| 1. |
- Andersson, Daniel P., et al.
(författare)
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Relation among hypertriglyceridaemia, cardiometabolic disease, and hereditary factors : design and rationale of the Stockholm hyperTRIglyceridaemia REGister study
- 2024
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Ingår i: European Heart Journal Open. - : Oxford University Press. - 2752-4191. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- AimsHypertriglyceridaemia (hTG) is associated with atherosclerotic cardiovascular disease, pancreatitis, and non-alcoholic fatty liver disease (NAFLD) in large population-based studies. The understanding of the impact of hereditary hTG and cardiometabolic disease status on the development of hTG and its associated cardiometabolic outcomes is more limited. We aimed to establish a multigenerational cohort to enable studies of the relationship between hTG, cardiometabolic disease and hereditary factors.Methods and resultsThe population-based observational Stockholm hyperTRIglyceridaemia REGister (STRIREG) study includes 1 460 184 index individuals who have measured plasma triglycerides in the clinical routine in Region Stockholm, Sweden, between 1 January 2000 and 31 December 2021. The laboratory measurements also included basic haematology, blood lipid panel, liver function tests, and HbA1c. Using the Swedish Multi-Generation register, 2 147 635 parents and siblings to the indexes were identified to form the complete study cohort. Laboratory data from participants were combined with data from several national registers that provided information on the cause of death, medical diagnoses, dispensed medicines, and socioeconomic factors including country of birth, education level, and marital status.ConclusionThe multi-generational longitudinal STRIREG cohort provides a unique opportunity to investigate different aspects of hTG as well as heredity for other metabolic diseases. Important outcome measures include mortality, cardiovascular mortality, major cardiovascular events, development of incident diabetes, and NAFLD. The STRIREG study will provide a deeper understanding of the impact of hereditary factors and associated cardiometabolic complications.
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| 2. |
- Björk, Jonas, et al.
(författare)
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Prospects for improved glomerular filtration rate estimation based on creatinine—results from a transnational multicentre study
- 2020
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Ingår i: Clinical Kidney Journal. - : Oxford University Press (OUP). - 2048-8505 .- 2048-8513. ; 13:4, s. 674-683
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Tidskriftsartikel (refereegranskat)abstract
- Background The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation is routinely used to assess renal function but exhibits varying accuracy depending on patient characteristics and clinical presentation. The overall aim of the present study was to assess if and to what extent glomerular filtration rate (GFR) estimation based on creatinine can be improved.MethodsIn a cross-sectional analysis covering the years 2003–17, CKD-EPI was validated against measured GFR (mGFR; using various tracer methods) in patients with high likelihood of chronic kidney disease (CKD; five CKD cohorts, n = 8365) and in patients with low likelihood of CKD (six community cohorts, n = 6759). Comparisons were made with the Lund–Malmö revised equation (LMR) and the Full Age Spectrum equation.Results7In patients aged 18–39 years old, CKD-EPI overestimated GFR with 5.0–16 mL/min/1.73 m2 in median in both cohort types at mGFR levels <120 mL/min/1.73 m2. LMR had greater accuracy than CKD-EPI in the CKD cohorts (P30, the percentage of estimated GFR within 30% of mGFR, 83.5% versus 76.6%). CKD-EPI was generally the most accurate equation in the community cohorts, but all three equations reached P30 above the Kidney Disease Outcomes Quality Initiative benchmark of 90%.ConclusionsNone of the evaluated equations made optimal use of available data. Prospects for improved GFR estimation procedures based on creatinine exist, particularly in young adults and in settings where patients with suspected or manifest CKD are investigated.
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| 3. |
- Björk, Jonas, et al.
(författare)
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Validation of standardized creatinine and cystatin C GFR estimating equations in a large multicentre European cohort of children
- 2019
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Ingår i: Pediatric Nephrology. - : Springer Science and Business Media LLC. - 0931-041X .- 1432-198X.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Most validations of paediatric glomerular filtration rate (GFR) estimating equations using standardized creatinine (CR) and cystatin C (CYS) assays have comprised relatively small cohorts, which makes accuracy across subgroups of GFR, age, body mass index (BMI) and gender uncertain. To overcome this, a large cohort of children referred for GFR determination has been established from several European medical centres. Methods: Three thousand four hundred eight measurements of GFR (mGFR) using plasma clearance of exogenous substances were performed in 2218 children aged 2–17 years. Validated equations included Schwartz-2009CR/2012CR/CYS/CR+CYS, FASCR/CYS/CR+CYS, LMRCR, Schwartz-LyonCR, BergCYS, CAPACYS, CKD-EPICYS, AndersenCR+CYS and arithmetic means of the best single-marker equations in explorative analysis. Five metrics were used to compare the performance of the GFR equations: bias, precision and three accuracy measures including the percentage of GFR estimates (eGFR) within ± 10% (P10) and ± 30% (P30) of mGFR. Results: Three of the cystatin C equations, BergCYS, CAPACYS and CKD-EPICYS, exhibited low bias and generally satisfactory accuracy across all levels of mGFR; CKD-EPICYS had more stable performance across gender than the two other equations. Among creatinine equations, Schwartz-LyonCR had the best performance but was inaccurate at mGFR < 30 mL/min/1.73 m2 and in underweight patients. Arithmetic means of the best creatinine and cystatin C equations above improved bias compared to the existing composite creatinine+cystatin C equations. Conclusions: The present study strongly suggests that cystatin C should be the primary biomarker of choice when estimating GFR in children with decreased GFR. Arithmetic means of well-performing single-marker equations improve accuracy further at most mGFR levels and have practical advantages compared to composite equations.
