Publications by authors named "Stefan H Jacobson"

97 Publications

Worldwide Early Impact of COVID-19 on Dialysis Patients and Staff and Lessons Learned: A DOPPS Roundtable Discussion.

Kidney Med 2021 Jul-Aug;3(4):619-634. Epub 2021 May 14.

Arbor Research Collaborative for Health, Ann Arbor, MI.

As the worst global pandemic of the past century, coronavirus disease 2019 (COVID-19) has had a disproportionate effect on maintenance dialysis patients and their health care providers. At a virtual roundtable on June 12, 2020, Dialysis Outcomes and Practice Patterns Study (DOPPS) investigators from 15 countries in Asia, Europe, and the Americas described and compared the effects of COVID-19 on dialysis care, with recent updates added. Most striking is the huge difference in risk to dialysis patients and staff across the world. Per-population cases and deaths among dialysis patients vary more than 100-fold across participating countries, mirroring burden in the general population. International data indicate that the case-fatality ratio remains at 10% to 30% among dialysis patients, confirming the gravity of infection, and that cases are much more common among in-center than home dialysis patients. This latter finding merits urgent study because in-center patients often have greater community exposure, and in-center transmission may be uncommon under optimal protocols. Greater telemedicine use is a welcome change here to stay, and our community needs to improve emergency planning and protect dialysis staff from the next pandemic. Finally, the pandemic's challenges have prompted widespread partnering and innovation in kidney care and research that must be sustained after this global health crisis.
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http://dx.doi.org/10.1016/j.xkme.2021.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120787PMC
May 2021

B cell and monocyte phenotyping: A quick asset to investigate the immune status in patients with IgA nephropathy.

PLoS One 2021 19;16(3):e0248056. Epub 2021 Mar 19.

Karolinska Institutet, Clinical Science and Education, Södersjukhuset, Stockholm, Sweden.

Background: IgA nephropathy (IgAN) advances from multiple pathogenic "hits" resulting in poorly O-galactosylated IgA1 glycoforms (Gd-IgA1), production of antibodies and glomerular deposition of immune complexes. A sequence of immune responses arising from plasma cells, T cells and antigen presenting cells (APCs), causes glomerular injury. This study was designed to phenotype subsets of B cells, monocytes and T cells in the peripheral circulation and their association with inflammatory cytokines and kidney function in patients with IgAN, healthy controls (HC) and disease controls with autosomal dominant polycystic kidney disease (ADPKD).

Methods: Patients with IgAN (n = 13), median estimated glomerular filtration rate (eGFR) of 57 ml/min/1.73m2 (IQR 42-84), patients with ADPKD (n = 13) matched for kidney function, gender and age and gender and age-matched HC (n = 13) were recruited. CD3+ and CD3- peripheral blood mononuclear cells were isolated and profiled based on their specific surface markers for different subsets of monocytes, B and T cells and analyzed by flow cytometry. Cytokines were analyzed by ELISA.

Results: We observed a significant decrease in the proportion of pre-switched B cells and plasmablasts, but an increase in long-lived plasma cells in the peripheral circulation of IgAN patients compared to HC. The proportion of non-classical monocytes was significantly higher in IgAN patients compared to both HC and ADPKD. We also report an association between sCD40L levels and the proportion of pre-switched B cells, as well as sCD40L and MCP-1 levels and albuminuria in IgAN patients.

Conclusions: We applied an easy-access method to analyze subsets of immune cells as well as relevant inflammatory mediators in IgAN patients. Our data demonstrate an altered B cell profile that indicates a pathophysiological role of the B cell lineage and an increased proportion of non-classical monocytes that suggests their role in the disease process.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248056PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978284PMC
March 2021

The combination of malnutrition-inflammation and functional status limitations is associated with mortality in hemodialysis patients.

Sci Rep 2021 01 15;11(1):1582. Epub 2021 Jan 15.

Arbor Research Collaborative for Health, Ann Arbor, MI, USA.

