Showing papers in "Current Opinion in Nephrology and Hypertension in 2002"
TL;DR: Long-term control of arterial pressure has been attributed to the kidney by virtue of its ability to couple the regulation of blood volume to the maintenance of sodium and water balance by the mechanisms of pressure natriuresis and diuresis.
Abstract: Long-term control of arterial pressure has been attributed to the kidney by virtue of its ability to couple the regulation of blood volume to the maintenance of sodium and water balance by the mechanisms of pressure natriuresis and diuresis. In the presence of a defect in renal excretory function, hypertension arises as the consequence of the need for an increase in arterial pressure to offset the abnormal pressure natriuresis and diuresis mechanisms, and to maintain sodium and water balance. There is growing evidence that an important cause of the defect in renal excretory function in hypertension is an increase in renal sympathetic nerve activity (RSNA). First, increased RSNA is found in animal models of hypertension and hypertensive humans. Second, renal denervation prevents or alleviates hypertension in virtually all animal models of hypertension. Finally, increased RSNA results in reduced renal excretory function by virtue of effects on the renal vasculature, the tubules, and the juxtaglomerular granular cells. The increase in RSNA is of central nervous system origin, with one of the stimuli being the action of angiotensin II, probably of central origin. By acting on brain stem nuclei that are important in the control of peripheral sympathetic vasomotor tone (e.g. rostral ventrolateral medulla), angiotensin II increases the basal level of RSNA and impairs its arterial baroreflex regulation. Therefore, the renal sympathetic nerves may serve as the link between central sympathetic nervous system regulatory sites and the kidney in contributing to the renal excretory defect in the development of hypertension.
351 citations
TL;DR: The administration of caspase inhibitors ameliorates ischemia-reperfusion injury in multiple organs including the kidney, however, the extent to which this protective effect ofcaspase inhibition is caused by reduced intrarenal inflammation, or by iselioration of renal tubular cell loss due to apoptosis, remains uncertain.
Abstract: Renal tubular cells die by apoptosis as well as necrosis in experimental models of ischemic and toxic acute renal failure as well as in humans with acute tubular necrosis. It is not yet possible, however, to determine the relative contribution of these two forms of cell death to loss of renal tubular cells in acute tubular necrosis. The beneficial effect of administering growth factors to animals with acute tubular necrosis is probably related to the potent antiapoptotic (survival) effects of growth factors as well as to their proliferative effects. Rapamycin inhibits both of these effects of growth factors and delays the recovery of renal function after acute tubular necrosis by inhibiting renal tubular cell regeneration and by increasing renal tubular cell loss by apoptosis. The administration of caspase inhibitors ameliorates ischemia-reperfusion injury in multiple organs including the kidney. However, the extent to which this protective effect of caspase inhibition is caused by reduced intrarenal inflammation, or by amelioration of renal tubular cell loss due to apoptosis, remains uncertain. In addition to caspase inhibition, the apoptotic pathway offers many potential targets for therapeutic interventions to prevent renal tubular cell apoptosis.
240 citations
TL;DR: The new classification of renal allograft rejection incorporates humoral and cellular mechanisms of injury, with the diagnostic criteria of each, should prove useful in guiding clinical treatment, and stratifying drug trials, replacing obsolete terms such as ‘vascular rejection’.
Abstract: Purpose of reviewEvidence from several transplant centers indicates that a substantial proportion of acute and chronic renal allograft rejection is caused by antibodies to donor antigens. Antibody-mediated injury arises despite potent anti-T cell pharmacological agents, and probably requires differe
194 citations
TL;DR: A significant amount of data now exists to suggest that there may be intrinsic mechanisms brought to bear by the kidney when exposed to a toxic or ischemic insult, which protect it against a subsequent exposure to ischemia.
Abstract: Ischemic injury to the kidney is associated with high morbidity and mortality. Improving the ability of the kidney to tolerate ischemic injury would have important implications. A significant amount of data now exists to suggest that there may be intrinsic mechanisms brought to bear by the kidney when exposed to a toxic or ischemic insult, which protect it against a subsequent exposure to ischemia. While it is frequently stated that this phenomenon, termed ischemic preconditioning, was first described in the heart, in fact there is almost a century of literature on the kidney that supports the concept that prior injury protects against a second insult. The protective effect of preconditioning is greater than most reported protective effects with pharmacological interventions in animals. There is compelling evidence in other organs that preconditioning occurs in humans. It therefore behooves us to understand the endogenous processes that the kidney has developed to protect itself against an ischemic insult. Armed with this understanding we can then attempt to mimic these processes and thereby prevent and treat ischemic acute renal failure.
