Elizabeth Maccariello - Academia.edu (original) (raw)

Papers by Elizabeth Maccariello

Research paper thumbnail of The Effects of Isradipine and Spirapril as Monotherapy and Combined Therapy on Blood Pressure, Renal Hemodynamics, Natriuresis, and Urinary Kallikrein in Hypertensive Nephropathy

American Journal of Hypertension, May 1, 1997

In this cross-over, double-blind study, 12 essential GFR did not change. UNaV increased significa... more In this cross-over, double-blind study, 12 essential GFR did not change. UNaV increased significantly after IS (0.17 v 0.22 mEq /min) and IS / SP (0.18 v hypertensive patients (stage I, II, and III) with 0.24 mEq /min). UKal increased significantly after glomerular filtration rate (GFR) between 50 to 80 IS (58.6%) and IS / SP (53.6%). UAE decreased mL /min / 1.73 m 2 , were submitted to 4 weeks of significantly only after SP. PRA increased placebo followed by 12 weeks with isradipine significantly after IS (1.31 v 2.84 ng /mL / h) , SP SRO (IS) 5 mg, spirapril (SP) 6 mg, and (1.10 v 2.15 ng /mL / h) , and after IS / SP (1.23 v isradipine plus spirapril (IS / SP). The study 3.21 ng /mL /min). In conclusion, IS, SP and IS / evaluated the effects of these drugs on GFR (99m Tc SP were effective in reducing blood pressure DTPA) , effective renal plasma flow (ERPF) (131 Iwhile keeping renal function stable. Only SP orthoiodohippurate) , urinary sodium excretion significantly decreased UAE. Enhanced UKal may (UNaV) , urinary kallikrein excretion (UKal) , have played a role in natriuresis observed after IS urinary albumin excretion (UAE) , and plasma and IS / SP. Am J Hypertens 1997; 10:541-545 renin activity (PRA). The three protocols ᭧ 1997 American Journal of Hypertension, Ltd. significantly reduced mean blood pressure (128 v 107 mm Hg; 126 v 112 mm Hg; 129 v 104 mm Hg KEY WORDS: Isradipine, spirapril, hypertensive with IS, SP and IS / SP, respectively). ERPF and nephropathy, renal hemodynamics, kallikrein.

Research paper thumbnail of Single use of cytokine-adsorption-membrane Oxiris® in the treatment of severe malaria with acute kidney injury: a case-report

Research Square (Research Square), Aug 1, 2022

Research paper thumbnail of Comparing Strategies to Prevent Extracorporeal Circuit Coagulation in Continuous Renal Replacement Therapies: Role of Citrate Anticoagulation

Jornal Brasileiro De Nefrologia, 2006

Research paper thumbnail of Estratégias de Prevenção de Coagulação do Circuito Extra-corpóreo em Procedimentos Contínuos de Suporte Renal: Papel da Anticoagulação Regional com Citrato

J. Bras. Nefrol., Jun 19, 2006

Research paper thumbnail of Desempenho de seis modelos de predição prognóstica em pacientes críticos que receberam suporte renal extracorpóreo

Revista Brasileira De Terapia Intensiva, Jun 1, 2008

RESUMO JUSTIFICATIVA E OBJETIVOS: Não existe consenso sobre qual modelo prognóstico deva ser util... more RESUMO JUSTIFICATIVA E OBJETIVOS: Não existe consenso sobre qual modelo prognóstico deva ser utilizado em pacientes com disfunção renal aguda (DRA). O objetivo deste estudo foi avaliar o desempenho de seis escores de prognóstico em pacientes que necessitaram de suporte renal. MÉTODO: Coorte prospectiva de pacientes internados nas unidades de terapia intensiva (UTI) de três hospitais terciários que necessitaram de suporte re

Research paper thumbnail of Contrast induced nephropathy

Brazilian Journal of Nephrology, 2016

Research paper thumbnail of Renal hemodynamics, sodium excretion, urinary kallicrein and microalbuminuria following treatment with spirapril, isradipine and the association of isradipine and spirapril

American Journal of Hypertension, Apr 1, 1996

Research paper thumbnail of Development and Validation of a Machine Learning Model to Predict the Use of Renal Replacement Therapy in 14,374 Patients COVID-19

Research paper thumbnail of A Prospective International Multicenter Study of AKI in the Intensive Care Unit