The identification of malnutrition-inflammation-complex (MIC) and functional status (FS) is key to improving patient experience on hemodialysis (HD). We investigate the association of MIC and FS combinations with mortality in HD patients. We analyzed data from 5630 HD patients from 9 countries in DOPPS phases 4-5 (2009-2015) with a median follow-up of 23 [IQR 11, 31] months. MIC was defined as serum albumin < 3.8 g/dL and serum C-reactive protein > 3 mg/L in Japan and > 10 mg/L elsewhere. FS score was defined as the sum of scores from the Katz Index of Independence in Activities of Daily Living and the Lawton-Brody Instrumental Activities of Daily Living Scale. We investigated the association between combinations of MIC (+/-) and FS (low [< 11]/high [≥ 11]) with death. Compared to the reference group (MIC-/high FS), the adjusted hazard ratios [HR (95% CI)] for all-cause mortality were 1.82 (1.49, 2.21) for MIC-/low FS, 1.57 (1.30, 1.89) for MIC+/high FS, and 3.44 (2.80, 4.23) for MIC+/low FS groups. Similar associations were observed with CVD-related and infection-related mortality. The combination of MIC and low FS is a strong predictor of mortality in HD patients. Identification of MIC and poor FS may direct interventions to lessen adverse clinical outcomes in the HD setting.
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http://dx.doi.org/10.1038/s41598-020-80716-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811014PMC
January 2021

Aerobic exercise capacity is maintained over a 5-year period in mild-to-moderate chronic kidney disease: a longitudinal study.

BMC Nephrol 2020 11 11;21(1):475. Epub 2020 Nov 11.

Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.

Background: Aerobic exercise capacity is reduced in non-dialysis chronic kidney disease (CKD), but the magnitude of changes in exercise capacity over time is less known. Our main hypothesis was that aerobic ExCap would decline over 5 years in individuals with mild-to-moderate CKD along with a decline in renal function. A secondary hypothesis was that such a decline in ExCap would be associated with a decline in muscle strength, cardiovascular function and physical activity.

Methods: We performed a 5-year-prospective study on individuals with mild-to-moderate CKD, who were closely monitored at a nephrology clinic. Fiftytwo individuals with CKD stage 2-3 and 54 age- and sex-matched healthy controls were included. Peak workload was assessed through a maximal cycle exercise test. Muscle strength and lean body mass, cardiac function, vascular stiffness, self-reported physical activity level, renal function and haemoglobin level were evaluated. Tests were repeated after 5 years. Statistical analysis of longitudinal data was performed using linear mixed models.

Results: Exercise capacity did not change significantly over time in either the CKD group or controls, although the absolute workloads were significantly lower in the CKD group. Only in a CKD subgroup reporting low physical activity at baseline, exercise capacity declined. Renal function decreased in both groups, with a larger decline in CKD (p = 0.05 between groups). Peak heart rate, haemoglobin level, handgrip strength, lean body mass and cardiovascular function did not decrease significantly over time in CKD individuals.

Conclusions: On a group level, aerobic exercise capacity and peak heart rate were maintained over 5 years in patients with well-controlled mild-to-moderate CKD, despite a slight reduction in glomerular filtration rate. In line with the maintained exercise capacity, cardiovascular and muscular function were also preserved. In individuals with mild-to-moderate CKD, physical activity level at baseline seems to have a predictive value for exercise capacity at follow-up.
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http://dx.doi.org/10.1186/s12882-020-02110-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7656689PMC
November 2020

Contemporary management of anaemia, erythropoietin resistance and cardiovascular risk in patients with advanced chronic kidney disease: a nationwide analysis.

Clin Kidney J 2020 Oct 1;13(5):821-827. Epub 2020 May 1.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: Optimal management of chronic kidney disease (CKD) anaemia remains controversial and few studies have evaluated real-world management of anaemia in advanced CKD in the context of guideline recommendations.

Methods: We performed an observational study from the Swedish Renal Registry evaluating the epidemiology and treatment patterns of anaemia across Stages 3b-5 in non-dialysis (ND) and dialysis-dependent (DD) CKD patients during 2015. Logistic regression and Cox models explored the associations between anaemia treatments, inflammation, erythropoietin resistance index (ERI) and subsequent 1-year risk of major adverse cardiovascular events (MACEs).

Results: Data from 14 415 (ND, 11 370; DD, 3045) patients were included. Anaemia occurred in 60% of ND and 93% of DD patients. DD patients used more erythropoiesis-stimulating agents (ESAs; 82% versus 24%) and iron (62% versus 21%) than ND patients. All weekly ESA doses were converted to a weight-adjusted weekly epoetin equivalent dose. The prescribed ESA doses were low to moderate [median 48.2 IU/kg/week (ND), 78.6 IU/kg/week (DD)]. Among ESA-treated patients, 6-21% had haemoglobin (Hb) >13 g/dL and 2-6% had Hb <9 g/dL. Inflammation (C-reactive protein >5 mg/L) was highly prevalent and associated with ERI and higher ESA doses. Higher (>88 IU/kg/week) versus lower (<44 IU/kg/week) ESA doses were associated with a higher risk of MACEs [{ND hazard ratio [HR] 1.36 [95% confidence interval (CI) 1.00-1.86]; DD HR 1.60 [95% CI 1.24-2.06]}. There was no association between iron use and inflammation or MACEs.

