Phosphorus Is Associated with Coronary Artery Disease in Patients with Preserved Renal Function

High serum phosphorus levels have been associated with mortality and cardiovascular events in patients with chronic kidney disease and in the general population. In addition, high phosphorus levels have been shown to induce vascular calcification and endothelial dysfunction in vitro. The aim of this study was to evaluate the relation of phosphorus and coronary calcification and atherosclerosis in the setting of normal renal function. This was a cross-sectional study involving 290 patients with suspected coronary artery disease and undergoing elective coronary angiography, with a creatinine clearance >60 ml/min/1.73 m(2). Coronary artery obstruction was assessed by the Friesinger score and coronary artery calcification by multislice computed tomography. Serum phosphorus was higher in patients with an Agatston score >10 than in those with an Agatston score <= 10 (3.63 +/- 0.55 versus 3.49 +/- 0.52 mg/dl; p = 0.02). In the patients with Friesinger scores >4, serum phosphorus was higher (3.6 +/- 0.5 versus 3.5 +/- 0.6 mg/dl, p = 0.04) and median intact fibroblast growth factor 23 was lower (40.3 pg/ml versus 45.7 pg/ml, p = 0.01). Each 0.1-mg/dl higher serum phosphate was associated with a 7.4% higher odds of having a Friesinger score >4 (p = 0.03) and a 6.1% greater risk of having an Agatston score >10 (p = 0.01). Fibroblast growth factor 23 was a negative predictor of Friesinger score ( p = 0.002). In conclusion, phosphorus is positively associated with coronary artery calcification and obstruction in patients with suspected coronary artery disease and preserved renal function.

Physicochemical analysis of blood and urine in the course of acute kidney injury in critically ill patients: a prospective, observational study

Abstract Background Sequential physicochemical alterations in blood and urine in the course of acute kidney injury (AKI) development have not been previously described. We aimed to describe these alterations in parallel to traditional renal and acid–base parameters. Methods One hundred and sixty eight consecutive critically ill patients with no previous kidney disease, who had an indwelling urinary catheter at ICU admission and who remained with the catheter for at least two days without dialysis were included. A sample of blood and spot urine were collected simultaneously, once daily, until catheter removal or dialysis requirement. Traditional acid–base and renal parameters were sequentially evaluated in parallel to blood and urinary physicochemical parameters. Patients were classified during this period as having or not AKI and, for patients with AKI, duration (transient or persistent) and severity (creatinine-based AKIN stage) were evaluated. Results One hundred and thirteen patients (67.3%) had AKI: 92 at ICU admission and 21 during the observation period. AKI development was characterized in blood by increased values of phosphate and unmeasured anions (SIG), decreased albumin, and in urine by decreased values of sodium (NaU), chloride (ClU) as well as high urinary strong ion difference (SIDu). These alterations began to occur before AKI diagnosis, and they reverted in transient AKI but remained in persistent AKI. NaU, ClU and albumin decreased, and phosphate, SIG and SIDu increased with AKI severity progression. NaU and ClU values increased again when AKIN stage 3 was reached. Conclusions Simultaneous physicochemical analysis of blood and urine revealed standardized alterations that characterize AKI development in critically ill patients. These alterations paralleled AKI duration and severity. Future studies should consider including sequential evaluation of urine biochemistry as part of the armamentarium for AKI diagnosis and management.

Diagnosis and treatment of coronary artery disease in hemodialysis patients evaluated for transplant

We present a review of current strategies for the diagnosis and treatment of coronary artery disease (CAD) in patients with advanced chronic kidney disease who are on the waiting list for transplants, based on data from the literature and originated from a single-center cohort of 1,250 patients with maximum follow-up of 12 years. We discuss the best way to select patients to be tested for CAD, how to choose the more adequate screening test for CAD and cardiovascular disease, how to select patients for invasive treatment studies and how to treat patients with significant CAD. We also suggest new research avenues to be explored to resolve some problems in this area.