Clinical Journal of The American Society of Nephrology, Jul 20, 2015

Background and objectives AKI is frequent and is associated with poor outcomes. There is limited ... more Background and objectives AKI is frequent and is associated with poor outcomes. There is limited information on the epidemiology of AKI worldwide. This study compared patients with AKI in emerging and developed countries to determine the association of clinical factors and processes of care with outcomes. Design, setting, participants, & measurements This prospective observational study was conducted among intensive care unit patients from nine centers in developed countries and five centers in emerging countries. AKI was defined as an increase in creatinine of $0.3 mg/dl within 48 hours. Results Between 2008 and 2012, 6647 patients were screened, of whom 1275 (19.2%) developed AKI. A total of 745 (58% of those with AKI) agreed to participate and had complete data. Patients in developed countries had more sepsis (52.1% versus 38.0%) and higher Acute Physiology and Chronic Health Evaluation (APACHE) scores (mean6SD, 61.1627.5 versus 51.1625.2); those from emerging countries had more CKD (54.3% versus 38.3%), GN (6.3% versus 0.9%), and interstitial nephritis (7.0% versus 0.6%) (all P,0.05). Patients from developed countries were less often treated with dialysis (15.5% versus 30.2%; P,0.001) and started dialysis later after AKI diagnosis (2.0 [interquartile range, 0.75-5.0] days versus 0 [interquartile range, 0-5.0] days; P=0.02). Hospital mortality was 22.0%, and 13.3% of survivors were dialysis dependent at discharge. Independent risk factors associated with hospital mortality included older age, residence in an emerging country, use of vasopressors (emerging countries only), dialysis and mechanical ventilation, and higher APACHE score and cumulative fluid balance (developed countries only). A lower probability of renal recovery was associated with residence in an emerging country, higher APACHE score (emerging countries only) and dialysis, while mechanical ventilation was associated with renal recovery (developed countries only). Conclusions This study contrasts the clinical features and management of AKI and demonstrates worse outcomes in emerging than in developed countries. Differences in variations in care may explain these findings and should be considered in future trials.

Research paper thumbnail of LPS-mediated upregulation of A20 protein expression is blunted in aortae of diabetic, as compared to non-diabetic mice

<p>(A) WB of A20 in abdominal aortae of diabetic and non-diabetic atherosclerosis-prone C57... more <p>(A) WB of A20 in abdominal aortae of diabetic and non-diabetic atherosclerosis-prone C57BL/6 and atherosclerosis-resistant FVB/N mice, 8 h after LPS treatment. GAPDH and βactin were used to correct for loading and quantify relative A20 expression by densitometry, as reported below the WB. Data shown are representative of 3 (non-diabetic) and 4 (diabetic) mice per time-point and illustrate the loss of LPS-induced A20 protein in diabetic mice, regardless of strain. The cuts between samples reflect the fact that these samples, while on the same gel and same experiment, were not contiguous. (B) A20 mRNA levels analyzed by real-time PCR 3 to 8 h after LPS injection in mouse abdominal aortae (n = 5 non-diabetic and 7 diabetic mice in C57BL/6 and 3 non-diabetic and 4 diabetic mice in FVB/N). Data shown demonstrates that LPS increases A20 mRNA levels in aortae of diabetic and non-diabetic C57BL/6 and FVB/N, albeit at a greater levels in diabetic mice. Expression of 18S ribosomal RNA was used to normalize expression of A20 mRNA, and the results were presented as mean±SEM of mRNA. Each sample was measured in duplicate.</p

Research paper thumbnail of Reply to

Nephrology Dialysis Transplantation, 2009

In this report, we reply to a recent comment by Carl M. Bender, Gregorio Benincasa and Hugh F. Jo... more In this report, we reply to a recent comment by Carl M. Bender, Gregorio Benincasa and Hugh F. Jones on our work 'New ansatz for metric operator calculation in pseudo-Hermitian field theory (Phys. Rev. D. 79, 107702 (2009)). In fact, they figured out that there exist sign errors in our work which leaded to the conclusion of the invalidity of

Research paper thumbnail of Increasing glucose (D-Glu) concentrations decreases TNF-mediated A20 protein up-regulation without affecting its transcriptional activation in SMC

<p>(A) Analysis of A20 expression by WB. SMC were cultured in 5, or 30 mM D-Glu, or the osm... more <p>(A) Analysis of A20 expression by WB. SMC were cultured in 5, or 30 mM D-Glu, or the osmotic control (25 mM L-Glu +5 mM D-Glu), and treated with TNF for 6 h. βactin was checked as a loading control and used to quantify relative A20 expression by densitometry, as reported beneath the WB. Densitometry of the bands of interest and was determined as the mean intensity of the areas delineated by Image J, then corrected by the main intensity of the corresponding housekeeping gene band. Fold induction was determined using the non-treated 5 mM D-glucose condition sample as one (1). Data are representative of 3 independent experiments. The cuts between samples reflect the fact that these samples, while on the same gel and same experiment, were not contiguous. (B) Analysis of A20 mRNA levels by real-time PCR. SMC were cultured in 5 or 30 mM D-Glu or mannitol (25 mM Mannitol +5 mM D-GLu), as an osmotic control, and treated with TNF for 1 or 3 h. 18S ribosomal RNA was used to normalize the data. Natural log transformed data (ln) are presented as mean±SEM of 3 independent experiments performed in duplicate. No significant differences (P>0.05) were noted between all groups and at all time-points.</p

Research paper thumbnail of High glucose promotes A20 O-glycosylation, ubiquitination and proteasomal degradation in EC and SMC

<p>High glucose increases protein O-GlcNAcylation, including that of A20 and possibly other... more <p>High glucose increases protein O-GlcNAcylation, including that of A20 and possibly other E3 Ubiquitin ligases. This leads to increased A20 ubiquitination either through auto-ubiquitination or increased activity of other O-GlcNAcylated E3 ubiquitin ligases. This targets A20 for degradation in the proteasome. Blockade of O-GlcNAcylation using DON, upstream of A20 Ubiquitination, or inhibition of proteasome activity, using MG132, downstream of A20 ubiquitination would inhibit its proteasomal degradation, restoring its expected protein levels.</p

Research paper thumbnail of Restoring A20 levels reverts glucose-mediated upregulation of RAGE and phosphorylation of PKCβII