188 citations
TL;DR: Labelled serum amyloid P component studies make a unique contribution to the diagnosis and management of individual patients with systemic amyloidsosis, and to systematic studies of existing and novel therapies.
Abstract: Serum amyloid P component is a normal plasma protein and a universal non-fibrillar constituent of amyloid deposits. Radiolabelled serum amyloid P component scintigraphy is a non-invasive and quantitative method for imaging amyloid deposits, which produces diagnostic images in most patients with systemic amyloidosis, and can be used repeatedly to monitor the course of the disease. The scintigraphy technique and biopsy histology are complementary, providing a detailed microscopic analysis and a quantitative whole body survey respectively. Clinically useful observations provided by the imaging method include different organ distributions of amyloid in different types of the disease, demonstration of amyloid in anatomic sites not available for biopsy, and evidence for rapid progression and sometimes regression of amyloid deposits with different rates in different organs. Labelled serum amyloid P component studies thus make a unique contribution to the diagnosis and management of individual patients with systemic amyloidosis, and to systematic studies of existing and novel therapies. The technique is available routinely for all known or suspected cases of amyloidosis in the NHS National Amyloidosis Centre at the Royal Free Hospital, but it has not been developed commercially.
133 citations
TL;DR: Prevention of hypertension-induced barotrauma will require blood pressure to be reduced well into the normotensive range in patients with diabetes or chronic renal disease, as is being recognized in the currently recommended blood pressure goals.
Abstract: Substantial evidence indicates that the adverse effects of hypertension on the kidney depend on the degree to which systemic blood pressure elevations are transmitted to the renal microvasculature. Such blood pressure transmission and consequent susceptibility to hypertensive renal damage is markedly exacerbated in states characterized by preglomerular vasodilation and an impairment of the normally protective renal autoregulatory mechanisms, e.g. diabetes or chronic renal disease. Moreover, this pathophysiology gives rise to the prediction that prevention of hypertension-induced barotrauma will require blood pressure to be reduced well into the normotensive range in such patients, as is being recognized in the currently recommended blood pressure goals. Agents that block the renin-angiotensin system should be preferred as initial therapy as they may provide additional risk reductions and minimize the potassium and magnesium depletion associated with the diuretic use usually necessary to achieve the lower blood pressure targets. The current failure to achieve optimal blood pressure reductions may be contributing not only to the still escalating incidence of end-stage renal disease in diabetic patients, but also to their greatly increased cardiovascular morbidity and mortality.
117 citations
TL;DR: It is confirmed that agents that interrupt the renin-angiotensin system confer renoprotection in type 1 and type 2 diabetic patients with early or advanced renal disease and that a range of antihypertensive drugs in diabetic subjects at risk of or with macrovascular disease are effective.
Abstract: Hypertension is often associated clinically with diabetes either as part of the insulin resistance syndrome or as a manifestation of renal disease. Elevated systemic blood pressure accelerates the progression of both microvascular and macrovascular complications in diabetes. Agents that interrupt the renin-angiotensin system confer renoprotection via a range of hemodynamic and nonhemodynamic mechanisms. Recent clinical trials confirm that these agents confer renoprotection in type 1 and type 2 diabetic patients with early or advanced renal disease. Hypertension also appears to accelerate vascular and cardiac abnormalities in diabetes, including increased atherosclerosis, arterial stiffness, left ventricular hypertrophy and diastolic dysfunction. A number of recently published and ongoing trials are exploring the role of aggressive antihypertensive treatment with a range of antihypertensive drugs in diabetic subjects at risk of or with macrovascular disease.
108 citations
TL;DR: Delivery of either HGF or its gene may hold promise as a novel therapeutic strategy for promoting initial protection and subsequently regenerative repair after acute insult, and for ameliorating renal fibrosis and kidney dysfunction in chronically diseased conditions.
