Thrombotic complications are common in Coronavirus disease 2019 (COVID-19) patients, with pulmonary embolism (PE) being the most frequent. Randomised trials have provided inconclusive results on the optimal dosage of thromboprophylaxis in critically ill COVID-19 patients. We utilized data from the multicentre CAPACITY-COVID patient registry to assess the effect of differential application of Low Molecular Weight Heparin (LMWH) dose protocols on PE and in-hospital mortality risk in critically ill COVID-19 patients. An instrumental variable analysis was performed to estimate the intention-to-treat effect, utilizing differences in thromboprophylaxis prescribing behaviour between hospitals. We included 939 patients with PCR confirmed SARS-CoV-2 infection from 34 hospitals. Two-hundred-and-one patients (21%) developed a PE. The adjusted cause-specific HR of PE was 0.92 (95% CI: 0.73-1.16) per doubling of LMWH dose. The adjusted cause-specific HR for in-hospital mortality was 0.82 (95% CI: 0.65-1.02) per doubling of LMWH dose. This dose-response relationship was shown to be non-linear. To conclude, this study did not find evidence for an effect of LMWH dose on the risk of PE, but suggested a non-linear decreased risk of in-hospital mortality for higher doses of LMWH. However, uncertainty remains, and the dose-response relationship between LMWH dose and in-hospital mortality needs further investigation in well-designed studies.

IntroductionPatients with a first venous thromboembolism (VTE) are at risk of recurrence. Recurrent VTE (rVTE) can be prevented by extended anticoagulant therapy, but this comes at the cost of an increased risk of bleeding. It is still uncertain whether patients with an intermediate recurrence risk or with a high recurrence and high bleeding risk will benefit from extended anticoagulant treatment, and whether a strategy where anticoagulant duration is tailored on the predicted risks of rVTE and bleeding can improve outcomes. The aim of the Leiden Thrombosis Recurrence Risk Prevention (L-TRRiP) study is to evaluate the outcomes of tailored duration of long-term anticoagulant treatment based on individualised assessment of rVTE and major bleeding risks.Methods and analysisThe L-TRRiP study is a multicentre, open-label, cohort-based, randomised controlled trial, including patients with a first VTE. We classify the risk of rVTE and major bleeding using the L-TRRiP and VTE-BLEED scores, respectively. After 3 months of anticoagulant therapy, patients with a low rVTE risk will discontinue anticoagulant treatment, patients with a high rVTE and low bleeding risk will continue anticoagulant treatment, whereas all other patients will be randomised to continue or discontinue anticoagulant treatment. All patients will be followed up for at least 2 years. Inclusion will continue until the randomised group consists of 608 patients; we estimate to include 1600 patients in total. The primary outcome is the combined incidence of rVTE and major bleeding in the randomised group after 2 years of follow-up. Secondary outcomes include the incidence of rVTE and major bleeding, functional outcomes, quality of life and cost-effectiveness in all patients.Ethics and disseminationThe protocol was approved by the Medical Research Ethics Committee Leiden-Den Haag-Delft. Results are expected in 2028 and will be disseminated through peer-reviewed journals and during (inter)national conferences.Trial registration numberNCT06087952.

Abstract Thrombotic complications are common in Coronavirus disease 2019 (COVID-19) patients, with pulmonary embolism (PE) being the most frequent. Randomised trials have provided inconclusive results on the optimal dosage of thromboprophylaxis in critically ill COVID-19 patients. We utilized data from the multicentre CAPACITY-COVID patient registry to assess the effect of differential application of Low Molecular Weight Heparin (LMWH) dose protocols on PE and in-hospital mortality risk in critically ill COVID-19 patients. An instrumental variable analysis was performed to estimate the intention-to-treat effect, utilizing differences in thromboprophylaxis prescribing behaviour between hospitals. We included 939 patients with PCR confirmed SARS-CoV-2 infection from 34 hospitals. Two-hundred-and-one patients (21%) developed a PE. The adjusted cause-specific HR of PE was 0.92 (95% CI: 0.73–1.16) per doubling of LMWH dose. The adjusted cause-specific HR for in-hospital mortality was 0.82 (95% CI: 0.65–1.02) per doubling of LMWH dose. This dose-response relationship was shown to be non-linear. To conclude, this study did not find evidence for an effect of LMWH dose on the risk of PE, but suggested a non-linear decreased risk of in-hospital mortality for higher doses of LMWH. However, uncertainty remains, and the dose-response relationship between LMWH dose and in-hospital mortality needs further investigation in well-designed studies.