Uso a longo prazo de enalapril e hidroclorotiazida em dois pacientes com novas mutações com doença de Dent tipo 1

A doença de Dent é uma tubulopatia ligada ao X causada por mutações no gene que codifica o canal de cloro CLCN-5 e é caracterizada por proteinúria de baixo peso molecular, hipercalciúria, nefrocalcinose e insuficiência renal. Vários casos têm sido descritos, nos quais o único sintoma na apresentação foi proteinúria assintomática e glomerulosclerose global ou segmentar. A insuficiência renal nesses pacientes pode ser causada pela hipercalciúria e proteinúria persistente. Portanto, o inibidor da enzima de conversão da angiotensina e os tiazídicos poderiam ser úteis. O objetivo desta pesquisa é relatar os efeitos destas drogas em dois pacientes com doença de Dent tipo 1 com mutações novas. Neste relato não foram observadas correlações significativas entre dose de hidroclorotiazida e calciúria e entre enalapril e proteinúria. Este achado é importante, pois, sendo pacientes poliúricos, o uso destas drogas poderia prejudicar a função renal

Echinococcus granulosus Antigen B Structure: Subunit Composition and Oligomeric States

Background: Antigen B (AgB) is the major protein secreted by the Echinococcus granulosus metacestode and is involved in key host-parasite interactions during infection. The full comprehension of AgB functions depends on the elucidation of several structural aspects that remain unknown, such as its subunit composition and oligomeric states. Methodology/Principal Findings: The subunit composition of E. granulosus AgB oligomers from individual bovine and human cysts was assessed by mass spectrometry associated with electrophoretic analysis. AgB8/1, AgB8/2, AgB8/3 and AgB8/4 subunits were identified in all samples analyzed, and an AgB8/2 variant (AgB8/2v8) was found in one bovine sample. The exponentially modified protein abundance index (emPAI) was used to estimate the relative abundance of the AgB subunits, revealing that AgB8/1 subunit was relatively overrepresented in all samples. The abundance of AgB8/3 subunit varied between bovine and human cysts. The oligomeric states formed by E. granulosus AgB and recombinant subunits available, rAgB8/1, rAgB8/2 and rAgB8/3, were characterized by native PAGE, light scattering and microscopy. Recombinant subunits showed markedly distinct oligomerization behaviors, forming oligomers with a maximum size relation of rAgB8/3 >rAgB8/2>rAgB8/1. Moreover, the oligomeric states formed by rAgB8/3 subunit were more similar to those observed for AgB purified from hydatid fluid. Pressure-induced dissociation experiments demonstrated that the molecular assemblies formed by the more aggregative subunits, rAgB8/2 and rAgB8/3, also display higher structural stability. Conclusions/Significance: For the first time, AgB subunit composition was analyzed in samples from single hydatid cysts, revealing qualitative and quantitative differences between samples. We showed that AgB oligomers are formed by different subunits, which have distinct abundances and oligomerization properties. Overall, our findings have significantly contributed to increase the current knowledge on AgB expression and structure, highlighting issues that may help to understand the parasite adaptive response during chronic infection.

Previous Exposure to Cigarette Smoke Aggravates Experimental Cyclosporine-Induced Nephrotoxicity

Background/Aims: The effects of cigarette smoke (CS) on cyclosporine (CsA)-induced nephrotoxicity are poorly studied. This study aims to assess the effects of previous exposure to CS on CsA nephrotoxicity. Methods: Rats were either exposed to CS or sham (S) procedures for 10 min twice a day for 20 weeks. From the 16th to the 20th week, they received a low-salt diet. Beginning with the 17th week, they were given 2.5 mg/day CsA or vehicle (VH) for 3 weeks. The final groups were VH/CS, CsA/CS, VH/S, and CsA/S. On day 141, glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistance (RVR), tubulointerstitial fibrosis, and CsA blood levels were measured and immunohistochemistry was analyzed for renal alpha-smooth muscle actin (SMA), nitrotyrosine, and vimentin. Results: CsA decrease in GFR was enhanced by CS exposure. CsA associated with CS induced higher periglomerular alpha-SMA and renal nitrotyrosine expression. CsA decreased RBF, but increased RVR, tubulointerstitial fibrosis, and alpha-SMA and renal vimentin expression. These changes and the CsA blood levels were not affected by CS exposure. Conclusion: CS aggravated the CsA-induced impairment of GFR and CS associated with CsA caused the development of periglomerular structural lesions and oxidative stress in a rat model of CsA nephrotoxicity. Copyright (C) 2012 S. Karger AG, Basel