Abstract: Hepatocyte growth factor (HGF) and its specific c-met receptor constitute a paired signaling system that plays an important role in renal development and in the maintenance of normal adult kidney structure and functions. HGF elicits potent mitogenic, motogenic, morphogenic, and antiapoptotic activit
108 citations
TL;DR: The serum levels of parathyroid hormone and magnesium depend on each other in a complex manner and the distal convoluted tubule is of crucial importance for parathyro hormone-regulated magnesium homeostasis.
Abstract: The serum levels of parathyroid hormone and magnesium depend on each other in a complex manner. The secretion of parathyroid hormone by the parathyroid is physiologically controlled by the serum calcium level, but magnesium can exert similar effects. While low levels of magnesium stimulate parathyroid hormone secretion, very low serum concentrations induce a paradoxical block. This block leads to clinically relevant hypocalcemia in severely hypomagnesiemic patients. The mechanism of this effect has recently been traced to an activation of the alpha-subunits of heterotrimeric G-proteins. This activation mimicks activation of the calcium sensing receptor and thus causes inhibition of parathyroid hormone secretion. In addition to the effects of magnesium on parathyroid hormone secretion, parathyroid hormone in turn regulates magnesium homeostasis by modulating renal magnesium reabsorption. The distal convoluted tubule is of crucial importance for parathyroid hormone-regulated magnesium homeostasis.
108 citations
TL;DR: Different carrier proteins exhibiting distinct transport properties participate in cationic amino acid transport, including sodium-independent systems, such as b+, y+, y+L and b0,+, and a sodium-dependent system B0,+.
Abstract: Different carrier proteins exhibiting distinct transport properties participate in cationic amino acid transport. There are sodium-independent systems, such as b+, y+, y+L and b0,+, and a sodium-dependent system B0,+, most of which have now been identified at the molecular level. In most non-epithelial cells, members of the cationic amino acid transporter (CAT) family mediating system y+ activity seem to be the major entry pathway for cationic amino acids. CAT proteins underlie complex regulation at the transcriptional, post-transcriptional and activity levels. Recent evidence indicates that individual CAT isoforms are necessary for providing the substrate for nitric oxide synthesis, for example CAT-1 for Ca2+-independent nitric oxide production in endothelial cells and CAT-2B for sustained nitric oxide production in macrophages.
105 citations
TL;DR: Regulation by dopamine of cardiovascular function, renal function and systemic blood pressure regulation is multifaceted, and each of the five dopamine receptor subtypes participates in the regulation of blood pressure by mechanisms specific for the subtype.
Abstract: Regulation by dopamine of cardiovascular function, renal function and systemic blood pressure regulation is multifaceted. Each of the five dopamine receptor subtypes participates in the regulation of blood pressure by mechanisms specific for the subtype. Some receptors regulate blood pressure by influencing the central or peripheral nervous system; others influence epithelial transport and regulate the secretion and receptors of several humoral agents. The D1, D3, and D4 receptors interact with the renin-angiotensin system, while the D2 and D5 receptors interact with the sympathetic nervous system to regulate blood pressure.
TL;DR: The proteinuria of the Fanconi syndrome is more generalized than previously suspected and high concentrations of polypeptides, including hormones, vitamin-binding proteins and chemokines in urine from patients and animals may play an important role in the progressive renal failure that is associated with the syndrome.
Abstract: Purpose of review In recent years, there have been significant advances in our understanding of the molecular mechanisms relating proximal tubule abnormalities to the pathogenesis of renal Fanconi syndrome. This review focuses on the role of intra-endosomal acidification-machinery proteins (V-ATPase, CLC-5, NHE-3), as well as apical receptors (megalin and cubilin), in the receptor-mediated endocytosis pathway and in the pathogenesis of proximal tubulopathies. Recent findings Animal models, including CLC-5 and megalin knockout mice, cubilin-deficient dogs and cadmium-toxicity studies in rats, have shed light on defects leading to low-molecular-weight proteinuria. In particular, the important contribution of defective endosomal acidification and membrane-protein recycling to the pathogenesis of the Fanconi syndrome has emerged from these studies. These observations, together with recent findings in patients with Dent's disease, Lowe's syndrome, autosomal-dominant idiopathic Fanconi syndrome and Imerslund-Grasbeck disease, show that the proteinuria of the Fanconi syndrome is more generalized than previously suspected. High concentrations of polypeptides, including hormones, vitamin-binding proteins and chemokines in urine from these patients and animals may play an important role in the progressive renal failure that is associated with the syndrome. Summary The molecular mechanism of proximal tubule protein reabsorption, which is defective in renal Fanconi syndrome, includes a crucial role for endosomal acidification-machinery proteins, in particular the V-ATPase and CLC-5 chloride channels, in the trafficking and acidification-dependent recycling of apical membrane proteins, including the endocytotic receptors megalin and cubilin. An increased understanding of the roles of V-ATPase and CLC-5 in proximal tubule endosomal acidification, in the regulation of the megalin/cubilin-mediated endocytosis pathway and finally in the pathogenesis of human Fanconi syndrome will help in the devising of appropriate strategies for therapeutic intervention for this disorder.
