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Arterial calcification in patients with chronic kidney disease

OBJECTIVEnIn patients with chronic kidney disease (CKD), aortic calcification is more frequent and severe and it is also predictive of adverse cardiovascular outcome. The aim of the present study was to characterize aortic calcification in renal compared with non-renal patients.nnnMETHODSnAortas of 31 patients with advanced CKD and of 31 age-and gender-matched controls were obtained at autopsy. Calcium and phosphorus content in the aorta was quantitated using x-ray analysis. The expression of calcification-promoting and calcification-inhibiting proteins was assessed using immunohistochemistry.nnnRESULTSnThe calcium and phosphorus content of the aorta was higher in CKD patients than in controls. Even in non-calcified aortic specimens of CKD, staining for Msx-2, BMP-2, bone sialo-protein, TNF-alpha and nitrotyrosine was significantly more marked compared to controls. The same proteins were immunodetected in calcified aortic specimens of both CKD and controls. In contrast, staining for transglutaminase-2 and Fetuin A was significantly reduced in CKD. Higher expression of cbfa-1 and Pit-1 was observed in all calcified aortas with no difference between CKD and controls. The expression of TNF-alpha, phospho-p38 and Msx-2 was correlated to the intensity of upregulation of BMP-2 and osteoblastic transdifferentiation by VSMC even in non-calcified areas of the aortas of CKD.nnnCONCLUSIONnThe expression of markers characteristic for calcification is not different in calcified aorta of CKD patients compared to controls, but in CKD patients, evidence of inflammation, transformation to an osteoblastic phenotype and reduced expression of transglutaminase are also found even in non-calcified aorta.

Both high and low maternal salt intake in pregnancy alter kidney development in the offspring

In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague-Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offsprings kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life.

Calcitriol ameliorates capillary deficit and fibrosis of the heart in subtotally nephrectomized rats

BACKGROUNDnRemodelling of the heart, characterized by hypertrophy, fibrosis and capillary/myocyte mismatch, is observed in patients with chronic renal failure. Low vitamin D levels have been associated with increased cardiovascular risk. In the present experimental study, we studied the effects of non-hypercalcaemic doses of calcitriol on microvascular disease and interstitial fibrosis of the heart.nnnMETHODSnThree-month-old male Sprague-Dawley rats were randomized to subtotal nephrectomy (SNX) or sham operation and received calcitriol (6 ng/kg) or vehicle starting immediately thereafter. Blood pressure was measured by tail pletysmography. Albuminuria was measured by rat-specific ELISA. Capillary length density, volume density of interstitial tissue, immunohistochemistry and western blots (vitamin D receptor, collagen I, III, TGF-beta(1), MAP kinases and nitrotyrosine) were assessed after 12 weeks of treatment.nnnRESULTSnAfter SNX blood pressure, albuminuria and heart weight were elevated, capillary length density reduced and interstitial fibrosis increased. Treatment with calcitriol reduced albuminuria and prevented reduction of capillary density and expansion of interstitium without affecting significant blood pressure and heart weight after perfusion fixation. Calcitriol left high VEGF unchanged, but upregulated VEGF receptor 2 (presumably reversing VEGF resistance). Calcitriol reduced expression of profibrotic TGF-beta(1) and the accumulation of collagens I and III.nnnCONCLUSIONSnNon-hypercalcaemic doses of calcitriol ameliorated, directly or indirectly, cardiac remodelling in sub- totally nephrectomized rats.

Multiple endocrine neoplasia type 1

The co-occurrence of parathyroid hyperplasia with pancreatic endocrine tumours and/or pituitary adenoma is classified as Multiple Endocrine Neoplasia type 1 (MEN-1) and is caused by a germ-line mutation in MEN-1 gene encoding a tumour suppressor protein, menin. This review presents clinical expressions, diagnosis and management of the MEN-1 syndrome. Properties and mechanisms of menin functions are also reviewed.

Calcimimetic R-568 or calcitriol: equally beneficial on progression of renal damage in subtotally nephrectomized rats

