S Ananth Karumanchi

Howard Hughes Medical Institute, Ashburn, Virginia, United States

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Publications (235)1719.1 Total impact

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    ABSTRACT: Thrombotic microangiopathy (TMA) is a life-threatening condition that affects some, but not all, recipients of vascular endothelial growth factor (VEGF) inhibitors given as part of chemotherapy. TMA is also a complication of preeclampsia, a disease characterized by excess production of the VEGF-scavenging soluble VEGF receptor 1 (soluble fms-like tyrosine kinase 1; sFlt-1). Risk factors for VEGF inhibitor-related TMA remain unknown. We hypothesized that deficiency of the VWF-cleaving ADAMTS13 endopeptidase contributes to the development of VEGF inhibitor-related TMA. ADAMTS13(-/-) mice overexpressing sFlt-1 presented all hallmarks of TMA, including thrombocytopenia, schistocytosis, anemia, and VWF-positive microthrombi in multiple organs. Similar to VEGF inhibitor-related TMA in humans, these mice exhibited severely impaired kidney function and hypertension. In contrast, wild-type mice overexpressing sFlt-1 developed modest hypertension but no other features of TMA. Recombinant ADAMTS13 therapy ameliorated all symptoms of TMA in ADAMTS13(-/-) mice overexpressing sFlt-1 and normalized BP in wild-type mice. ADAMTS13 activity may thus be a critical determinant for the development of TMA secondary to VEGF inhibition. Administration of recombinant ADAMTS13 may serve as a therapeutic approach to treat or prevent thrombotic complications of VEGF inhibition. Copyright © 2015 by the American Society of Nephrology.
    Journal of the American Society of Nephrology 06/2015; DOI:10.1681/ASN.2014121165 · 9.47 Impact Factor
  • PLoS ONE 05/2015; 10(5):e0126815. DOI:10.1371/journal.pone.0126815 · 3.53 Impact Factor
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    ABSTRACT: A growing body of evidence suggests that complement dysregulation plays a role in the pathogenesis of preeclampsia. The kidney is one of the major organs affected in preeclampsia. Because the kidney is highly susceptible to complement activation, we hypothesized that preeclampsia is associated with renal complement activation. We performed a nationwide search for renal autopsy material in the Netherlands using a computerized database (PALGA). Renal tissue was obtained from 11 women with preeclampsia, 25 pregnant controls, and 14 nonpregnant controls with hypertension. The samples were immunostained for C4d, C1q, mannose-binding lectin, properdin, C3d, C5b-9, IgA, IgG, and IgM. Preeclampsia was significantly associated with renal C4d-a stable marker of complement activation-and the classical pathway marker C1q. In addition, the prevalence of IgM was significantly higher in the kidneys of the preeclamptic women. No other complement markers studied differed between the groups. Our findings in human samples were validated using a soluble fms-like tyrosine kinase 1 mouse model of preeclampsia. The kidneys in the soluble fms-like tyrosine kinase 1-injected mice had significantly more C4 deposits than the control mice. The association between preeclampsia and renal C4d, C1q, and IgM levels suggests that the classical complement pathway is involved in the renal injury in preeclampsia. Moreover, our finding that soluble fms-like tyrosine kinase 1-injected mice develop excess C4 deposits indicates that angiogenic dysregulation may play a role in complement activation within the kidney. We suggest that inhibiting complement activation may be beneficial for preventing the renal manifestations of preeclampsia. © 2015 American Heart Association, Inc.