TL;DR: Although angiotensin-converting enzyme inhibition has proven to have an impact, perhaps temporarily, on obesity-associated proteinuria in humans, weight reduction early in the course of the disease would appear the most important therapeutic approach.
Abstract: Obesity, which has reached epidemic proportions in the United States and other western countries, may be complicated by hypertension, an increased incidence of renal cancer or proteinuria. Patients with obesity-associated proteinuria show focal glomerulosclerosis and glomerulomegaly on biopsy, usually have minimal clinical edema and relatively normal levels of serum albumin, cholesterol and blood pressure, and can progress to end-stage renal disease. Severe obesity may also be an additive risk factor in patients with preexisting nephropathy or reduced renal mass. The pathophysiology of obesity-associated proteinuria is unclear but may include hyperfiltration, increased renal venous pressure, glomerular hypertrophy, hyperlipidemia and increased synthesis of vasoactive and fibrogenic substances, including angiotensin II, insulin, leptin and transforming growth factor-beta1. These substances may individually or interactively affect glomerular hyperfiltration, mesangial cell hypertrophy and matrix production, and the production of collagen, fibronectin, transforming growth factor-beta and other fibrogenic mediators of change. Although angiotensin-converting enzyme inhibition has proven to have an impact, perhaps temporarily, on obesity-associated proteinuria in humans, weight reduction early in the course of the disease would appear the most important therapeutic approach.
TL;DR: This review highlights the genetic abnormalities seen in renal cell carcinomas and reviews current and future therapeutic options.
Abstract: Renal cell carcinomas account for 80-85% of all primary renal neoplasms. Recent identification of VHL, c-met and TSC as candidate genes mutated in various types of renal carcinomas has greatly enhanced our understanding of the pathogenesis of renal carcinomas and has provided novel therapeutic options for patients with renal cancer. Furthermore, developments in angiogenesis and in tumor immunology have given us additional treatment modalities for cancer patients, especially those with renal cancer. This review highlights the genetic abnormalities seen in renal cell carcinomas and reviews current and future therapeutic options.
TL;DR: Cessation of smoking should be recommended to renal patients - a recommendation which is infrequently given and even less frequently followed.
Abstract: Purpose of reviewSmoking increases the renal risk both in diabetic and in nondiabetic renal disease. The purpose of the present review is to summarize the current state of knowledge about this important remediable renal risk factor.Recent findingsThe deleterious effect of smoking on renal function e
TL;DR: Results support the hypothesis that measurement of aortic pulse wave velocity could help, not only in risk assessment strategies, but also in risk reduction strategies by monitoring arterial stiffness under different pharmacological regimens.
Abstract: Purpose of review As epidemiological and clinical studies have shown that damage of large arteries is a major contributory factor to the high cardiovascular morbidity of patients with end-stage renal disease, such a population is particularly appropriate for analysis the impact of arterial stiffness on cardiovascular risk assessment and reduction strategies. Recent findings Aortic pulse wave velocity, a marker of aortic stiffness, has been shown to be a strong independent predictor of cardiovascular and all-cause mortality in patients with end-stage renal disease on hemodialysis. Local arterial stiffness assessment, namely carotid distensibility was also shown to predict cardiovascular risk, both in end-stage renal disease patients and in renal transplant recipients. Furthermore, it was shown in a therapeutic trial that the lack of aortic pulse wave velocity attenuation, despite significant drug-induced reduction in mean blood pressure, was a significant predictor of cardiovascular death in subjects with end-stage renal disease. These results support the hypothesis that measurement of aortic pulse wave velocity could help, not only in risk assessment strategies, but also in risk reduction strategies by monitoring arterial stiffness under different pharmacological regimens. The drug-related reduction of aortic pulse wave velocity could then give prognostic information, in addition to blood pressure reduction. Summary Aortic stiffness measurements could serve as an important tool in identifying end-stage renal disease patients at higher risk of cardiovascular disease. The ability to identify these patients would lead to better risk stratification and earlier and more cost-effective preventive therapy.