Patients with renal insufficiency develop secondary hyperparathyroidism. Monotherapy with active vitamin D or calcimimetics ameliorates secondary hyperparathyroidism. We compared kidney damage in subtotally nephrectomized (SNX) rats treated with active vitamin D (calcitriol) or the calcimimetic R-568. Male Sprague-Dawley SNX and sham-operated (sham-op) rats were randomized into the following treatment groups: SNX + R-568, SNX + calcitriol, SNX + vehicle, sham-op + R-568, sham-op + calcitriol, and sham-op + vehicle. Albuminuria and blood pressure were monitored and kidneys were examined using morphometry, immunohistochemistry, quantitative RT-PCR, and in situ hybridization. Parathyroid hormone concentrations were lowered to the same extent by the two interventions, although phosphorus and the calcium-phosphorus product were reduced only by R-568 treatment. SNX rats developed marked albuminuria, which was significantly reduced in ad libitum- and pair-fed animals treated with R-568 and animals treated with calcitriol. Mean glomerular volume (6.05 +/- 1.46 vs. 2.70 +/- 0.91 mm(3)), podocyte volume (831 +/- 127 vs. 397 +/- 67 microm(3)), the degree of foot process fusion (mean width of foot processes = 958 +/- 364 vs. 272 +/- 35 nm), and glomerular basement membrane thickness (244 +/- 6 vs. 267 +/- 23 nm), as well as desmin staining, were significantly higher in vehicle-treated SNX than sham-operated animals. These changes were ameliorated with R-568 and calcitriol. In SNX, as well as sham-operated, animals, expression of the calcium-sensing receptor (protein and mRNA) was upregulated by treatment with the calcimimetic, but not calcitriol. Calcitriol and R-568 were similarly effective in ameliorating kidney damage.

Endogenous cardiotonic steroids in chronic renal failure

BACKGROUNDnPrevious reports demonstrated that digitalis-like cardiotonic steroids (CTS) contribute to the pathogenesis of end-stage renal disease. The goal of the present study was to define the nature of CTS in patients with chronic kidney disease (CKD) and in partially nephrectomized (PNx) rats.nnnMETHODSnIn patients with CKD and in healthy controls, we determined plasma levels of marinobufagenin (MBG) and endogenous ouabain (EO) and erythrocyte Na/K-ATPase activity in the absence and in the presence of 3E9 anti-MBG monoclonal antibody (mAb) and Digibind. Levels of MBG and EO were also determined in sham-operated Sprague-Dawley rats and in rats following 4 weeks of PNx.nnnRESULTSnIn 25 patients with CKD plasma, MBG but not EO was increased (0.86 ± 0.07 versus 0.28 ± 0.02 nmol/L, P < 0.01) and erythrocyte Na/K-ATPase was inhibited (1.24 ± 0.10 versus 2.80 ± 0.09 μmol Pi/mL/h, P < 0.01) as compared to that in 19 healthy subjects. Ex vivo, 3E9 mAb restored Na/K-ATPase in erythrocytes from patients with CKD but did not affect Na/K-ATPase from control subjects. Following chromatographic fractionation of uremic versus normal plasma, a competitive immunoassay based on anti-MBG mAb detected a 3-fold increase in the level of endogenous material having retention time similar to that seen with MBG. A similar pattern of CTS changes was observed in uremic rats. As compared to sham-operated animals, PNx rats exhibited 3-fold elevated levels of MBG but not that of EO.nnnCONCLUSIONSnIn chronic renal failure, elevated levels of a bufadienolide CTS, MBG, contribute to Na/K-ATPase inhibition and may represent a potential target for therapy.

Is there an obesity-metabolic syndrome related glomerulopathy?

Purpose of reviewThere is an increasing evidence for a specific form of focal segmental glomerulosclerosis (FSGS) related to obesity. Its prevalence has progressively increased in past decades. This form of FSGS represents the tip of an iceberg: a much broader spectrum of renal malfunction is linked to visceral obesity, which is closely connected to, but not completely identical with, the concept of ‘metabolic syndrome’. Recent findingsThe obesity-associated FSGS (obFSGS) is characterized by massive proteinuria and glomerular lesions which are similar to but less pronounced than in idiopathic FSGS, but the long-term prognosis is still dubious.The patholophysiology underlying obesity-associated renal pathology includes insulin resistance and salt sensitivity of blood pressure (BP); more recently adiponectin deficiency, hyperaldosteronism and many other pathogenetic factors have been identified. The abnormalities of renal structure in obese and morbidly obese individuals include increased kidney weight, glomerulomegaly, disorder of podocytes, mesangial expansion and more recently also abnormalities of the renal interstitium. This is accompanied by functional abnormalities, that is renal hyperperfusion, increased filtration fraction and albuminuria. Both obesity and metabolic syndrome have been identified as powerful predictors of chronic kidney disease (CKD) and end-stage renal disease (ESRD). This correlation is not fully explained by associated hypertension and prediabetes/diabetes. SummaryThe link between progressive kidney disease and visceral obesity is of enormous public health importance. Apart from causing obFSGS, obesity aggravates most primary kidney diseases. Beyond standard therapy and weight loss, bariatric surgery has recently emerged as a successful intervention for obFSGS.