Conclusions: Anaemia remains highly prevalent in advanced CKD. Patients with anaemia received moderate ESA doses with a relatively low prevalence of iron use. Higher doses of ESA were associated with inflammation and a higher risk of MACE.
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http://dx.doi.org/10.1093/ckj/sfaa054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577763PMC
October 2020

The risk of medically uncontrolled secondary hyperparathyroidism depends on parathyroid hormone levels at haemodialysis initiation.

Nephrol Dial Transplant 2021 01;36(1):160-169

Arbor Research Collaborative for Health, Ann Arbor, MI, USA.

Background: Optimal parathyroid hormone (PTH) control during non-dialysis chronic kidney disease (ND-CKD) might decrease the subsequent risk of parathyroid hyperplasia and uncontrolled secondary hyperparathyroidism (SHPT) on dialysis. However, the evidence for recommending PTH targets and therapeutic strategies is weak for ND-CKD. We evaluated the patient characteristics, treatment patterns and PTH control over the first year of haemodialysis (HD) by PTH prior to HD initiation.

Methods: We studied 5683 incident HD patients from 21 countries in Dialysis Outcomes and Practice Patterns Study Phases 4-6 (2009-18). We stratified by PTH measured immediately prior to HD initiation and reported the monthly prescription prevalence of active vitamin D and calcimimetics over the first year of HD and risk of PTH >600 pg/mL after 9-12 months on HD.

Results: The 16% of patients with PTH >600 pg/mL prior to HD initiation were more likely to be prescribed active vitamin D and calcimimetics during the first year of HD. The prevalence of PTH >600 pg/mL 9-12 months after start of HD was greater for patients who initiated HD with PTH >600 (29%) versus 150-300 (7%) pg/mL (adjusted risk difference: 19%; 95% confidence interval : 15%, 23%). The patients with sustained PTH >600 pg/mL after 9-12 months on HD were younger, more likely to be black, and had higher serum phosphorus and estimated glomerular filtration rates at HD initiation.

Conclusions: Increased PTH before HD start predicted a higher PTH level 9-12 months later, despite greater use of active vitamin D and calcimimetics. More targeted PTH control during ND-CKD may influence outcomes during HD, raising the need for PTH target guidelines in these patients.
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http://dx.doi.org/10.1093/ndt/gfaa195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771977PMC
January 2021

Low hemoglobin at hemodialysis initiation: an international study of anemia management and mortality in the early dialysis period.

Clin Kidney J 2020 Jun 5;13(3):425-433. Epub 2019 Jul 5.

Arbor Research Collaborative for Health, Ann Arbor, MI, USA.

Background: Anemia at hemodialysis (HD) initiation is common. Correcting low hemoglobin (Hgb) before HD initiation may improve survival by avoiding potential harms of chronic anemia, high doses of erythropoiesis-stimulating agents (ESAs) and intravenous (IV) iron in the early HD period, and/or rapid Hgb rise.

Methods: We included 4604 incident HD patients from 21 countries in the Dialysis Outcomes and Practice Patterns Study Phases 4-5 (2009-15). Because low Hgb at HD start may reflect comorbidity or ESA hyporesponse, we restricted our analysis to the 80% of patients who achieved Hgb ≥10 g/dL 91-120 days after HD start (Month 4).

Results: About 53% of these patients had Hgb <10 g/dL in Month 1 (<30 days after HD start); they were younger with a similar comorbidity profile (versus Hgb ≥10 g/dL). Month 1 Hgb was associated with first-year HD mortality (adjusted hazard ratio for 1 g/dL higher Hgb was 0.89; 95% confidence interval: 0.81-0.97), despite minimal differences in Month 4 Hgb. Patients with lower Hgb in Month 1 received higher doses of ESA, but not IV iron, over the first 3 months of HD. Results were consistent when excluding catheter users or adjusting for IV iron and ESA dose over the first 3 months.