TL;DR: Animal studies support the notion that a combined therapeutic strategy of inhibiting angiotensin II and endothelin-1 generation or blocking their effects at the receptor level would be superior to either strategy alone.
Abstract: Angiotensin II and endothelin-1 can both be regulated by nuclear factor-kappaB. They are to varying degrees also capable of activating nuclear factor-kappaB and increasing the expression of nuclear factor-kappaB dependent genes. Angiotensin II related vascular effects are in part mediated by endothelin-1. Nitric oxide synthase inhibition facilitates angiotensin II related effects, which can be inhibited both by angiotensin II type 1 receptor blockers and by endothelin system inhibitors. This supports the notion that a combined therapeutic strategy of inhibiting angiotensin II and endothelin-1 generation or blocking their effects at the receptor level would be superior to either strategy alone. Animal studies are encouraging but not without conflicting results. Angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers have a superb track record in experimental animal models and in a host of clinical studies. Selective and nonselective blockers of the endothelin-1 receptors are important research tools and are also undergoing clinical trials. Inhibitors of the endothelin converting enzyme have been developed. The recent elucidation of the endothelin converting enzyme's physical structure should facilitate the development of still more novel compounds to inhibit endothelin-1 generation.
TL;DR: This article reviews the latest studies concerning the characterization of endothelium-derived hyperpolarizing factors, the mechanisms of factor release and alterations of the factors.
Abstract: The chemical identification and functional characterization of endothelium-derived hyperpolarizing factors varies depending on vascular size, vascular bed and species. Three major candidates are the epoxyeicosatrienoic acids, cytochrome P450 metabolites of arachidonic acid, potassium ion and hydrogen peroxide. Additionally, electrical coupling through myoendothelial gap junctions serves to conduct electrical changes from the endothelium to the smooth muscle and may mediate or propagate hyperpolarization. Endothelium-derived hyperpolarizing factors are important mediators of vascular relaxation most specifically in resistance sized arteries where they regulate tissue blood flow. The release of the factors is modulated by a number of influences including agonist stimulation, shear stress, estrogen and disease. This article reviews the latest studies concerning the characterization of endothelium-derived hyperpolarizing factors, the mechanisms of factor release and alterations of the factors.
TL;DR: Findings concerning a humoral factor which causes TIO, and the nature of phosphatonin are summarized, will certainly contribute to the development of new diagnostic and therapeutic maneuvers for hypophosphatemic diseases.
Abstract: Purpose of review Three hypophosphatemic diseases, X-linked dominant hypophosphatemic rickets/osteomalacia (XLH), autosomal dominant hypophosphatemic rickets/osteomalacia (ADHR) and tumor-induced rickets/osteomalacia (TIO), show very similar clinical features including hypophosphatemia due to renal phosphate wasting. Because of some evidence that XLH and TIO are caused by a humoral mechanism, the presence of a phosphate-regulating hormone, phosphatonin, was hypothesized. The causative factor of TIO has been thought to be a strong candidate for phosphatonin. In this review, we summarize recent findings concerning a humoral factor which causes TIO, and discuss the nature of phosphatonin. Recent findings The PHEX gene and fibroblast growth factor (FGF)-23 were identified as responsible genes for XLH and ADHR, respectively. In addition, FGF-23 was cloned as a gene abundantly expressed in a responsible tumor for TIO and was shown to reproduce almost all characteristics of TIO when overexpressed in mice. Furthermore, FGF-23 was proteolytically processed between Arg(179) and Ser(180), and all mutations found in ADHR existed in this proteolytic consensus site. Mutant FGF-23 proteins were resistant to the processing and seem to have somehow increased biological activity. There is not yet enough evidence that FGF-23 is phosphatonin, and the relation between PHEX and FGF-23 is unclear. Summary FGF-23 plays important roles in the development of hypophosphatemic diseases. These findings will certainly contribute to the development of new diagnostic and therapeutic maneuvers for hypophosphatemic diseases.