<p>(A) WB analysis for RAGE and A20 expression in SMC cultured in 5 or 30 mM D-Glu for 24 h... more <p>(A) WB analysis for RAGE and A20 expression in SMC cultured in 5 or 30 mM D-Glu for 24 h and treated with TNF in the presence or absence of 20 mM of Azaserine (prior to TNF) or 10 mM of MG132 (following TNF). Corrected RAGE fold-inductions are listed below the WB. The RAGE protein is detected as a doublet as a result of pre and post-N-glycosylated form of the protein. Both bands were used for densitometry evaluation. (B) WB analysis of phospho-PKCβII (pPKCβII) and total (c) PKCβII in NT SMC, and in SMC transduced with rAd.A20 or rAd.βgal, and treated with PMA or challenged with 30 mM D-Glu for 1 h. Data shown in A and B are representative of 3 independent experiments. NT = non-transduced cells. GAPDH was used as loading control to quantify the relative expression of RAGE and pPKCβII by densitometry.</p

Research paper thumbnail of Expression of A20 in the ascending aorta and aortic arch of diabetic ApoE-null mice prevents the development of atherosclerotic lesions by inhibiting PKCβII phosphorylation and blunting the induction of RAGE

<p>(A) Transgene expression was confirmed by X-gal staining in rAd.βgal-transduced vessels ... more <p>(A) Transgene expression was confirmed by X-gal staining in rAd.βgal-transduced vessels 5 days following transgene delivery (n = 3 mice/group) and demonstrate the expression of the transgene in medial SMC (M) as well as the adventitia at the level of the aortic root, albeit not in all cells. Image amplification 100× and 400×. (B) A20 expression was verified by real time RT-PCR in two rAd.A20-transduced vessels, using human A20 specific primers that do not recognize mouse A20. Our data indicate significant expression of human A20 in aortic roots of rAd.A20 but not saline treated mice. Results are shown as average± SE. (C) H&E stained aortic root sections at the level of the first coronary from 20 week-old diabetic ApoE-null mice treated with saline, rAd.A20 or rAd.βgal. Images are shown at 100× and 400× as indicated by the scale bar. The asterisk indicates the level of the first coronary branch, Arrows define the intima (I) and the media (M). ApoE-competent, non-diabetic C57BL/6 and non-diabetic ApoE-null mice were used as controls. Blood glucose and cholesterol levels (cholest) are listed below the sections. *P<0.05 compared to saline, ** P<0.01 compared to rAd. βGal. Data shown are representative of 4 to 6 mice per group. I/M ratios were calculated after analysis of 10 serial sections per vessel. (D) phospho-(p)PKCβII (5 days) and RAGE (14 days) immunostaining in aortic arches 5 and 14 days after transgene delivery. Data shown in C are representative of all sections analyzed (n = 3 mice per group, 2–3 sections analyzed per vessel). Image amplification 200×.</p

Research paper thumbnail of O-GlcNAcylation and ubiquitination of A20 modulate its expression

<p>(A) WB analysis of total A20 and co-immunoblotted, overlapping GlcNAc-A20 (RL-2) in SMC ... more <p>(A) WB analysis of total A20 and co-immunoblotted, overlapping GlcNAc-A20 (RL-2) in SMC cultured in 5, 15 and 30 mM of D-glucose (D-Glu), and treated or not with TNF for 6 h. β-actin was used as a control for loading. (B) WB analysis of WGA captured proteins from SMC cultured in 5 and 30 mM D-Glu demonstrate the presence of glycosylated (GlcNAcA20), and co-immunoblotted, overlapping, ubiquitinated A20 (Ub-A20). (C) WB analysis of cell lysates immunoprecipitated with the A20 antibody from SMC cultured in 5 and 30 mM of D-Glu and treated or not with TNF for 6 h, and analyzed WB for total A20 and GlcNAc-A20 using the RL2 antibody demonstrate increased GlcNAc-A20 in high glucose medium. (D) WB analysis of cell lysates immunoprecipitated with the A20 antibody from SMC cultured in 5 and 30 mM D-Glu and treated or not with TNF for 6 h, and analyzed by WB for total and Ub-A20 demonstrate increased Ub-A20 in high glucose medium. (E) WB analysis of total and overlapping GlcNAc-A20 (RL-2) in SMC cultured in 30 mM D-Glu and treated with DON (prior to TNF) or MG132 (after TNF). (F) WB analysis of total and phospho-A20 in SMC cultured in 5, 15 and 30 mM D-Glu and treated with TNF for 6 h demonstrated that relative phosphorylation levels of A20 (pA20) were not decreased by high glucose, despite decreased TNF-mediated upregulation of A20 protein in cells cultured in high glucose. GAPDH or βactin was checked as a loading control to quantify A20 expression by densitometry. Corrected A20 fold-inductions are listed below the WB. RL2/A20 and Ubiquitin/A20 ratios were also calculated by densitometry. Data shown in A, C, D, and E are representative of 3 independent experiments. Data shown in B and F are representative of 2 independent experiments.</p

Research paper thumbnail of Intravenous administration of rAd.A20 to diabetic ApoE-null mice fails to protect them from accelerated atherosclerosis

