Medial arterial calcification is accelerated in patients with CKD and strongly associated with increased arterial rigidity and cardiovascular mortality. Recently, a novel in vitro blood test that provides an overall measure of calcification propensity by monitoring the maturation time (T 50 ) of calciprotein particles in serum was described. We used this test to measure serum T 50 in a prospective cohort of 184 patients with stages 3 and 4 CKD, with a median of 5.3 years of follow-up. At baseline, the major determinants of serum calcification propensity included higher serum phosphate, ionized calcium, increased bone osteoclastic activity, and lower free fetuin-A, plasma pyrophosphate, and albumin concentrations, which accounted for 49% of the variation in this parameter. Increased serum calcification propensity at baseline independently associated with aortic pulse wave velocity in the complete cohort and progressive aortic stiffening over 30 months in a subgroup of 93 patients. After adjustment for demographic, renal, cardiovascular, and biochemical covariates, including serum phosphate, risk of death among patients in the lowest T 50 tertile was more than two times the risk among patients in the highest T 50 tertile (adjusted hazard ratio, 2.2; 95% confidence interval, 1.1 to 5.4; P=0.04). This effect was lost, however, after additional adjustment for aortic stiffness, suggesting a shared causal pathway. Longitudinally, serum calcification propensity measurements remained temporally stable (intraclass correlation=0.81). These results suggest that serum T 50 may be helpful as a biomarker in designing methods to improve defenses against vascular calcification.

Muscle injury (rhabdomyolysis) and subsequent deposition of myoglobin in the kidney causes renal vasoconstriction and renal failure. We tested the hypothesis that myoglobin induces oxidant injury to the kidney and the formation of F 2 -isoprostanes, potent renal vasoconstrictors formed during lipid peroxidation. In low density lipoprotein (LDL), myoglobin induced a 30-fold increase in the formation of F 2 -isoprostanes by a mechanism involving redox cycling between ferric and ferryl forms of myoglobin. In an animal model of rhabdomyolysis, urinary excretion of F 2 -isoprostanes increased by 7.3-fold compared with controls. Administration of alkali, a treatment for rhabdomyolysis, improved renal function and significantly reduced the urinary excretion of F 2 -isoprostanes by ϳ80%. EPR and UV spectroscopy demonstrated that myoglobin was deposited in the kidneys as the redox competent ferric myoglobin and that it's concentration was not decreased by alkalinization. Kinetic studies demonstrated that the reactivity of ferryl myoglobin, which is responsible for inducing lipid peroxidation, is markedly attenuated at alkaline pH. This was further supported by demonstrating that myoglobin-induced oxidation of LDL was inhibited at alkaline pH. These data strongly support a causative role for oxidative injury in the renal failure of rhabdomyolysis and suggest that the protective effect of alkalinization may be attributed to inhibition of myoglobin-induced lipid peroxidation.

Increased CPP fetuin-A levels reflect an increasingly procalcific milieu and are associated with increased aortic stiffness in patients with pre-dialysis CKD.

The formation of fetuin-A-containing calciprotein particles (CPP) may facilitate the clearance of calcium phosphate nanocrystals from the extracellular fluid. These crystals may otherwise seed extra-osseous mineralization. Fetuin-A is a partially phosphorylated glycoprotein that plays a critical role in stabilizing these particles, inhibiting crystal growth and aggregation. CPP removal is thought to be predominantly mediated by cells of the reticuloendothelial system via type I and type II class A scavenger receptor (SR-AI/II). Naked calcium phosphate crystals are known to stimulate macrophages and other cell types in vitro, but little is known of the effect of CPP on these cells. We report here, for the first time, that CPP induce expression and secretion of tumour necrosis factor (TNF)-α, interleukin (IL)-1β in murine RAW 264.7 macrophages. Importantly, however, CPP induced significantly lower cytokine secretion than hydroxyapatite (HAP) crystals of equivalent size and calcium content. Furthermore, CPP only had a modest effect on macrophage viability and apoptosis, even at very high levels, compared to HAP crystals, which were strongly pro-apoptotic at much lower levels. Fetuin-A phosphorylation was found to modulate the effect of CPP on cytokine secretion and apoptosis, but not uptake via SR-AI/II. Prolonged exposure of macrophages to CPP was found to result in up-regulated expression of SR-AI/II. CPP formation may help protect against some of the pro-inflammatory and harmful effects of calcium phosphate nanocrystals, perhaps representing a natural defense system for calcium mineral stress. However, in pathological states where production exceeds clearance capacity, these particles may still stimulate pro-inflammatory and pro-apoptotic cascades in macrophages, which may be important in the pathogenesis of vascular calcification.