    Hypertension 05/2015; DOI:10.1161/HYPERTENSIONAHA.115.05484 · 7.63 Impact Factor
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    ABSTRACT: 24,25-Dihydroxyvitamin D [24,25(OH)2D] is a metabolite of 25-hydroxyvitamin D (25D). Blacks frequently have low total 25D without manifestations of vitamin D deficiency, suggesting that total serum 25D may incorrectly reflect vitamin D status in different racial groups. The ratio of serum 24,25(OH)2D to 25D [vitamin D metabolite ratio (VMR)] represents a new candidate biomarker for vitamin D status. We measured 24,25(OH)2D3 and 25D3 by mass spectrometry in a random community cohort of black (n = 212) and white (n = 164) Americans to evaluate VMR as a marker for vitamin D status. We measured parathyroid hormone concentrations by immunoassay to compare VMR and 25D3 against a physiological indicator of vitamin D deficiency. Serum 24,25(OH)2D3 strongly correlated with 25D3 in both black and white study participants (r = 0.90, P < 0.001 and r = 0.86, P < 0.001 respectively). Blacks had lower mean 25D3 than whites [17.0 (7.8) vs 27.5 (11.3) ng/mL; 42.4 (19.5) vs 68.6 (28.2) nmol/L, P < 0.001] and lower mean 24,25(OH)2D3 [2.1 (1.3) vs 3.6 (2.0) ng/mL; 5.1 (3.1) vs 8.7 (4.8) nmol/L, P < 0.001]. In contrast to total 25D3 concentrations, mean VMR values were similar in blacks and whites [11.9 (4.0) vs 12.5 (3.4), P = 0.16, respectively] and were negatively correlated with parathyroid hormone concentrations in both races (rs = -0.26, P < 0.001, and rs = -0.25, P < 0.001, respectively). Our results provide further evidence that measurement of total 25D for assessment of vitamin D status in patients of African descent deserves reevaluation and suggest that alternative measures such as VMR should be considered. © 2015 American Association for Clinical Chemistry.
    Clinical Chemistry 04/2015; 61(6). DOI:10.1373/clinchem.2015.240051 · 7.77 Impact Factor
  • Geburtshilfe und Frauenheilkunde 04/2015; 75(03). DOI:10.1055/s-0035-1548707 · 0.96 Impact Factor
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    ABSTRACT: Protein carbamylation is a urea-driven post-translational protein modification associated with mortality in dialysis patients. Free amino acids (AAs) are competitive inhibitors of protein carbamylation and animal studies suggest increasing AA concentrations reduces carbamylation burden. We hypothesized that AA therapy in maintenance hemodialysis patients would reduce carbamylation, carrying the potential to improve clinical outcomes. Prospective pilot clinical trial (NCT1612429). The study was conducted from March 2013 to March 2014 in outpatient dialysis facilities in the Boston metropolitan area. We enrolled 23 consecutively consenting hemodialysis subjects, infusing the first 12 individuals with 250 cc of AAs 3 times per week postdialysis over 8 weeks. The remaining 11 subjects served as controls. Change in carbamylated albumin (C-Alb), a measure of total body carbamylation burden, between baseline and 8 weeks was the primary outcome. The treated and control groups had similar clinical characteristics and similar baseline C-Alb levels (mean ± SE 9.5 ± 2.4 and 9.3 ± 1.3 mmol/mol, respectively; P = .61). The treated arm showed a significant reduction in C-Alb compared with controls at 4 weeks (8.4% reduction in the treated arm vs. 4.3% increase in controls; P = .03) and the effect was greater by 8 weeks (15% reduction in the treated vs. 1% decrease in controls; P = .01). In this pilot study, AA therapy appeared safe and effective at reducing C-Alb levels in hemodialysis patients compared with no treatment. The impact of reduced protein carbamylation on clinical outcomes should be further investigated. Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
    Journal of Renal Nutrition 03/2015; DOI:10.1053/j.jrn.2015.01.019 · 2.55 Impact Factor
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    ABSTRACT: Cardiovascular disease (CVD) remains the leading killer of women in developed nations. One sex-specific risk factor is preeclampsia, a syndrome of hypertension and proteinuria that complicates 5% of pregnancies. Although preeclampsia resolves after delivery, exposed women are at increased long-term risk of premature CVD and mortality. Pre-existing CVD risk factors are associated with increased risk of developing preeclampsia but whether preeclampsia merely uncovers risk or contributes directly to future CVD remains a critical unanswered question. A mouse preeclampsia model was used to test the hypothesis that preeclampsia causes an enhanced vascular response to future vessel injury. A preeclampsia-like state was induced in pregnant CD1 mice by overexpressing soluble fms-like tyrosine kinase-1, a circulating antiangiogenic protein that induces hypertension and glomerular disease resembling human preeclampsia. Two months postpartum, soluble fms-like tyrosine kinase-1 levels and blood pressure normalized and cardiac size and function by echocardiography and renal histology were indistinguishable in preeclampsia-exposed compared with control mice. Mice were then challenged with unilateral carotid injury. Preeclampsia-exposed mice had significantly enhanced vascular remodeling with increased vascular smooth muscle cell proliferation (180% increase; P<0.01) and vessel fibrosis (216% increase; P<0.001) compared with control pregnancy. In the contralateral uninjured vessel, there was no difference in remodeling after exposure to preeclampsia. These data support a new model in which vessels exposed to preeclampsia retain a persistently enhanced vascular response to injury despite resolution of preeclampsia after delivery. This new paradigm may contribute to the substantially increased risk of CVD in woman exposed to preeclampsia. © 2015 American Heart Association, Inc.