<p>Evaluation of I/M ratio on H&E stained aortic arch sections from 20-week old mice (8... more <p>Evaluation of I/M ratio on H&E stained aortic arch sections from 20-week old mice (8 weeks following intravenous administration of 2.5×10<sup>9</sup> pfu/mice of rAd.A20 or saline) demonstrated comparable intimal lesions in saline and rAd.A20-treated mice (n = 6 mice/group). Images are shown at the level of the first coronary artery at 100× magnification. The asterisk indicates the level of the first coronary artery branch. Arrows define the intima (I). Immunohistochemistry analysis of RAGE and phospho-PKCβII (pPKCβII) demonstrate equally intense staining in the neointima of saline and rAd.A20-treated mice. Image amplification 400×.</p

Research paper thumbnail of Increasing glucose (D-Glu) concentrations decreases TNF-mediated A20 protein up-regulation without affecting its transcriptional activation in EC

<p>(A) Analysis of A20 expression by WB. EC cultured in medium containing 5, 15 or 30 mM D-... more <p>(A) Analysis of A20 expression by WB. EC cultured in medium containing 5, 15 or 30 mM D-glucose (D-Glu) or L-glucose (L-Glu), as an osmotic control, were stimulated with TNF for 6 h˜βactin was checked as loading control and to quantify relative A20 expression by densitometry, as reported below the WB. Densitometry of the bands of interest and was determined as the mean intensity of the areas delineated by Image J, then corrected by the main intensity of the corresponding house keeping gene band. Fold induction was determined using the non-treated 5 mM D-glucose condition sample as one (1). A20 protein migrates as a doublet in EC and hence both bands were scanned. Data are representative of 3 independent experiments. (B) Analysis of A20 mRNA levels by real-time PCR. EC cultured in medium containing 5, 15 or 30 mM D-Glu or L-Glu as an osmotic control, were stimulated with TNF for 1 and 3 h. Expression of 18S ribosomal RNA was used to normalize the expression of A20 mRNA. Natural log transformed data (ln) are presented as mean±SEM of 3 independent experiments performed in duplicate. No significant differences (P>0.05) were observed between all groups and at all time-points.</p

Research paper thumbnail of Effects of early changes in organ dysfunctions on the outcomes of critically ill patients in need of renal replacement therapy

Clinics, 2008

INTRODUCTION: Acute kidney injury usually develops in critically ill patients in the context of m... more INTRODUCTION: Acute kidney injury usually develops in critically ill patients in the context of multiple organ dysfunctions. OBJECTIVE: To evaluate the effect of changes in associated organ dysfunctions over the first three days of renal replacement therapy on the outcomes of patients with acute kidney injury. METHODS: Over a 19-month period, we evaluated 260 patients admitted to the intensive care units of three tertiary-care hospitals who required renal replacement therapy for > 48 h. Organ dysfunctions were evaluated by SOFA score (excluding renal points) on the first (D1) and third (D3) days of renal replacement therapy. Absolute (A-SOFA) and relative (∆-SOFA) changes in SOFA scores were also calculated. RESULTS: Hospital mortality rate was 75%. Organ dysfunctions worsened (A-SOFA>0) in 53%, remained unchanged (A-SOFA=0) in 17% and improved (A-SOFA<0) in 30% of patients; and mortality was lower in the last group (80% vs. 84% vs. 61%, p=0.003). SOFA on D1 (p<0.001), SOFA on D3 (p<0.001), A-SOFA (p=0.019) and ∆-SOFA (p=0.016) were higher in non-survivors. However, neither A-SOFA nor ∆-SOFA discriminated survivors from non-survivors on an individual basis. Adjusting for other covariates (including SOFA on D1), A-SOFA and ∆-SOFA were associated with increased mortality, and patients in whom SOFA scores worsened or remained unchanged had poorer outcomes. CONCLUSIONS: In addition to baseline values, early changes in SOFA score after the start of renal replacement therapy were associated with hospital mortality. However, no prognostic score should be used as the only parameter to predict individual outcomes.

Research paper thumbnail of Early Gestational Hemolytic Uremic Syndrome: Case Report and Review of Literature

Renal Failure, 1997

Hemolytic uremic syndrome (HUS) is a rare condition which most frequently follows gastrointestina... more Hemolytic uremic syndrome (HUS) is a rare condition which most frequently follows gastrointestinal or respiratory infection episodes in young children, but it can also occur in other settings such as the postpartum period and during use of drugs such as oral contraconceptives, immunosuppressors, and antineoplastics. In early pregnancy, however, its frequency is thought to be very low. The authors report a case of a 30-year-old woman who developed HUS early in her first pregnancy. She had persistent aqueous diarrhea from the beginning of the pregnancy. At the 21st week she developed hypertension which in 2 weeks was followed by seizures, oliguria, and acute pulmonary edema despite intensive medical efforts to control her blood pressure. Surgical intervention for fetal delivery was performed. The patient was initially kept on continuous hemodialysis (CVVHD) followed by an alternate-day conventional hemodialysis schedule. A peripheral blood analysis showed a microangiopathic hemolytic anemia with thrombocytopenia; blood coagulation tests were completely normal. A brain CT scan and an abdominal MRI showed no major abnormalities. HUS was confirmed by a percutaneal kidney biopsy, performed at the 21st day of anuria. Techniques for identification of verotoxin-producing E. coli were not available. Renal function did not recover and the patient has been undergoing regular maintenance hemodialysis for a year.