Effect of Brazil Nut Supplementation on Plasma Levels of Selenium in Hemodialysis Patients: 12 Months of Follow-up

Background: Large amounts of reactive oxygen species are produced in hemodialysis (HD) patients, and, at higher concentrations, reactive oxygen species are thought to be involved in the pathogenesis of cardiovascular disease. It has been proposed that selenium (Se) may exert an antiatherogenic influence by reducing oxidative stress. The richest known food source of Se is the Brazil nut (Bertholletia excelsa, family Lecythidaceae), found in the Amazon region. Objective: The objective of this work was to determine if Se plasma levels in HD patients submitted to a program of supplementation during 3 months with 1 Brazil nut by day could be sustained after 12 months. Methods: A total of 21 HD patients (54.2 +/- 15.2 years old; average time on dialysis, 82.3 +/- 51.6 months; body mass index, 24.4 +/- 3.8 kg/m(2)) from the RenalCor Clinic in Rio de Janeiro, Brazil, were followed up 12 months after the supplementation study ended. The Se plasma levels were determined by atomic absorption spectrophotometry with hydride generation. Results: The Se Plasma levels (17.3 +/- 19.9 mg/L) were below the normal range (60 to 120 mu g/L) before nut supplementation, and after 3 months of supplementation, the levels increased to 106.8 +/- 50.3 mu g/L (P < .0001). Twelve months after supplementation, the plasma Se levels decreased to 31.9 +/- 14.8 mu g/L (P < .0001). Conclusions: The data showed that these patients were Se deficient and that the consumption of Brazil nut was effective to increase the Se parameters of nutritional status. Se levels 12 months after the supplementation period were not as low as presupplementation levels but yet significantly lower, and we needed to motivate patients to adopt different dietary intake patterns. (C) 2012 by the National Kidney Foundation, Inc. All rights reserved.

Association Between Circulating Electronegative Low-Density Lipoproteins and Serum Ferritin in Hemodialysis Patients: A Pilot Study

Background: Iron supplementation is a common recommendation to chronic kidney disease patients undergoing hemodialysis (HD). However, iron excess is closely associated with lipid peroxidation and, it is well known that electronegative low-density lipoproteins (LDL[-]) are present at higher plasma concentrations in diseases with high cardiovascular risk such as chronic kidney disease. Thus, the aim of this study was to investigate whether ferritin levels are associated with LDL(-) levels in HD patients. Design: This was a cross-sectional study. Setting: This study was conducted from a private clinic in Rio de Janeiro, Brazil. Patients: The study included 27 HD patients and 15 healthy subjects. Methods and Procedures: Twenty-seven HD patients (14 men, 58.6 +/- 10 years, 62.2 +/- 51.4 months on dialysis, and body mass index: 24.4 +/- 4.2 kg/m(2)) were studied and compared with 15 healthy individuals (6 men, 53.8 +/- 15.4 years, body mass index: 24.5 +/- 4.3 kg/m(2)). Serum LDL(-) levels were measured using the enzyme-linked immunosorbent assay method; ferritin levels by commercially available kits, and tumor necrosis factor-alpha, interleukin-6, monocyte chemoattractant protein-1, and plasminogen activator inhibitor-1 were determined with a multiplex assay kit manufactured by R&D Systems. Results: The HD patients presented higher LDL(-) and tumor necrosis factor-alpha levels (0.15 +/- 0.13 U/L and 5.9 +/- 2.3 pg/mL, respectively) than healthy subjects (0.07 +/- 0.05 U/L and 2.3 +/- 1.3 pg/mL, respectively) (P = .0001). The mean ferritin level in HD patients was 1,117.5 +/- 610.4 ng/mL, and 90% of patients showed ferritin levels exceeding 500 ng/mL. We found a positive correlation between LDL(-) and ferritin in the patients (r = 0.48; P = .01), and ferritin was a significant contributor to LDL(-) concentrations independent of inflammation. Conclusions: Excess body iron stores for HD patients was associated with signs of increased oxidative stress, as reflected by increased LDL(-) levels in HD patients. (C) 2012 by the National Kidney Foundation, Inc. All rights reserved.