    Hypertension 02/2015; 65(4). DOI:10.1161/HYPERTENSIONAHA.114.04971 · 7.63 Impact Factor
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    ABSTRACT: Several clinical and basic science reports have elucidated partial aspects of the pathophysiology of preeclampsia and have led many authors to conclude that different "subtypes" of the disease exist. All these subtypes share the main clinical features of the disease and present additional characteristics that define different clinical phenotypes. Nevertheless, immunological alterations, endothelial dysfunction, and insulin resistance constantly characterize this syndrome. These aspects are intimately related at a molecular level; thus, we propose an alternative approach to explaining biologically the main intracellular processes that occur in preeclampsia and this may yield an insight into the pathogenesis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Journal of Reproductive Immunology 02/2015; 108. DOI:10.1016/j.jri.2015.01.009 · 2.37 Impact Factor
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    ABSTRACT: Serum carbamylated albumin (C-Alb) levels are associated with excess mortality in patients with diabetic end-stage renal disease. To gain insight into the pathophysiology of carbamylation, we determined associations between C-Alb and causes of death in patients on chronic hemodialysis. The Die Deutsche Diabetes Dialyse Studie (4D study) was a randomized controlled trial testing the effects of atorvastatin on survival in diabetic patients on dialysis during a median follow-up of 4 years. We stratified 1161 patients by C-Alb to see whether differences in carbamylation altered the effects of atorvastatin on survival. Baseline C-Alb significantly correlated with serum cardiac stress markers troponin T and N-terminal pro-B-type-natriuretic peptide and was associated with a history of heart failure and arrhythmia. C-Alb was strongly associated with 1-year adjusted risk of cardiovascular mortality, sudden cardiac death, and the 4-year risk of death from congestive heart failure (hazard ratios of 3.06, 3.78, and 4.64, respectively) but not with myocardial infarction or stroke. Patients with low C-Alb, treated with atorvastatin, experienced a significant improvement in their 4-year survival (hazard ratio 0.692). High C-Alb levels are associated with ongoing cardiac damage, risk of congestive heart failure, and sudden cardiac death. Thus, carbamylation and uremic cardiomyopathy are associated in patients with diabetes mellitus and kidney disease. In addition, statins were specifically beneficial to hemodialysis patients with low C-Alb.Kidney International advance online publication, 11 February 2015; doi:10.1038/ki.2014.429.