Research paper thumbnail of The Effects of Isradipine and Spirapril as Monotherapy and Combined Therapy on Blood Pressure, Renal Hemodynamics, Natriuresis, and Urinary Kallikrein in Hypertensive Nephropathy

American Journal of Hypertension, May 1, 1997

In this cross-over, double-blind study, 12 essential GFR did not change. UNaV increased significa... more In this cross-over, double-blind study, 12 essential GFR did not change. UNaV increased significantly after IS (0.17 v 0.22 mEq /min) and IS / SP (0.18 v hypertensive patients (stage I, II, and III) with 0.24 mEq /min). UKal increased significantly after glomerular filtration rate (GFR) between 50 to 80 IS (58.6%) and IS / SP (53.6%). UAE decreased mL /min / 1.73 m 2 , were submitted to 4 weeks of significantly only after SP. PRA increased placebo followed by 12 weeks with isradipine significantly after IS (1.31 v 2.84 ng /mL / h) , SP SRO (IS) 5 mg, spirapril (SP) 6 mg, and (1.10 v 2.15 ng /mL / h) , and after IS / SP (1.23 v isradipine plus spirapril (IS / SP). The study 3.21 ng /mL /min). In conclusion, IS, SP and IS / evaluated the effects of these drugs on GFR (99m Tc SP were effective in reducing blood pressure DTPA) , effective renal plasma flow (ERPF) (131 Iwhile keeping renal function stable. Only SP orthoiodohippurate) , urinary sodium excretion significantly decreased UAE. Enhanced UKal may (UNaV) , urinary kallikrein excretion (UKal) , have played a role in natriuresis observed after IS urinary albumin excretion (UAE) , and plasma and IS / SP. Am J Hypertens 1997; 10:541-545 renin activity (PRA). The three protocols ᭧ 1997 American Journal of Hypertension, Ltd. significantly reduced mean blood pressure (128 v 107 mm Hg; 126 v 112 mm Hg; 129 v 104 mm Hg KEY WORDS: Isradipine, spirapril, hypertensive with IS, SP and IS / SP, respectively). ERPF and nephropathy, renal hemodynamics, kallikrein.

Research paper thumbnail of Single use of cytokine-adsorption-membrane Oxiris® in the treatment of severe malaria with acute kidney injury: a case-report

Research Square (Research Square), Aug 1, 2022

Research paper thumbnail of Comparing Strategies to Prevent Extracorporeal Circuit Coagulation in Continuous Renal Replacement Therapies: Role of Citrate Anticoagulation

Jornal Brasileiro De Nefrologia, 2006

Research paper thumbnail of Estratégias de Prevenção de Coagulação do Circuito Extra-corpóreo em Procedimentos Contínuos de Suporte Renal: Papel da Anticoagulação Regional com Citrato

J. Bras. Nefrol., Jun 19, 2006

Research paper thumbnail of Desempenho de seis modelos de predição prognóstica em pacientes críticos que receberam suporte renal extracorpóreo

Revista Brasileira De Terapia Intensiva, Jun 1, 2008

RESUMO JUSTIFICATIVA E OBJETIVOS: Não existe consenso sobre qual modelo prognóstico deva ser util... more RESUMO JUSTIFICATIVA E OBJETIVOS: Não existe consenso sobre qual modelo prognóstico deva ser utilizado em pacientes com disfunção renal aguda (DRA). O objetivo deste estudo foi avaliar o desempenho de seis escores de prognóstico em pacientes que necessitaram de suporte renal. MÉTODO: Coorte prospectiva de pacientes internados nas unidades de terapia intensiva (UTI) de três hospitais terciários que necessitaram de suporte re

Research paper thumbnail of Contrast induced nephropathy

Brazilian Journal of Nephrology, 2016

Research paper thumbnail of Renal hemodynamics, sodium excretion, urinary kallicrein and microalbuminuria following treatment with spirapril, isradipine and the association of isradipine and spirapril

American Journal of Hypertension, Apr 1, 1996

Research paper thumbnail of Development and Validation of a Machine Learning Model to Predict the Use of Renal Replacement Therapy in 14,374 Patients COVID-19

Research paper thumbnail of A Prospective International Multicenter Study of AKI in the Intensive Care Unit

