Renal failure, osteomalacia

Cholecalciferol Regulate gene transcription via the vitamin D receptor Stimulate intestinal calcium absorption, bone resorption, renal calcium and phosphate reabsorption decrease parathyroid hormone (PTH) promote innate immunity inhibit adaptive immunity Osteoporosis, osteomalacia, renal failure, malabsorption Hypercalcemia, hypercalciuria the vitamin D preparations have much longer half-life than the metabolites and analogs... 

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. 

Chronic exposure to high levels of cadmium in food has caused bone disorders including osteoporosis and osteomalacia. Long-term ingestion of water, beans, and rice contaminated with cadmium by a Japanese population was associated with a crippling condition, Itai-Itai disease. The affliction is characterized by pain in the back and joints, osteomalacia, bone fractures, and occasional renal failure, and it most often affected women with multiple risk factors such as multiparity and poor nutrition. ... 

The pharmacotherapeutic uses of vitamin D include vitamin D deficiencies, rickets in children and osteomalacia in adults, and renal osteodystrophy in patients with chronic renal failure. For metabolic rickets in patients with a deficiency of... 

Calcium play vital role in excitation - contraction coupling in myocardium. Calcium mediates contraction in vascular and other smooth muscles. Calcium is required for exocytosis and also involved in neurotransmitters release. Calcium also help in maintaining integrity of mucosal membranes and mediating cell adhesions. Hypercalcemia may occur in hyperthyroidism, vitamin D intoxication and renal insufficiency, which can be treated by administration of calcitonin, edetate sodium, oral phosphate etc. Hypocalcemia may occur in hypothyroidism, malabsorption, osteomalacia secondary to leak of vitamin D or vitamin D resistance, pancreatitis and renal failure. Hypocalcemia can be treated by chloride, gluconate, gluceptate, lactate and carbonate salts of calcium. 

Gastrointestinal complaints (eg, nausea, diarrhea, vomiting, flatulence) are the most common adverse effects but rarely require discontinuation of therapy. Other potential adverse effects include headache and asthenia. Tenofbvir-associated proximal renal tubulopathy causes excessive renal phosphate and calcium losses and 1-hydroxylation defects of vitamin D, and preclinical studies in several animal species have demonstrated bone toxicity (eg, osteomalacia). Monitoring of bone mineral density should be considered with long-term use in those with risk factors for or with known osteoporosis, as well as in children. Reduction of renal function over time, as well as cases of acute renal failure and Fanconi s syndrome, have been reported in patients receiving tenofovir alone or in combination with emtricitabine. For this reason, tenofovir should be used with caution in patients at risk for renal dysfunction. Tenofovir may compete with other drugs that are actively secreted by the kidneys, such as cidofovir, acyclovir, and ganciclovir. 

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. 

No studies were located regarding developmental effects of various forms of aluminum following acute-or chronic-duration oral exposure in healthy humans. The only human data on developmental effects come from infants with renal failure and premature infants. Their responses are probably not indicative of responses expected in normal infants. Osteomalacia and increased bone and serum levels of aluminum were reported in 3 infants with kidney failure who had been treated orally with more than 100 mg of Al/kg/day as aluminum hydroxide from the first or sixth month of life (Andreoli et al. 1984 Griswold et al. 1983), and in healthy infants ingesting aluminum-containing antacids (Pivnick et al. 1995). 

The major population at risk for aluminum loading and toxicity consists of individuals with renal failure. In a study by Alfrey (1980), 82% of nondialyzed uremic patients and 100% of dialyzed uremic patients had an increased body burden of aluminum. The decreased renal function and loss of the ability to excrete aluminum, ingestion of aluminum compounds to lessen gastrointestinal absorption of phosphate, the aluminum present in the water used for dialysate, and the possible increase in gastrointestinal absorption of aluminum in uremic patients can result in elevated aluminum body burdens. The increased body burdens in uremic patients has been associated with dialysis encephalopathy (also referred to as dialysis dementia), skeletal toxicity (osteomalacia, bone pain, pathological fractures, and proximal myopathy), and hematopoietic toxicity (microcytic, hypochromic anemia). Pre-term infants may also be particularly sensitive to the toxicity of aluminum due to reduced renal capacity (Tsou et al. 1991)... 

Vitamin D-binding protein and its associated vitamin are lost in nephrotic urine. Biochemical abnormalities in nephrotic patients (children and adults) include hypocalcemia, both total (protein-bound) and ionized hypocalciuria, reduced intestinal calcium absorption and negative calcium balance reduced plasma 25-hydroxycholecalciferol and 24,25-dihydroxycholecalciferol and, surprisingly, also 1,25-dihydroxycholecalciferol and blunted response to parathormon (PTH) administration and increased PTH levels. Clinically, both osteomalacia and hyperparathyroidism have been described in nephrotic patients, more commonly in children than in adults, but bone biopsies are commonly normal, and clinically significant bone disease is very rare in nephrotic subjects. There is, however, evidence that patients with renal failure accompanied by nephrotic range proteinuria may be particularly prone to develop renal osteodystrophy. 

Because the kidney is the only significant source of la-OHase, inadequate formation of l,25-(OH)2D3 occurs in renal failure [168], Not only is the mass of kidney tissue and therefore of enzyme decreased, but also with renal failure, phosphate excretion is reduced and serum phosphate rises. Increased phosphate inhibits la-OHase so that little l,25-(OH)2D3 is formed. Acidosis, a frequent result of renal failure, also impairs la-OHase activity [169, 170]. Deficiency of the active form of vitamin D causes osteomalacia, a prominent feature of renal osteodystrophy. Therapy is directed toward use of l,25-(OH)2D3, reduction of serum phosphate, and correction of acidosis, so that residual la-OHase can be expressed. 