Low-Level Laser Therapy Decreases Renal Interstitial Fibrosis

Objective: the purpose of this study was to investigate the effect of low-level laser therapy (LLLT) on chronic kidney disease (CKD) in a model of unilateral ureteral obstruction (UUO). Background data: Regardless of the etiology, CKD involves progressive widespread tissue fibrosis, tubular atrophy, and loss of kidney function. This process also occurs in kidney allograft. At present, effective therapies for this condition are lacking. We investigated the effects of LLLT on the interstitial fibrosis that occurs after experimental UUO in rats. Methods: The occluded kidney of half of the 32 Wistar rats that underwent UUO received a single intraoperative dose of LLLT (AlGaAs laser, 780 nm, 22.5 J/cm(2), 30mW, 0.75W/cm(2), 30 sec on each of nine points). After 14 days, renal fibrosis was assessed by Sirius red staining under polarized light. Immunohistochemical analyses quantitated the renal tissue cells that expressed fibroblast (FSP-1) and myofibroblast (alpha-SMA) markers. Reverse transcriptase polymerase chain reaction (RT-PCR) was performed to determine the mRNA expression of interleukin (IL)-6, monocyte chemotactic protein-1 (MCP-1), transforming growth factor (TGF)-beta 1 and Smad3. Results: The UUO and LLLT animals had less fibrosis than the UUO animals, as well having decreased expression inflammatory and pro-fibrotic markers. Conclusions: For the first time, we showed that LLLT had a protective effect regarding renal interstitial fibrosis. It is conceivable that by attenuating inflammation, LLLT can prevent tubular activation and transdifferentiation, which are the two processes that mainly drive the renal fibrosis of the UUO model.

Previous Exercise Training Has a Beneficial Effect on Renal and Cardiovascular Function in a Model of Diabetes

Exercise training (ET) is an important intervention for chronic diseases such as diabetes mellitus (DM). However, it is not known whether previous exercise training intervention alters the physiological and medical complications of these diseases. We investigated the effects of previous ET on the progression of renal disease and cardiovascular autonomic control in rats with streptozotocin (STZ)-induced DM. Male Wistar rats were divided into five groups. All groups were followed for 15 weeks. Trained control and trained diabetic rats underwent 10 weeks of exercise training, whereas previously trained diabetic rats underwent 14 weeks of exercise training. Renal function, proteinuria, renal sympathetic nerve activity (RSNA) and the echocardiographic parameters autonomic modulation and baroreflex sensitivity (BRS) were evaluated. In the previously trained group, the urinary albumin/creatinine ratio was reduced compared with the sedentary diabetic and trained diabetic groups (p < 0.05). Additionally, RSNA was normalized in the trained diabetic and previously trained diabetic animals (p < 0.05). The ejection fraction was increased in the previously trained diabetic animals compared with the diabetic and trained diabetic groups (p < 0.05), and the myocardial performance index was improved in the previously trained diabetic group compared with the diabetic and trained diabetic groups (p < 0.05). In addition, the previously trained rats had improved heart rate variability and BRS in the tachycardic response and bradycardic response in relation to the diabetic group (p < 0.05). This study demonstrates that previous ET improves the functional damage that affects DM. Additionally, our findings suggest that the development of renal and cardiac dysfunction can be minimized by 4 weeks of ET before the induction of DM by STZ.

