ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewThe discovery of the extracellular calcium-sensing receptor, CasR has broadened our understanding of calcium homeostasis and led to the development of new pharmacological agents, calcimimetics, for treating hyperparathyroidism. In the present review, I discuss the function of CasR as well as provide evidence for the presence of additional calcium-sensing mechanisms in the skeleton and possibly other tissues.Recent findingsInactivating and activating mutations of the CasR respectively cause hereditary hyperparathyroidism, and demonstrate the predominant role of the CasR in controlling parathyroid gland function. Calcimimetics, which increase the sensitivity of CasR to extracellular calcium have been developed to treat secondary and primary hyperparathyroidism. In recent clinical trials in patients with end stage kidney disease, the calcimimetic cinacalcet suppressed parathyroid hormone to a greater degree than conventional therapy with vitamin D analogues without causing hypercalcemia or hyperphosphatemia. CasR receptor also has functions in other tissues, including regulation of renal calcium excretion and calcitonin secretion by thyroidal C-cells, but the presence of redundant sensing mechanisms for extracellular calcium in other tissues, including bone, confounds the assessment of the receptor's function at these sites. Mouse genetic approaches have so far failed to identify any essential, non-redundant role for the calcium-sensing receptor in regulating chondrogenesis or osteogenesis, and have failed to establish a function for the protein outside of the parathyroid gland, kidney, and thyroidal C-cells. Rather, there is evidence for other putative calcium sensing receptor-like mechanisms in osteoblasts that remain to be identified.SummarySensing of extracellular calcium by CasR is important in regulating calcium homeostasis, but CasR may have vestigial function in various tissues where it is expressed in low abundance. The relative importance of CasR and the novel calcium-sensing mechanisms in mediating response to extracellular calcium in many of these tissues remain to be determined.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewThe present review summarizes recent findings that may help in understanding how the cell senses changes in serum phosphate.Recent findingsThe sensing of phosphate determines the organism's response to change in supply of this essential nutrient. Phosphate depletion or surfeit results in homeostatic responses that involve changes in transcription, transcript stability, transporter recruitment or breakdown, and cell replication. These responses are shared across the biological kingdoms, and lessons from unicellular organisms may be relevant to multicellular mammals. An understanding of nutrient sensing in general may help in determining how the cell senses changes in phosphate concentration.SummaryResearch has yielded important advances in unravelling phosphate sensing and the response to nutrient phosphate supply. However, the actual sensing event for phosphate and most other nutrients must still be defined. Lessons may be learned from those examples in which the sensing event is known, and these are summarized here.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewThe aim of this article is to review the most recent development on the reversibility of secondary hyperparathyroidism after kidney transplantation. A successful kidney transplantation is expected to correct the abnormalities of mineral metabolism that during uremia lead to secondary hyperparathyroidism. Kidney transplanted patients might, however, still present persistent hyperparathyroidism and hypercalcemia. In order to improve the understanding of the fate of secondary hyperparathyroidism after kidney transplantation an experimental model on reversal of uremia by an experimental isogenic kidney transplantation was established.Recent findingsIn recent years clinical and experimental studies have suggested an important role of the calcium sensing receptor and vitamin D receptor in the parathyroid glands for the abnormal regulation of parathyroid hormone secretion and parathyroid cell proliferation in uremia. The expression of these receptors is diminished in the parathyroid glands of uremic patients with severe secondary hyperparathyroidism and in experimental models of uremic rats on a high phosphorus diet. Secondary hyperparathyroidism is reversed rapidly by reversal of uremia by an experimental kidney transplantation in the rat. Despite normalization of the circulating parathyroid hormone levels, diminished expression of parathyroid calcium sensing and vitamin D receptor messenger RNA persist. Implantation of several isogenic parathyroid glands into a single rat results in a transient, short lasting period of hypercalcemia followed by normalization of parathyroid hormone and plasma calcium levels, despite persistent increased parathyroid mass.SummaryAdvances are clearly being made in the understanding of the molecular mechanisms of disturbed parathyroid function in uremia. How the hyperplastic uremic parathyroid glands are regulated after reversal of uremia by kidney transplantation remains, however, to be elucidated.