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Risk of Arterial Thromboembolism, Venous Thromboembolism, and Bleeding in Patients with Nephrotic Syndrome: A Population-Based Cohort Study

Published:December 30, 2021DOI:https://doi.org/10.1016/j.amjmed.2021.11.018

      Abstract

      Background

      Although venous thromboembolism is a well-known complication of nephrotic syndrome, the long-term absolute and relative risks of arterial thromboembolism, venous thromboembolism, and bleeding in adults with nephrotic syndrome remain unclarified.

      Methods

      In this matched cohort study, we identified every adult with first-time recorded nephrotic syndrome from admissions, outpatient clinics, or emergency department visits in Denmark during 1995-2018. Each patient was matched by age and sex with 10 individuals from the general population. We estimated the 10-year cumulative risks of recorded arterial thromboembolism, venous thromboembolism, and bleeding accounting for the competing risk of death. Using Cox models, we computed crude and adjusted hazard ratios (HRs) of the outcomes in patients with nephrotic syndrome versus comparators.

      Results

      Among 3967 adults with first-time nephrotic syndrome, the 1-year risk of arterial thromboembolism was 4.2% (95% confidence interval [CI] 3.6-4.8), of venous thromboembolism was 2.8% (95% CI 2.3-3.3), and of bleeding was 5.2% (95% CI 4.5-5.9). The 10-year risk of arterial thromboembolism was 14.0% (95% CI 12.8-15.2), of venous thromboembolism 7.7% (95% CI 6.8-8.6), and of bleeding 17.0% (95% CI 15.7-18.3), with highest risks of ischemic stroke (8.1%), myocardial infarction (6.0%), and gastrointestinal bleeding (8.2%). During the first year, patients with nephrotic syndrome had increased rates of both arterial thromboembolism (adjusted HR [HRadj] = 3.11 [95% CI 2.60-3.73]), venous thromboembolism (HRadj = 7.11 [5.49-9.19]), and bleeding (HRadj = 4.02 [3.40-4.75]) compared with the general population comparators after adjusting for confounders.

      Conclusion

      Adults with nephrotic syndrome have a high risk of arterial thromboembolism, venous thromboembolism, and bleeding compared with the general population. The mechanisms and consequences of this needs to be clarified.