The IgA1 immune complex-mediated activation of the MAPK/ERK kinase pathway in mesangial cells is associated with glomerular damage in IgA nephropathy

IgA nephropathy (IgAN), the most common primary glomerulonephritis worldwide, has significant morbidity and mortality as 20-40% of patients progress to end-stage renal disease within 20 years of onset. In order to gain insight into the molecular mechanisms involved in the progression of IgAN, we systematically evaluated renal biopsies from such patients. This showed that the MAPK/ERK signaling pathway was activated in the mesangium of patients presenting with over 1 g/day proteinuria and elevated blood pressure, but absent in biopsy specimens of patients with IgAN and modest proteinuria (<1 g/day). ERK activation was not associated with elevated galactose-deficient IgA1 or IgG specific for galactose-deficient IgA1 in the serum. In human mesangial cells in vitro, ERK activation through mesangial IgA1 receptor (CD71) controlled pro-inflammatory cytokine secretion and was induced by large-molecular-mass IgA1-containing circulating immune complexes purified from patient sera. Moreover, IgA1-dependent ERK activation required renin-angiotensin system as its blockade was efficient in reducing proteinuria in those patients exhibiting substantial mesangial activation of ERK. Thus, ERK activation alters mesangial cell-podocyte crosstalk, leading to renal dysfunction in IgAN. Assessment of MAPK/ERK activation in diagnostic renal biopsies may predict the therapeutic efficacy of renin-angiotensin system blockers in IgAN. Kidney International (2012) 82, 1284-1296; doi:10.1038/ki.2012.192; published online 5 September 2012

Ankle-Brachial Index: A Simple Way to Predict Mortality among Patients on Hemodialysis - A Prospective Study

Background: Ankle-brachial index (ABI) can access peripheral artery disease and predict mortality in prevalent patients on hemodialysis. However, ABI has not yet been tested in incident patients, who present significant mortality. Typically, ABI is measured by Doppler, which is not always available, limiting its use in most patients. We therefore hypothesized that ABI, evaluated by a simplified method, can predict mortality in an incident hemodialysis population. Methodology/Principal Findings: We studied 119 patients with ESRD who had started hemodialysis three times weekly. ABI was calculated by using two oscillometric blood pressure devices simultaneously. Patients were followed until death or the end of the study. ABI was categorized in two groups normal (0.9-1.3) or abnormal (<0.9 and >1.3). There were 33 deaths during a median follow-up of 12 months (from 3 to 24 months). Age (1 year) (hazard of ratio, 1.026; p = 0.014) and ABI abnormal (hazard ratio, 3.664; p = 0.001) were independently related to mortality in a multiple regression analysis. Conclusions: An easy and inexpensive technique to measure ABI was tested and showed to be significant in predicting mortality. Both low and high ABI were associated to mortality in incident patients on hemodialysis. This technique allows nephrologists to identify high-risk patients and gives the opportunity of early intervention that could alter the natural progression of this population.

Which patients are more likely to benefit from renal transplantation?

Background: We evaluated whether the advantages conferred by renal transplantation encompass all individuals or whether they favor more specific groups of patients. Methods: One thousand and fifty-eight patients on the transplant waiting list and 270 receiving renal transplant were studied. End points were the composite incidence of CV events and death. Patients were followed up from date of placement on the list until transplantation, CV event, or death (dialysis patients), or from the date of transplantation, CV event, return to dialysis, or death (transplant patients). Results: Younger patients with no comorbidities had a lower incidence of CV events and death independently of the treatment modality (log-rank = 0.0001). Renal transplantation was associated with better prognosis only in high-risk patients (p = 0.003). Conclusions: Age and comorbidities influenced the prevalence of CV complications and death independently of the treatment modality. A positive effect of renal transplantation was documented only in high-risk patients. These findings suggest that age and comorbidities should be considered indication for early transplantation even considering that, as a group, such patients have a shorter survival compared with low-risk individuals.