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewHyperphosphatemia in patients with end-stage renal disease leads to secondary hyperparathyroidism and renal osteodystrophy, and is independently associated with mortality risk. How hyperphosphatemia increases mortality risk is unknown but it may promote cardiovascular calcification. It is recommended that dialysis patients be treated to maintain normal serum phosphorus. Although calcium-based phosphate binders are cost-effective, their long-term safety has been questioned because of their postulated role in progression of cardiovascular calcification. In this regard, sevelamer hydrochloride has been recommended as an alternative phosphate binder. In this review, we will examine these issues and provide rational guidelines for the use of calcium-based phosphate binders.Recent findingsResults from the calcium acetate Renagel evaluation study indicate that calcium acetate is more effective than sevelamer in controlling serum phosphorus and calcium x phosphorus product in hemodialysis patients. However, in the Treat-to-Goal study dialysis patients treated with sevelamer had less progression of coronary and aortic calcification than patients treated with calcium-containing binders. The mechanism underlying the slower rate of progression of cardiovascular calcification in sevelamer-treated patients remains uncertain but may relate to decreased calcium loading or to dramatic reductions in LDL cholesterol.SummaryAt present, evidence incriminating calcium-containing phosphate binders in the progression of cardiovascular calcification in end-stage renal disease remains largely circumstantial. As calcium acetate is more efficacious and cost-effective than sevelamer, it remains an accepted first-line drug. Treatment with sevelamer hydrochloride should be considered for patients with persistent hypercalcemia during calcium-based binder therapy despite appropriate adjustment of vitamin D therapy.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewOsteoporosis is the most prevalent bone disorder in the general population, particularly in the middle and older age groups. Although more than half of the prevalent dialysis population is within these age groups, little concern has been given to the possible role of estrogen deficiency in the pathogenesis of bone disease in end-stage renal disease. The purpose of this review is to summarize the recent published evidence that supports a potential role of the postmenopausal state in the pathogenesis of bone disease in end-stage renal disease and their implications for treatment.Recent findingsRecent studies have shown that although the risk factors for fracture in end-stage renal disease are similar to the general population, the incidence is three to fourfold higher. The high prevalence of older population, the frequently observed premature amenorrhea and early menopause in dialysis patients may play a role. Similarly, the proportion of end-stage renal disease women receiving hormone replacement therapy is at least three times lower than the general population. Recent evidence on the risk of hormone replacement therapy should caution about its use in end-stage renal disease patients. New evidence suggests that selective estrogen receptor modulators may increase bone mass without significant secondary effects. Other alternatives, such as the use of bisphosphonates, should be considered with caution due to the risk of excessive suppression of bone turnover, worsening or favoring the development of adynamic bone disease.SummaryOsteoporosis should be recognized as an important entity that may modify the current conception of renal osteodystrophy in postmenopausal patients with end-stage renal disease. Further clinical studies are needed in order to propose strategies that may reduce the impact of postmenopausal osteoporosis in the dialysis population.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

My purpose in this article is to restore the histologic appraisal of renal bone disease to the mainstream of bone and mineral metabolism from which it has been separated for many years. Historically, both the two major components were found in varying degrees in most patients, although one or other of them often predominated. For more than 15 years bone biopsy has been used almost exclusively to classify individual patients into hyperparathyroid, osteomalacic, mixed and adynamic categories according to rigid non-overlapping criteria, and remarkably few histologic data have been reported. All metabolic bone diseases result from disordered bone remodeling, the physiologic mechanism for replacing bone that has become too old to carry out its mechanical or metabolic functions. Bone remodeling is not directly concerned with the regulation of plasma calcium, which reflects the level of equilibration at quiescent bone surfaces between systemic and bone extracellular fluid set by parathyroid hormone. The separation of remodeling from homeostasis explains the concurrence of increased turnover and decreased plasma calcium in chronic renal failure; it is the homeostatic system, rather than the remodeling system, which is resistant to parathyroid hormone. The effect of mild hyperparathyroidism is a nonspecific increase in bone turnover, of which the best index is the bone formation rate measured by double tetracycline labeling expressed per unit of bone surface. Increased turnover is always accompanied by increased reversible mineral deficit. In prolonged hyperparathyroidism there is also accelerated irreversible bone loss manifested mainly as thinning of cortical bone, detectable in chronic renal failure before any symptoms, due to increased resorption depth on the endocortical surface. In severe