Conclusions: Even among patients with Hgb ≥10 g/dL 3 months later, anemia at HD initiation was common and associated with elevated mortality. A more proactive approach to anemia management in advanced chronic kidney disease (CKD) may thus improve survival on HD, though long-term prospective studies of non-dialysis CKD patients are needed.
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http://dx.doi.org/10.1093/ckj/sfz065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367115PMC
June 2020

Influence of gender and age on haemodialysis practices: a European multicentre analysis.

Clin Kidney J 2020 Apr 17;13(2):217-224. Epub 2019 Jun 17.

Division of Nephrology, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden.

Background: Women of all ages and elderly patients of both genders comprise an increasing proportion of the haemodialysis population. Worldwide, significant differences in practice patterns and treatment results exist between genders and among younger versus older patients. Although efforts to mitigate sex-based differences have been attempted, significant disparities still exist.

Methods: This retrospective cohort study included all 1247 prevalent haemodialysis patients in DaVita units in Portugal (five dialysis centres,  = 730) and Poland (seven centres,  = 517). Demographic data, dialysis practice patterns, vascular access prevalence and the achievement of a variety of Kidney Disease: Improving Global Outcomes (KDIGO) treatment targets were evaluated in relation to gender and age groups.

Results: Body weight and the prescribed dialysis blood flow rate were lower in women (P < 0.001), whereas treated blood volume per kilogram per session was higher (P < 0.01), resulting in higher single-pool in women than in men (P < 0.001). Haemoglobin was significantly higher in men (P = 0.01), but the proportion of patients within target range (10-12 g/dL) was similar. Men more often had an arteriovenous fistula than women (80% versus 73%; P < 0.01) with a similar percentage of central venous catheters. There were no gender-specific differences in terms of dialysis adequacy, anaemia parameters or mineral and bone disorder parameters, or in the attainment of KDIGO targets between women and men >80 years of age.

Conclusions: This large, multicentre real-world analysis indicates that haemodialysis practices and treatment targets are similar for women and men, including the most elderly, in DaVita haemodialysis clinics in Europe.
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http://dx.doi.org/10.1093/ckj/sfz069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7147302PMC
April 2020

Cardiovascular changes in patients with mild-to-moderate chronic kidney disease compared with healthy subjects: a 5-year follow-up study.

Clin Physiol Funct Imaging 2020 Mar 22;40(2):91-98. Epub 2019 Nov 22.

Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.

Background: There is limited knowledge about how cardiovascular parameters change over time in patients with mild-to-moderate chronic kidney disease (CKD). We studied several cardiovascular biomarkers over a 5-year period in patients with mild-to-moderate CKD and in healthy controls.

Methods: Fifty-four patients with CKD stages 2-3 and 54 controls were included. The CKD patients were closely monitored and well controlled for hypertension and other cardiovascular risk factors. Ambulatory blood pressure (BP) monitoring, ankle-brachial index (ABI), carotid and cardiac ultrasound (including measurement of the left ventricular mass index (LVMI)), and biochemical analyses were evaluated.

Results: Renal function decreased in both groups, with no significant difference in the change over time. In the CKD patients, none of the BP variables increased over time, but in the controls, average 24-h and daytime systolic BP increased significantly. ABI increased slightly in the CKD patients (P<0·001), but not in the controls (P = 0·963), and phosphate had a significant positive effect on ABI. Although in the CKD patients, there was no significant increase over time in common carotid artery diameter (P = 0·274), there was a small but significant increase in the controls (P = 0·001). LVMI increased significantly over time in both groups.

Conclusions: In our study of patients with mild-to-moderate CKD, the progression of cardiovascular changes over time was relatively slow. Good BP control and treatment of other risk factors may have contributed to slow the progress of cardiovascular involvement, which emphasizes the importance of dedicated care in this population.
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http://dx.doi.org/10.1111/cpf.12607DOI Listing
March 2020

Changes in microparticle profiles by vitamin D receptor activation in chronic kidney disease - a randomized trial.

BMC Nephrol 2019 08 1;20(1):290. Epub 2019 Aug 1.

Department of Cardiology, Danderyd University Hospital, 182 88, Stockholm, Sweden.

