Heparin in pregnant women with previous placenta-mediated pregnancy complications: a prospective, randomized, multicenter, controlled clinical trial.

To assess whether antithrombotic prophylaxis with low-molecular-weight heparin effectively prevents recurrence of late pregnancy complications, 135 women with previous history of preeclampsia, hemolytic anemia, elevated liver enzymes and low platelet count syndrome, intrauterine fetal death, fetal growth restriction, or placental abruption who had been referred within the 12th gestational week were randomized to medical surveillance alone (n = 68) or combined to open-label nadroparin (3800 IU daily subcutaneous injections) treatment (n = 67) in the setting of a randomized, parallel-group, superiority trial, run in Italy from April 2007 to April 2010. Primary outcome was a composite end point of late-pregnancy complications. Analysis was by intention to treat. The study was stopped for futility at the time of the first planned interim analysis. Among the 128 women eventually available for final analyses, 13 of the 63 (21%) randomized to nadroparin compared with 12 of the 65 (18%) on medical surveillance alone progressed to the primary end point. The absolute event risk difference between treatment arms (2.2; -1.6 to 16.0) was not statistically significant (P = .76). Thus, nadroparin did not prevent late-pregnancy complications in women at risk of recurrence. This finding challenges the role of antithrombotic prophylaxis with low-molecular-weight heparin in the prevention of recurrent late pregnancy complications The trial was registered at http://ricerca-clinica.agenziafarmaco.it as EudraCT 2006-004205-26.

Hypertension and kidney function in an adult population of West Bengal, India: role of body weight, waist circumference, proteinuria and rural area living.

AIM: Hypertension (HTN) and chronic kidney disease (CKD) are important emerging problems in low-income countries, with an increasing number of patients dying from their consequences. METHODS: A project for investigating these issues was carried out in West Bengal, India, in 2536 adult subjects. Body mass index (BMI) was classified using traditional and new cut-offs identified by the World Health Organization for Asian populations. HTN was classified according to the Joint National Committee 7 and CKD according to presence of estimated glomerular filtration rate (eGFR) of less than 60 mL/min per 1.73 m(2) . RESULTS: Normal BMI (Asian reference) was found in 41.5% of subjects, while 33.4% were underweight, 19.3% overweight and 5.8% obese. Prevalence of stage 1 and 2 HTN was 39.4%. Proteinuria (urine dipstick >1+) was present in 7.7% of the sample. In a subsample of 1526 subjects, eGFR of less than 60 mL/min per 1.73 m(2) was found in 4.2%. At multivariate analysis, factors associated with HTN were weight classes (P<0.001), presence of proteinuria (P<0.001) and family history of HTN (P=0.028), while living in rural areas was associated with lower risk for HTN (P=0.003). eGFR was inversely related to BMI (P=0.03), the presence of proteinuria (P<0.001) and HTN (P<0.003), and directly related to living in rural areas (P=0.003). CONCLUSION: High prevalence of HTN was found in subjects with very limited access to health care in West Bengal. HTN was more common in overweight individuals, but also affected normal weight and underweight subjects in a significant part of the tested population. Preventive medicine should be a strong priority in this setting.

Sirolimus therapy to halt the progression of ADPKD.

Activation of mammalian target of rapamycin (mTOR) pathways may contribute to uncontrolled cell proliferation and secondary cyst growth in patients with autosomal dominant polycystic kidney disease (ADPKD). To assess the effects of mTOR inhibition on disease progression, we performed a randomized, crossover study (The SIRENA Study) comparing a 6-month treatment with sirolimus or conventional therapy alone on the growth of kidney volume and its compartments in 21 patients with ADPKD and GFR>or=40 ml/min per 1.73 m2. In 10 of the 15 patients who completed the study, aphthous stomatitis complicated sirolimus treatment but was effectively controlled by topical therapy. Compared with pretreatment, posttreatment mean total kidney volume increased less on sirolimus (46+/-81 ml; P=0.047) than on conventional therapy (70+/-72 ml; P=0.002), but we did not detect a difference between the two treatments (P=0.45). Cyst volume was stable on sirolimus and increased by 55+/-75 ml (P=0.013) on conventional therapy, whereas parenchymal volume increased by 26+/-30 ml (P=0.005) on sirolimus and was stable on conventional therapy. Percentage changes in cyst and parenchyma volumes were significantly different between the two treatment periods. Sirolimus had no appreciable effects on intermediate volume and GFR. Albuminuria and proteinuria marginally but significantly increased during sirolimus treatment. In summary, sirolimus halted cyst growth and increased parenchymal volume in patients with ADPKD. Whether these effects translate into improved long-term outcomes requires further investigation.