Clinical Journal of The American Society of Nephrology, Jul 20, 2015

Background and objectives AKI is frequent and is associated with poor outcomes. There is limited ... more Background and objectives AKI is frequent and is associated with poor outcomes. There is limited information on the epidemiology of AKI worldwide. This study compared patients with AKI in emerging and developed countries to determine the association of clinical factors and processes of care with outcomes. Design, setting, participants, & measurements This prospective observational study was conducted among intensive care unit patients from nine centers in developed countries and five centers in emerging countries. AKI was defined as an increase in creatinine of $0.3 mg/dl within 48 hours. Results Between 2008 and 2012, 6647 patients were screened, of whom 1275 (19.2%) developed AKI. A total of 745 (58% of those with AKI) agreed to participate and had complete data. Patients in developed countries had more sepsis (52.1% versus 38.0%) and higher Acute Physiology and Chronic Health Evaluation (APACHE) scores (mean6SD, 61.1627.5 versus 51.1625.2); those from emerging countries had more CKD (54.3% versus 38.3%), GN (6.3% versus 0.9%), and interstitial nephritis (7.0% versus 0.6%) (all P,0.05). Patients from developed countries were less often treated with dialysis (15.5% versus 30.2%; P,0.001) and started dialysis later after AKI diagnosis (2.0 [interquartile range, 0.75-5.0] days versus 0 [interquartile range, 0-5.0] days; P=0.02). Hospital mortality was 22.0%, and 13.3% of survivors were dialysis dependent at discharge. Independent risk factors associated with hospital mortality included older age, residence in an emerging country, use of vasopressors (emerging countries only), dialysis and mechanical ventilation, and higher APACHE score and cumulative fluid balance (developed countries only). A lower probability of renal recovery was associated with residence in an emerging country, higher APACHE score (emerging countries only) and dialysis, while mechanical ventilation was associated with renal recovery (developed countries only). Conclusions This study contrasts the clinical features and management of AKI and demonstrates worse outcomes in emerging than in developed countries. Differences in variations in care may explain these findings and should be considered in future trials.

Research paper thumbnail of LPS-mediated upregulation of A20 protein expression is blunted in aortae of diabetic, as compared to non-diabetic mice

<p>(A) WB of A20 in abdominal aortae of diabetic and non-diabetic atherosclerosis-prone C57... more <p>(A) WB of A20 in abdominal aortae of diabetic and non-diabetic atherosclerosis-prone C57BL/6 and atherosclerosis-resistant FVB/N mice, 8 h after LPS treatment. GAPDH and βactin were used to correct for loading and quantify relative A20 expression by densitometry, as reported below the WB. Data shown are representative of 3 (non-diabetic) and 4 (diabetic) mice per time-point and illustrate the loss of LPS-induced A20 protein in diabetic mice, regardless of strain. The cuts between samples reflect the fact that these samples, while on the same gel and same experiment, were not contiguous. (B) A20 mRNA levels analyzed by real-time PCR 3 to 8 h after LPS injection in mouse abdominal aortae (n = 5 non-diabetic and 7 diabetic mice in C57BL/6 and 3 non-diabetic and 4 diabetic mice in FVB/N). Data shown demonstrates that LPS increases A20 mRNA levels in aortae of diabetic and non-diabetic C57BL/6 and FVB/N, albeit at a greater levels in diabetic mice. Expression of 18S ribosomal RNA was used to normalize expression of A20 mRNA, and the results were presented as mean±SEM of mRNA. Each sample was measured in duplicate.</p

Research paper thumbnail of Reply to

Nephrology Dialysis Transplantation, 2009

In this report, we reply to a recent comment by Carl M. Bender, Gregorio Benincasa and Hugh F. Jo... more In this report, we reply to a recent comment by Carl M. Bender, Gregorio Benincasa and Hugh F. Jones on our work 'New ansatz for metric operator calculation in pseudo-Hermitian field theory (Phys. Rev. D. 79, 107702 (2009)). In fact, they figured out that there exist sign errors in our work which leaded to the conclusion of the invalidity of

Research paper thumbnail of Increasing glucose (D-Glu) concentrations decreases TNF-mediated A20 protein up-regulation without affecting its transcriptional activation in SMC

<p>(A) Analysis of A20 expression by WB. SMC were cultured in 5, or 30 mM D-Glu, or the osm... more <p>(A) Analysis of A20 expression by WB. SMC were cultured in 5, or 30 mM D-Glu, or the osmotic control (25 mM L-Glu +5 mM D-Glu), and treated with TNF for 6 h. βactin was checked as a loading control and used to quantify relative A20 expression by densitometry, as reported beneath the WB. Densitometry of the bands of interest and was determined as the mean intensity of the areas delineated by Image J, then corrected by the main intensity of the corresponding housekeeping gene band. Fold induction was determined using the non-treated 5 mM D-glucose condition sample as one (1). Data are representative of 3 independent experiments. The cuts between samples reflect the fact that these samples, while on the same gel and same experiment, were not contiguous. (B) Analysis of A20 mRNA levels by real-time PCR. SMC were cultured in 5 or 30 mM D-Glu or mannitol (25 mM Mannitol +5 mM D-GLu), as an osmotic control, and treated with TNF for 1 or 3 h. 18S ribosomal RNA was used to normalize the data. Natural log transformed data (ln) are presented as mean±SEM of 3 independent experiments performed in duplicate. No significant differences (P>0.05) were noted between all groups and at all time-points.</p

Research paper thumbnail of High glucose promotes A20 O-glycosylation, ubiquitination and proteasomal degradation in EC and SMC

<p>High glucose increases protein O-GlcNAcylation, including that of A20 and possibly other... more <p>High glucose increases protein O-GlcNAcylation, including that of A20 and possibly other E3 Ubiquitin ligases. This leads to increased A20 ubiquitination either through auto-ubiquitination or increased activity of other O-GlcNAcylated E3 ubiquitin ligases. This targets A20 for degradation in the proteasome. Blockade of O-GlcNAcylation using DON, upstream of A20 Ubiquitination, or inhibition of proteasome activity, using MG132, downstream of A20 ubiquitination would inhibit its proteasomal degradation, restoring its expected protein levels.</p

Research paper thumbnail of Restoring A20 levels reverts glucose-mediated upregulation of RAGE and phosphorylation of PKCβII