Effect of paricalcitol and calcitriol on aortic wall remodeling in uninephrectomized ApoE knockout mice

Despite an only minor reduction in the glomerular filtration rate, uninephrectomy (UNX) markedly accelerates the rate of growth of atherosclerotic plaques in ApoE-/- mice. It has been suggested that vitamin D receptor (VDR) activation exerts an antiproliferative effect on vascular smooth muscle cells, but the side effects may limit its use. To assess a potentially different spectrum of actions, we compared the effects of paricalcitol and calcitriol on remodeling and calcification of the aortic wall in sham-operated and UNX ApoE-/- mice on a diet with normal cholesterol content. Sham-operated and UNX mice were randomly allotted to treatment with solvent, calcitriol (0.03 μg/kg) or paricalcitol (0.1 μg/kg) 5 times/wk intraperitoneally for 10 wk. Semithin (0.6 μm) sections of the aorta were analyzed by 1) morphometry, 2) immunohistochemistry, and 3) Western blotting of key proteins involved in vascular calcification and growth. Compared with sham-operated animals (5.6 ± 0.24), the wall-to-lumen ratio (x100) of the aorta was significantly higher in solvent- and calcitriol-treated UNX animals (6.64 ± 0.27 and 7.17 ± 0.81, respectively, P < 0.05), but not in paricalcitol-treated UNX (6.1 5 ± 0.32). Similar differences were seen with respect to maximal plaque height. Expression of transforming growth factor (TGF)-β1 in aortic intima/plaque was also significantly higher in UNX solvent and UNX calcitriol compared with sham-operated and UNX paricalcitol animals. Treatment with both paricalcitol and calcitriol caused significant elevation of VDR expression in the aorta. While at the dose employed paricalcitol significantly reduced TGF-β expression in plaques, calcitriol in contrast caused significant vascular calcification and elevated expression of related proteins (BMP2, RANKL, and Runx2).

Interstitial fibrosis and microvascular disease of the heart in uremia: amelioration by a calcimimetic

In patients with chronic renal failure, the heart undergoes remodeling, characterized by hypertrophy, fibrosis, and capillary/myocyte mismatch. In this study, we observed the effects of the calcimimetic agent R-568 on microvascular disease and interstitial fibrosis of the heart. Three-month-old male Sprague–Dawley rats were randomized to subtotal nephrectomy (SNX) or sham operation and subsequently received vehicle or R-568 under two experimental protocols, one for 1 month and the other for 3 months. Echocardiography, capillary length density, volume density of interstitial tissue, and immunohistochemistry and western blots (calcium-sensing receptor, collagen I and III, transforming growth factor (TGF)-β, mitogen-activated protein kinases, and nitrotyrosine) were assessed. After SNX, weight and wall thickness of the left and the right ventricle were elevated. The ratio of heart to body weight and interventricular septum thickness were not changed by R-568 treatment. The left ventricle fractional shortening (by echocardiography) was lower in SNX; this was ameliorated by R-568. Reduced capillary length density and increased interstitial fibrosis in SNX were improved by R-568, which also reduced the expression of TGF-β, and collagen I and III. The calcimimetic increased the activation of ERK-1/2, normalized p38 and JNK signaling, and prevented oxidative stress. We conclude that lowering parathyroid hormone with a calcimimetic significantly improves cardiac histology and function but not the left ventricular mass in SNX.

Indapamide Decreases Plasma Adiponectin Concentration in Patients with Essential Hypertension

Background/Aim: Adiponectin is an adipose tissue-specific protein with antiatherogenic and insulin-sensitizing properties. In patients with essential hypertension, plasma adiponectin concentrations are lower than in healthy subjects. Antihypertensive drugs do not uniformly influence components of the metabolic syndrome. Therefore, the aim of this study was to evaluate the influence of 6 months’ monotherapy with different antihypertensive drugs on plasma adiponectin concentration in essential hypertension patients. Methods: Forty essential hypertension patients were randomized to receive enalapril, metoprolol, amlodipine or indapamide. Plasma concentrations of adiponectin, insulin, glucose and body fat content were estimated twice: before and after 6 months of antihypertensive monotherapy. Results: Plasma adiponectin concentration did not change significantly after enalapril (11.5 ± 4.8 vs. 11.1 ± 4.1 mg/l), metoprolol (10.2 ± 4.2 vs. 9.8 ± 4.5 mg/l), and amlodipine (9.0 ± 6.0 vs. 8.5 ± 5.4 mg/l) treatment. However, a significant decrease of plasma adiponectin concentration (from 11.6 ± 4.6 to 10.2 ± 4.2 mg/l, p = 0.047) was observed in patients treated with indapamide. Additionally in these patients, a significant increase of the HOMA-IR index was found (p = 0.021). Conclusion: Treatment with indapamide was followed by a significant decrease of plasma adiponectin concentration. This may participate in the pathogenesis of carbohydrate metabolism disturbances often found in patients treated with thiazide-type diuretics.