      Keywords

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      References

        • Hull RP
        • Goldsmith DJ.
        Nephrotic syndrome in adults.
        BMJ. 2008; 336: 1185-1189
        • Loscalzo J.
        Venous thrombosis in the nephrotic syndrome.
        N Engl J Med. 2013; 368: 956-958
        • Prandoni P.
        Venous and arterial thrombosis: two aspects of the same disease?.
        Eur J Intern Med. 2009; 20: 660-661
        • Crew RJ
        • Radhakrishnan J
        • Appel G.
        Complications of the nephrotic syndrome and their treatment.
        Clin Nephrol. 2004; 62: 245-259
        • Glassock RJ.
        Prophylactic anticoagulation in nephrotic syndrome: a clinical conundrum.
        J Am Soc Nephrol. 2007; 18: 2221-2225
        • Johannesdottir SA
        • Horváth-Puhó E
        • Dekkers OM
        • et al.
        Use of glucocorticoids and risk of venous thromboembolism: a nationwide population-based case-control study.
        JAMA Intern Med. 2013; 173: 743-752
        • Iodice S
        • Gandini S
        • Löhr M
        • Lowenfels AB
        • Maisonneuve P.
        Venous thromboembolic events and organ-specific occult cancers: a review and meta-analysis.
        J Thromb Haemost. 2008; 6: 781-788
        • Navi BB
        • Reiner AS
        • Kamel H
        • et al.
        Risk of arterial thromboembolism in patients with cancer.
        J Am Coll Cardiol. 2017; 70: 926-938
        • Bell EJ
        • Folsom AR
        • Lutsey PL
        • et al.
        Diabetes mellitus and venous thromboembolism: a systematic review and meta-analysis.
        Diabetes Res Clin Pract. 2016; 111: 10-18
        • Olesen KKW
        • Madsen M
        • Gyldenkerne C
        • et al.
        Diabetes mellitus is associated with increased risk of ischemic stroke in patients with and without coronary artery disease.
        Stroke. 2019; 50: 3347-3354
        • Ocak G
        • Rookmaaker MB
        • Algra A
        • et al.
        Chronic kidney disease and bleeding risk in patients at high cardiovascular risk: a cohort study.
        J Thromb Haemost. 2018; 16: 65-73
        • Molnar AO
        • Bota SE
        • Garg AX
        • et al.
        The risk of major hemorrhage with CKD.
        J Am Soc Nephrol. 2016; 27: 2825-2832
        • Viborg S
        • Søgaard KK
        • Farkas DK
        • Nørrelund H
        • Pedersen L
        • Sørensen HT.
        Lower gastrointestinal bleeding and risk of gastrointestinal cancer.
        Clin Transl Gastroenterol. 2016; 7: e162
        • Narum S
        • Westergren T
        • Klemp M.
        Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis.
        BMJ Open. 2014; 4e004587
        • Schulman S
        • Beyth RJ
        • Kearon C
        • Levine MN.
        Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).
        Chest. 2008; 133: 257s-298s
        • Christiansen CF
        • Schmidt M
        • Lamberg AL
        • et al.
        Kidney disease and risk of venous thromboembolism: a nationwide population-based case-control study.
        J Thromb Haemost. 2014; 12: 1449-1454
        • Go AS
        • Tan TC
        • Chertow GM
        • et al.
        Primary nephrotic syndrome and risks of ESKD, Cardiovascular Events, and death: The Kaiser Permanente Nephrotic Syndrome Study.
        J Am Soc Nephrol. 2021; 32: 2303
        • Ordonez JD
        • Hiatt RA
        • Killebrew EJ
        • Fireman BH.
        The increased risk of coronary heart disease associated with nephrotic syndrome.
        Kidney Int. 1993; 44: 638-642
        • Huang JA
        • Lin CH
        • Chang YT
        • Lee CT
        • Wu MJ.
        Nephrotic syndrome is associated with increased risk of ischemic stroke.
        J Stroke Cerebrovasc Dis. 2019; 28104322
        • Shinkawa K
        • Yoshida S
        • Seki T
        • Yanagita M
        • Kawakami K
        Risk factors of venous thromboembolism in patients with nephrotic syndrome: a retrospective cohort study.
        Nephrol Dial Transplant. 2021; 36: 1199-1206
        • Rankin AJ
        • McQuarrie EP
        • Fox JG
        • Geddes CC
        • MacKinnon B.
        Venous thromboembolism in primary nephrotic syndrome - is the risk high enough to justify prophylactic anticoagulation?.
        Nephron. 2017; 135: 39-45
        • Gyamlani G
        • Molnar MZ
        • Lu JL
        • Sumida K
        • Kalantar-Zadeh K
        • Kovesdy CP.
        Association of serum albumin level and venous thromboembolic events in a large cohort of patients with nephrotic syndrome.
        Nephrol Dial Transplant. 2017; 32: 157-164
        • Mahmoodi BK
        • ten Kate MK
        • Waanders F
        • et al.
        High absolute risks and predictors of venous and arterial thromboembolic events in patients with nephrotic syndrome: results from a large retrospective cohort study.
        Circulation. 2008; 117: 224-230
        • Lee T
        • Derebail VK
        • Kshirsagar AV
        • et al.
        Patients with primary membranous nephropathy are at high risk of cardiovascular events.
        Kidney Int. 2016; 89: 1111-1118
        • Gebregeorgis W
        • Pillai U
        • Mamdani H
        • Yang J
        • Rossi NF
        Coagulopathy and spontaneous hemorrhage in a patient with nephrotic syndrome.