<p>(A) WB analysis for RAGE and A20 expression in SMC cultured in 5 or 30 mM D-Glu for 24 h... more <p>(A) WB analysis for RAGE and A20 expression in SMC cultured in 5 or 30 mM D-Glu for 24 h and treated with TNF in the presence or absence of 20 mM of Azaserine (prior to TNF) or 10 mM of MG132 (following TNF). Corrected RAGE fold-inductions are listed below the WB. The RAGE protein is detected as a doublet as a result of pre and post-N-glycosylated form of the protein. Both bands were used for densitometry evaluation. (B) WB analysis of phospho-PKCβII (pPKCβII) and total (c) PKCβII in NT SMC, and in SMC transduced with rAd.A20 or rAd.βgal, and treated with PMA or challenged with 30 mM D-Glu for 1 h. Data shown in A and B are representative of 3 independent experiments. NT = non-transduced cells. GAPDH was used as loading control to quantify the relative expression of RAGE and pPKCβII by densitometry.</p

Research paper thumbnail of Expression of A20 in the ascending aorta and aortic arch of diabetic ApoE-null mice prevents the development of atherosclerotic lesions by inhibiting PKCβII phosphorylation and blunting the induction of RAGE

<p>(A) Transgene expression was confirmed by X-gal staining in rAd.βgal-transduced vessels ... more <p>(A) Transgene expression was confirmed by X-gal staining in rAd.βgal-transduced vessels 5 days following transgene delivery (n = 3 mice/group) and demonstrate the expression of the transgene in medial SMC (M) as well as the adventitia at the level of the aortic root, albeit not in all cells. Image amplification 100× and 400×. (B) A20 expression was verified by real time RT-PCR in two rAd.A20-transduced vessels, using human A20 specific primers that do not recognize mouse A20. Our data indicate significant expression of human A20 in aortic roots of rAd.A20 but not saline treated mice. Results are shown as average± SE. (C) H&E stained aortic root sections at the level of the first coronary from 20 week-old diabetic ApoE-null mice treated with saline, rAd.A20 or rAd.βgal. Images are shown at 100× and 400× as indicated by the scale bar. The asterisk indicates the level of the first coronary branch, Arrows define the intima (I) and the media (M). ApoE-competent, non-diabetic C57BL/6 and non-diabetic ApoE-null mice were used as controls. Blood glucose and cholesterol levels (cholest) are listed below the sections. *P<0.05 compared to saline, ** P<0.01 compared to rAd. βGal. Data shown are representative of 4 to 6 mice per group. I/M ratios were calculated after analysis of 10 serial sections per vessel. (D) phospho-(p)PKCβII (5 days) and RAGE (14 days) immunostaining in aortic arches 5 and 14 days after transgene delivery. Data shown in C are representative of all sections analyzed (n = 3 mice per group, 2–3 sections analyzed per vessel). Image amplification 200×.</p

Research paper thumbnail of O-GlcNAcylation and ubiquitination of A20 modulate its expression

<p>(A) WB analysis of total A20 and co-immunoblotted, overlapping GlcNAc-A20 (RL-2) in SMC ... more <p>(A) WB analysis of total A20 and co-immunoblotted, overlapping GlcNAc-A20 (RL-2) in SMC cultured in 5, 15 and 30 mM of D-glucose (D-Glu), and treated or not with TNF for 6 h. β-actin was used as a control for loading. (B) WB analysis of WGA captured proteins from SMC cultured in 5 and 30 mM D-Glu demonstrate the presence of glycosylated (GlcNAcA20), and co-immunoblotted, overlapping, ubiquitinated A20 (Ub-A20). (C) WB analysis of cell lysates immunoprecipitated with the A20 antibody from SMC cultured in 5 and 30 mM of D-Glu and treated or not with TNF for 6 h, and analyzed WB for total A20 and GlcNAc-A20 using the RL2 antibody demonstrate increased GlcNAc-A20 in high glucose medium. (D) WB analysis of cell lysates immunoprecipitated with the A20 antibody from SMC cultured in 5 and 30 mM D-Glu and treated or not with TNF for 6 h, and analyzed by WB for total and Ub-A20 demonstrate increased Ub-A20 in high glucose medium. (E) WB analysis of total and overlapping GlcNAc-A20 (RL-2) in SMC cultured in 30 mM D-Glu and treated with DON (prior to TNF) or MG132 (after TNF). (F) WB analysis of total and phospho-A20 in SMC cultured in 5, 15 and 30 mM D-Glu and treated with TNF for 6 h demonstrated that relative phosphorylation levels of A20 (pA20) were not decreased by high glucose, despite decreased TNF-mediated upregulation of A20 protein in cells cultured in high glucose. GAPDH or βactin was checked as a loading control to quantify A20 expression by densitometry. Corrected A20 fold-inductions are listed below the WB. RL2/A20 and Ubiquitin/A20 ratios were also calculated by densitometry. Data shown in A, C, D, and E are representative of 3 independent experiments. Data shown in B and F are representative of 2 independent experiments.</p

Research paper thumbnail of Intravenous administration of rAd.A20 to diabetic ApoE-null mice fails to protect them from accelerated atherosclerosis

