[Optimal use of proton pump inhibitors in primary care]. / Utilisation optimale des inhibiteurs de la pompe á protons dans le cadre des soins primaires.

Acid peptic diseases such as peptic ulcer and gastrointestinal reflux disease have a high prevalence; they can have an important impact on the patient's quality of life and generate a considerable health care cost. Proton pump inhibitors are the most potent pharmacological inhibitors of gastric acid secretion currently available and are the mainstay medical therapy for acid peptic diseases. This review provides primary care clinicians with best practice guidelines for optimal use of these drugs.

Optimal use of proton pump inhibitors for treating acid peptic diseases in primary care.

Heartburn, reflux and epigastric pain are frequently encountered symptoms in primary care medicine. Acid peptic diseases such as peptic ulcer and gastrointestinal reflux disease have a high prevalence, can have important impact on patient quality of life and represent a considerable health care cost. Proton pump inhibitors (PPIs) are the most potent pharmacological inhibitors of gastric acid secretion currently available and are the mainstay medical therapy for acid peptic diseases. This review summarizes current evidence on treatment of acid-peptic diseases with proton pump inhibitors and provides primary care clinicians with best practice guidelines for optimal use of these drugs.

Possibilities and limits of X-ray microtomography for in vivo and ex vivo detection of vascular calcifications.

In the present paper, vascular calcifications due to chronic renal failure in rats are studied by X-ray microtomography (micro-CT). Although micro-CT is traditionally used as an imaging technique, a quantitative analysis of data obtained by in vivo and ex vivo micro-CT is described and discussed. By comparison with traditional destructive methods, such as histomorphometry and atomic absorption, the detection limits for calcium were determined in living rats and in extracted aortas. micro-CT proved to be an effective non-invasive imaging technique allowing non-destructive quantification of ectopic calcifications.

[Experimental study of the mechanism for vascular calcification in chronic kidney disease]. / Experimenteel onderzoek naar de mechanismen van vaatverkalking bij chronisch nierlijden.

Vascular calcification or ectopic calcification ofblood vessels forms an important element of the increased cardiovascular risk observed in patients with chronic kidney disease. In addition to the classical Framingham risk factors, specific uremia-related factors such as hyperphosphatemia and disturbed calcium and phosphorus metabolism contribute to the development of vascular calcification. To gain a better insight into the mechanism of this calcification process, experimental techniques were developed to induce and detect vascular calcification in rats with in vivo micro-CT imaging. By means of synchrotron-based micro-X-ray diffraction the mineral phase deposited in arteries of rats with adenine-induced chronic renal failure was found to consist mainly of hydroxyapatite, whereas calcifications induced with high dose vitamin D administration additionally contained whitlockite, a magnesium-containing mineral. Vascular calcification is an active, cell-regulated process. By immunohistochemically investigating the expression of bone-specific proteins in calciying arteries, we demonstrated that calcifying vascular smooth muscle cells are not only able to acquire an osteoblast-like phenotype, but can moreover transdifferentiate to chondrocyte-like cells, expressing the cartilage transcription factor sox9 and the cartilage extracellular matrix protein collagen II. This cartilage phenotype was also found in human aortic tissue. Finally, treatment of uremic rats with the calcium-free phosphate binder lanthanum carbonate was shown to inhibit the development of vascular calcification, implying that adequate phosphorus control without additional calcium load reduces vascular calcification. In the future, we will map the proteome of calcifying vascular smooth muscle cells and investigate the paradoxical association of vascular calcification with impaired bone mineralisation.

Balanced calcitriol treatment to make children grow.

Short stature is an important clinical problem in children with chronic kidney disease. Calcitriol is used as standard therapy to control secondary hyperparathyroidism, but its effect on linear growth remains controversial. Sanchez and He report multiple effects of calcitriol on chondrocyte proliferation and maturation that might help to clarify this controversy.

Endochondral bone formation is involved in media calcification in rats and in men.