Background:Whereas accumulating studies on patients with coronavirus disease 2019 (COVID-19) report high incidences of thrombotic complications, large studies on clinically relevant thrombosis in patients with other respiratory tract infections are lacking. How this high risk in COVID-19 patients compares to those observed in hospitalized patients with other viral pneumonias such as influenza is unknown. Objectives:To assess the incidence of venous and arterial thrombotic complications in hospitalized patients with influenza as opposed to that observed in hospitalized patients with COVID-19. Methods:This was a retrospective cohort study; we used data from Statistics Netherlands (study period: 2018) on thrombotic complications in hospitalized patients with influenza. In parallel, we assessed the cumulative incidence of thrombotic complications-adjusted for competing risk of death-in patients with COVID-19 in three Dutch hospitals (February 24 to April 26, 2020). Results:Of the 13 217 hospitalized patients with influenza, 437 (3.3%) were diagnosed with thrombotic complications, versus 66 (11%) of the 579 hospitalized patients with COVID-19. The 30-day cumulative incidence of any thrombotic complication in influenza was 11% (95% confidence interval [CI], 9.4-12) versus 25% (95% CI, 18-32) in COVID-19. For venous thrombotic (VTC) complications and arterial thrombotic complications alone, these numbers were, respectively, 3.6% (95% CI, 2.7-4.6) and 7.5% (95% CI, 6.3-8.8) in influenza versus 23% (95% CI, 16-29) and 4.4% (95% CI, 1.9-8.8) in COVID-19. Conclusions:The incidence of thrombotic complications in hospitalized patients with influenza was lower than in hospitalized patients with COVID-19. This difference was mainly driven by a high risk of VTC complications in the patients with COVID-19 admitted to the Intensive Care Unit. Remarkably, patients with influenza were more often diagnosed with arterial thrombotic complications.

A 29-year-old patient presented with an appendicular infiltrate, initially treated with intravenous antibiotics, but later requiring percutaneous drainage. Both prothrombin time (PT) and activated partial thromboplastin time (aPTT) were prolonged on 3 days of antibiotic treatment and unresponsive to vitamin K or prothrombin complex concentrate. Laboratory investigation ultimately showed reduced factor V activity and factor V antibodies. In contrast to previously described cases of factor V antibodies, PT and aPTT were only mildly prolonged and residual factor V activity was still >20%. Draining of the abscess did not induce significant bleeding. Afterwards, no haemostatic medication was required. The patient was discharged from the hospital without complications. One week after cessation of the antibiotic treatment, PT and aPTT were within normal range again, with a factor V activity level of 36%. In conclusion, we present a patient with transient factor V antibodies, induced by antibiotics, without clinical bleeding tendency.

