Systemic mastocytosis

Systemic mastocytosis is characterized by abnormal mast cell proliferation in different organs. The 2001 consensus classification distinguishes in separate categories indolent systemic mastocytosis, systemic mastocytosis with concomitant blood disease, aggressive systemic mastocytosis and mast cell leukemia. Clinical manifestations are caused by tissue infiltration by proliferating mastocytes and by release of mediators. The principal organs affected are the skin, bones, digestive tract, liver, spleen and lymph nodes. Diagnosis of mastocytosis is based on appropriate stains (Giemsa, toluidine blue) and immunophenotype features (tryptase, CD117, also known as c-KIT and stem cell factor receptor). Serum tryptase levels reflect the total mast cell burden. Treatment must prevent release of mast cell mediators (histamine antagonists, cromolyn sodium, corticosteroids, or leukotriene-receptor inhibitors), limit bone involvement (bisphosphonates) and reduce the number of circulating mast cells (interferon, cladribine, or tyrosine kinase inhibitors). Enhanced understanding of the pathogenic mechanisms (mutation of c-kit and platelet-derived growth factor receptor alpha has led to the development of targeted treatments, including new inhibitors of tyrosine kinase and of nuclear factor Kappa B.     

Effect of a long-term treatment with 1,25-dihydroxyvitamin D3 on osteocalcin in postmenopausal osteoporosis

Summary Serum bone Gla-protein (BGP or osteocalcin) was measured in 25 women with histologically confirmed postmenopausal osteoporosis before and during long-term treatment with 1 μg/day of 1,25-dihydroxyvitamin D₃(1,25(OH)₂D₃). Basal serum BGP was significantly lower in osteoporotic women (3.8±1.4 ng/ml) than in agematched controls (6.8±2.0 ng/ml). During 1,25(OH)₂D₃ therapy serum BGP increased so that the mean of the values observed on treatment (4.8±1.5) was significantly higher than the mean basal value. It is known that BGP synthesis is stimulated by 1,25 (OH)₂D₃ and that serum BGP is a specific marker of bone formation; therefore, it is possible that the low basal levels of osteocalcin we observed were related to the low serum 1,25(OH)₂D concentrations reported in osteoporotic women and that the increase in BGP levels observed under 1,25(OH)₂D₃ treatment was a consequence of osteoblast stimulation.     

Parathyroid hormone and rates of bone formation are raised in perimenopausal rural Gambian women

To investigate rates of bone turnover and calcium homeostasis in Gambian women, we recruited 103 peri- and postmenopausal women, aged 45 to 80+ years and 11 women of reproductive age. Fasting blood was analyzed for plasma osteocalcin, PTH, 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], total- and bone-specific alkaline phosphatase. Plasma and urinary calcium, inorganic phosphate, sodium, potassium, creatinine, and albumin and urine free deoxypyridinoline (Dpd) was also measured. Samples from 20 premenopausal and 31 postmenopausal women from Cambridge, UK were analyzed, using the same methodology for comparison. For the Gambian women, peak calcium excretion occurred at around 50 years of age. For women aged > or =45 years, calcium excretion decreased by 3.0% per year of age (SE 1%; P < 0.005). In this age group, 25(OH)D also decreased with age (P < 0.005). Urinary sodium output, pH, and titratable acid output decreased (all P < 0.05) and total alkaline phosphatase (P < 0.005), osteocalcin (P < 0.005), and PTH (P < 0.05) increased with age. Comparisons were made between the following groups of Gambian and British women: premenopausal, early (age 55-64 years)- and late (age 65+ years)-postmenopausal. Gambian women of all ages were lighter (P < 0.001), shorter (P < 0.01), and had higher plasma bone-specific alkaline phosphatase activity (P < 0.05) and higher concentrations of osteocalcin (P < 0.05), PTH (P < 0.001), 1,25(OH)(2)D (P < 0.001), and 25(OH)D (P < 0.001). There were no consistent differences in calcitonin, while urinary free Dpd outputs were lower in the Gambians (P < 0.001). Plasma calcium, phosphate, and albumin (P < 0.01) were significantly lower. Urinary calcium, phosphate, sodium, and potassium excretion were lower, particularly in the postmenopausal group (P < 0.001). Although Gambian urine pH was more acidic, titratable acid output was lower (P < 0.01). These data show that Gambian women with low dietary calcium intakes and good vitamin D status have low urinary calcium excretion and that menopausal changes in calcium and bone metabolism among Gambian women are similar to those seen in other populations. In addition, they demonstrate that Gambian women of all ages have raised plasma PTH and 1,25(OH)(2)D concentrations and raised markers of osteoblast activity. We postulate that high endogenous PTH concentrations may be beneficial to bone health in Gambian women, removing fatigue damage and improving bone quality.     