Background: Microparticles (MPs) are biomarkers and mediators of disease through their expression of surface receptors, reflecting activation or stress in their parent cells. Endothelial markers, ICAM-1 and VCAM-1, are implicated in atherosclerosis and associated with cardiovascular risk. Chronic kidney disease (CKD) patients have endothelial dysfunction and high levels of endothelial derived MPs. Vitamin D treatment has been reported to ameliorate endothelial function in CKD patients. We aimed to examine cell specific MP profiles and concentrations of MPs expressing the atherosclerotic markers ICAM-1 and VCAM-1 after treatment with paricalcitol in patients with CKD stage 3-4.

Methods: Sub-study of the previously reported SOLID trial where 36 patients were randomly assigned to placebo, 1 or 2 μg paricalcitol, for 12 weeks. MPs were measured by flow cytometry after labelling with antibodies against endothelial (CD62E), platelet (CD62P, CD41, CD154) leukocyte (CD45) and vascular (CD54, CD106) markers.

Results: Patients had a mean age of 65 years with a mean eGFR of 40 mL/min/1.73m. Concentrations of ICAM-1 positive MPs were significantly reduced by treatment (repeated measures ANOVA p = 0.04). Repeated measures MANOVA of concentrations of endothelial, platelet and leukocyte MPs showed sustained levels in the 2 μg treatment group (p = 0.85) but a decline in the 1 μg (p = 0.04) and placebo groups (p = 0.005).

Conclusions: Treatment with paricalcitol reduces concentrations of ICAM-1 positive MPs. This is accompanied by sustained concentrations of all cell specific MPs in the 2 μg group, and decreasing concentrations in the other groups, possibly due to a more healthy and reactive endothelium with paricalcitol treatment.
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http://dx.doi.org/10.1186/s12882-019-1445-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670162PMC
August 2019

International and Racial Differences in Mineral and Bone Disorder Markers and Treatments Over the First 5 Years of Hemodialysis in the Dialysis Outcomes and Practice Patterns Study.

Kidney Med 2019 May-Jun;1(3):86-96. Epub 2019 May 10.

Arbor Research Collaborative for Health, University of Michigan Medical School, Ann Arbor, MI.

Rationale & Objective: Normalization of parathyroid hormone (PTH), serum calcium, and phosphorus levels may prevent coronary and bone disease in hemodialysis (HD) patients. We describe the trajectory of these mineral bone disorder parameters and treatments during the first 5 years of HD by international region and race.

Study Design: Prospective cohort study.

Setting & Participants: 33,517 US black/African American, US non-black/African American, European, and Japanese HD patients from the Dialysis Outcomes and Practice Patterns Study (DOPPS) phases 4 to 5 (2009-2015).

Predictor: Time since HD initiation.

Outcomes: Monthly cross-sections of mineral bone disorder parameters (PTH, serum calcium, and phosphorus) and medications (cinacalcet, active vitamin D, and phosphate binders).

Results: Mean PTH levels declined precipitously during the first 4 months of HD in all 4 groups, then steadily increased during the next 4.5 years in the United States/Europe but not in Japan. 3 years after HD initiation (month 36), mean PTH level was highest in US black/African Americans (496 pg/mL), despite greater prescription of cinacalcet (23%) and active vitamin D (85%), and lowest in Japan (151 pg/mL). Mean serum calcium and phosphorus levels increased during the first 4 months of HD. By month 36, the mean calcium level was lower in Japan (8.8 mg/dL) than United States/Europe (9.0-9.1 mg/dL), while the mean phosphorus level was lower in Europe (4.8 mg/dL) than United States/Japan (5.1-5.3 mg/dL).

Limitations: Lack of data for medication dosages; most patients were not followed from HD onset.

Conclusions: Large differences exist in the levels, trajectories, and therapies for PTH, calcium, and phosphorus by country and race in the first 5 years of HD. Higher PTH levels were observed in the United States, especially among black/African American patients, despite greater use of cinacalcet and active vitamin D than in Japan or Europe. Potential contributors to differences in PTH levels should be explored to study their impact on PTH management strategies and consequent bone and cardiovascular complications.
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http://dx.doi.org/10.1016/j.xkme.2019.04.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380354PMC
May 2019

Health-related quality of life as predictor of mortality in end-stage renal disease patients: an observational study.

BMC Nephrol 2019 04 29;20(1):144. Epub 2019 Apr 29.

Renal Medicine and Baxter Novum, Clintec, M99, Karolinska University Hospital Huddinge, 141 86, Stockholm, Sweden.

Background: Health-related quality of life (HRQoL) is an important component of patient-centered outcomes and a useful parameter for monitoring quality of care. We assessed HRQoL, its determinants, and associations with mortality in patients with end-stage renal disease (ESRD).