BACKGROUND:Arterial stiffness is increased in chronic kidney disease (CKD). Intervention studies aimed at reduction of arterial stiffness in dialysis patients have been disappointing. We therefore investigated the effect of pravastatin, vitamin E, and homocysteine lowering on arterial compliance and distensibility coefficients in mild-to-moderate CKD.METHODS:This is a sub-study of the ATIC study, a randomized, double-blind trial in 93 CKD patients. The treatment group received pravastatin to which vitamin E supplementation was added after 6 months and homocysteine lowering therapy after another 6 months. Measurement of the distensibility coefficient (DC) and the compliance coefficient (CC) of the common carotid (CCA), femoral (FA) and brachial artery (BA) was performed at 0, 6, 12, 18 months. Young's elastic modulus (YEM) was measured in the common carotid artery.RESULTS:After 18 months, CCA-DC increased from mean (SD) 15.15 (6.67) to 16.52 (6.37) × 10-3kPa-1 in the treatment and decreased from 18.44 (8.19) to 16.26 (7.35) in the placebo group (p = 0.057). CCA-CC increased from 0.64 (0.24) to 0.71 (0.26) mm2kPa-1 in the treatment and decreased from 0.77 (0.28) to 0.69 (0.25) in the placebo group (p < 0.0001). FA-DC had increased from 6.64 (3.45) to 11.46 (6.83) in the treatment group, and from 6.46 (2.85) to 7.08 (2.73) in the placebo group (p = 0.0001). FA-CC had increased from 0.46 (0.24) to 0.74 (0.44) in the treatment group, and from 0.48 (0.27) to 0.53 (0.21) in the placebo group (p = 0.008). BA-DC and CC, and CCA YEM were not significantly different between the groups.CONCLUSION:In patients with mild-to-moderate CKD, 18 months of treatment consisting of pravastatin, vitamin E and homocysteine lowering resulted in significant improvement of compliance and distensibility in CCA and FA. Since pravastatin was used throughout the observation period, it remains unclear whether the beneficial effects are attributable solely to the ongoing effect of pravastatin treatment, or if the additional interventions further slowed the progression of vascular stiffness. Therefore, larger studies with a longer period of follow-up observing the separate effects are needed.

BACKGROUND:Psychological research has shown that people tend toward accepting rather than refuting hypotheses. Diagnostic suggestions may evoke such confirmatory tendencies in physicians, which may lead to diagnostic errors.PURPOSE:This study investigated the influence of a suggested diagnosis on physicians' diagnostic decisions on written clinical cases. It was hypothesized that physicians would tend to go along with the suggestions and therefore would have more difficulty rejecting incorrect suggestions than accepting correct suggestions.METHODS:Residents (N = 24) had to accept or reject suggested diagnoses on 6 cases. Three of those suggested diagnoses were correct, and 3 were incorrect.RESULTS:Results showed the mean correct evaluation score on cases with a correct suggested diagnosis (M = 2.21, SD = 0.88) was significantly higher than the score on cases with an incorrect suggested diagnosis (M = 1.42, SD = 0.97), meaning physicians indeed found it easier to accept correct diagnoses than to reject incorrect diagnoses, t(23) = 2.74, p < .05, d = .85, despite equal experience with the diagnoses.CONCLUSION:These findings indicate that suggested diagnoses may evoke confirmatory tendencies and consequently may lead to diagnostic errors.

Mesenteric panniculitis is a non-specific inflammation of the mesenteric adipose tissue, with varying degrees of fibrosis and fat necrosis. It can be associated with varying diseases and conditions, such as autoimmune disease and cancer. Many doctors are not familiar with this disease or do not know how to interpret the signs and symptoms. Here, we describe three patients illustrating the variety of clinical course, diagnostics, prognosis and treatment. A 44-year-old woman suffering from episodic abdominal pain was diagnosed with uncomplicated mesenteric panniculitis. The disease was stable while maintaining a conservative approach. In a 43-year-old woman, mesenteric panniculitis was complicated by autoimmune haemolytic anaemia. After treatment with corticosteroids, she made a full recovery from both disorders. Finally, a 73-year-old man was diagnosed with mesenteric panniculitis and auto-immune haemolytic anaemia, which both appeared to be consequences of an angioimmunoblastic T-cell lymphoma.