Effects of bone associated growth factors on DNA, collagen and osteocalcin synthesis in cultured fetal rat calvariae

Studies in bone and bone cell cultures have shown that osteocalcin synthesis is dependent on the maturity of the osteoblast and the presence of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3. The bone matrix is a rich source of growth factors that play a role in bone formation, but their effects on osteocalcin synthesis and their interactions with 1,25(OH)2D3 have not been examined. Insulin-like growth factor I (IGF I), basic and acidic fibroblast growth factor (bFGF and aFGF), platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF beta), are growth factors associated with the bone matrix. These factors were shown to stimulate [3H]thymidine incorporation into DNA in 24 h cultures of fetal rat calvariae, and their effect was not modified by 1,25(OH)2D3. IGF I and TGF beta stimulated [3H]proline incorporation into calvarial collagen while the other growth factors studied did not; 1,25(OH)2D3 inhibited collagen synthesis in control as well as in IGF I and TGF beta treated calvariae. IGF I, bFGF and aFGF stimulated osteocalcin synthesis 1.5 to 2.5 fold but only IGF I was synergistic with the stimulatory effect of 1,25(OH)2D3. PDGF and TGF beta had no effect on osteocalcin synthesis. In conclusion, bone matrix-associated factors have important mitogenic effects in bone cultures, but only IGF I and FGFs stimulate osteocalcin synthesis, an effect that is of small magnitude when compared to that of 1,25(OH)2D3.     

Procollagen type I C-terminal extension peptide in predialysis chronic renal failure.

Collagen type 1 is the most abundant protein of bone. Serum levels of type 1 procollagen carboxy-terminal extension peptide (Procoll-1-C) may give a measure of the rate of synthesis of the collagen of bone and be therefore a marker of bone turnover. We have studied 38 patients with predialysis chronic renal failure; 14 of them were under long-term treatment with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] for prevention of secondary hyperparathyroidism. In all patients a transiliac bone biopsy for histomorphometry and determination of dynamic parameters was performed following double tetracycline labeling. In addition serum Procoll-1-C, intact and C-terminal parathyroid hormone (PTH), osteocalcin and alkaline phosphatase were determined. In the patients not receiving 1,25(OH)2D3, serum levels of Procoll-1-C were higher than normal. Procoll-1-C did not correlate with any of the humoral parameters, including serum creatinine, nor with static histomorphometric parameters. Contrarily to osteocalcin, the collagen type 1 marker correlated significantly with all dynamic parameters. Treatment with 1,25(OH)2D3 was accompanied by lower levels of osteocalcin, iPTH (n.s.), osteoblastic surface and by normal levels of Procoll-1-C (p < 0.001, compared to untreated patients), without substantial change in bone formation parameters (bone formation rate). In conclusion Procoll-1-C in predialysis chronic renal failure is a marker of bone turnover unparalleled by other markers. 1,25(OH)2D3 administration is associated with lower serum levels of the peptide unaccompanied by a decrement of bone formation parameters, therefore with an apparently better utilization of collagen type 1 in the mineralization process.(ABSTRACT TRUNCATED AT 250 WORDS)     

Measurement of vitamin D metabolites in anephric subjects

Circulating concentrations of 1,25-dihydroxyvitamin D, 24,25-dihydroxyvitamin D and 25-hydroxyvitamin D were measured in 21 anephric subjects. 13 subjects had no therapy with vitamin D, dihydrotachysterol or 1 alpha-hydroxyvitamin D3. In 7 subjects of this group 1,25-dihydroxyvitamin D was undetectable (less than 5 pmol/l). In the other 6 patients concentrations ranged from 10 to 43 pmol/l (reference value 111 +/- 33 pmol/l). All subjects taking high doses of vitamin D showed detectable 1,25-dihydroxyvitamin D concentrations in the same range. Dihydrotachysterol therapy caused spuriously high '1,25-dihydroxyvitamin D' values, probably by interference of a metabolite of dihydrotachysterol in our assay. In subjects on vitamin D or dihydrotachysterol therapy 25-hydroxyvitamin D concentrations were significantly elevated (314 +/- 146 nmol/l and 98 +/- 19 nmol/l, respectively; reference value 52 +/- 22 nmol/l). Concentrations of 24,25-dihydroxyvitamin D were only measured in subjects without vitamin D2 intake. In general very low but detectable concentrations were found. One subject on a high dose of vitamin D3 showed a 24,25-dihydroxyvitamin D3 concentration of 10.2 nmol/l (reference value 4.4 +/- 2.9 nmol/l). Our results therefore confirm earlier reports on extrarenal synthesis of 24,25-dihydroxyvitamin D and suggest that there may be extrarenal production of 1,25-dihydroxyvitamin D as well.     