        Clin Nephrol. 2015; 84: 55-60
        • Taille C
        • Fartoukh M
        • Houel R
        • Kobeiter H
        • Remy P
        • Lemaire F.
        Spontaneous hemomediastinum complicating steroid-induced mediastinal lipomatosis.
        Chest. 2001; 120: 311-313
        • Okada M
        • Akimoto T
        • Kawamata M
        • et al.
        Retroperitoneal bleeding: an experience during prophylactic anticoagulation in a patient with nephrotic syndrome.
        Clin Med Insights Case Rep. 2017; 101179547617723317
        • Schmidt M
        • Schmidt SA
        • Sandegaard JL
        • Ehrenstein V
        • Pedersen L
        • Sorensen HT.
        The Danish National Patient Registry: a review of content, data quality, and research potential.
        Clin Epidemiol. 2015; 7: 449-490
        • Pottegard A
        • Schmidt SAJ
        • Wallach-Kildemoes H
        • Sorensen HT
        • Hallas J
        • Schmidt M.
        Data resource profile: the Danish National Prescription Registry.
        Int J Epidemiol. 2017; 46798-798f
        • Erichsen R
        • Lash TL
        • Hamilton-Dutoit SJ
        • Bjerregaard B
        • Vyberg M
        • Pedersen L.
        Existing data sources for clinical epidemiology: the Danish National Pathology Registry and Data Bank.
        Clin Epidemiol. 2010; 2: 51-56
        • Arendt JFH
        • Hansen AT
        • Ladefoged SA
        • Sørensen HT
        • Pedersen L
        • Adelborg K.
        Existing Data sources in Clinical Epidemiology: laboratory information system databases in Denmark.
        Clin Epidemiol. 2020; 12: 469-475
        • Schmidt M
        • Pedersen L
        • Sorensen HT.
        The Danish Civil Registration System as a tool in epidemiology.
        Eur J Epidemiol. 2014; 29: 541-549
        • Schmidt M
        • Schmidt SAJ
        • Adelborg K
        • et al.
        The Danish health care system and epidemiological research: from health care contacts to database records.
        Clin Epidemiol. 2019; 11: 563-591
        • Heide-Jørgensen U
        • Adelborg K
        • Kahlert J
        • Sørensen HT
        • Pedersen L.
        Sampling strategies for selecting general population comparison cohorts.
        Clin Epidemiol. 2018; 10: 1325-1337
        • Levey AS
        • Stevens LA
        • Schmid CH
        • et al.
        A new equation to estimate glomerular filtration rate.
        Ann Intern Med. 2009; 150: 604-612
        • Noordzij M
        • Leffondré K
        • van Stralen KJ
        • Zoccali C
        • Dekker FW
        • Jager KJ.
        When do we need competing risks methods for survival analysis in nephrology?.
        Nephrol Dial Transplant. 2013; 28: 2670-2677
        • CKD Work Group
        Kidney Disease: Improving Global Outcomes (KDIGO) KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease.
        Kidney Int Suppl. 2013; : 1-150
        • R Core Team
        R: A Language and Environment for Statistical Computing.
        R Core Team, Vienna, Austria2021
        • Wickham H
        • Averick M
        • Bryan J
        • et al.
        Welcome to the Tidyverse.
        J Open Source Softw. 2019; 4: 1686
        • Li SJ
        • Guo JZ
        • Zuo K
        • et al.
        Thromboembolic complications in membranous nephropathy patients with nephrotic syndrome-a prospective study.
        Thromb Res. 2012; 130: 501-505
        • Zhang LJ
        • Zhang Z
        • Li SJ
        • et al.
        Pulmonary embolism and renal vein thrombosis in patients with nephrotic syndrome: prospective evaluation of prevalence and risk factors with CT.
        Radiology. 2014; 273: 897-906
        • Li SJ
        • Tu YM
        • Zhou CS
        • Zhang LH
        • Liu ZH.
        Risk factors of venous thromboembolism in focal segmental glomerulosclerosis with nephrotic syndrome.
        Clin Exp Nephrol. 2016; 20: 212-217
        • Verduijn M
        • Grootendorst DC
        • Dekker FW
        • Jager KJ
        • le Cessie S.
        The analysis of competing events like cause-specific mortality–beware of the Kaplan-Meier method.
        Nephrol Dial Transplant. 2011; 26: 56-61
        • Orth SR
        • Ritz E.
        The nephrotic syndrome.
        N Engl J Med. 1998; 338: 1202-1211
        • Kerlin BA
        • Ayoob R
        • Smoyer WE.
        Epidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease.
        Clin J Am Soc Nephrol. 2012; 7: 513-520
        • Vestergaard SV
        • Birn H
        • Hansen AT
        • Nørgaard M
        • Nitsch D
        • Christiansen CF.
        Comparison of patients with hospital-recorded nephrotic syndrome and patients with nephrotic proteinuria and hypoalbuminemia: a nationwide study in Denmark.
        Kidney 360. 2021; 2: 1482-1490
        • Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group
        KDIGO Clinical Practice Guideline for Glomerulonephritis.
        Kidney Int Suppl. 2012; 2: 139-274
        • VanderWeele TJ
        • Ding P.
        Sensitivity analysis in observational research: introducing the e-value.
        Ann Intern Med. 2017; 167: 268-274
        • Inker LA
        • Shaffi K
        • Levey AS.
        Estimating glomerular filtration rate using the chronic kidney disease-epidemiology collaboration creatinine equation: better risk predictions.
        Circ Heart Fail. 2012; 5: 303-306