    Kidney International 02/2015; 87(6). DOI:10.1038/ki.2014.429 · 8.52 Impact Factor
  • Monica Sircar, Ravi Thadhani, S Ananth Karumanchi
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    ABSTRACT: Preeclampsia is a gestational kidney disease characterized by glomerular endothelial injury, leading to maternal hypertension and proteinuria. If not addressed promptly, there is significant maternal and fetal morbidity and mortality. When severe, this disorder can cause hepatic and neurologic dysfunction. Understandably, this placental disease enters the focus of the obstetrician first; however, with progression, the nephrologist can also be enlisted. Typical complications include acute kidney injury, refractory hypertension, and acute pulmonary edema. This review summarizes recent literature on the pathogenesis of this condition and will highlight new diagnostic and therapeutic options for preeclampsia. Over the past decade, the role of soluble vascular factors in preeclampsia has shed light on the mechanism underlying this disease. During the last 2 years, several new therapeutics have been developed that target implicated circulating angiogenic factors, including soluble fms-like tyrosine kinase 1, an endogenous vascular endothelial growth factor inhibitor. Serum levels of angiogenic factors have been correlated with a constellation of hemodynamic and pathophysiologic changes. Thus, circulating levels of these factors may serve both diagnostic and prognostic purposes. Overall, our understanding of preeclampsia has developed significantly and the future holds promise for mechanism-based novel diagnostics and therapeutics.
    Current Opinion in Nephrology and Hypertension 01/2015; 24(2). DOI:10.1097/MNH.0000000000000105 · 4.24 Impact Factor
  • Clinical Chemistry 01/2015; 61(5). DOI:10.1373/clinchem.2014.230565 · 7.77 Impact Factor
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    ABSTRACT: Objective: To investigate whether elevated IFN-α early in pregnancy is associated with poor pregnancy outcomes and examine its relationship to angiogenic imbalance. Methods: Women were enrolled in a case-control longitudinal study of lupus pregnancies. Serum samples obtained monthly through pregnancy were assayed for IFN-α and for antiangiogenic factor, sFlt1, and proangiogenic factor, (PlGF). Each of 28 SLE patients with poor pregnancy outcome was matched to an SLE patient with an uncomplicated pregnancy and to a pregnant healthy control. The effects of IFN-α and/or sFlt1on human endothelial cells and endothelial-trophoblast interactions was assessed. Results: Compared to SLE patients with uncomplicated pregnancies, patients with preeclampsia had increased IFN-α before clinical symptoms. Non-autoimmune patients destined for preeclampsia did not have increased IFN-α. In SLE patients with low IFN-α, marked angiogenic imbalance (higher sFlt1, lower PlGF and higher sFlt1/PlGF ratios) precedes maternal manifestations of preeclampsia, whereas in SLE with high IFN-α, preeclampsia occurs without evidence of systemic angiogenic imbalance. Treatment of human endothelial cells with sFlt1 induced expression of sFlt1 mRNA, and IFN-α dramatically amplified responses to sFlt1. In a model of spiral artery transformation, only IFN-α and sFlt1 together disrupted the ability of trophoblast cells to remodel endothelial tube structures. Conclusions: Our studies identify a new mechanism by which IFN-α induces an antiangiogenic milieu, increases the sensitivity of endothelial cells to sFlt1, and suggest that elevated IFN-α may contribute to pathogenesis of preeclampsia in some SLE pregnancies. This article is protected by copyright. All rights reserved. Copyright © 2015 American College of Rheumatology. PMID: 25603823 [PubMed - as supplied by publisher]
    Arthritis & Rheumatology 01/2015; 67(4). DOI:10.1002/art.39029 · 7.87 Impact Factor
  • Kim M Holwerda, S Ananth Karumanchi, A Titia Lely
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    ABSTRACT: Hydrogen sulfide (H2S), a colorless gas that is endogenously generated in mammals from cysteine, has important biological functions. Within the vasculature it regulates vessel tone and outgrowth of new vessels. This review summarizes recent literature on H2S signaling in the vasculature and its therapeutic potential in vascular disorders RECENT FINDINGS: H2S is able to induce vasorelaxation via ATP-sensitive potassium channels in vascular smooth muscle cells. Large-conductance calcium-dependent K-channels and Kv7 voltage-gated K-channels are also involved in H2S signaling. Vascular endothelial growth factor is the key downstream mediator that is involved in H2S induced angiogenesis. By having both direct effects on its receptor and increasing the bioavailability of vascular endothelial growth factor, H2S is proangiogenic. H2S-based therapies in vascular diseases are an expanding area of research. The applications of several compounds, such as natural donors and synthetic slow release compounds, have been extensively studied in vascular diseases such as hypertension, ischemia-reperfusion disorders and preeclampsia. H2S has a key role in vascular homeostasis during physiology and in pathological states. H2S-based therapies may have a role in several vascular diseases.