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| 4. |
- Delanaye, Pierre, et al.
(författare)
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Performance of creatinine-based equations to estimate glomerular filtration rate in White and Black populations in Europe, Brazil, and Africa.
- 2022
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Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385.
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: A new Chronic Kidney Disease Epidemiology equation without race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside USA nor compared to the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts.METHODS: Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n = 13 856 including 6031 individuals in the external validation cohort), from France, (n = 4429, including 964 Black Europeans), from Brazil (n = 100), and from Africa (n = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed.RESULTS: In White Europeans (n = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of -0.6 and -3.2, respectively versus 5.0 mL/min/1.73m², and accuracy within 30% of 86.9 and 87.4, respectively versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value ( = concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans, and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males.CONCLUSION: In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated, population-specific Q-values presents the best performance in the whole age range in the European and African populations included in this study.
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| 5. |
- Delanaye, Pierre, et al.
(författare)
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Performance of creatinine-based equations to estimate glomerular filtration rate with a methodology adapted to the context of drug dosage adjustment
- 2022
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley-Blackwell Publishing Inc.. - 0306-5251 .- 1365-2125. ; 88:5, s. 2118-2127
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Tidskriftsartikel (refereegranskat)abstract
- AIM: The Cockcroft-Gault (CG) creatinine-based equation is still used to estimate glomerular filtration rate (eGFR) for drug dosage adjustment. Incorrect eGFR may lead to hazardous over- or underdosing METHODS: In a cross-sectional analysis, CG was validated against measured GFR (mGFR) in 14,804 participants and compared with the Modification-of-Diet-in-Renal-Diseases (MDRD), Chronic-Kidney-Disease-Epidemiology (CKD-EPI), Lund-Malmö-Revised (LMR), and European-Kidney-Function-Consortium (EKFC) equations. Validation focused on bias, imprecision, and accuracy (percentage of estimates within ±30% of mGFR, P30), overall and stratified for mGFR, age, and body mass index at mGFR <60 mL/min, as well as classification in mGFR stages.RESULTS: The CG equation performed worse than the other equations, overall and in mGFR, age and BMI subgroups in terms of bias (systematic overestimation), imprecision and accuracy except for patients ≥65 years where bias and P30 were similar to MDRD and CKD-EPI, but worse than LMR and EKFC. In subjects with mGFR<60 mL/min and at BMI [18.5-25[kg/m2 , all equations performed similarly and for BMI<18.5kg/m2 CG and LMR had the best results though all equations had poor P30-accuracy. At BMI≥25kg/m2 the bias of the CG increased with increasing BMI (+17.2mL/min at BMI≥40kg/m2 ). The four more recent equations also classified mGFR stages better than CG.CONCLUSIONS: The CG equation showed poor ability to estimate GFR overall and in analyses stratified for GFR, age, and BMI. CG was inferior to correctly classify the patients in the mGFR staging compared to more recent creatinine-based equations.