Burden of CKD, proteinuria, and cardiovascular risk among Chinese, Mongolian, and Nepalese participants in the International Society of Nephrology screening programs.

BACKGROUND: In 2007, the International Society of Nephrology funded the Kidney Disease Data Center database to house data from sponsored programs aimed at preventing chronic kidney disease and its complications in developing nations. This study compares baseline characteristics and burden of illness among participants from centers in China, Mongolia, and Nepal. An important secondary objective is to show the feasibility of screening for chronic kidney disease and its major risk factors in a diverse group of lower income settings. STUDY DESIGN: Cross-sectional screening study. SETTING & PARTICIPANTS: Participants from Nepal (n = 8,398), China (n = 1,999), and Mongolia (n = 997). Screening was open to the public for participants in China and Nepal; referral from a general practitioner was required for participants in Mongolia. OUTCOMES: Estimated glomerular filtration rate (eGFR), proteinuria, hypertension, diabetes, obesity, cardiovascular risk. MEASUREMENT: Demographic and clinical data were collected prospectively using a standard format. Blood and urine specimens were provided according to local protocol. RESULTS: Of 11,394 participants, decreased eGFR (<60 mL/min/1.73 m(2)) was present in 7.3%-14% of participants across centers; proteinuria (≥1+) on dipstick (2.4%-10%), hypertension (26%-36%), diabetes (3%-8%), and obesity (body mass index ≥30 kg/m(2); 2%-20%) were all common. Predicted 5-year cardiovascular risk ≥10% ranged from 20%-89%. Numbers needed to screen to detect a new case of eGFR <60 mL/min/1.73 m(2), hypertension, or diabetes were 2.6 (95% CI, 2.5-2.7), 3.4 (95% CI, 3.1-3.7), and 4.7 (95% CI, 3.3-8.0) for Nepal, China, and Mongolia, respectively. LIMITATIONS: May not be representative of the general population. CONCLUSIONS: The acceptable diagnostic yield of abnormalities across these 3 diverse settings suggests that trials of targeted screening and intervention are feasible and warranted in such countries.

Actin dynamics and Rho GTPases regulate the size and formation of parasitophorous vacuoles containing Coxiella burnetii.

Q fever is a disease caused by Coxiella burnetii. In the host cell, this pathogen generates a large parasitophorous vacuole (PV) with lysosomal characteristics. Here we show that F-actin not only is recruited to but also is involved in the formation of the typical PV. Treatment of infected cells with F-actin-depolymerizing agents alters PV development. The small PVs formed in latrunculin B-treated cells were loaded with transferrin and Lysotracker and labeled with an antibody against cathepsin D, suggesting that latrunculin B did not affect vacuole cargo and its lysosomal characteristics. Nevertheless, the vacuoles were unable to fuse with latex bead phagosomes. It is known that actin dynamics are regulated by the Rho family GTPases. To assess the role of these GTPases in PV formation, infected cells were transfected with pEGFP expressing wild-type and mutant Rac1, Cdc42, and RhoA proteins. Rac1 did not show significant PV association. In contrast, PVs were decorated by both the wild types and constitutively active mutants of Cdc42 and RhoA. This association was inhibited by treatment of infected cells with chloramphenicol, suggesting a role for bacterial protein synthesis in the recruitment of these proteins. Interestingly, a decrease in vacuole size was observed in cells expressing dominant-negative RhoA; however, these small vacuoles accumulated transferrin, Lysotracker, and DQ-BSA. In summary, these results suggest that actin, likely modulated by the GTPases RhoA and Cdc42 and by bacterial proteins, is involved in the formation of the typical PV.