Methods: Short Form-36 was used to assess HRQoL, its domain components, and physical (PCS) and mental (MCS) composite summary scores in altogether 400 (338 incident and 62 prevalent) dialysis patients with median age 64 years, 37% women, 24% diabetes mellitus (DM), 49% cardiovascular disease (CVD), and median estimated glomerular filtration rate (eGFR) of 5.3 (3.0-9.4) ml/min/1.73. Results were analyzed separately for 338 incident patients starting on hemodialysis (HD; 68%) or peritoneal dialysis (PD; 32%), and 62 prevalent PD patients. Mortality risk was analyzed during up to 60 months (median 28 months).

Results: Linear multivariate regression analysis showed that in incident dialysis patients, 1-SD higher PCS associated negatively with 1-SD higher age, DM and CVD, and positively with 1-SD higher hemoglobin and sodium (adjusted r = 0.17). In 62 prevalent PD patients, 1-SD higher PCS was negatively associated with 1-SD higher age. MCS was not associated to any of the investigated factors. Multivariate Cox regression analysis showed that in incident dialysis patients, 1-SD increase of PCS associated with lower all-cause mortality, hazard ratio 0.65 (95% confidence interval 0.52-0.81), after adjustments for age, sex, DM, CVD, plasma albumin, C-reactive protein and eGFR whereas 1-SD lower MCS did not associate with mortality. In PD patients, neither PCS nor MCS associated with mortality.

Conclusions: MCS did not associate with any of the investigated clinical factors, whereas lower PCS associated with higher age, CVD, DM, and lower hemoglobin and sodium levels. MCS was not associated with mortality, whereas lower PCS associated with increased mortality risk. These results suggest that HRQoL - in addition to its role as patient-centered outcome - matters also for hard clinical outcomes in ESRD patients. Our knowledge about factors influencing MCS in ESRD patients is limited and should motivate further studies.
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http://dx.doi.org/10.1186/s12882-019-1318-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489294PMC
April 2019

Increased concentrations of platelet- and endothelial-derived microparticles in patients with myocardial infarction and reduced renal function- a descriptive study.

BMC Nephrol 2019 03 1;20(1):71. Epub 2019 Mar 1.

Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden.

Background: Patients with chronic kidney disease (CKD) have a high risk of recurring thrombotic events following acute myocardial infarction (AMI). Microparticles (MPs) are circulating small vesicles shed from various cells. Platelet microparticles (PMPs) reflect platelet activation and endothelial microparticles (EMPs) reflect endothelial activation or dysfunction. Both increase following AMI, and may mediate important biological effects. We hypothesized that AMI patients with CKD have further elevated PMPs and EMPs compared with non-CKD patients, despite concurrent antithrombotic treatment.

Methods: We performed a descriptive study of patients with AMI. Fasting blood samples were acquired from 47 patients on dual antiplatelet treatment. Patients were stratified by renal function: normal (H; n = 19) mean eGFR 88; moderate CKD (CKD3; n = 15) mean eGFR 47, and severe CKD (CKD4-5; n = 13) mean eGFR 20 mL/min/1.73 m. MPs were measured by flow-cytometry and phenotyped according to size (< 1.0 μm) and expression of CD41 (GPIIb; PMPs) and CD62E (E-selectin; EMPs). In addition, expression of platelet activation markers P-selectin (CD62P) and CD40ligand (CD154) were also investigated.

Results: PMPs expressing CD40 ligand were higher in CKD4-5: 210 /μl (174-237); median and interquartile range; vs. group H; 101 /μl (71-134; p < 0.0001) and CKD 3: 142 /μl (125-187; p = 0.006). PMPs expressing P-selectin were higher in CKD4-5 compared with H, but not in CKD3. EMPs were higher in CKD4-5; 245 /μl (189-308) compared with H; 83 /μl (53-140; p < 0.0001) and CKD3; 197 /μl (120-245; p < 0.002).

Conclusions: In AMI patients, PMPs and EMPs from activated platelets and endothelial cell are further elevated in CKD patients. This indicate impaired endothelial function and higher platelet activation in CKD patients, despite concurrent antiplatelet treatment.
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http://dx.doi.org/10.1186/s12882-019-1261-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397450PMC
March 2019

Achievement of renal anemia KDIGO targets by two different clinical strategies - a European hemodialysis multicenter analysis.

