Ananth Karumanchi

Statin Use and Calcific Uremic Arteriolopathy: A Matched Case-Control Study

Background: Calcific uremic arteriolopathy (CUA), also known as calciphylaxis, is characterized by vascular calcification, thrombosis and intense inflammation. Prior research has shown that statins have anticalcification, antithrombotic and antiinflammatory properties; however, the association between statin use and CUA has not been investigated. Methods: This matched case-control study included 62 adult maintenance hemodialysis (HD) patients with biopsy-confirmed CUA diagnosed between the years 2002 and 2011 (cases). All cases were hospitalized at the time of diagnosis. Controls (n = 124) were hospitalized maintenance HD patients without CUA (matched to cases by gender and timing of hospitalization). Univariate and multivariable logistic regression models were applied to compute odds ratio (OR) and 95% confidence intervals (CI) for CUA in statin users, and also to examine previously described associations. -Results: The mean age of cases was 58 years. Most were females (68%), and of white race (64%). Statin use was more common in controls than in cases (39 vs. 19%, p < 0.01). Statin use was associated with lower odds of CUA in unadjusted (OR 0.38, 95% CI 0.18-0.79) and adjusted (OR 0.20, 95% CI 0.05-0.88) analyses. Hypercalcemia (OR 2.25, 95% CI 1.14-4.43), hypoalbuminemia (OR 5.73, 95% CI 2.79-11.77), calcitriol use (OR 5.69, 95% CI 1.02-31.77) and warfarin use (OR 4.30, 95% CI 1.57-11.74) were positively associated with CUA in adjusted analyses whereas paricalcitol and doxercalciferol were not (OR 1.33, 95% CI 0.54-3.27). Conclusion: Statin use may be negatively associated with odds of CUA. Further large prospective studies with attention to potential confounders are needed to confirm these findings.

Two Variants of the C-Reactive Protein Gene Are Associated with Risk of Pre-Eclampsia in an American Indian Population

Background The etiology of pre-eclampsia (PE) is unknown; but it is accepted that normal pregnancy represents a distinctive challenge to the maternal immune system. C-reactive protein is a prominent component of the innate immune system; and we previously reported an association between PE and the CRP polymorphism, rs1205. Our aim was to explore the effects of additional CRP variants. The IBC (Cardiochip) genotyping microarray focuses on candidate genes and pathways related to the pathophysiology of cardiovascular disease. Methods This study recruited 140 cases of PE and 270 matched controls, of which 95 cases met criteria as severe PE, from an American Indian community. IBC array genotypes from 10 suitable CRP SNPs were analyzed. A replication sample of 178 cases and 427 controls of European ancestry was also genotyped. Results A nominally significant difference (p value <0.05) was seen in the distribution of discordant matched pairs for rs3093068; and Bonferroni corrected differences (P<0.005) were seen for rs876538, rs2794521, and rs3091244. Univariate conditional logistic regression odds ratios (OR) were nominally significant for rs3093068 and rs876538 models only. Multivariate logistic models with adjustment for mothers age, nulliparity and BMI attenuated the effect (OR 1.58, P = 0.066, 95% CI 0.97–2.58) for rs876538 and (OR 2.59, P = 0.050, 95% CI 1.00–6.68) for rs3093068. An additive risk score of the above two risk genotypes shows a multivariate adjusted OR of 2.04 (P = 0.013, 95% CI 1.16–3.56). The replication sample also demonstrated significant association between PE and the rs876538 allele (OR = 1.55, P = 0.01, 95% CI 2.16–1.10). We also show putative functionality for the rs876538 and rs3093068 CRP variants. Conclusion The CRP variants, rs876538 and rs3093068, previously associated with other cardiovascular disease phenotypes, show suggestive association with PE in this American Indian population, further supporting a possible role for CRP in PE.

Levels of angiogenic factors in pregnancy and post‐partum bleeding

We have studied if serum levels of soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and placenta growth factor (PlGF) in pregnancy could predict excess post‐partum bleeding. In 392 normotensive singleton pregnancies, concentrations of sFlt‐1 and PlGF in the first, second, and third trimester were compared between women with and without excess post‐partum bleeding, defined as blood loss volume of at least 500 mL. Mean concentrations of sFlt‐1 were consistently higher in all three trimesters among women who had excess post‐partum bleeding compared to women without this, but significantly higher only in the second trimester. For PlGF, there were no significant differences between the groups. High concentrations of the anti‐angiogenic factor sFlt‐1 in maternal circulation during pregnancy may be associated with an increased risk of excess post‐partum bleeding.