Arterial media calcification is often considered a cell-regulated process resembling intramembranous bone formation, implying a conversion of vascular tissue into a bone-like structure without a cartilage intermediate. In this study, we examined the association of chondrocyte-specific marker expression with media calcification in arterial samples derived from rats with chronic renal failure (CRF) and from human transplant donors. CRF was induced in rats with a diet supplemented with adenine. Vascular calcification was evaluated histomorphometrically on Von Kossa-stained sections and the expression of the chondrocyte markers sox9 and collagen II with the osteogenic marker core-binding factor alpha1 (cbfa1) was determined immunohistochemically. Media calcification was detected in more than half of the rats with CRF. In over half of the rats with severe media calcification, a typical cartilage matrix was found by morphology. All of the animals with severe calcification showed the presence of chondrocyte-like cells expressing the markers sox9, collagen II, and cbfa1. Human aorta specimens showing mild to moderate media calcification also showed sox9, collagen II, and cbfa1 expression. The presence of chondrocytes in association with calcification of the media in aortas of rats with CRF mimics endochondral bone formation. The relevance of this association is further demonstrated by the chondrogenic conversion of medial smooth muscle cells in the human aorta.

Uremia-related vascular calcification: more than apatite deposition.

In the present study, we characterized and compared the mineral phase deposited in the aortic wall of two different frequently used chronic renal failure rat models of vascular calcification. Vascular calcification was induced in rats by either a 4-week adenine treatment followed by a 10-week high-phosphate diet or 5/6 nephrectomy followed by 6 weeks of 0.25 microg/kg/day calcitriol treatment and a high-phosphate diet. Multi-element mapping for calcium and phosphate together with mineral identification was performed on several regions of aortic sections by means of synchrotron X-ray-mu-fluorescence and diffraction. Bulk calcium and magnesium content of the aorta was assessed using flame atomic absorption spectrometry. Based on the diffraction data the Von Kossa-positive precipitate in the aortic regions (N=38) could be classified into three groups: (1) amorphous precipitate (absence of any diffraction peak pattern, N=12); (2) apatite (N=16); (3) a combination of apatite and magnesium-containing whitlockite (N=10). The occurrence of these precipitates differed significantly between the two models. Furthermore, the combination of apatite and whitlockite was exclusively found in the calcitriol-treated animals. These data indicate that in adenine/phosphate-induced uremia-related vascular calcification, apatite is the main component of the mineral phase. The presence of magnesium-containing whitlockite found in addition to apatite in the vitamin D-treated rats, has to be seen in view of the well-known vitamin D-stimulated gastrointestinal absorption of magnesium.

Bisphosphonates prevent experimental vascular calcification: Treat the bone to cure the vessels?

Bisphosphonates are inhibitors of bone resorption that are widely used to treat osteoporosis. Price and colleagues demonstrate that ibandronate suppressed the development of uremia-related vascular calcification in rats. These findings extend the link between bone remodeling and vascular calcification to the context of chronic renal failure, opening perspectives toward novel therapeutic strategies.

Anti-B7-1 blocks mononuclear cell adherence in vasa recta after ischemia.

BACKGROUND: Blocking the costimulatory pathway by CTLA-4 Ig, reactive with both B7-1 and B7-2 costimulatory molecules, protects the kidney during acute ischemia/reperfusion injury. This study investigated whether and how B7-1 and/or B7-2 proteins are involved in renal ischemia/reperfusion injury (IRI). METHODS: Uninephrectomized rats were submitted to warm renal ischemia (30 min) and received control monoclonal antibody (mAb; 17E3), anti-B7-1 (3H5), anti-B7-2 (24F), a combination of anti-B7-1/B7-2, or CTLA-4 Ig. Renal function, morphology, and the kinetics of inflammatory cells were studied for a ten-day period. Binding sites of the injected antibodies were detected by secondary staining with anti-mouse Ab. RESULTS: Compared with controls, acute renal failure (ARF) in the anti-B7-1 group was attenuated both functionally and morphologically. Anti-B7-1/B7-2 and CTLA-4 Ig also were protective in IRI. ARF was not altered by anti-B7-2 treatment. Two hours after reperfusion, B7-1 was expressed along the endothelial cells of the ascending vasa recta. Expression of B7-1 increased over time during the first 24 hours and decreased thereafter. Two hours after reperfusion, adherence/accumulation of T cells and monocytes/macrophages was found in the vasa recta of the ischemic kidney. Anti-B7-1-treated animals had fewer T cells and monocytes/macrophages in the vasa recta compared with controls. Leukocyte accumulation in these vessels after anti-B7-2 treatment was not different from IRI controls. CONCLUSION: These observations strongly support the key role of the B7-1 protein in the protection of renal IRI through inhibition of T cell and monocyte adherence at the level of the ascending vasa recta.