BMC Nephrol 2019 01 7;20(1). Epub 2019 Jan 7.

Division of Nephrology, Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden.

Background: The optimal treatment algorithm for iron therapy and the use of erythropoiesis-stimulating agents (ESA) in anemic hemodialysis (HD) patients has not been established. Hemoglobin (Hb) target levels can be achieved through more frequent intravenous (IV) iron use with lower ESA dose, or with less iron dosing but higher ESA. ESA therapy to correct anemia may result in severe arterial and venous thrombotic complications and the evidence base evaluating hard clinical outcomes related to the use of IV iron is sparse.

Methods: A total of 1247 maintenance HD patients from 12 dialysis centers in Portugal (n = 730) and Poland (n = 517) were considered. We assessed achievement of KDIGO renal anemia targets with focus on treatment strategies, which typically differ between countries. In Poland the use and dose of IV iron was 35-72% higher than that in Portugal (p <  0.001) during three consecutive months; use and dose of ESA was 61% higher in Portugal (5034 vs 3133 IU (adjusted)/week, p <  0.001).

Results: Mean Hb concentration was similar (11.0 vs 11.0 g/dL) in patients treated in both countries and the proportion of patients within KDIGO anemia target was 69.5% in Poland vs 65.8% in Portugal (NS). Ferritin and TSAT levels and the proportion of patients with TSAT > 20 and > 50% were both significantly higher in patients in Poland (88.8 and 14.6%) than in Portugal (76.3 and 5.7% respectively, p <  0.001). Significantly more patients in Poland had a ferritin concentration > 800 μg/L (35.6%) compared to Portugal (15.8%, p <  0.001). The ESA resistance index (ERI) was significantly higher in patients treated in Portugal (p <  0.001). Correlation analyses showed confounding by treatment indication in unadjusted models. Multiple and logistic regression analyses showed that with ferritin within KDIGO recommended range of 200-800 μg/L the odds for Hb within guidelines increased significantly. Annual gross mortality was 16% in Poland and 13% in Portugal (NS); there were no differences in cause-specific mortality.

Conclusions: Administration of high doses of IV iron in routine clinical HD practice may not be associated with considerable harm. However, large randomized controlled trials are needed to provide absolute evidence of iron safety.
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http://dx.doi.org/10.1186/s12882-018-1196-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323791PMC
January 2019

Gradual reduction in exercise capacity in chronic kidney disease is associated with systemic oxygen delivery factors.

PLoS One 2018 19;13(12):e0209325. Epub 2018 Dec 19.

Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.

Background: The cause of reduced exercise capacity (ExCap) in chronic kidney disease (CKD) is multifactorial. The aim of this study was to investigate determinants of aerobic ExCap in patients with mild to severe CKD not undergoing dialysis.

Methods: We included 52 individuals with CKD stage 2-3, 47 with stage 4-5, and 54 healthy controls. Peak workload and peak heart rate (HR) were assessed by a maximal cycle exercise test. Cardiac function including stroke volume (SV) and vascular stiffness were evaluated by ultrasound at rest. Handgrip strength, body composition, haemoglobin level and self-reported physical activity were assessed.

Results: Peak workload (221±60, 185±59, 150±54 W for controls, CKD 2-3 and CKD 4-5 respectively), peak HR (177±11, 161±24, 144±31 beats/min) and haemoglobin level (14.2±1.2, 13.5±1.4, 12.2±1.3 g/dL) were all three significantly lower in CKD 2-3 than in controls, (p = 0.001, 0.001 and 0.03 respectively) and were even lower in stages 4-5 CKD than in CKD 2-3 (p = 0.01, 0.001 and <0.001 respectively). Resting SV and lean body mass did not differ between groups and handgrip strength was significantly lower only in CKD 4-5 compared to controls (p = 0.02). Peak workload was strongly associated with the systemic oxygen delivery factors: SV, peak HR and haemoglobin level. These three factors along with age, sex and height2 explained 82% of variation in peak workload. Peak HR contributed most to the variation; the peripheral variables handgrip strength and vascular stiffness did not improve the explanatory value in regression analysis.

Conclusions: In this cross-sectional study of CKD patients not on dialysis, aerobic ExCap decreased gradually with disease severity. ExCap was associated mainly with systemic oxygen delivery factors, in particular peak HR. Neither muscle function and mass, nor vascular stiffness were independent determinants of aerobic ExCap in this group of CKD patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209325PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300328PMC
May 2019

Treating endothelial dysfunction with vitamin D in chronic kidney disease: a meta-analysis.