Exposure of luminal membranes of LLC-PK1 cells to ANG II induces dimerization of AT(1)/AT(2) receptors to activate SERCA and to promote Ca2+ mobilization

Ferrao FM, Lara LS, Axelband F, Dias J, Carmona AK, Reis RI, Costa-Neto CM, Vieyra A, Lowe J. Exposure of luminal membranes of LLC-PK1 cells to ANG II induces dimerization of AT(1)/AT(2) receptors to activate SERCA and to promote Ca2+ mobilization. Am J Physiol Renal Physiol 302: F875-F883, 2012. First published January 4, 2012; doi:10.1152/ajprenal.00381.2011.-ANG II is secreted into the lumens of proximal tubules where it is also synthesized, thus increasing the local concentration of the peptide to levels of potential physiological relevance. In the present work, we studied the effect of ANG II via the luminal membranes of LLC-PK1 cells on Ca2+-ATPase of the sarco(endo) plasmic reticulum (SERCA) and plasma membrane (PMCA). ANG II (at concentrations found in the lumen) stimulated rapid (30 s) and persistent (30 min) SERCA activity by more than 100% and increased Ca2+ mobilization. Pretreatment with ANG II for 30 min enhanced the ANG II-induced Ca2+ spark, demonstrating a positively self-sustained stimulus of Ca2+ mobilization by ANG II. ANG II in the medium facing the luminal side of the cells decreased with time with no formation of metabolites, indicating peptide internalization. ANG II increased heterodimerization of AT(1) and AT(2) receptors by 140%, and either losartan or PD123319 completely blocked the stimulation of SERCA by ANG II. Using the PLC inhibitor U73122, PMA, and calphostin C, it was possible to demonstrate the involvement of a PLC -> DAG(PMA)-> PKC pathway in the stimulation of SERCA by ANG II with no effect on PMCA. We conclude that ANG II triggers SERCA activation via the luminal membrane, increasing the Ca2+ stock in the reticulum to ensure a more efficient subsequent mobilization of Ca2+. This first report on the regulation of SERCA activity by ANG II shows a new mechanism for Ca2+ homeostasis in renal cells and also for regulation of Ca2+-modulated fluid reabsorption in proximal tubules.

Increased clopidogrel response is associated with ABCC3 expression: A pilot study

Background: The aim of this study was investigate the relationship between ABCB1 and ABCC3 gene expressions in peripheral blood cells (PBC) and the response to clopidogrel in patients with coronary arterial disease (CAD). Methods: Twenty-six male CAD patients (50-70 years) under treatment with clopidogrel (75 mg/day) for at least 5 days were selected. Blood samples were obtained to evaluate platelet reactivity and ABCB1 and ABCC3 mRNA expression. Platelet reactivity was measured in P2Y12 Reaction Units (PRU) using VerifyNow. RNA was extracted from PBC and mRNA levels were measured by qPCR, using GAPD as a reference gene. Results: Platelet response to clopidogrel was categorized in to PRU quartiles. Individuals with PRU values within the first quartile (Q1, <151 units) were considered good responders, while those who had PRU within the fourth quartile (Q4. PRU>260) were considered non-responders. ABCC3 was 1.7 times more expressed in Q4 than in Q1 PRU group (p=0.048). Moreover, CAD patients with low ABCC3 expression (Qe1, <2.5x10(-3)) had higher probability to have a good response to clopidogrel (OR: 18.00, 95%CI: 1.90-169.99, p=0.001). Univariate linear regression analysis demonstrated that low ABCC3 mRNA expression contributed with a reduction of 73 PRU in relation to the patients with expression value higher than 2.5x10(-3) (p=0.027). Neither ABCB1 mRNA levels nor clinical variables studied influenced PRU values. Conclusions: Low ABCC3 mRNA expression in peripheral blood cells is associated with increased clopidogrel response, but further studies are needed to describe the functional relationship of clopidogrel with the ABCC3. Crown Copyright (C) 2011 Published by Elsevier B.V. All rights reserved.