Renal osteopontin protein and mRNA upregulation during acute nephrotoxicity in the rat.

BACKGROUND: The effect of segment-specific proximal tubular injury on spatio-temporal osteopontin (OPN) distribution was determined in two different nephrotoxic rat models to evaluate its conceivability with a possible role for OPN in acute renal failure (ARF). OPN gene expression was further determined in proximal and distal tubular cells to investigate the origin of increased renal OPN. METHODS: Renal OPN protein and mRNA expression were compared in the rat during mercuric-chloride- vs gentamicin-induced ARF using immunohistochemistry and in situ hybridization. RESULTS: Mercuric chloride primarily induced tubular injury and subsequent cell proliferation in proximal straight tubules (PST), whereas gentamicin predominantly injured proximal convoluted tubules (PCT). In both models, the distribution of OPN protein was associated with increased OPN mRNA levels in proximal as well as distal tubular cells. However, upregulation was delayed in the proximal tubular segment suffering most from injury, i.e. PCT in gentamicin ARF vs PST in mercuric-chloride ARF. OPN immunostaining at the apical cell membrane from distal tubules was in contrast to perinuclear vesicular staining in proximal tubular cells. CONCLUSIONS: OPN gene and protein expression is induced in both proximal and distal tubular cells during rat toxic ARF. The distinct subcellular localization in proximal vs distal tubular cells indicates differences in OPN processing and/or handling. The spatio-temporal distribution is consistent with a possible role in renal injury and regeneration.

Differences in osteopontin up-regulation between proximal and distal tubules after renal ischemia/reperfusion.

BACKGROUND: Osteopontin (OPN) is a highly acidic phosphoprotein containing an arginine-glycine-aspartic acid (RGD) cell adhesion motif. High OPN expression has been found in tissues with high cell turnover, and OPN up-regulation has been demonstrated in several models of renal injury, suggesting a possible role in tissue remodeling and repair. However, its exact function in the kidney remains unknown. In this study, the possible contribution of OPN to regeneration and repair in the kidney was explored by studying the time course and subcellular localization of OPN up-regulation after renal ischemia/reperfusion injury in different nephron segments and by investigating its relationship with tubular morphology. METHODS: Rats that underwent 60 minutes of left renal ischemia and a right nephrectomy sacrificed at 10 different time points (from 1 hr to 10 days after reperfusion) were compared with uninephrectomized rats at each time point. In renal tissue sections immunostained for OPN, proximal (PTs) and distal tubules (DTs) in both the renal cortex and outer stripe of the outer medulla (OSOM) were scored for the degree of OPN expression and tubular morphology. RESULTS: Kidneys of uninephrectomized rats showed no injury, and the localization and intensity of their OPN expression remained unaltered compared with normal rats. After ischemia/reperfusion, morphological damage was most severe in PTs of the OSOM, but all examined nephron segments showed a significant increase in OPN expression. The time course of OPN up-regulation was different in PTs and DTs. DTs in both cortex and OSOM rapidly increased their OPN expression, with a maximum at 24 hours after reperfusion followed by a slow decrease. In contrast, PTs showed a delayed increase in OPN staining, with a maximum after five to seven days, higher in the OSOM than in the cortex. In OSOM PTs, OPN expression was predominantly associated with morphological regeneration, whereas DTs showed a substantial OPN up-regulation without major morphological damage. PTs and DTs displayed a different subcellular OPN staining pattern: OPN staining in DTs was located to the apical side of the cell; PTs, however, presented a vesicular, perinuclear staining pattern. CONCLUSIONS: Our study found a different pattern of OPN up-regulation after renal ischemia/reperfusion in PTs versus DTs, both with regard to time course and subcellular localization. DTs show an early and persistent increase in OPN staining in the absence of major morphological injury, whereas OPN staining in PTs is delayed and is mostly associated with morphological regeneration. PTs show a vesicular, perinuclear OPN staining pattern, whereas DTs show OPN staining at the apical cell side.