How fibroblast growth factor 23 works

There is a discontinuum of hereditary and acquired disorders of phosphate homeostasis that are caused by either high or low circulating levels of the novel phosphaturic hormone fibroblastic growth factor 23 (FGF23). Disorders that are caused by high circulating levels of FGF23 are characterized by hypophosphatemia, decreased production of 1,25-dihydroxyvitamin D, and rickets/osteomalacia. On the other end of the spectrum are disorders that are caused by low circulating levels of FGF23, which are characterized by hyperphosphatemia, elevated production of 1,25-dihydroxyvitamin D, soft tissue calcifications, and hyperostosis. Knowledge of the genetic basis of these hereditary disorders of phosphate homeostasis and studies of their mouse homologues have uncovered a bone-kidney axis and new systems biology that govern bone mineralization, vitamin D metabolism, parathyroid gland function, and renal phosphate handling. Further understanding of this primary phosphate homeostatic pathway has the potential to have a significant impact on the diagnosis and treatment of disorders of bone and mineral metabolism.     

Comparative effects of a novel vitamin D analogue MC-903 and 1,25-dihydroxyvitamin D3 on alkaline phosphatase activity, osteocalcin and DNA synthesis by human osteoblastic cells in culture

MC-903 is a novel vitamin D analogue which has been shown to promote epidermal cell differentiation but is 100 times less active than 1,25 dihydroxyvitamin D3 (1,25(OH)2D) in causing hypercalcemia. In order to determine the activity of this compound on bone cells, we have compared the effects of MC-903 and 1,25 dihydroxyvitamin D3 (1,25(OH)2D) on parameters of cell proliferation and differentiation in cultured normal human osteoblastic cells derived by migration from trabecular bone fragments. Dose response curves showed that MC-903 was 10 to 100 times less effective than 1,25(OH)2D in stimulating the synthesis of the osteoblast specific protein osteocalcin by human bone cells depending on the basal osteocalcin production. In cells showing high basal osteocalcin synthesis, 1,25(OH)2D (10(-8) M) was 2- to 3-fold more potent than MC-903 (10(-8) M) in inducing osteocalcin from 48 to 96 h of treatment. The greater activity of 1,25(OH)2D over MC-903 was observed in human bone cell cultures with elevated basal osteocalcin levels, indicating that the response to 1,25(OH)2D but not to MC-903 was amplified in cells with the higher osteoblastic characteristics. The effects of MC-903 and 1,25(OH)2D on alkaline phosphatase activity were not markedly different. Transforming Growth Factor-beta (TGF beta) (0.5 ng/mL, 48 h) was found to completely suppress the osteocalcin synthesis induced by 1,25(OH)2D (10(-8) and 10(-9) M), whereas the MC-903-induced osteocalcin synthesis was not affected, suggesting a negative interaction between TGF beta and 1,25(OH)2D but not MC-903 on osteocalcin synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)     

24- and 26-homo-1,25-dihydroxyvitamin D3 analogs: potencies on in vitro bone resorption differ from those reported for cell differentiation

It has been proposed that the stimulatory effects of 1,25-dihydroxyvitamin D on bone resorption may be mediated through actions on differentiation of marrow cells into monocytic osteoclast precursors. In human promyelocytic leukemia cells (HL-60), 24- and 26-homo-1,25-dihydroxyvitamin D3 and their delta 22 analogs and 24,24-dihomo-1,25-dihydroxyvitamin D3 are 10-fold more potent than 1,25-dihydroxyvitamin D3, and delta 22-24,24,24-trihomo-1,25-dihydroxyvitamin D3 is equipotent with 1,25-dihydroxyvitamin D3 in inducing differentiation into the monocytic phenotype. The effect of these 1,25-dihydroxyvitamin D3 analogous on resorption of fetal rat limb bones in vitro was determined in the present study. 1,25-Dihydroxyvitamin D3 was equipotent with 24-homo-1,25-dihydroxyvitamin D3, delta 22-24-homo-1,25-dihydroxyvitamin D3, 26-homo-1,25-dihydroxyvitamin D3, and delta 22-26-homo-1,25-dihydroxyvitamin D3 for in vitro bone resorption, whereas 24,24-dihomo-1,25-dihydroxyvitamin D3 and delta 22-24,24,24-trihomo-1,25-dihydroxyvitamin D3 were inactive. The failure of these analogs to show a higher bone-resorbing activity than 1,25-dihydroxyvitamin D3 were inactive. The failure of these analogs to show a higher bone-resorbing activity than 1,25-dihydroxyvitamin D3 provides evidence to suggest that the mechanism of 1,25-dihydroxyvitamin D3-induced bone resorption may not involve stimulation of monocytic cell differentiation.     