Developing regulatory-compliant electronic case report forms for clinical trials: experience with the demand trial.

The use of electronic case report forms (CRF) to gather data in randomized clinical trials has grown to progressively replace paper-based forms. Computerized form designs must ensure the same data quality expected of paper CRF, by following Good Clinical Practice rules. Electronic data capture (EDC) tools must also comply with applicable statutory and regulatory requirements. Here the authors focus on the development of computerized systems for clinical trials implementing FDA and EU recommendations and regulations, and describe a laptop-based electronic CRF used in a randomized, multicenter clinical trial.

Do attributes of persons with chronic kidney disease differ in low-income and middle-income countries compared with high-income countries? Evidence from population-based data in six countries.

Kidney biopsies to elucidate the cause of chronic kidney disease (CKD) are performed in a minority of persons with CKD living in high-income countries, since associated conditions-that is, diabetes mellitus, vascular disease or obesity with pre-diabetes, prehypertension or dyslipidaemia-can inform management targeted at slowing CKD progression in a majority. However, attributes of CKD may differ substantially among persons living in low-income and middle-income countries (LMICs). We used data from population or community-based studies from five LMICs (China, urban India, Moldova, Nepal and Nigeria) to determine what proportion of persons with CKD living in diverse regions fit one of the three major clinical profiles, with data from the US National Health Nutrition and Examination Survey as reference. In the USA, urban India and Moldova, 79.0%-83.9%; in China and Nepal, 62.4%-66.7% and in Nigeria, 51.6% persons with CKD fit one of three established risk profiles. Diabetes was most common in urban India and vascular disease in Moldova (50.7% and 33.2% of persons with CKD in urban India and Moldova, respectively). In Nigeria, 17.8% of persons with CKD without established risk factors had albuminuria ≥300 mg/g, the highest proportion in any country. While the majority of persons with CKD in LMICs fit into one of three established risk profiles, the proportion of persons who have CKD without established risk factors is higher than in the USA. These findings can inform tailored CKD detection and management systems and highlight the importance of studying potential causes and outcomes of CKD without established risk factors in LMICs.

Chronic kidney disease and cardiovascular risk in six regions of the world (ISN-KDDC): a cross-sectional study.

BACKGROUND: Chronic kidney disease is an important cause of global mortality and morbidity. Data for epidemiological features of chronic kidney disease and its risk factors are limited for low-income and middle-income countries. The International Society of Nephrology's Kidney Disease Data Center (ISN-KDDC) aimed to assess the prevalence and awareness of chronic kidney disease and its risk factors, and to investigate the risk of cardiovascular disease, in countries of low and middle income. METHODS: We did a cross-sectional study in 12 countries from six world regions: Bangladesh, Bolivia, Bosnia and Herzegovina, China, Egypt, Georgia, India, Iran, Moldova, Mongolia, Nepal, and Nigeria. We analysed data from screening programmes in these countries, matching eight general and four high-risk population cohorts collected in the ISN-KDDC database. High-risk cohorts were individuals at risk of or with a diagnosis of either chronic kidney disease, hypertension, diabetes, or cardiovascular disease. Participants completed a self-report questionnaire, had their blood pressure measured, and blood and urine samples taken. We defined chronic kidney disease according to modified KDIGO (Kidney Disease: Improving Global Outcomes) criteria; risk of cardiovascular disease development was estimated with the Framingham risk score. FINDINGS: 75,058 individuals were included in the study. The prevalence of chronic kidney disease was 14·3% (95% CI 14·0-14·5) in general populations and 36·1% (34·7-37·6) in high-risk populations. Overall awareness of chronic kidney disease was low, with 409 (6%) of 6631 individuals in general populations and 150 (10%) of 1524 participants from high-risk populations aware they had chronic kidney disease. Moreover, in the general population, 5600 (44%) of 12,751 individuals with hypertension did not know they had the disorder, and 973 (31%) of 3130 people with diabetes were unaware they had that disease. The number of participants at high risk of cardiovascular disease, according to the Framingham risk score, was underestimated compared with KDIGO guidelines. For example, all individuals with chronic kidney disease should be considered at high risk of cardiovascular disease, but the Framingham risk score detects only 23% in the general population, and only 38% in high-risk cohorts. INTERPRETATION: Prevalence of chronic kidney disease was high in general and high-risk populations from countries of low and middle income. Moreover, awareness of chronic kidney disease and other non-communicable diseases was low, and a substantial number of individuals who knew they were ill did not receive treatment. Prospective programmes with repeat testing are needed to confirm the diagnosis of chronic kidney disease and its risk factors. Furthermore, in general, health-care workforces in countries of low and middle income need strengthening. FUNDING: International Society of Nephrology.