    Current Opinion in Nephrology and Hypertension 01/2015; 24(2). DOI:10.1097/MNH.0000000000000096 · 4.24 Impact Factor
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    ABSTRACT: IntroductionPreeclampsia (PE) is a pregnancy-specific syndrome associated with adverse maternal and fetal outcomes. Patient-specific risks based on angiogenic factors might better categorize those who might have a severe adverse outcome.Methods Women evaluated for suspected PE at a tertiary hospital (2009–2012) had pregnancy outcomes categorized as ‘Referent’ or ‘Severe’, based solely on maternal / fetal findings. Outcomes that may have be influenced by a PE finding were considered ‘Unclassified’. Soluble fms-like tyrosine kinase (sFlt1) and placental growth factor (PlGF) were subjected to bivariate discriminant modeling, allowing patient-specific risks to be assigned for “Severe” outcomes.Results328 singleton pregnancies presented at ≤34.0 weeks’ gestation. sFlt1 and PlGF levels were adjusted for gestational age. Risks above 5:1 (10 fold over background) occurred in 77% of Severe (95% CI 66 to 87%) and 0.7% of Referent (95% CI <0.1 to 3.8%) outcomes. Positive likelihood ratios for the modeling and validation datasets were 19 (95% CI 6.2-58) and 15 (95% CI 5.8-40) fold, respectively.Conclusions This validated model assigns patient-specific risks of any Severe outcome among women attending PE triage. In practice, women with high risks would receive close surveillance with the added potential for reducing unnecessary preterm deliveries among remaining women. © 2015 John Wiley & Sons, Ltd.
    Prenatal Diagnosis 01/2015; 5(1). DOI:10.1002/pd.4554 · 3.27 Impact Factor
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    ABSTRACT: Assess the accuracy of serum soluble fms-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF) and soluble endoglin (sEng) and urinary PlGF as predictors of preeclampsia in a prospective multicountry study. From 2006-9, 5121 pregnant women from centers in Argentina, Colombia, India, Italy, Kenya, Peru, Switzerland and Thailand had their serum tested for sFlt-1, PlGF and sEng levels and their urine for PlGF levels at ⩽20 (index tests, results kept blind from care givers), 23-27 and 32-35weeks' gestation. During prenatal care, women were closely monitored for signs of preeclampsia, diagnosed by systolic blood pressure ⩾140mmHg and/or diastolic blood pressure ⩾90mmHg, and proteinuria with protein/creatinine ratio ⩾0.3, protein ⩾1g/l or, one dipstick measurement ⩾2+ appearing after gestational week 20, and defined as early preeclampsia when these signs appeared before 34 weeks' gestation. Preeclampsia was diagnosed in 3.9% (198 of the 5121 women) whom 47 (0.9%) had early disease. No test performed well at <20 weeks for either early or all preeclampsia (area under receiver operating characteristics curve, AUC ⩽0.6). Multivariable models combining biomarkers with clinical features (age, body mass index, smoking, multiple pregnancy, hypertension or treatment for it) did not improve the prediction capability before 20weeks. Serum PlGF was the best predictor of preeclampsia at any gestation (AUC 0.82 at 32-35weeks) and at early onset (AUC 0.82 at 23-27weeks). Angiogenic biomarkers, alone or combined with clinical risk factors, performed poorly as predictors of preeclampsia, when measured early in pregnancy (<20weeks). M. Widmer: None. C.B. Cuesta: None. K. Khan: None. A.M. Gülmezoglu: None. S.A. Karumanchi: Consultant: Roche, Beckman, Siemens. M.D. Lindheimer: None. Copyright © 2014.