Q7 Calcium is present in both intracellular fluid (ICF) and ECF, but the concentration in the ECF is twice as high as that in the ICF. Calcium is found in both ionized and bound forms, and Ca2+ homeostasis is mainly controlled by parathyroid hormone, which increases absorption of calcium in the intestine and reabsorption in the nephron. Calcitonin also affects ECF calcium concentration by promoting renal excretion when there is an excess of calcium in the body. The normal kidney filters and reabsorbs most of the filtered calcium however, in renal disease this is reduced and blood calcium decreases. Calcium and phosphate imbalance can occur in patients with renal failure, leading to osteomalacia (defective mineralization of bone). Osteomalacia is mainly due to reduced production of 1,25-dihydroxycholecalciferol, an active form of vitamin D metabolized in the kidney. Deficiency of 1,25-dihydroxycholecalciferol reduces the absorption of calcium salts by the intestine. 

Potassium (K+) and calcium (Ca2+) levels in blood are affected by renal failure. High K+ leads to muscle weakness and may cause cardiac rhythm disturbance. The low blood Ca2+ leads to defective mineralization of bones (osteomalacia)... 

Calcidiol la-hydroxylase is not restricted to the kidney, but is also found in placenta, bone cells (in culture), mammary glands, and keratinocytes. The placental enzyme makes a significant contribution to fetal calcitriol, but it is not clear whether the calcidiol 1-hydroxylase activity of other tissues is physiologically significant or not. Acutely nephrectomized animals given a single dose of calcidiol do not form any detectable calcitriol, but there is some formation of calcitriol in anephric patients, which increases on the administration of cholecalciferol or calcidiol. However, thus extrarenal synthesis is not adequate to meet requirements, so that osteomalacia develops in renal failure (Section 3.4.1). The enzyme is inhibited, or possibly repressed, by strontium ions this is the basis of strontium-induced vitamin D-resistant rickets, which responds to the administration of calcitriol or la-hydroxycalciol, but not calciferol or calcidiol (Omdahl and DeLuca, 1971). 

Renal failure is associated with an osteomalacia-like syndrome, renal osteodystrophy, as a result of the loss of calcidiol 1-hydroxylase activity. The condition may be complicated by defective reabsorption of calcium and phosphate from the urine. Furthermore, the half-life of parathyroid hormone is increased, because the principal site of its catabolism is the kidney, so there is increased parathyroid hormone-stimulated osteoclastic action without the compensatory action of calcitriol (Mawer etal., 1973). 

The distribution of the element is similar to that of calcium which means that 99% of the body burden is deposited in bone [44]. Within the dialysis population, bone strontium levels were found to be significantly higher in subjects with osteomalacia as compared to this presenting the other types of renal osteodystrophy [45]. A causal, dose-dependent role of strontium in the development of this bone disease has been established in a chronic renal failure ratmodel [46,47]. Moreover the bone osteomalacic lesions were found to be reversible after withdrawal of strontium [9,48]. 

Oste L, Bervoets AR, Behets GJ, Dams G, Marijnissen RL, Geryl Fi, Lamberts LV, Verberckmoes SC, Van Fioof VO, De Broe ME, D Fiaese PC. Time-evolution and reversibility of strontium-induced osteomalacia in chronic renal failure rats. Kidney Int 2005 67 920-930. 

Low-turnover bone diseases include osteomalacia and adynamic (also known as aplastic) bone diseases. Osteomalacia and adynamic bone disease are distinguished by the extent of unmineralized bone matrix or osteoid osteoid is increased in osteomalacia and normal or low in adynamic bone disease. Osteomalacia in chronic renal failure may reflect vitamin D deficiency because of the decreased renal synthesis of l,25(OH)2D (see Osteomalacia and Rickets) or aluminum-related disease. In the 1970s and 1980s, aluminum intoxication was a significant contributing factor to the development of osteomalacia and adynamic bone... 

The skeletal abnormalities associated with renal failure include osteomalacia, parathyroid osteopathy, osteoporosis, and osteosclerosis, in various combinations and degrees of severity (16). 

The prevalence of skeletal disease among patients with nonterminal renal failure is not known. The majority of such patients do not complain of skeletal symptoms and their serum alkaline phosphatase activities are not markedly elevated. The mean for all patients in one study (15) was 1.5 times the upper reference limit for adults. In some patients with nonterminal renal failure, systemic acidosis is out of proportion to the degree of nitrogenous retention, and it currently seems that acidotic patients are more liable to develop skeletal abnormalities. Mean serum alkaline phosphatase in a group of such patients was 3.5 times the upper reference limit, with individual values of almost 10 times the upper reference limit (15). The rise in total serum alkaline phosphatase, which is largely due to increases in the bone isoenzyme (15, P15), shows a significant positive correlation with the severity of parathyroid osteopathy, irrespective of the presence or absence of concurrent osteomalacia (P15). 

Skeletal disease is common in patients with renal failure treated by chronic dialysis. The majority of these patients have histologically demonstrable bone disease, even in the absence of clinical symptoms (B21). However, serum alkaline phosphatase activities are either within reference limits or only moderately elevated (B21), with spectacular elevations occurring only rarely in both adults (B21, KIO) and children (P34). High serum alkaline phosphatase values have been described in patients on chronic dialysis with severe hypophosphatemic osteomalacia (M3). 

Schrooten I, Cabrera W, Goodman WG, et al. 1998. Strontium causes osteomalacia in chronic renal failure rats. Kidney Int 54 448-456. 

Fig. 16. Relationship between plasma calchim and phosphorus concentrations in osteomalacia, rickets, normal subjects, and renal failure. Reproduced by permission of Clinical EndrocHnology.

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