Cortactin is involved in the entry of Coxiella burnetii into non-phagocytic cells.

BACKGROUND: Cortactin is a key regulator of the actin cytoskeleton and is involved in pathogen-host cell interactions. Numerous pathogens exploit the phagocytic process and actin cytoskeleton to infect host cells. Coxiella burnetii, the etiologic agent of Q fever, is internalized by host cells through a molecular mechanism that is poorly understood. METHODOLOGY/PRINCIPAL FINDING: Here we analyzed the role of different cortactin motifs in the internalization of C. burnetii by non-phagocytic cells. C. burnetii internalization into HeLa cells was significantly reduced when the cells expressed GFP-cortactin W525K, which carries a mutation in the SH3 domain that renders the protein unable to bind targets such as N-WASP. However, internalization was unaffected when the cells expressed the W22A mutant, which has a mutation in the N-terminal acidic region that destroys the protein's ability to bind and activate Arp2/3. We also determined whether the phosphorylation status of cortactin is important for internalization. Expression of GFP-cortactin 3F, which lacks phosphorylatable tyrosines, significantly increased internalization of C. burnetii, while expression of GFP-cortactin 3D, a phosphotyrosine mimic, did not affect it. In contrast, expression of GFP-cortactin 2A, which lacks phosphorylatable serines, inhibited C. burnetii internalization, while expression of GFP-cortactin SD, a phosphoserine mimic, did not affect it. Interestingly, inhibitors of Src kinase and the MEK-ERK kinase pathway blocked internalization. In fact, both kinases reached maximal activity at 15 min of C. burnetii infection, after which activity decreased to basal levels. Despite the decrease in kinase activity, cortactin phosphorylation at Tyr421 reached a peak at 1 h of infection. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the SH3 domain of cortactin is implicated in C. burnetii entry into HeLa cells. Furthermore, cortactin phosphorylation at serine and dephosphorylation at tyrosine favor C. burnetii internalization. We present evidence that ERK and Src kinases play a role early in infection by this pathogen.

Prevalence of hypertension and diabetes and coexistence of chronic kidney disease and cardiovascular risk in the population of the republic of moldova.

In 2005, the International Society of Nephrology (ISN) established the Global Outreach Program (GO) aimed at building a capacity for detecting and managing chronic kidney disease and its complications in low- and middle-income countries. Here we report data from the 2006-2007 screening program (1025 subjects from the general population) in the Republic of Moldova aimed to determine the prevalence of hypertension, diabetes, and their coexistence with microalbuminuria. The likelihood of a serious cardiovascular (CV) event was also estimated. Hypertension and diabetes were very common among screened subjects. The prevalence of microalbuminuria was 16.9% and that of estimated GFR <60 ml/min/1.73 m(2) (decreased renal function) was 9.4%. Male gender was associated with an increased prevalence of hypertension and microalbuminuria. Hypertension and diabetes clustered in subjects with microalbuminuria and renal dysfunction. Risk factors such as preobesity/obesity, physical inactivity and smoking were relatively common, even in younger participants. The prevalence of subjects with predicted 10-year CV risk ≥10% was 10.0%. In conclusion, in the Republic of Moldova patients with hypertension and diabetes should be screened for the coexistence of renal abnormalities, with the intention of developing disease-specific health-care interventions with the primary goal to reduce CV morbidity and mortality and prevent renal disease progression to end stage renal disease.