Background: Adult-type hypolactasia is caused by genetic lactase non-persistence. It is the most common cause of lactose intolerance, which results in gastrointestinal symptoms after ingestion of dairy products. Currently, lactose intolerance is investigated by the hydrogen breath test (HBT), which is considered the preferred diagnostic test. Adult-type hypolactasia may also be diagnosed by genotyping. The single nucleotide polymorphism -13910C> T, which is located upstream of the lactase gene (LCT), is tightly associated with lactase persistence. Several other variants, mostly in non-European populations, can also lead to lactase persistence. This study investigated the accuracy of a modified, recently proposed algorithm which includes genotyping for the diagnosis of adult-type hypolactasia in a patient population with unexplained abdominal complaints.Methods: In 126 patients with unexplained abdominal symptoms or who were suspected to have adult-type hypolactasia, LCT genotyping by melting curve analysis on a LightCycler was performed. Those patients with CC-13910 genotype (indicating loss of lactase expression) were directly referred to a dietician for a lactose-free diet. Those identified as CT-13910 or TT-13910 genotype underwent a HBT Those who tested positive for hydrogen were also referred to a dietician for a lactose-free diet. The response to diet modification was recorded.Results: Genotype prevalences were: CC-13910: 43 (34.1%); CT-13910: 48 (38.1%); TT-13910: 33 (26.2%); TG(-13915): 2 (1.6%). Eleven of 48 (23%) patients with CT-13910-genotype and 1/33 (3%) patients with TT-13910-genotype had a positive hydrogen breath test. They all improved after a lactose-free diet. Four of 43 (9%) patients with CC-13910-genotype still had symptoms after a lactose-free diet.Conclusions: The results show that lactase-genotype testing can be used as a first step to diagnose lactose intolerance in a patient population with unexplained abdominal complaints. It accurately identifies the group of patients sensitive to lactose, those who need further breath testing and those in whom adult-type hypolactasia can be excluded with high probability without performing a HBT. This algorithm would save hydrogen breath testing in more than 50% of the patients who present with unexplained abdominal symptoms.

CONTEXTDiagnostic errors have been associated with bias in clinical reasoning. Empirical evidence on the cognitive mechanisms underlying biases and effectiveness of educational strategies to counteract them is lacking.OBJECTIVESTo investigate whether recent experience with clinical problems provokes availability bias (overestimation of the likelihood of a diagnosis based on the ease with which it comes to mind) resulting in diagnostic errors and whether reflection (structured reanalysis of the case findings) counteracts this bias.DESIGN, SETTING, AND PARTICIPANTSExperimental study conducted in 2009 at the Erasmus Medical Centre, Rotterdam, with 18 first-year and 18 second-year internal medicine residents. Participants first evaluated diagnoses of 6 clinical cases (phase 1). Subsequently, they diagnosed 8 different cases through nonanalytical reasoning, 4 of which had findings similar to previously evaluated cases but different diagnoses (phase 2). These 4 cases were subsequently diagnosed again through reflective reasoning (phase 3).MAIN OUTCOME MEASURESMean diagnostic accuracy scores (perfect score, 4.0) on cases solved with or without previous exposure to similar problems through nonanalytical (phase 2) or reflective (phase 3) reasoning and frequency that a potentially biased (ie, phase 1) diagnosis was given.RESULTSThere were no main effects, but there was a significant interaction effect between "years of training" and "recent experiences with similar problems." Results consistent with an availability bias occurred for the second-year residents, who scored lower on the cases similar to those previously encountered (1.55; 95% confidence interval [CI], 1.15-1.96) than on the other cases (2.19; 95% CI, 1.73-2.66; P =.03). This pattern was not seen among the first-year residents (2.03; 95% CI, 1.55-2.51 vs 1.42; 95% CI, 0.92-1.92; P =.046). Second-year residents provided the phase 1 diagnosis more frequently for phase 2 cases they had previously encountered than for those they had not (mean frequency per resident, 1.44; 95% CI, 0.93-1.96 vs 0.72; 95% CI, 0.28-1.17; P =.04). A significant main effect of reasoning mode was found: reflection improved the diagnoses of the similar cases compared with nonanalytical reasoning for the second-year residents (2.03; 95% CI, 1.49-2.57) and the first-year residents (2.31; 95% CI, 1.89-2.73; P =.006).CONCLUSIONWhen faced with cases similar to previous ones and using nonanalytic reasoning, second-year residents made errors consistent with the availability bias. Subsequent application of diagnostic reflection tended to counter this bias; it improved diagnostic accuracy in both first- and second-year residents.