Angiogenic proteins as markers for predicting preeclampsia

Preeclampsia/eclampsia remains a major cause of maternal and fetal morbidity worldwide, most devastating in developing countries. It also remains a leading cause of prematurity, as delivery is currently the only way to successfully treat the disorder. Preeclampsia requires expert care to avoid adverse outcomes for both fetus and mother and thus the ability to predict preeclampsia would be of great value, permitting the caregiver to identify women at risk and permit closer surveillance, or early referral when necessary. The latter is especially relevant in developing nations where tertiary care is limited and often at great distance from the gravidas home. In this respect, an extensive systematic review published in 2004 found no single test reliable to predict preeclampsia. However, the systemic review did not include the predictive value of combinations of tests, as well as promising recent advances regarding angiogenic proteins in the pathophysiology and prediction of preeclampsia. This review will summ...

Screening for Preeclampsia

AbstractPre-eclampsia, still continues to be a major cause of maternal and fetal morbidity and mortality, inspite of being an active area of research. The importance of early prediction of pre-eclampsia lies in the fact that it allows for timely initiation of preventive therapy. A combination of biophysical and biochemical markers are superior to other tests for early prediction of the development of pre-eclampsia. With the inversion of pyramid of antenatal care, preeclampsia screening in the first trimester needs to become the standard of care. Researchers now talk of predicting preeclampsia even in the third trimester to increase surveillance.

OS061. Placental growth factor reduces blood pressure and proteinuria in experimental preeclampsia

INTRODUCTION Preeclampsia is a disorder related to an imbalance in the angiogenesis axis manifesting as endothelial dysfunction. Animal and human studies have shown that sFLT-1 (soluble fms like tyrosine kinase 1) is increased and PlGF (placental growth factor) reduced during the disease state. There are a paucity of studies investigating the clinical significance of normalising angiogenic axis. OBJECTIVES To use a non-human primate uteroplacental ischemic (UPI) model of preeclampsia to assess if reversing the angiogenic imbalance, by increasing circulating PlGF, is able to ameliorate the hypertension and proteinuria. METHODS Hypertensive proteinuria was induced in a non-human primate (Papio hamadryas) by ligation of a unilateral uterine artery at 130days of an 182day pregnancy. After two weeks of UPI, PlGF was administered by subcutaneous injection (100mg/kg/day) for 5 days (n=3) or normal saline in an equivalent volume (n=3). Blood pressure was monitored via intra-arterial radiotelemetry, sFLT-1 measured via ELISA and spot urinary protein:creatinine ratios were measured to monitor proteinuria. Data was analysed using SPSS by t-tests and analysis of repeated measures. Significance was set at p<0.05 and data expressed as the mean ±SEM. RESULTS After two weeks of UPI both groups demonstrated a significant elevation in blood pressure, proteinuria (p<0.05) and sFLT-1 (p<0.001). The systolic BP increased by 12.4±2.3mmHg and 11.7±2.9mmHg in the PlGF and control groups respectively compared to baseline (p<0.005). After PlGF administration, there was a significant reduction in blood pressure in the treated group (-5.2s±0.8mmHg) compared to the increase in BP in the control group (+6.5±3mmHg). Proteinuria also reduced in the treated group from 112±51mg/mmol to 38±12mg/mmol whilst proteinuria in the control group was unchanged. The total circulating sFLT-1 was not significantly affected by the administration of PlGF after 5days. Although this study was not designed to assess fetal safety or outcomes, there was no adverse fetal outcome attributable to the administration of the PlGF. CONCLUSION Administration of PlGF resulted in a reduction in BP and proteinuria without significantly affecting total sFLT-1 levels. Correcting the angiogenic axis imbalance may improve the clinical parameters in a non-human primate animal model of preeclampsia.

Labor therapeutics and BMI as risk factors for postpartum preeclampsia: A case-control study

OBJECTIVES This study aims at identifying associations between therapeutics used during labor and the occurrence of postpartum preeclampsia (PPPE), a poorly understood entity. STUDY DESIGN AND MAIN OUTCOME MEASURES This is a case-control study of women who received an ICD-9 code for PPPE (cases) during the years 2009-2011, compared to women with a normotensive term pregnancy, delivery and postpartum period until discharge (controls), matched on age (±1year) and delivery date (±3months). Cases were defined as women having a normotensive term pregnancy, delivery and initial postpartum period (48h post-delivery) but developing hypertension between 48h and 6weeks postpartum. Single variable and multiple variable models were used to determine significant risk factors. RESULTS Forty-three women with PPPE were compared to 86 controls. Use of vasopressors and oxytocin did not differ between cases and controls, but rate of fluids administered during labor (OR=1.68 per 100cc/h; 95% CI: 1.09-2.59, p=0.02) and an elevated pre-pregnancy/first trimester BMI (OR=1.18 per kg/m2, 95% CI: 1.07-1.3, p=0.001) were identified as significant risk factors in multivariate analysis. CONCLUSIONS We identified two potentially modifiable risk factors for PPPE; further studies are needed to better define the role of these two variables in the development of PPPE.