TL;DR: Improved mutation analysis in autosomal dominant polycystic kidney disease has led to the finding of genotype/phenotype correlations which could be related to possible cleavage of polycystin-1, and a role in regulating intracellular calcium levels seems likely, with the many cellular abnormalities associated with cystogenesis due to a disruption of calcium homeostasis.
Abstract: Recent developments have helped elucidate the function of the autosomal dominant polycystic kidney disease proteins, polycystin-1 and polycystin-2, and have revealed the primary defect in autosomal recessive polycystic kidney disease, by positional cloning of the gene, PKHD1. Several studies demonstrating that polycystin-2 can act as a calcium-ion-permeable cation channel, and that polycystin-1 may be involved in regulating/localizing this channel, have provided compelling evidence of the function of these proteins. A role in regulating intracellular calcium levels seems likely, with the many cellular abnormalities associated with cystogenesis due to a disruption of calcium homeostasis. Improved mutation analysis in autosomal dominant polycystic kidney disease has led to the finding of genotype/phenotype correlations which could be related to possible cleavage of polycystin-1. A major recent breakthrough has revealed the primary defect in autosomal recessive polycystic kidney disease. Genetic analysis showed that the PCK rat model is orthologous to autosomal recessive polycystic kidney disease, and allowed the human gene, PKHD1, to be precisely localized and identified. PKHD1 is a large gene, encoding a protein, fibrocystin, of 4074 amino acids, which is predicted to have a large extracellular region, a single transmembrane domain and a short cytoplasmic tail. Fibrocystin may act as a receptor with critical roles in collecting-duct and biliary development.
TL;DR: These multiple regulatory pathways permit fine control over cell invasion during angiogenesis and provide new, precise strategies for targeting abnormal angiogenic, through control of matrix metalloproteinase activity.
Abstract: Angiogenesis is a prominent feature of numerous diseases, including cancer and arthritis, and appears to play an important role in kidney disease and hypertension. The matrix metalloproteinases, especially matrix metalloproteinase-2, play a vital role during angiogenesis by degrading the surrounding extracellular matrix and allowing endothelial cell invasion. Membrane type 1 matrix metalloproteinase directly degrades matrix components as well as activating matrix metalloproteinase-2 on the cell surface. The integrin receptors, particularly alpha(v)beta(3), can recruit and possibly activate matrix metalloproteinases to localized microdomains on the cell membrane. This restricts matrix metalloproteinase activity to the pericellular region, preventing excessive matrix degradation which would otherwise impede endothelial invasion. Inhibitors of matrix metalloproteinase activity may actually promote cell invasion by preventing uncontrolled matrix degradation. In addition to degrading the matrix, matrix metalloproteinases produce protein fragments that impede their angiogenic action. These multiple regulatory pathways permit fine control over cell invasion during angiogenesis and provide new, precise strategies for targeting abnormal angiogenesis, through control of matrix metalloproteinase activity.
TL;DR: It is proposed that the cap regulates ureteric branching morphogenesis, the source for the pretubular aggregates, and the role of the cap condensate is unknown.
Abstract: Conversion of mesenchyme to epithelium in the metanephric kidney is clearly a multimolecular, multistep and partly redundant process. The present short review focuses on a neglected morphological aspect of kidney differentiation: the development of two transitory mesenchymal condensations that precede epithelial differentiation of nephrons. The first appearing condensate covers the tips of the collecting ducts and is termed a cap condensate. In the early kidney rudiment this structure has been referred to as a primary or early condensate. A few cells of the cap condensate (maybe only four to six cells), situated at the lateral edge of the cap, start proliferating rapidly and form a pretubular aggregate (or pretubular condensate), which converts to secretory nephron epithelia and finally segregates to different tubule segments. Throughout nephrogenesis, the cap condensates and pretubular aggregates are clearly distinguishable structures that show only partly overlapping gene expression profiles. Apart from being the source for the pretubular aggregates, the role of the cap condensate is unknown. It is now proposed that the cap regulates ureteric branching morphogenesis.
TL;DR: The phosphatonins are a growing family of substances that may act on multiple organs in autocrine, paracrine, and endocrine modes to regulate phosphate metabolism and provide a clearer understanding of how individual phosphatonin regulate phosphate in normal and disease physiology.