ThyroidVol. 20, No. 12 Letters to the EditorTakotsubo Cardiomyopathy Precipitated by ThyrotoxicosisFazil Alidjan, Mustafa Ezzhati, Wim Bruggeling, and Coen van GuldenerFazil AlidjanDepartment of Internal Medicine, Amphia Hospital, Breda, The Netherlands.Search for more papers by this author, Mustafa EzzhatiDepartment of Internal Medicine, Amphia Hospital, Breda, The Netherlands.Search for more papers by this author, Wim BruggelingDepartment of Cardiology, Amphia Hospital, Breda, The Netherlands.Search for more papers by this author, and Coen van GuldenerDepartment of Internal Medicine, Amphia Hospital, Breda, The Netherlands.Search for more papers by this authorPublished Online:29 Nov 2010https://doi.org/10.1089/thy.2009.0444AboutSectionsView articleView Full TextSupplemental MaterialPDF/EPUBView Supplemental Data ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"Takotsubo Cardiomyopathy Precipitated by Thyrotoxicosis." , 20(12), pp. 1427–1428FiguresReferencesRelatedDetailsCited ByThe association between Takotsubo cardiomyopathy and thyrotoxicosis: A systematic review26 August 2022 | Endocrine, Vol. 21Association of Endocrine Conditions With Takotsubo Cardiomyopathy: A Comprehensive ReviewJournal of the American Heart Association, Vol. 7, No. 19Congestive Heart Failure Secondary to a TSH-Secreting Pituitary Adenoma Aggravated by Takotsubo Cardiomyopathy in an Elderly PatientAACE Clinical Case Reports, Vol. 4, No. 2Recurrent Takotsubo Cardiomyopathy Related to Recurrent Thyrotoxicosis1 April 2016 | Texas Heart Institute Journal, Vol. 43, No. 2Takotsubo cardiomyopathy and transient thyrotoxicosis during combination therapy with interferon-alpha and ribavirin for chronic hepatitis C3 February 2014 | BMC Endocrine Disorders, Vol. 14, No. 1Takotsubo cardiomyopathy and endocrine disorders: a mini-review of case reportsThe American Journal of Emergency Medicine, Vol. 32, No. 11Takotsubo Cardiomyopathy Associated with Thyrotoxicosis: A Case Report and Review of the Literature11 February 2014 | Thyroid, Vol. 24, No. 2Pathophysiology of Takotsubo SyndromeCirculation Journal, Vol. 78, No. 7Broken heart syndrome triggered by an obstructive goiter not associated with thyrotoxicosis11 July 2013 | Canadian Journal of Anesthesia/Journal canadien d'anesthésie, Vol. 60, No. 8Takotsubo Cardiomyopathy Complicating Thyroidectomy for Graves' Disease27 August 2012 | Thyroid, Vol. 22, No. 9Thyroid Storm and Reversible Thyrotoxic Cardiomyopathy After Ingestion of Seafood Stew Thought to Contain Marine Neurotoxin10 June 2011 | Thyroid, Vol. 21, No. 6 Volume 20Issue 12Dec 2010 InformationCopyright 2010, Mary Ann Liebert, Inc.To cite this article:Fazil Alidjan, Mustafa Ezzhati, Wim Bruggeling, and Coen van Guldener.Takotsubo Cardiomyopathy Precipitated by Thyrotoxicosis.Thyroid.Dec 2010.1427-1428.http://doi.org/10.1089/thy.2009.0444Published in Volume: 20 Issue 12: November 29, 2010Online Ahead of Print:November 7, 2010PDF download

Sodium phosphate is widely used as a bowel cleansing preparation. Its use is, however, not without risk. It can induce serious adverse effects like hypocalcemia, hyperphosphatemia and renal failure. In this case, a 75-year-old woman without known contraindications developed hypocalcemic tetany, hyperphosphatemia and renal failure after oral sodium phosphate. Asymptomatic hypoparathyroidism owing to previous thyroid surgery was identified as a new contributing risk factor for this complication.