PP016. Circulating lymphangiogenic factors in preeclampsia.

INTRODUCTION Preeclampsia, a human pregnancy specific disorder is characterized by an anti-angiogenic state due to high levels of circulating soluble vascular endothelial growth factor 1 (sVEGFR1). However, the role of lymphangiogenesis in preeclampsia has not been investigated. Recently, impaired VEGF-C (factor that regulates lymphangiogenesis) signalling has been implicated in the pathogenesis of interstitial edema and salt-sensitive hypertension. OBJECTIVES Therefore, we hypothesized that circulating VEGF-C and its circulating receptors (sVEGFR2 and sVEGFR3) may also be altered in preeclampsia and correlate with the severity of the phenotype. METHODS We analyzed plasma levels of VEGF-C, sVEGFR1, sVEGFR2 and sVEGFR3 in women with gestational hypertension (GHTN, n=20), preeclampsia (PE, n=20) and normotensive pregnancies (NP, n=20) in the third trimester and values reported as mean±SD in pg/ml. RESULTS As previously reported, sVEGFR1 levels were significantly higher in subjects with PE (19938 ± 12973) than in GHTN (7156±5432), p<0.01 or NP (7760±6018), p<0.01. VEGF-C levels were lower in subjects with GHTN (676±323) than in PE (1335±625), p<0.01, but not statistically different than in NP (971±556), p=0.11. There was a trend towards lower sVEGFR-2 in PE as compared to GHTN or NP. Interestingly sVEGFR-3 was significantly lower in PE (54,371±21,107) as compared to NP (83,709±24,983), p<0.01, but not different as compared to GHTN (54,642±26,947). The ratio of sVEGFR-2+sVEGFR-3/VEGF-C was dramatically lower during PE (57±38) as compared to GHTN (113±72), p<0.01 or NP (133±91), p<0.01. CONCLUSION Preeclampsia is characterized by circulating pro-lymphangiogenic state as evidenced by decreased sVEGFR-3, slightly decreased VEGFR-2, increased VEGF-C and a dramatically lower ratio of sVEGFR2+sVEGFR3/VEGF-C. Our data suggests that the circulating pro-lymphoangiogenic state during preeclampsia may be a compensatory response to edema and hypertension. Additional studies are needed to evaluate the clinical relevance of the altered lymphangiogenic signalling pathway during preeclampsia.

P80 The imbalance between angiogenic and anti-angiogenic factors in preeclampsia – preliminary data

Aims: To evaluate whether circulating angiogenic and anti-angiogenic factors may differentiate early-onset from late-onset preeclampsia. Methods: The study was conducted in 86 women with preeclampsia diagnosed in the third trimester of pregnancy. Preeclampsia was classified according to the onset of clinical manifestation in early-onset (before 34 weeks of gestation; n=31) or in late-onset (from 34 weeks of gestation on; n=55) preeclampsia. Serum was obtained from the patients in the moment of the diagnosis and assayed for placental growth factor (PlGF), vascular endothelial growth factor (VEGF), Endostatin, soluble Endoglin (sEng) and soluble form of vascular endothelial growth factor receptor (sVEGFR-1) determination by enzyme-linked immunosorbent assay. Results: Early-onset preeclampsia was characterized by significant lower levels of PlGF (median 38.3 vs 123.5 pg/mL) and VEGF (median 23.1 vs 35.3 pg/mL) in serum as well as by higher serum levels of Endostatin (median 33.9 vs 22.6 ng/mL), sEng (median 54.7 vs 42.1 pg/mL) and sVEGFR-1 (median 5211.0 vs 4657.6 pg/mL) compared with late-onset preeclampsia. Conclusions: In this study serum levels of angiogenic and antiangiogenic factors prove useful in differentiating early-onset from lateonset preeclampsia in the third trimester of pregnancy. Therefore, these findings suggest that angiogenic factors determination may indicate that earlyand late-onset preeclampsia have different pathophysiology.