<p>Evaluation of I/M ratio on H&E stained aortic arch sections from 20-week old mice (8... more <p>Evaluation of I/M ratio on H&E stained aortic arch sections from 20-week old mice (8 weeks following intravenous administration of 2.5×10<sup>9</sup> pfu/mice of rAd.A20 or saline) demonstrated comparable intimal lesions in saline and rAd.A20-treated mice (n = 6 mice/group). Images are shown at the level of the first coronary artery at 100× magnification. The asterisk indicates the level of the first coronary artery branch. Arrows define the intima (I). Immunohistochemistry analysis of RAGE and phospho-PKCβII (pPKCβII) demonstrate equally intense staining in the neointima of saline and rAd.A20-treated mice. Image amplification 400×.</p

Research paper thumbnail of Increasing glucose (D-Glu) concentrations decreases TNF-mediated A20 protein up-regulation without affecting its transcriptional activation in EC

<p>(A) Analysis of A20 expression by WB. EC cultured in medium containing 5, 15 or 30 mM D-... more <p>(A) Analysis of A20 expression by WB. EC cultured in medium containing 5, 15 or 30 mM D-glucose (D-Glu) or L-glucose (L-Glu), as an osmotic control, were stimulated with TNF for 6 h˜βactin was checked as loading control and to quantify relative A20 expression by densitometry, as reported below the WB. Densitometry of the bands of interest and was determined as the mean intensity of the areas delineated by Image J, then corrected by the main intensity of the corresponding house keeping gene band. Fold induction was determined using the non-treated 5 mM D-glucose condition sample as one (1). A20 protein migrates as a doublet in EC and hence both bands were scanned. Data are representative of 3 independent experiments. (B) Analysis of A20 mRNA levels by real-time PCR. EC cultured in medium containing 5, 15 or 30 mM D-Glu or L-Glu as an osmotic control, were stimulated with TNF for 1 and 3 h. Expression of 18S ribosomal RNA was used to normalize the expression of A20 mRNA. Natural log transformed data (ln) are presented as mean±SEM of 3 independent experiments performed in duplicate. No significant differences (P>0.05) were observed between all groups and at all time-points.</p

Research paper thumbnail of Effects of early changes in organ dysfunctions on the outcomes of critically ill patients in need of renal replacement therapy

Clinics, 2008

INTRODUCTION: Acute kidney injury usually develops in critically ill patients in the context of m... more INTRODUCTION: Acute kidney injury usually develops in critically ill patients in the context of multiple organ dysfunctions. OBJECTIVE: To evaluate the effect of changes in associated organ dysfunctions over the first three days of renal replacement therapy on the outcomes of patients with acute kidney injury. METHODS: Over a 19-month period, we evaluated 260 patients admitted to the intensive care units of three tertiary-care hospitals who required renal replacement therapy for > 48 h. Organ dysfunctions were evaluated by SOFA score (excluding renal points) on the first (D1) and third (D3) days of renal replacement therapy. Absolute (A-SOFA) and relative (∆-SOFA) changes in SOFA scores were also calculated. RESULTS: Hospital mortality rate was 75%. Organ dysfunctions worsened (A-SOFA>0) in 53%, remained unchanged (A-SOFA=0) in 17% and improved (A-SOFA<0) in 30% of patients; and mortality was lower in the last group (80% vs. 84% vs. 61%, p=0.003). SOFA on D1 (p<0.001), SOFA on D3 (p<0.001), A-SOFA (p=0.019) and ∆-SOFA (p=0.016) were higher in non-survivors. However, neither A-SOFA nor ∆-SOFA discriminated survivors from non-survivors on an individual basis. Adjusting for other covariates (including SOFA on D1), A-SOFA and ∆-SOFA were associated with increased mortality, and patients in whom SOFA scores worsened or remained unchanged had poorer outcomes. CONCLUSIONS: In addition to baseline values, early changes in SOFA score after the start of renal replacement therapy were associated with hospital mortality. However, no prognostic score should be used as the only parameter to predict individual outcomes.

Research paper thumbnail of Early Gestational Hemolytic Uremic Syndrome: Case Report and Review of Literature

Renal Failure, 1997

Hemolytic uremic syndrome (HUS) is a rare condition which most frequently follows gastrointestina... more Hemolytic uremic syndrome (HUS) is a rare condition which most frequently follows gastrointestinal or respiratory infection episodes in young children, but it can also occur in other settings such as the postpartum period and during use of drugs such as oral contraconceptives, immunosuppressors, and antineoplastics. In early pregnancy, however, its frequency is thought to be very low. The authors report a case of a 30-year-old woman who developed HUS early in her first pregnancy. She had persistent aqueous diarrhea from the beginning of the pregnancy. At the 21st week she developed hypertension which in 2 weeks was followed by seizures, oliguria, and acute pulmonary edema despite intensive medical efforts to control her blood pressure. Surgical intervention for fetal delivery was performed. The patient was initially kept on continuous hemodialysis (CVVHD) followed by an alternate-day conventional hemodialysis schedule. A peripheral blood analysis showed a microangiopathic hemolytic anemia with thrombocytopenia; blood coagulation tests were completely normal. A brain CT scan and an abdominal MRI showed no major abnormalities. HUS was confirmed by a percutaneal kidney biopsy, performed at the 21st day of anuria. Techniques for identification of verotoxin-producing E. coli were not available. Renal function did not recover and the patient has been undergoing regular maintenance hemodialysis for a year.