BACKGROUND:Patients with chronic kidney disease (CKD) have an increased risk of cardiovascular disease (CVD). Preliminary evidence suggests a role for global DNA hypomethylation in the pathogenesis of atherosclerotic complications in CKD. The aims of this study in patients with stage 2-4 CKD were (1) to assess the association between renal function and DNA methylation, (2) to assess the association between DNA methylation and two markers of atherosclerosis [common carotid intima-media thickness (CCA-IMT)] and brachial artery endothelium-dependent, flow-mediated dilatation (BA-FMD) and (3) to examine the effect of a multi-step treatment strategy on DNA methylation.METHODS:In the Anti-Oxidant Therapy In Chronic Renal Insufficiency study (ATIC-study), 93 patients with stage 2-4 CKD were included. In a randomized, double-blind, placebo-controlled design, the treatment group received pravastatin to which vitamin E was added after 6 months and homocysteine-lowering B-vitamin therapy after another 6 months. DNA methylation was assessed using tandem mass spectrometry. CCA-IMT and BA-FMD were assessed using B-mode ultrasonography.RESULTS:At baseline, global DNA methylation was not associated with the estimated glomerular filtration rate (P = 0.32) or with CCA-IMT (P = 0.62) or BA-FMD (P = 0.51). No effect of the treatment strategy including B-vitamin on global DNA methylation was found either in the total study group or within separate strata of homocysteine concentration and renal function.CONCLUSION:In patients with stage 2-4 CKD, global DNA methylation is not associated with renal function or with CCA-IMT or BA-FMD. A treatment strategy that includes B-vitamins did not alter global DNA methylation in these patients. These data do not support the role of DNA hypomethylation in CKD-associated vascular disease in patients with stage 2-4 CKD.

Background: Chronic kidney disease (CKD) is associated with an increased incidence of cardiovascular disease (CVD). The Anti-oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study showed that a multistep treatment strategy improved carotid intima-media thickness, endothelial function, and microalbuminuria in patients with stages 2 to 4 CKD. Increased plasma concentrations of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, have been linked to greater CVD risk in patients with CKD. The aim of this study is to assess effects of the multistep intervention on plasma ADMA concentrations in the ATIC Study.Study Design: Secondary analysis of a randomized double-blind placebo-controlled trial.Setting & Participants: 93 patients with creatinine clearance of 15 to 70 mL/min/1.73 m(2) (according to the Cockcroft-Gault equation) from 7 outpatient clinics in Amsterdam, The Netherlands.Intervention: The treatment group received sequential treatment consisting of pravastatin, 40 mg/d. After 6 months, vitamin E, 300 mg/d, was added, and after another 6 months, homocysteine-lowering therapy (folic acid, 5 mg/d; pyridoxine, 100 mg/d; and vitamin 13121 1 mg/d, all in I tablet) were added and continued for another year. The control group received matching placebos.Outcome & Measures: Plasma ADMA levels.Results: 36 participants (77%) in the treatment group and 38 (83%) in the placebo group completed the study. Mean ADMA and symmetric dimethylarginine concentrations in the total study population were 0.53 +/- 0.07 (SD) and 1.14 +/- 0.46 mu mol/L, respectively. After 24 months, there was no overall effect of the treatment strategy on ADMA concentrations (beta = -0.006; P = 0.27). Analysis of separate treatment effects suggested that vitamin E significantly decreased ADMA levels by 4% in the treatment group compared with the placebo group (multiple adjusted P = 0.02).Limitations: The study was a secondary analysis, power calculation was based on the primary end point of carotid intima-media thickness, mean plasma ADMA levels were relatively low.Conclusion: Overall, a multistep treatment strategy consisting of pravastatin, vitamin E, and B vitamins had no effect on plasma ADMA levels in a stage 2 to 4 CKD population. This suggests that the beneficial effects of the intervention were not mediated by changes in ADMA levels. Possible ADMA-lowering effects of vitamin E deserve further attention. Am J Kidney Dis 53:41-50. (C) 2008 by the National Kidney Foundation, Inc.