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| 6. |
- Littmann, Karin
(författare)
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Establishment of new potential biomarkers for cardiometabolic diseases
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cardiometabolic diseases is a growing health issue worldwide. New knowledge about the pathophysiological processes have been gained and several research discoveries have contributed to better management of the diseases. Even so, the prognosis, diagnosis, and treatment of cardiometabolic diseases needs to be further improved. For this, the discovery and implementation of additional biomarkers is extremely relevant. New advancing technologies have increased the opportunities to perform discovery studies and to identify new potential biomarkers. However, for several reasons, only few biomarkers survive the long journey from discovery into clinical implementation and there is a need to make this process more efficient. The objective of the thesis was to evaluate new potential biomarkers to improve the diagnosis and management of cardiometabolic diseases. An additional aim was to establish an efficient process for rapid transfer of new potential biomarkers, identified in discovery studies into evaluation in the routine care setting. Four studies in different patient cohorts, characterized by separate designs, and reflecting diverse phases in the implementation of biomarkers for cardiometabolic diseases are presented. Lipoprotein (a) [Lp(a)] is a modified low-density lipoprotein (LDL) particle and its concentration in plasma is mainly genetically determined. High levels of Lp(a) is associated with an increased risk for cardiovascular diseases (CVD). Despite the fact that it is not yet clear whether reduction of plasma Lp(a) levels translate into a reduced CVD risk, more knowledge about its role as a risk factor in different cohorts and diagnoses is needed to better understand how patients with high Lp(a) levels should be managed. In Paper I we investigated the distribution of plasma Lp(a) levels and its association with CVD in a large cohort of patients who had their plasma levels of Lp(a) determined in routine care. Laboratory data from 23 398 patients was linked to data retrieved from National Board of Health and Welfare registers and National Quality registers. Lp(a) levels had a skewed distribution, increased with age, and was higher in females. Patients with Lp(a) levels in the 4th quartile had a 1.36-fold (95% Confidence Interval (CI) 1.14-1.61, p=0.001) increased risk for ischemic heart disease compared to patients belonging to the 1st quartile. The risk was independent of age, previous CVD, diabetes, and LDL-cholesterol levels. Hence, Lp(a) is an important risk factor for ischemic heart disease also in patients referred from hospitals, out-patient clinics, and general practitioners in the Region Stockholm. Very little is known about the role of Lp(a) as a risk factor for CVD in patients with type 1 diabetes. Therefore, in Paper II we investigated the association of Lp(a) with cardiovascular complications and metabolic control in 1860 subjects with type 1 diabetes. Lp(a) levels had a skewed distribution, increased with age, and was not influenced by sex. Patients with poor metabolic control (HbA1c >52 mmol/mol) had higher Lp(a) levels compared to patients with good metabolic control. Patients with high Lp(a) levels (>120 nmol/L) had a 1.51-fold (95 % CI 1.01-2.28, p=0.048) increased risk for any macrovascular diseases, a 1.68-fold (95% CI 1.12-2.50, p=0.01) increased risk for albuminuria, and a 2.03-fold (95 % CI 1.02-4.01, p=0.043) increased risk for calcified aortic valve disease compared to patients with very low levels (<10 nmol/L). In summary, Lp(a) is a relevant risk factor also in patients with type 1 diabetes. In Paper III we aimed to establish an efficient process for transfer of newly discovered potential biomarkers into evaluation in the routine care setting. The prototype was based on the evaluation of chemokine ligand 16 (CCL-16), previously identified as interesting biomarker for acute coronary syndrome (ACS) in a discovery project called Vinncardio, initiated by the Science for Life laboratory, Royal Institute of Technology (KTH), Stockholm, Sweden. Patients eligible for inclusion were identified when their plasma was analyzed for high sensitive Troponin T at the Karolinska University Laboratory, Stockholm, Sweden. The plasma samples were temporarily stored and meanwhile the patients received a letter of invitation to participate in the study. A positive response was retrieved from ~40 % and 1631 patients were included. No significant differences in CCL-16 were observed between patients with ACS and other diagnosis and CCL-16 do not appear to be a valid biomarker for ACS. Despite this negative result, we manage to establish a process for early evaluation of new potential biomarkers in routine care settings and to rapidly create a biobank and include patients referred to the hospital with an acute medical condition. Clinical randomized trials have shown that addition of ezetimibe to simvastatin treatment further improve the reduction of CVD events, especially in patients with type 2 diabetes where elevation of remnant-cholesterol is characteristic. Remnant-cholesterol is a new and interesting biomarker and mendelian randomization studies have identified it as an independent risk factor for CVD, also promoting and sustaining low grade inflammation. In Paper IV we aimed to in detail study how the lipoprotein metabolism is affected by simvastatin and ezetimibe treatment, alone or in combination, to gain further understanding of the molecular effects of these two widely used lipid lowering drugs. Forty patients eligible for cholecystectomy were randomized to four-week treatment before surgery to placebo, simvastatin (80 mg daily), ezetimibe (10 mg daily), or to combination of both. The combination of simvastatin and ezetimibe resulted in further reduction of cholesterol and cholesteryl esters in remnant- and LDL-particles, as well as reduction of apolipoprotein B (apoB) containing particles, and reduced apoB-containing lipoprotein affinity for arterial proteoglycans compared to simvastatin. These additional positive effects on atherogenic lipoproteins and especially remnant-particles can possibly explain the further reduction of CVD events previously observed, and the combination of ezetimibe and simvastatin seems to be the optimal treatment in conditions with elevated remnant-cholesterol. In conclusion, these four studies have provided further knowledge about the different biomarkers investigated. Also, they can contribute to an improved management of patients with cardiometabolic diseases and indicate the way to a rapid recruitment of patients in clinical studies. Hence, this thesis adds to a deeper understanding of the complexity in the process to validate and implement new biomarkers.