Mineral metabolism in infants with malignant osteopetrosis: heterogeneity in plasma 1,25-dihydroxyvitamin D levels and bone histology.

A group of 16 infants, 2 weeks to 11 months old, with malignant osteopetrosis were investigated to examine their vitamin D metabolism and parathyroid function. Bone biopsies from 6 children were studied by light microscopic histomorphometry and by electron microscopy. Considerable heterogeneity existed among the patients with respect to the parameters reflecting mineral metabolism and with respect to the histological manifestations of the disease. The most constant findings were as follows. Immunoreactive parathyroid hormone (iPTH) was elevated in all children, except in 1 patient who had tubular acidosis, and plasma calcium was low or normal, suggesting skeletal resistance to PTH. Plasma 1,25-dihydroxyvitamin D [1,25-(OH)2D] was not constantly elevated and appeared to depend on plasma phosphorus, as both parameters were negatively correlated (r = 0.704, p less than 0.01). Osteoblast activity, as evaluated by circulating alkaline phosphatase and osteocalcin and osteoblast number, measured for 6 children by bone histology, were not increased, despite hyperparathyroidism, suggesting PTH resistance or defective osteoblasts. Osteoclasts could be detected in 5 of the 6 children who had a biopsy. Osteoclast number (5.7-13.3% of bone surface) was normal or mildly increased, and marrow spaces were relatively well developed in 4 patients, whereas 1 child had markedly increased osteoclast number (28.3% of bone surface) and reduced marrow cavities. These 5 children received transplants, and engraftment occurred in all, except in the "hyperosteoclastic" patient. Further studies are necessary to establish the prognostic significance of this histologic feature.     

Vitamin D depletion following burn injury in children: a possible factor in post-burn osteopenia

BACKGROUND: Children burned > 40% total body surface area (TBSA) have chronically low bone mineral density (BMD) and increased risk for fractures and adult-onset osteoporosis. Because they are advised to avoid sunlight to prevent burn scar hyperpigmentation, we hypothesized that they develop vitamin D depletion, which could contribute to post-burn osteopenia. METHODS: We studied 24 children, ages 5-20 years, burned > or = 40% TBSA 7.1 +/- 3.8 (SD) years, range 1.9-13.3 years, previously (n = 12) and 2.0 +/- 0.2, range 1.4-2.1 years, previously (n = 12), of which half received recombinant human growth hormone during the first post-burn year. We measured lumbar spine BMD, serum 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)2D), intact PTH (iPTH), and osteocalcin. RESULTS: Serum 25(OH)D was low in 10/11 patients and 1,25(OH)2D was low in 5/11 at 7 years post-burn. Serum 25(OH)D was low in 10/12, while 1,25(OH)2D was low in 0/12 at 2 years; osteocalcin was low in 9/12 in the 7-year group; iPTH levels were in the lowest quartile in 5/12 patients at 7 years and 10/12 patients at 2 years. Serum 25(OH)D levels correlated with BMD z-scores, r = 0.53, p < 0.05, and inversely with iPTH levels, r = -0.66, p < 0.05, in the 7-year group. CONCLUSION: Burned children have low circulating levels of 25(OH)D which correlated with BMD z-scores, suggesting that post-burn vitamin D depletion may play a role in the chronically low bone density observed in these children.     