Abstract-Aortic stiffness and chronic kidney disease are closely linked by shared risk factors and associated increased cardiovascular mortality. At lower levels of renal function, aortic stiffness is independently associated with glomerular filtration rate. However, the longitudinal impact of aortic stiffness on renal function has not been reported previously. A cohort of 133 patients with chronic kidney disease stages 3 and 4 (estimated glomerular filtration rate: 15 to 59 mL/min per 1.73 m 2 ) underwent prospective measurement of arterial stiffness parameters and monitoring of renal function. Aortic pulse wave velocity measurement was performed in 120 patients. The mean age was 69Ϯ12 years (meanϮSD; 103 men, 30 women, and 23.3% diabetic). Mean systolic blood pressure was 155Ϯ21 mm Hg, and mean diastolic blood pressure was 83Ϯ11 mm Hg. The mean Modification of Diet in Renal Disease estimated glomerular filtration rate was 32Ϯ11 mL/min per 1.73 m 2 . Change in renal function was measured using reciprocal creatinine plots and the dichotomous combined end point of Ն25% decline in renal function or start of renal replacement therapy. After stepwise multivariate analysis, aortic pulse wave velocity was independently associated with gradient of reciprocal creatinine plot (rϭ0.46; Pϭ0.014). In multivariate analysis of the end point of Ն25% decline in renal function or start of renal replacement therapy, independent predictors were aortic pulse wave velocity (rϭ0.48; Pϭ0.002), systolic blood pressure (rϭ0.17; Pϭ0.039), and urine protein:creatinine ratio (rϭ0.20; Pϭ0.021). We, therefore, conclude that aortic stiffening is independently associated with rate of change in renal function in patients with chronic kidney disease stages 3 and 4. (Hypertension. 2010;55:1110-1115.) Key Words: aorta Ⅲ pulse pressure Ⅲ microvessels Ⅲ kidney Ⅲ creatinine Ⅲ pulse pressure Ⅲ renal insufficiency C hronic kidney disease (CKD) is a common condition, affecting 10% to 13% of the population of the United States, 1 associated with a dramatically increased cardiovascular (CV) mortality, which increases with severity of renal impairment. This excess CV risk is in part attributed to an increase of traditional risk factors among people with CKD 2 but may also relate to the complex metabolic and vascular changes of CKD, including arterial stiffening. Aortic stiffness increases progressively as renal function declines 3 and has been independently associated with CV mortality in patients with renal failure. 4,5 Although much research has investigated the role of aortic stiffening in the causation of CV disease in patients with CKD, less attention has been paid to its potential etiologic role in the causation and progression of renal impairment. Aortic stiffening causes increased systolic blood pressure (BP; SBP) and widened pulse pressure (PP), both factors associated in longitudinal studies with increased rate of decline of renal function. 6,7 In addition, aortic stiffening results in loss of the dampening of ventricular ejection and could lead ...