Abstract: Purpose of review There is an intimate relationship between phosphate and calcium homeostasis throughout the animal kingdom. One traditional assumption is that all phosphate-regulating hormones are primarily calcium-regulating hormones. Although the notion of a circulating substance dedicated to phosphate homeostasis has existed for more than a decade, it is not until recently that these hormones have been identified. The molecular characterization of these substances will prove to be critical for understanding phosphate physiology and clinical disorders of phosphate metabolism. Recent findings This review will focus primarily on the first two proteins recently shown to have phosphatonin properties. Using three human diseases as models and a combination of positional cloning and differential gene expression, fibroblast growth factor 23 and frizzled-related protein 4 were shown to be associated with one or more of these diseases. Although both of these substances have phosphaturic action, their biological effects are likely to extend beyond epithelial phosphate transport. Summary The phosphatonins are a growing family of substances that may act on multiple organs in autocrine, paracrine, and endocrine modes to regulate phosphate metabolism. As this list expands, the need for a more rigid definition of the term phosphatonin becomes evident. The identification and characterization of these phosphate-regulatory compounds will provide a clearer understanding of how individual phosphatonins regulate phosphate in normal and disease physiology.
TL;DR: The fact that angiotensin-converting enzyme inhibitors and angiotENSin receptor blockers antagonize the renin-angiotensIn system at different levels suggests that these agents, already each of confirmed clinical benefit in retarding the progression of chronic renal disease, may have had an impact on this disease.
Abstract: Purpose of reviewThe fact that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers antagonize the renin-angiotensin system at different levels suggests that these agents, already each of confirmed clinical benefit in retarding the progression of chronic renal disease, may have
TL;DR: This review assesses publications that relate to the analytical techniques used to measure cyclosporin, tacrolimus, mycophenolic acid, sirolimus and everolimus, as well as the clinical data obtained, to assess the clinical value of drug monitoring.
Abstract: Purpose of reviewDrug monitoring has become an accepted adjunct to optimizing therapy with immunosuppressive drugs. This review assesses publications that relate to the analytical techniques used to measure cyclosporin, tacrolimus, mycophenolic acid, sirolimus and everolimus, as well as the clinical
TL;DR: How these disorders may be mechanistically related to one another is discussed, as excessive production of factors such as FGF 23 and frizzled-related protein-4 is associated with inability of endogenous proteolytic enzymes to degrade these individual substances, with resultant hyperphosphaturia, hypophosphatemia, and rickets.
Abstract: Purpose of review Studies of patients with tumors associated with osteomalacia (tumor-induced osteomalacia), X-linked hypophosphatemia (XLH) and autosomal-dominant hypophosphatemic rickets have provided important new insights into the identity and mechanisms of action of factors that play a role in controlling renal phosphate excretion and serum phosphate concentrations. In the present review I discuss how these disorders may be mechanistically related to one another. Recent findings Patients (or mice) with these disorders manifest rickets as a result of excessive urinary phosphate losses. Tumors associated with osteomalacia elaborate factors ('phosphatonins') that increase renal phosphate excretion and reduce serum phosphate concentrations. These factors include fibroblast growth factor (FGF) 23 and frizzled-related protein-4. Mice with XLH (Hyp) elaborate a circulating factor that induces changes in mineral metabolism similar to those in patients with tumor-induced osteomalacia. In mice and humans with XLH, a mutant enzyme, phex/PHEX, cannot degrade the phosphaturic factor. Patients with autosomal-dominant hypophosphatemic rickets produce a mutant FGF 23 that is resistant to proteolytic degradation. Excessive FGF 23 activity is associated with increased renal phosphate excretion and hypophosphatemia. Summary In tumor-induced osteomalacia, excessive production of factors such as FGF 23 and frizzled-related protein-4 is associated with inability of endogenous proteolytic enzymes to degrade these individual substances, with resultant hyperphosphaturia, hypophosphatemia, and rickets. In XLH, mutant PHEX/phex (phosphate-regulating gene with homology to endopeptidases located on the X-chromosome) activity prevents degradation of a phosphaturic factor. In autosomal-dominant hypophosphatemic rickets, a mutant form of FGF 23 that is resistant to proteolytic degradation causes increased renal phosphate losses and hypophosphatemia.
TL;DR: The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and low-dose fibrates could be effective therapies for lipid disorders and clinical trials with statins and other drugs that improve dyslipidemia also need to be undertaken.