    01/2015; 5(1):50. DOI:10.1016/j.preghy.2014.10.097
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    ABSTRACT: Natural Killer (NK) cells are key regulators of normal placental development. In contrast to peripheral blood NK (pNK) cells, NK cells located at the maternal-fetal interface constitute the main local lymphocyte population in early pregnancy, are non-cytotoxic and pro-angiogenic. Decidual NK cells (dNK) regulate remodeling of uterine spiral arteries (SA), a process leading to increased blood supply to the developing fetal-placental unit. When SA remodeling is impaired, reduced placental perfusion results in elevated plasma sFlt1 levels, triggering preeclampsia systemic symptoms, (hypertension, edema and proteinuria). We aim to model a NK cell based therapy for preeclampsia. Ex vivo manipulation of human pNK cells by a combination of hypoxia, TGFb-1 and 5-aza-2'-deoxycytidine (AZA) yields cells, termed idNK cells, with phenotypic and in vitro functional similarities to dNK cells including expression of dNK cell surface markers and chemokine receptors, proangiogenic capacity and reduced cytotoxicity. idNK cells were further characterized by microarray gene expression profiling, and their capacity to remodel SA was evaluated in immunodeficient mice presenting narrow SA. Although distinct from dNK cells, idNK cells acquired the gene expression signature that differentiates dNK cells from pNK cells. Most importantly, i-dNK cell injection increased placental perfusion in a mouse model with narrow SA as evidenced by decreased uterine artery resistance evaluated by Doppler ultrasound, and ameliorated SA remodeling. Ex vivo conversion of peripheral blood NK cells into i-dNK cells may be a potential approach for the prevention or treatment of preeclampsia and related disorders. R. de Carvalho Cavalli: None. A. Cerdeira: None. H. Korkes: None. S. Burke: None. A. Rajakumar: None. M. Bhasin: None. S. Karumanchi: Consultant, Commercial Interest: Aggamin LLC. H. Kopcow: None. Copyright © 2014.
    01/2015; 5(1):15. DOI:10.1016/j.preghy.2014.10.035
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    ABSTRACT: The purpose of this study was to compare longitudinally sampled maternal angiogenic proteins between singleton and twin pregnancies. Placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and soluble endoglin (sEng) from healthy pregnant women were quantified at 10, 18, 26 and 35 weeks' gestation (n=91), and during the third trimester (31-39 weeks) and at delivery (33-41 weeks; n=41). Geometric means and 95% confidence intervals were calculated for gestational age adjusted angiogenic protein concentrations and compared between matched twin and singleton pregnancies. Maternal sFlt-1 concentrations and the sFlt-1/PlGF ratio were higher in twins than singletons across pregnancy and at delivery, with the greatest differences at week 35 [sFlt-1: 36916 vs. 10151 pg/mL; p<0.0001; sFlt-1/PlGF: 168.4 vs. 29.0; p<0.0001]. Maternal concentrations of s-endoglin also were higher in the third trimester and delivery. Maternal PlGF concentrations were lower in twin than singleton pregnancies at week 35 only [219.2 vs. 350.2 pg/mL; p<0.0001]. Placental weight appeared to be inversely correlated with maternal sFlt-1/PlGF ratio at the end of the pregnancy in both twins and singletons. Higher maternal anti-angiogenic proteins in twin than singleton pregnancies does not appear to be due to greater placental mass in the former, and may be one explanation for the increased risk of preeclampsia in women carrying multiple gestations. Determining whether women with a history of multiple gestations have an altered cardiovascular disease and breast cancer risk, like those with a history of preeclampsia, is warranted. Copyright © 2014 Elsevier Inc. All rights reserved.