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The aim of the study was to investigate the prevalence and aetiology of chronic kidney disease (CKD) and trends in estimated glomerular filtration rate (eGFR) in HIV-infected patients. MethodsAscertainment and review of CKD cases among patients attending King's College and Brighton Hospitals, UK were carried out. CKD was defined as eGFR o60 mL/min for ! 3 months. Longitudinal eGFR slopes were produced to examine trends in renal function before, during and after exposure to indinavir (IDV) or tenofovir (TFV). ResultsCKD prevalence was 2.4%. While HIV-associated nephropathy accounted for 62% of CKD in black patients, 95% of CKD in white/other patients was associated with diabetes mellitus, hypertension, atherosclerosis and/or drug toxicity. Exposure to IDV or TFV was associated with an accelerated decline in renal function (4.6-fold and 3.7-fold, respectively) in patients with CKD. In patients initiating IDV, age ! 50 years increased the odds of CKD [odds ratio (OR) 4.9], while in patients initiating TFV, age ! 50 years (OR 5.4) and eGFR 60-75 mL/min (OR 17.2) were associated with developing CKD. ConclusionThis study highlights the importance of metabolic and vascular disease to the burden of CKD in an ageing HIV-infected cohort. In patients who developed CKD, treatment with IDV or TFV was associated with an accelerated decline in renal function.Keywords: glomerular filtration rate, HIV, indinavir, kidney, tenofovir Accepted 20 November 2008 Introduction Acute renal failure (ARF) and chronic kidney disease (CKD) are important complications of HIV infection [1]. Approximately 6% of HIV-infected patients develop one or multiple episodes of ARF [2], and 15% of patients have evidence of CKD [3,4]. ARF usually occurs in the setting of severe (opportunistic) infections, malignancy or liver disease [2,5], and both ARF and CKD are associated with advanced immunodeficiency [2][3][4][5][6]. Black HIV-infected patients are at risk of developing HIV-associated nephropathy (HIVAN), which is characterized by heavy proteinuria and rapid progression to end-stage renal disease (ESRD) [7][8][9]. HIVAN, idiopathic noncollapsing focal and segmental glomerulonephritis (FSGS), immune complex kidney disease and other glomerulopathies predominate in biopsy series and among black patients with ESRD [7,[10][11][12][13].In the general, HIV-uninfected population, the prevalence of CKD increases dramatically in those aged 50 years and over [14]. CKD in these patients is associated with diabetes mellitus, hypertension and atherosclerosis [15], and is an independent risk factor for coronary heart disease [16]. CKD in this setting is often insidious in onset and may take decades to become clinically manifest. The objectives of this study were to describe the prevalence and aetiology of CKD in HIV-infected patients receiving care in the UK, and to examine trends in renal function before, during and after exposure to IDV or TFV in patients with CKD. Methods Case ascertainmentAll HIV-infected adults with CKD who attended King's College Hospital ...

Summary Background Understanding of the role of vitamin D in health and disease has increased markedly in the past decade, with its involvement extending well beyond traditional roles in calcium and phosphate homeostasis and musculoskeletal health. This conceptual expansion has been underpinned by identification and exploration of components of this axis including vitamin D‐binding protein, key enzymes and receptors in multiple cell types, and a greater recognition of nonclassical autocrine and paracrine effects. Its influence in IBD remains uncertain. Aim To review the role of vitamin D in bone health, immune regulation and cancer prevention in IBD, and to outline practical issues and limitations of its use. Methods An extensive online literature review including PubMed and Medline. Results In patients with IBD, the vitamin D axis provides an important and often underutilised pathway to preserving bone health. Furthermore, an exciting body of clinical and basic science research demonstrates that these pathways may have an integral part to play in regulation of the immune response in IBD, through effects on the intestinal barrier, antigen presenting cells and adaptive T cells. The possibility of chemoprevention requires further study. The optimal target level of 25‐hydroxy vitamin D in patients with IBD is currently uncertain, as is the best therapeutic modality. Conclusions Study of vitamin D pathways may result in the development of relatively inexpensive therapeutic options to optimise patient outcomes. Further prospective clinical research is required to address efficacy and long‐term safety.