Prevalence,pathogenesis, and treatment options for mastocytosis-related osteoporosis

Mastocytosis is a rare condition characterized by abnormal mast cell proliferation and a broad spectrum of manifestations, including various organs and tissues. Osteoporosis is one of the most frequent manifestations of systemic mastocytosis, particularly in adults. Osteoporosis secondary to systemic mastocytosis is a cause of unexplained low bone mineral density that should be investigated when accompanied by suspicious clinical elements. Bone involvement is often complicated by a high recurrence of fragility fractures, mainly vertebral, leading to severe disability. The mechanism of bone loss is the result of different pathways, not yet fully discovered. The main actor is the osteoclast with a relative or absolute predominance of bone resorption. Among the stimuli that drive osteoclast activity, the most important one seems to be the RANK-RANKL signaling, but also histamine and other cytokines play a significant role in the process. The central role of osteoclasts made bisphosphonates, as anti-resorptive drugs, the most rational treatment for bone involvement in systemic mastocytosis. There are a few small studies supporting this approach, with large heterogeneity of drug and administration scheme. Currently, zoledronate has the best evidence in terms of gain in bone mineral density and bone turnover suppression, two surrogate markers of anti-fracture efficacy.     

Dahl salt-sensitive rats develop hypovitaminosis D and hyperparathyroidism when fed a standard diet

The Dahl salt-sensitive rat (S), a model for salt-sensitive hypertension, excretes protein-bound 25-hydroxyvitamin D (25-OHD) into urine when fed a low salt diet. Urinary 25-OHD increases during high salt intake. We tested the hypothesis that continuous loss of 25-OHD into urine would result in low plasma 25-OHD concentration in mature S rats raised on a standard diet. Dahl S and salt-resistant (R) male rats were raised to maturity (12-month-old) on a commercial rat diet (1% salt) and switched to 0.3% (low) or 2% (high) salt diets 3 weeks before euthanasia. Urine (24 h) was collected at the end of the dietary treatments. Urinary 25-OHD and urinary 25-OHD binding activity of S rats were three times that of R rats, resulting in lower plasma 25-OHD and 24,25-dihydroxyvitamin D concentrations in S rats than in R rats (P < 0.001). Plasma parathyroid hormone concentrations of S rats were twice that of R rats. S rats fed 2% salt had higher plasma 1,25-dihydroxyvitamin D concentrations than those fed 0.3% salt (P = 0.002). S rats excreted more calcium into urine than R rats (P < 0.001) and did not exhibit the expected calciuric response to salt. Proteinuria of the S rats was three times that of the R rats, suggesting kidney damage in the S rats. Low plasma 25-OHD and 24,25-dihydroxyvitamin D and high plasma 1,25-dihydroxyvitamin D and PTH concentrations seen in the mature S rats have also been reported for elderly patients with low-renin (salt-induced) hypertension. An implication of this study is that low vitamin D status may occur with age in salt-sensitive individuals, even when salt intake is normal.     

Combined treatment with cyclosporin A and cortisone acetate minimizes the adverse bone effects of either agent alone

Although cyclosporin A (CsA) and cortisone acetate (CRT) adversely affect bone, their combined effect on bone is unknown. Sprague Dawley rats were therefore administered either vehicle or CsA (7.5 mg/kg/day) by gavage and saline or CRT (2 mg/100 mg/day) by s.c. injection for 28 days. Group A received vehicle plus saline, group B CsA plus saline, group C vehicle plus CRT, and group D CsA/CRT. Serial bloods were sampled over a 28-day period for ionized calcium (Ca), PTH, 1,25 dihydroxyvitamin D (1,25(OH)2D), and bone gla protein (BGP osteocalcin) and tibia were examined on day 28 for histomorphometry. Results were compared with group A. Ca and PTH levels in groups B, C, and D were similar to those in group A during the study period. Group B had lower body weights, elevated levels of BGP, and an increase in 1,25(OH)2D. Group C developed weight loss and a decrease in BGP and 1,25(OH)2D. Group D had weight loss, BGP levels between those of group A and group C, and 1,25(OH)2D values similar to group A. Bone histomorphometry revealed high turnover osteopenia in group B and hyperostosis in group C with a decrease in bone formation and osteoclastlike cells. Combination therapy returned these to control values. In conclusion, the adverse effects of either CsA or CRT on bone in rats are minimized by combined therapy.     