hyperparathyroidism resorbed bone is replaced, not by a lesser quantity of normal bone, but by a mixture of vascular fibrous tissue and woven bone, referred to as osteitis fibrosa. In osteomalacia there is increased accumulation of osteoid, due not to increased turnover, but to prolongation of mineralization lag time, which in conjunction with increased thickness, surface and volume of osteoid is diagnostic. Converting histomorphometric data into category assignment discards most of the useful information, which can be retained by two-dimensional representation of severity. For the hyperparathyroid dimension, bone formation rate measured by double tetracycline labeling expressed per unit of bone surface is the most useful although not ideal. For the osteomalacic dimension a mineralization index was constructed that is unaffected by age or race. In patients with osteitis fibrosa, bone formation rate per unit of bone surface and mineralization index were inversely correlated. For the third dimension a structure/formation index was constructed which increases with age in healthy women and shows weak inverse correlation with bone formation rate. The structure/formation index is lower than normal in patients with osteitis fibrosa, and should be useful in the study of osteopenia in chronic renal failure. Bone formation rate is low in osteomalacia, but some patients have subnormal rates through quite a different mechanism. The frequency of this finding has been overestimated for several reasons: failure to exclude atypical osteomalacia (increased surface and volume but not thickness of osteoid), use of inappropriate reference values, and failure to measure the bone formation rate on endocortical and intracortical surfaces. In healthy women bone formation rate can be zero on the cancellous surface alone. Low bone formation rate is sometimes due to diabetes but most often is the expected response to subnormal parathyroid hormone secretion accompanying an excess of calcium, a situation recognized only recently because of improvement in parathyroid hormone assay methodology. Low cancellous bone formation rate should not increase fracture risk because turnover is much lower in the peripheral than in the central skeleton, and all reports of increased fracture risk are flawed or open to different interpretation. Low bone formation rate is associated with reduced skeletal buffering of calcium and increased soft tissue calcification. This is not a new disease needing its own treatment, however, but represents the final stage of skeletal adaptation to a surfeit of calcium. The concept of adynamic bone disease has been harmful by directing attention away from the most important consequence of over-treatment of hyperparathyroidism.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewExpression profiling using serial analysis of gene expression and microarray technologies allows global description of expressed genes present in biological systems. Although relatively new technologies, each having been developed in the mid-1990s, both have become established and widely used tools for identification of gene networks and gene function.Recent findingsThis review highlights DNA expression analyses published in 2002, emphasizing primarily serial analysis of gene expression and microarray technologies. We focus on the applicability of DNA expression analysis to renal disease, especially as some investigators have developed custom serial analysis of gene expression kidney libraries and kidney disease-specific ‘designer chip’ microarrays. Data analysis techniques and statistics are also discussed, since the challenge is generation of accurate messenger RNA profiles and interpretation of data in a manner that is both coherent and reproducible.SummaryBecause kidney disease pathophysiology is complex, expression analysis can identify candidate nephropathy pathogenesis genes and gene networks, which eventually could become targets for therapeutic intervention.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewMessenger RNA, transfer RNA and ribosomal RNA were defined long ago as essential components for transmission of genetic code from DNA. However, there are many other, less commonly recognized RNAs, such as ribozymes and small interfering RNAs, which are distinguished by their ability to inhibit RNA function. This review describes the basic molecular concepts and potential therapeutic applications of RNA inhibition by a variety of molecules, including ribozymes, antisense oligonucleotides, aptamers and small interfering RNAs.Recent findingsA tremendous amount of data has recently emerged about double-stranded small interfering RNAs, which bind and degrade corresponding messenger RNAs by a process called RNA interference. Though native small interfering RNAs have been shown to be biologically relevant in animals and plants, synthetic types have rapidly become powerful tools for post-transcriptional inhibition of specific gene products to determine functional consequences in simple organisms and in-vitro model systems. More established means of RNA inhibition, such as with ribozyme and antisense strategies, continue to be viable options for in-vitro experiments, and form the basis for many ongoing clinical trials.SummaryRibozymes, antisense oligonucleotides, aptamers and small interfering RNAs are potentially useful reagents for in-vitro investigation and for treatment of kidney and hypertension diseases.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID