed, as well as an increase in severity of myoclonus, asterixis, and lower extremity weakness. Patients with a positive DIT also showed significant impairment in memory; however, no differences were noted on tests of dementia, depression, or language. There was no significant correlation between sex, age, presence of diabetes, mode of dialysis, years of chronic renal failure, years of dialysis or years of aluminum ingestion and any neurologic or neurobehavioral measurement, serum aluminum level, or DIT. These changes may represent early aluminum-associated neurologic dysfunction.
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PMID:Relationship of aluminum to neurocognitive dysfunction in chronic dialysis patients. 317 74

Bone disease related to aluminum toxicity (aluminum-related bone disease) presents with variable clinical and biochemical findings in patients with renal failure. Bone pain and muscle weakness are common, although afflicted patients can be asymptomatic. Bone pain can be generalized or localized to the hips, back, feet, or ankles; proximal muscle weakness is common. Most cases in the United States arise from the ingestion of aluminum-containing gels by patients on long-term dialysis treatment. Patients at increased risk for developing aluminum-related bone disease include those with earlier parathyroidectomy, failed renal transplant, previous bilateral nephrectomy, and diabetes mellitus. Biochemical features that are common with aluminum-related bone disease include plasma aluminum levels greater than 100 to 150 micrograms/L, serum parathyroid hormone (PTH) levels equal to or lower than those in dialysis patients without bone disease, and normal or slightly elevated serum calcium levels. Plasma alkaline phosphatase levels are often elevated. In our experience, microcytic anemia has been uncommon. An increase in plasma aluminum levels greater than 200 micrograms/L 24 to 48 hours after the infusion of the chelating agent deferoxamine (DFO) correlates with an increased bone aluminum content, and an increment greater than 400 micrograms/L suggests marked aluminum accumulation. Radiographs are usually nonspecific. When results from indirect diagnostic procedures are equivocal, a bone biopsy is necessary. After a diagnosis of aluminum-related bone disease is established, therapy with DFO may be useful. DFO increases both the total plasma aluminum level and its ultrafilterable fraction. After an infusion of DFO, the removal of aluminum increases from 50 to 300 micrograms to 4 to 8 mg per dialysis session. Aluminum removal is similar during continuous ambulatory peritoneal dialysis after either intravenous (IV) or intraperitoneal (IP) administration of DFO. Usually, 2 to 4 g of DFO is administered once weekly, but the optimal dose and duration of therapy have not been determined. Symptoms usually improve after 4 to 12 weeks, and bone biopsies show improvement after treatment for 6 to 12 months. Further experience with DFO is needed, both to identify the optimal dosage and to clarify the risks of long-term therapy in patients with renal failure.
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PMID:Diagnosis of aluminum-related bone disease and treatment of aluminum toxicity with deferoxamine. 329 88

Bone biopsies and plasma parathyroid hormone (PTH) from 27 diabetic dialysis patients were compared to biopsies and PTH levels from matched patients without diabetes to determine if PTH has a role in preserving bone mass in diabetic renal osteodystrophy. Significantly lower values were present in the diabetic group for mineralized bone area (p less than 0.003), osteoblastic osteoid (p less than 0.01), resorptive surface (p less than 0.001), fibrosis (p less than 0.005), bone apposition rate (p less than 0.01), bone formation rate (BMU level) (p less than 0.04), and plasma PTH (p less than 0.05). Bone-surface aluminum was higher in the diabetic group (44 +/- 5% vs. 20 +/- 5%, p less than 0.005). Linear regression analysis revealed significant positive correlations of mineralized bone area with time on dialysis, bone formation rate, bone resorption, and PTH only in the group without diabetes. While both groups had significant positive correlations of PTH with osteoblastic osteoid and bone resorption, only in the nondiabetic group was there a positive correlation of PTH with bone apposition and bone formation rate (BMU level), observations suggesting that the lower bone formation in the diabetic patients may have arisen in part from a failure of PTH to promote bone mineralization. We conclude that relatively low PTH levels and high bone aluminum in diabetic patients with chronic renal failure may be responsible in part for low bone mass when compared to uremic patients without diabetes.
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PMID:Bone histomorphometry of renal osteodystrophy in diabetic patients. 345 34

Two maintenance hemodialysis patients receiving deferoxamine to chelate iron and aluminum developed intestinal mucormycosis. One patient had pulmonary mucormycosis as well. The patients lacked the usual predisposing factors to mucormycosis, ie, diabetes and acidosis, but both had liver disease. The role of siderophores such as deferoxamine in promoting certain infections is discussed with reference to this particular clinical setting.
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PMID:Intestinal mucormycosis in hemodialysis patients following deferoxamine. 360 86