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| 7. |
- Littmann, Karin, et al.
(författare)
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Plasma lipoprotein(a) measured in the routine clinical care is associated to atherosclerotic cardiovascular disease during a 14-year follow-up.
- 2021
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Ingår i: European Journal of Preventive Cardiology. - : Oxford University Press. - 2047-4873 .- 2047-4881. ; 28:18, s. 2038-2047
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: To investigate plasma lipoprotein(a) [Lp(a)] levels measured in routine clinical care and their association with mortality and cardiovascular disease.METHODS AND RESULTS: This retrospective registry-based observational cohort study includes all individuals with plasma Lp(a) results measured at the Karolinska University Laboratory 2003-17. Outcome data were captured in national outcome registries. Levels of Lp(a) expressed in mass or molar units were examined separately. In adjusted Cox regression models, association between deciles of plasma Lp(a) concentrations, mortality, and cardiovascular outcomes were assessed. A total of 23 398 individuals [52% females, mean (standard deviation) age 55.5 (17.2) years, median Lp(a) levels 17 mg/dL or 19.5 nmol/L] were included. Individuals with an Lp(a) level >90th decile (>90 mg/dL or >180 nmol/L) had hazard ratios (95% confidence interval) of 1.25 (1.05-1.50) for major adverse cardiovascular events (P = 0.013), 1.37 (1.14-1.64) for atherosclerotic cardiovascular disease (P = 0.001), and 1.62 (1.28-2.05) for coronary artery disease (P ≤ 0.001), compared to individuals with Lp(a) ≤50th decile. No association between Lp(a) and mortality, peripheral artery disease, or ischaemic stroke was observed.CONCLUSION: High Lp(a) levels are associated with adverse cardiovascular disease outcomes also in individuals with Lp(a) measured in routine clinical care. This supports the 2019 ESC/EAS recommendation to measure Lp(a) at least once during lifetime to assess cardiovascular risk and implies the need for intensive preventive therapy in patients with elevated Lp(a).
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| 8. |
- Nyman, Ulf, et al.
(författare)
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[GFR estimation in children - age-adjusted creatinine makes the adult Lund-Malmö equation applicable in children and facilitates automatic GFR reporting from the clinical laboratory]
- 2021
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Ingår i: Läkartidningen. - : Läkartidningen Förlag AB. - 0023-7205 .- 1652-7518. ; 118
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Tidskriftsartikel (refereegranskat)abstract
- Age-adjustment of creatinine, i.e. recalculation of childhood levels of creatinine to corresponding levels at 18 years of age and applied in the adult revised Lund-Malmö GFR equation led to markedly improved accuracy in Swedish children (n=1 718) at measured GFR <75 mL/min/1.73 m2 (n=318) and preserved high accuracy at ≥75 mL/min/1.73 m2 (n=1 400). The adjusted LMR equation performed as well as dedicated paediatric equations based on height. The proposed adjustment strategy has four strengths: (i) the original coefficients of the adult GFR equation can be used, (ii) the same equation can be used across the entire lifespan without artificial changes in estimated GFR when switching from paediatric to adult care, (iii) the lack of height factor makes it easier to automatically report estimated GFR by the laboratories and (iv) age-adjusted creatinine values imply that well-established creatinine reference intervals for adults can also be used for children.
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| 9. |
- Nyman, Ulf, et al.
(författare)
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Så kan formel för vuxna skatta glomerulär filtration hos barn
- 2021
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Ingår i: Lakartidningen. - 0023-7205. ; 118
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Tidskriftsartikel (refereegranskat)abstract
- Age-adjustment of creatinine, i.e. recalculation of childhood levels of creatinine to corresponding levels at 18 years of age and applied in the adult revised Lund-Malmö GFR equation led to markedly improved accuracy in Swedish children (n=1 718) at measured GFR <75 mL/min/1.73 m2 (n=318) and preserved high accuracy at ≥75 mL/min/1.73 m2 (n=1 400). The adjusted LMR equation performed as well as dedicated paediatric equations based on height. The proposed adjustment strategy has four strengths: (i) the original coefficients of the adult GFR equation can be used, (ii) the same equation can be used across the entire lifespan without artificial changes in estimated GFR when switching from paediatric to adult care, (iii) the lack of height factor makes it easier to automatically report estimated GFR by the laboratories and (iv) age-adjusted creatinine values imply that well-established creatinine reference intervals for adults can also be used for children.
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| 10. |
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