    American Journal of Obstetrics and Gynecology 11/2014; 212(5). DOI:10.1016/j.ajog.2014.11.035 · 3.97 Impact Factor
  • Sahir Kalim, S. Ananth Karumanchi, Ravi I. Thadhani, Anders H. Berg
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    ABSTRACT: Carbamylation describes a nonenzymatic posttranslational protein modification mediated by cyanate, a dissociation product of urea. When kidney function declines and urea accumulates, the burden of carbamylation naturally increases. Free amino acids may protect proteins from carbamylation, and protein carbamylation has been shown to increase in uremic patients with amino acid deficiencies. Carbamylation reactions are capable of altering the structure and functional properties of certain proteins and have been implicated directly in the underlying mechanisms of various disease conditions. A broad range of studies has demonstrated how the irreversible binding of urea-derived cyanate to proteins in the human body causes inappropriate cellular responses leading to adverse outcomes such as accelerated atherosclerosis and inflammation. Given carbamylation’s relationship to urea and the evidence that it contributes to disease pathogenesis, measurements of carbamylated proteins may serve as useful quantitative biomarkers of time-averaged urea concentrations while also offering risk assessment in patients with kidney disease. Moreover, the link between carbamylated proteins and disease pathophysiology creates an enticing therapeutic target for reducing the rate of carbamylation. This article reviews the biochemistry of the carbamylation reaction, its role in specific diseases, and the potential diagnostic and therapeutic implications of these findings based on recent advances.
    American Journal of Kidney Diseases 11/2014; 64(5). DOI:10.1053/j.ajkd.2014.04.034 · 5.76 Impact Factor
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    ABSTRACT: Preeclampsia (PE) remains a leading cause of maternal and neonatal morbidity and mortality worldwide. Smoking cigarettes is associated with a decreased incidence of PE. Based on this observation and previous work, we hypothesize that women who smoke have a lower risk of developing PE because of elevated levels of carbon monoxide (CO) in their blood. The objective of this study was to determine if low-dose CO in ambient air could attenuate the late pregnancy hypertension (HTN) and proteinuria in the Adenovirus (Ad) sFlt-1 PE-like mouse model. Continuous low-dose CO treatment (250 ppm) was started on E10.5 and maintained until E17.5. Compared to control and Ad empty vector, AdsFlt-1 mice displayed late- gestation HTN (E14.5-17.5) (P<0.05), proteinuria (P<0.05) and reduced Bowman's space which were all prevented with CO treatment. Use of the Ad (with/without sFlt-1) or CO had no effect (p>0.05) on litter size, fetal resorption numbers and fetal or placental weights. This study shows that treatment with CO can prevent HTN and proteinuria in a mouse model of PE. It provides a possible mechanism for the reduced incidence of PE in smoking women, and supports the possibility of using CO as a future treatment for PE.
    PLoS ONE 09/2014; 9(9):e106502. DOI:10.1371/journal.pone.0106502 · 3.53 Impact Factor
  • American Journal of Epidemiology 08/2014; DOI:10.1093/aje/kwu216 · 4.98 Impact Factor

Publication Stats

13k Citations
1,719.10 Total Impact Points


  • 2009–2015
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 2002–2015
    • Harvard University
      Cambridge, Massachusetts, United States
  • 2001–2015
    • Beth Israel Deaconess Medical Center
      • • Center for Vascular Biology Research
      • • Department of Medicine
      • • Division of Nephrology
      Boston, Massachusetts, United States
  • 2007–2014
    • Harvard Medical School
      • Department of Medicine
      Boston, Massachusetts, United States
  • 2012
    • University of Groningen
      • Department of Obstetrics and Gynaecology
      Groningen, Province of Groningen, Netherlands
  • 2011
    • Boston University
      • Department of Pediatrics
      Boston, MA, United States
  • 2008
    • University of Chicago
      • Department of Obstetrics & Gynecology
      Chicago, Illinois, United States
  • 2006
    • George Washington University
      Washington, Washington, D.C., United States
    • University of Miami
      كورال غيبلز، فلوريدا, Florida, United States
  • 2005
    • University of Pittsburgh
      • Department of Obstetrics, Gynecology and Reproductive Sciences
      Pittsburgh, Pennsylvania, United States
  • 2004–2005
    • National Institute of Child Health and Human Development
      베서스다, Maryland, United States
    • Ewha Womans University
      Sŏul, Seoul, South Korea
    • Baylor College of Medicine
      • Department of Pediatrics
      Houston, TX, United States