To determine the significance of serum aluminum levels in dialysis patients, the authors retrospectively analyzed a series of patients on maintenance hemodialysis (HD) and continuous ambulatory peritoneal dialysis (CAPD). All patients had always been treated with a dialysate containing negligible amounts of aluminum. The serum aluminum levels of hemodialysis and CAPD patients were not significantly different, not related to age or sex, and not affected by the presence of diabetes or vitamin D intake. The most important determinant of serum aluminum level in the hemodialysis patients was the current dose of aluminum-containing phosphate-binding medication. This relationship was most striking in the compliant patients. In hemodialysis patients, after an increase during the first one to two years, the aluminum levels plateaued. Aluminum levels remained stable more than five years in CAPD patients. Red blood cell mean corpuscular volume was negatively correlated with serum aluminum level. In 28 dialysis patients who had bone biopsy, aluminum levels were positively correlated to histochemical aluminum staining and bone aluminum content. A level greater than 100 ng/mL was a reliable indicator of aluminum-associated osteomalacia, although a lower level did not exclude the presence of low turnover bone disease or mixed uremic osteodystrophy--two disorders possibly related to aluminum. In the presence of a high serum aluminum, elevated levels of immunoreactive parathyroid hormone (iPTH) were useful in detecting the presence of hyperparathyroidism; low levels of iPTH did not allow the authors to distinguish between other subtypes of uremic osteodystrophy.
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PMID:Interpretation of serum aluminum values in dialysis patients. 377 14

Aluminum-associated bone disease is a special problem in uremic patients on hemodialysis. We have observed this disorder in uremic patients with insulin-dependent diabetes soon after the start of dialysis treatments. We therefore studied bone biopsy specimens from 18 diabetic patients on hemodialysis to determine whether aluminum accumulates on bone surfaces at an accelerated rate in diabetes. We also measured the rates of bone formation, because lower rates may enhance the accumulation of aluminum on bone surfaces. As compared with 18 nondiabetic controls with uremia who were matched for age and duration of dialysis, the patients with diabetes had a higher rate of aluminum accumulation on bone surfaces (2.1 +/- 0.7 vs. 0.4 +/- 0.2 percent per month, P less than 0.01) and a lower rate of bone formation (117 +/- 50 vs. 396 +/- 81 microns 2 per square millimeter per day, P less than 0.01). Also, the patients with diabetes whose cumulative aluminum intake exceeded 0.5 kg had higher serum aluminum levels after an infusion of deferoxamine, as compared with controls matched for aluminum intake (P less than 0.01). These measurements reflected a higher aluminum content in the whole body in patients with diabetes. We suggest that the enhanced rate of aluminum accumulation on bone surfaces in uremic patients with diabetes occurs as a result of a low rate of bone formation and an increased accumulation of aluminum in the whole body.
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PMID:Early deposition of aluminum in bone in diabetic patients on hemodialysis. 380 61

Larger-than-conventional doses of nonsteroidal antiinflammatory drugs (NSAIDs) are known to lower plasma glucose levels. This phenomenon has raised the questions whether or not NSAIDs in conventional dosage can be used for the treatment of hyperglycemia in patients who have non-insulin-dependent diabetes mellitus and whether or not NSAIDs added to preexistent hypoglycemic drug therapy taken orally may lead to unanticipated hypoglycemia. In this study we evaluated aspirin, sodium salicylate and ibuprofen given in conventional dosage to hyperglycemic patients with adult-onset (type II) diabetes. Half the patients were usually treated for hyperglycemia by means of diet only and half with diet plus hypoglycemic drugs given orally. Significant changes in plasma glucose levels were not seen after the administration of a combination drug containing aspirin and magnesium-aluminum hydroxide (Ascriptin, 650 mg three times a day; glucose change = 236+/-30 to 236+/-31 mg per dl) or sodium salicylate (600 mg three times a day; glucose change=284+/-76 to 273+/-84 mg per dl). A statistically significant but small change was seen with the administration of ibuprofen (600 mg three times a day; glucose change=196+/-60 to 179+/-47 mg per dl) but not when giving ibuprofen (300 mg three times a day; glucose change=267+/-78 to 282+/-60 mg per dl). The results of this study indicate that conventional doses of NSAIDs should not be used for treating hyperglycemia and that, since the additive hypoglycemic effect of NSAIDs in conventional doses was minimal or negligible, they can be used safely for other purposes in diabetic patients taking hypoglycemic drugs orally.
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PMID:Effects of nonsteroidal antiinflammatory drugs in conventional dosage on glucose homeostasis in patients with diabetes. 662 82

Amylin is co-secreted with insulin from the pancreas of patients with non-insulin dependent diabetes mellitus, and its deposition may contribute to the central nervous system (CNS) manifestations of this disease. Amylin, but not its mRNA, is found in brain, suggesting that CNS amylin is derived from the circulation. This would require amylin to cross the blood-brain barrier (BBB). We used multiple-time regression analysis to determine the unidirectional influx constant (Ki) of blood-borne, radioactively labeled amylin (I-Amy) into the brain of mice. The Ki was 8.99(10(-4)) ml/g-min and was not inhibited with doses up to 100 micrograms/kg, but it was inhibited by aluminum (Al). About 0.11 to 0.13 percent of the injected dose of I-Amy entered each gram of brain. Radioactivity recovered from brain and analyzed by HPLC showed that the majority of radioactivity taken up by the brain represented intact I-Amy. Capillary depletion confirmed that blood-borne I-Amy completely crossed the BBB to enter the parenchymal/interstitial fluid space of the cerebral cortex. Taken together, these results show that blood-borne amylin has access to brain tissue and may be involved in some of the CNS manifestations of diabetes mellitus.
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PMID:Permeability of the blood-brain barrier to amylin. 747 50


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