Preventing renal and cardiovascular risk by renal function assessment: insights from a cross-sectional study in low-income countries and the USA.

OBJECTIVE: To assess the prevalence of microalbuminuria and kidney dysfunction in low-income countries and in the USA. DESIGN: Cross-sectional study of screening programmes in five countries. SETTING: Screening programmes in Nepal, Bolivia, the USA (National Health and Nutrition Examination Survey (NHANES) 2005-2008) Bangladesh and Georgia. PARTICIPANTS: General population in Nepal (n=20 811), Bolivia (n=3436) and in the USA (n=4299) and high-risk subjects in Bangladesh (n=1518) and Georgia (n=1549). PRIMARY AND SECONDARY OUTCOME MEASURES: Estimated glomerular filtration rate (eGFR)<60ml/min/1.73 m(2) and microalbuminuria (defined as urinary albumin creatinine ratio values of 30-300 mg/g) were the main outcome measures. The cardiovascular (CV) risk was also evaluated on the basis of demographic, clinical and blood data. RESULTS: The prevalence of eGFR<60ml/min/1.73 m(2) was 19%, 3.2% and 7% in Nepal, Bolivia and the USA, respectively. In Nepal, 7% of subjects were microalbuminuric compared to 8.6% in the USA. The prevalence of participants with predicted 10-year CV disease (CVD) risk ≥10% was 16.9%, 9.4% and 17% in Nepal, Bolivia and in the USA, respectively. In Bangladesh and Georgia, subjects with eGFR<60 ml/min/1.73 m(2) were 8.6% and 4.9%, whereas those with microalbuminuria were 45.4% and 56.5%, respectively. Predicted 10-year CVD risk ≥10% was 25.4% and 25% in Bangladesh and Georgia, respectively. CONCLUSIONS: Renal abnormalities are common among low-income countries and in the USA. Prevention programmes, particularly focused on those with renal abnormalities, should be established worldwide to prevent CVD and progression to end-stage renal disease.

Effects of add-on fluvastatin therapy in patients with chronic proteinuric nephropathy on dual renin-angiotensin system blockade: the ESPLANADE trial.

BACKGROUND AND OBJECTIVES: This open, prospective, randomized trial aimed to assess the effects of statins in chronic kidney disease patients on optimized antiproteinuric treatment with combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: After 1-month benazepril therapy followed by 1-month benazepril-valsartan combined therapy (run-in), 186 consenting patients with residual proteinuria >0.5 g/24 h were randomized to 6-month benazepril-valsartan therapy alone or combined with fluvastatin. Between-groups changes in proteinuria (primary outcome), serum lipids, and GFR were compared by ANCOVA. Analyses were blinded and by intention to treat. RESULTS: During the run-in, proteinuria decreased more on benazepril-valsartan than on benazepril alone. Proteinuria reduction correlated with concomitant reduction in total, LDL, and HDL cholesterol, and apolipoprotein B and apolipoprotein A levels. After randomization, median proteinuria similarly decreased from 1.2 (0.6 to 2.2) to 1.1 (0.5 to 1.7) g/24 h on fluvastatin and from 1.5 (0.8 to 2.7) to 1.0 (0.5 to 2.4) g/24 h on benazapril-valsartan therapy alone. Fluvastatin further reduced total and LDL cholesterol and apolipoprotein B versus benazepril-valsartan alone, but did not affect serum triglycerides and GFR. Treatment was well tolerated. CONCLUSIONS: In chronic kidney disease patients with residual proteinuria despite combined angiotensin-converting enzyme inhibitor and angiotensin receptor blockade therapy, add-on fluvastatin does not affect urinary proteins, but further reduces serum lipids and is safe. Whether combined angiotensin-converting enzyme inhibitor, angiotensin receptor blockade, and statin therapy may improve cardiovascular outcomes in this high-risk population is worth investigating.