The effect of short-term treatment with vitamin D metabolites on bone lipid and mineral composition in healing vitamin D-deficient rats

Vitamin D deficiency is known to cause alterations in the lipid and mineral components of bone and cartilage. In this study, second generation, normal phosphatemic, vitamin D-deficient rats, treated with low and high doses of three different vitamin D metabolites were sacrificed 24 h after treatment and their bones analyzed in order to determine which metabolites were most effective in altering the lipid composition. In the untreated vitamin D-deficient rats, tissues undergoing endochondral ossification (epimetaphyses), periosteal and endosteal bone formation (diaphyseal bone), and intramembranous bone formation (calvaria) all contained lower amounts of complexed acidic phospholipids, as well as decreased amounts of mineral. Twenty-four hours following treatment, the complexed acidic phospholipid content was significantly increased relative to both untreated and normal (vitamin D-replete) animals, the greatest increases occurring in animals treated with 1,25-dihydroxyvitamin D. All metabolites tested altered histomorphometric and/or mineral parameters, but only 1,25-dihydroxyvitamin D, in low and high doses, significantly increased the content of the complexed acidic phospholipids in all tissues studied. High doses of other metabolites increased complexed acidic phospholipid content in some tissues, perhaps due to their conversion to 1,25-dihydroxyvitamin D. Linear relationships between serum 1,25-dihydroxyvitamin D levels and tissue complexed acidic phospholipid content are reported. It is suggested that one way in which this metabolite may directly contribute to calcification is by facilitating formation of lipids involved in this process.     

Short-term course of 1,25(OH)2D3 stimulates osteoblasts but not osteoclasts in osteoporosis and osteoarthritis

Summary We investigated the effect of short-term, 1,25-dihydroxyvitamin D₃ therapy (4 μg/day for 4 days) on calcium metabolism in 27 postmenopausal women (11 cases with osteoporosis and 16 cases with osteoarthritis). Bone mass at the axial and appendicular skeleton was higher in osteoarthritis than in osteoporosis. Initial values of calcium metabolism were similar. Osteoporotic and osteoarthritic patients responded with a similar significant increase in serum osteocalcin (+61% and +54%, respectively), fasting urinary calcium excretion (+178% and +124%, respectively) and 24 hour calcium excretion (+148% and +142%, respectively). Parathyroid hormone (PTH) levels decreased significantly in both groups (−30% and −18%, respectively). Osteoclastic bone resorption, evaluated by urinary hydroxyproline excretion, was not stimulated in either group. We conclude that in osteoporosis and also in osteoarthritis (1) 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) stimulation of osteoblast function is similar in production of osteocalcin; (2) the vitamin D target tissues react adequately to 1,25(OH)₂D₃ stimulation; (3) short-term high dose of 1,25(OH)₂D₃ does not stimulate bone resorption; and (4) the differences in bone mass between osteoarthritis and osteoporosis are not related to an alteration of the responsiveness to stimulation by 1,25 (OH)₂D₃.     

Vitamin D and calcium receptors: links to hypercalciuria

PURPOSE OF REVIEW: In idiopathic hypercalciuria, patients have increased intestinal Ca absorption and decreased renal Ca reabsorption, with either elevated or normal serum levels of 1,25-dihydroxyvitamin D. As 1,25-dihydroxyvitamin D exerts its biologic effects through interactions with the vitamin D receptor, we examine the actions of this receptor and 1,25-dihydroxyvitamin D in animals with genetic hypercalciuria. RECENT FINDINGS: In genetic hypercalciuric stone-forming rats intestinal calcium transport is increased and renal calcium reabsorption is reduced, yet serum 1,25-dihydroxyvitamin D levels are normal. Elevated intestinal and kidney vitamin D receptors suggest that increased tissue 1,25-dihydroxyvitamin D-vitamin D receptor complexes enhance 1,25-dihydroxyvitamin D actions on intestine and kidney, and vitamin D-dependent over-expression of renal calcium-sensing receptor alone can decrease tubule calcium reabsorption. In TRPV5-knockout mice, ablation of the renal calcium-influx channel decreases tubular calcium reabsorption, and secondary elevations in 1,25-dihydroxyvitamin D increase intestinal calcium transport. SUMMARY: 1,25-Dihydroxyvitamin D or vitamin D receptor may change intestinal and renal epithelial calcium transport simultaneously or calcium-transport changes across renal epithelia may be primary with a vitamin D-mediated secondary increase in intestinal transport. The extent of homology between the animal models and human idiopathic hypercalciuria remains to be determined.     

Systemic mastocytosis presenting with acute oliguric renal failure: report of a case and review of the literature

A 61-year old African-American woman presented with abdominal pain, tender splenomegaly, anemia, and renal insufficiency. Bone marrow biopsy demonstrated systemic mastocytosis. She was treated with mediator-specific therapy and imatinib, but her renal and hepatic function deteriorated and she required maintenance hemodialysis. Renal biopsy demonstrated interstitial infiltration with mast cells and acute tubular necrosis. Acute kidney injury in the setting of systemic mastocytosis and imatinib therapy is discussed.