Abstract: Premature atherosclerosis is a major cause of morbidity and mortality in end-stage renal disease patients. Dyslipidemia and increased oxidative stress contribute to premature atherogenesis in these patients. The dyslipidemia of end-stage renal disease consists of both quantitative and qualitative abnormalities in serum lipoproteins. Qualitative changes include hypertriglyceridemia (increased remnant lipoproteins), low high-density lipoprotein-cholesterol, and increased lipoprotein (a). In addition to quantitative changes, lipoproteins in end-stage renal disease undergo compositional and qualitative changes that make them pro-atherogenic, such as various modifications of apolipoprotein B, including oxidation, and modification by advanced glycation end-products. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and low-dose fibrates could be effective therapies for lipid disorders. The best evidence for increased oxidative stress in end-stage renal disease is the demonstration of increased plasma F2-isoprostanes. Confirmation of the positive findings with high-dose alpha-tocopherol in the Secondary Prevention with Antioxidants of Cardiovascular Disease in End-stage Renal Disease Study is urgently needed. Clinical trials with statins and other drugs that improve dyslipidemia also need to be undertaken. These therapies could clearly lead to a reduction in cardiovascular morbidity and mortality in these patients.
TL;DR: The effects of bone morphogenetic protein-7 on vascular calcification in an animal model is reviewed, a potential complication of this therapy given its osseous Morphogenetic effect.
Abstract: Bone morphogenetic proteins are members of the transforming growth factor-beta superfamily of cytokines and consist of a group of at least 15 morphogens involved in intracellular messaging through complex bone morphogenetic protein receptor mediated Smad signaling. Bone morphogenetic protein-7 knockout mice die shortly after birth due to uremia, demonstrating that this morphogenetic protein is essential for renal development. Recent investigations have characterized renal bone morphogenetic protein-7 receptors, shown exogenous bone morphogenetic protein-7 to prevent fibrogenesis associated with ureteral obstruction, indicated a loss of renal bone morphogenetic protein-7 associated with diabetic nephropathy, and an improvement in glomerular pathology in rodent streptozocin-induced diabetes with bone morphogenetic protein-7 treatment. In addition, this morphogenetic protein has been shown to reduce glomerulonephritis and tubulointerstitial fibrosis in a murine model of lupus nephritis as well as decrease the peritrabecular fibrosis associated with murine high turnover renal osteodystrophy. Finally, we review the effects of bone morphogenetic protein-7 on vascular calcification in an animal model, a potential complication of this therapy given its osseous morphogenetic effect.
TL;DR: A significant number of publications support the evidence for improved outcomes in most of the study areas, including financial benefits, and Convincing data of improved outcomes and evidence of cost efficiency of daily hemodialysis are being generated.
Abstract: The interest in daily hemodialysis in the form of short daily hemodialysis and nocturnal hemodialysis has continued to increase over the past few years. A significant number of publications support the evidence for improved outcomes in most of the study areas, including financial benefits. The increased direct cost of the provision of daily hemodialysis seems to be the main obstacle to the wider acceptance of these methods. Convincing data of improved outcomes and evidence of cost efficiency of daily hemodialysis are being generated. These data may increase the interest of the institutional payors as well as of the dialysis industry to create the proper infrastructure for the use of daily hemodialysis. These dialysis regimens promise to have a major impact on the management of end-stage renal disease.
TL;DR: The influence of a relative malfunction of the nitric oxide system on the vascular tone and vascular structure, and the effects of hypertension on this system, are discussed.
Abstract: Nitric oxide, the metabolic product of L-arginine by the enzyme nitric oxide synthase, plays a pivotal role in the regulation of vascular homeostasis. Its complex interaction with the autocrine and paracrine systems, particularly angiotensin II, modulates vasoconstriction and vasodilatation as well as the architectural remodeling of the vascular bed. The major vascular hormones known to be involved are angiotensin II and endothelin-1. Upregulation of endothelin-1, a potent molecule, appears to be a consequence of the nitric oxide-angiotensin II imbalance that contributes to end-organ injury. Increased oxidative stress, common to different diseases including diabetes mellitus and hypertension, is also a determinant player in the interaction between angiotensin II and nitric oxide. The influence of a relative malfunction of the nitric oxide system on the vascular tone and vascular structure, and the effects of hypertension on this system, are discussed.