BACKGROUND:Patients with chronic kidney disease have an increased risk of cardiovascular disease. Oxidative stress has been proposed to play a role in the development of cardiovascular disease among these patients. METHODS:We conducted a randomized, double-blind trial in 93 patients (Cockcroft-Gault equation: creatinine clearance, 38+/-15 [mean+/-SD] mL/min per 1.73 m2 [0.63+/-0.25 mL/s per m2]) to investigate the effect of a treatment strategy designed primarily to achieve stepwise oxidative stress reduction on common carotid intima-media thickness (CC-IMT), brachial artery flow-mediated dilatation (BA-FMD), albuminuria, and renal function. The treatment group received a regimen of pravastatin to which vitamin E supplementation was added after 6 months and homocysteine-lowering therapy after another 6 months. Blood pressure in both groups was managed according to a standard protocol. The placebo group received matching placebos. Measurement of CC-IMT and BA-FMD was performed at randomization after 6, 12, and 18 months. Patients were followed up for 2 years. Generalized estimating equations were used for analysis. RESULTS:Compared with placebo, active treatment was associated with a decrease in CC-IMT (after 18 months: from 0.68 to 0.63 mm in the treatment group and from 0.65 to 0.71 mm in the placebo group; P<.001), an increase in BA-FMD (after 18 months: from 4.66% to 7.56% in the treatment group and from 6.21% to 4.73% in the placebo group; P<.001), and an attenuated increase in urinary albumin excretion over time (P=.04 for between-group difference after 24 months), but no effect was observed on renal function. CONCLUSION:In patients with mild to moderate chronic kidney disease, 18 months of a treatment strategy along with well-controlled blood pressure reduced CC-IMT and urinary albumin excretion and increased BA-FMD. TRIAL REGISTRATION:clinicaltrials.gov Identifier: NCT00384618.

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is formed by methylation of arginine residues in proteins and released after proteolysis. In this reaction, S-adenosylmethionine is methyldonor and S-adenosylhomocysteine the demethylated product. ADMA and homocysteine are thus biochemically linked. Both plasma homocysteine and ADMA concentrations are increased in patients with renal dysfunction, probably as a result of an impairment in their metabolic, but not urinary, clearance. Hyperhomocysteinemia has been associated with an increased risk of cardiovascular disease in end-stage renal disease, especially in patients without malnutrition and inflammation. Also, plasma ADMA levels have been associated with cardiovascular disease in renal failure patients. Both homocysteine and ADMA are thought to mediate their adverse vascular effects by impairing endothelial , nitric oxide-dependent function resulting in decreased vasodilatation, increased smooth muscle cell proliferation, platelet dysfunction and increased monocyte adhesion. At the same time, it has been shown that the correlation between plasma ADMA and homocysteine is weak and that, in renal patients, the association of plasma ADMA carotid intima-media thickness, cardiovascular events and overall mortality is independent of homocysteine. This indicates that the negative vascular effects of ADMA and homocysteine have a different etiology. Treatment with folic acid substantially lowers homocysteine, but not ADMA concentration. So far, homocysteine-lowering therapy has not been very successful in decreasing cardiovascular disease. In patients with renal failure, ADMA reduction may be an interesting new goal in the prevention of cardiovascular disease.

High plasma concentrations of the amino acid homocysteine have been associated with atherothrombotic disease, first in individuals with inborn errors of homocysteine metabolism, who have very high plasma homocysteine concentrations, and later also in the general population. In general, the cardiovascular risk associated with hyperhomocysteinemia is significant, but modest and probably differs between populations. High homocysteine concentrations are thought to impair endothelial function, increase oxidative stress, impair methylation reactions, and alter protein structure. Although some studies have shown improvement of vascular surrogate end points, homocysteine-lowering treatment has not yet been associated with a significant reduction of cardiovascular events. Studies that have examined the relationship between plasma homocysteine and arterial stiffness parameters have shown heterogenous results.