BMC Nephrol 2018 09 25;19(1):247. Epub 2018 Sep 25.

Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden.

Background: Vitamin D deficiency is common in patients with chronic kidney disease (CKD), and is associated with endothelial dysfunction and cardiovascular disease. We performed a meta-analysis to assess the effect of vitamin D treatment on flow mediated vasodilation (FMD) in CKD patients.

Methods: PubMed/Medline, Web of Science, Embase and Cochrane trials and reviews were searched systematically for randomized controlled trials (RCT:s) using any vitamin D compound, at any stage of CKD, with FMD as outcome. Fixed and random effects models were performed using the standardized mean difference effect size post treatment for each trial. Heterogeneity was assessed by I statistics.

Results: 4 trials were included, comprising 305 patients. One used both 1 and 2 μg for two intervention groups and was therefore split in two during the analysis. Patients in the included trials had a mean age of 44-65 years and were all in CKD 3 to 4. One study used cholecalciferol, the others all used paricalcitol as treatment. Study duration was 12-16 weeks. Intervention with vitamin D was associated with ameliorated FMD (STANDmean ES 0.78, 95% CI 0.55-1.01) in a fixed model. Heterogeneity was substantial (I = 84%). Secondary analysis with random model analysis also showed significant results.

Conclusions: Short term intervention with vitamin D is associated with improvements in endothelial function, as measured by FMD. This indicates positive effects of vitamin D on vascular disease in CKD. Limitations of this meta-analysis are the small number of studies performed, and the short duration of intervention.
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http://dx.doi.org/10.1186/s12882-018-1042-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156877PMC
September 2018

Missed Hemodialysis Treatments: International Variation, Predictors, and Outcomes in the Dialysis Outcomes and Practice Patterns Study (DOPPS).

Am J Kidney Dis 2018 11 23;72(5):634-643. Epub 2018 Aug 23.

Arbor Research Collaborative for Health, Ann Arbor, MI. Electronic address:

Rationale & Objective: Missed hemodialysis (HD) treatments not due to hospitalization have been associated with poor clinical outcomes and related in part to treatment nonadherence. Using data from the Dialysis Outcomes and Practice Patterns Study (DOPPS) phase 5 (2012-2015), we report findings from an international investigation of missed treatments among patients prescribed thrice-weekly HD.

Study Design: Prospective observational study.

Setting & Participants: 8,501 patients participating in DOPPS, on HD therapy for more than 120 days, from 20 countries. Longitudinal and cross-sectional analyses were performed based on the 4,493 patients from countries in which 4-month missed treatment risk was > 5%.

Predictors: The main predictor of patient outcomes was 1 or more missed treatments in the 4 months before DOPPS phase 5 enrollment; predictors of missed treatments included country, patient characteristics, and clinical factors.

Outcomes: Mortality, hospitalization, laboratory measures, patient-reported outcomes, and 4-month missed treatment risk.

Analytical Approach: Outcomes were assessed using Cox proportional hazards, logistic, and linear regression, adjusting for case-mix and country.

Results: The 4-month missed treatment risk varied more than 50-fold across all 20 DOPPS countries, ranging from < 1% in Italy and Japan to 24% in the United States. Missed treatments were more likely with younger age, less time on dialysis therapy, shorter HD treatment time, lower Kt/V, longer travel time to HD centers, and more symptoms of depression. Missed treatments were positively associated with all-cause mortality (HR, 1.68; 95% CI, 1.37-2.05), cardiovascular mortality, sudden death/cardiac arrest, hospitalization, serum phosphorus level > 5.5mg/dL, parathyroid hormone level > 300pg/mL, hemoglobin level < 10g/dL, higher kidney disease burden, and worse general and mental health.

Limitations: Possible residual confounding; temporal ambiguity in the cross-sectional analyses.

Conclusions: In the countries with a 4-month missed treatment risk > 5%, HD patients were more likely to die, be hospitalized, and have poorer patient-reported outcomes and laboratory measures when 1 or more missed treatments occurred in a 4-month period. The large variation in missed treatments across 20 nations suggests that their occurrence is potentially modifiable, especially in the United States and other countries in which missed treatment risk is high.
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http://dx.doi.org/10.1053/j.ajkd.2018.04.019DOI Listing
November 2018

Association between serum ferritin and mortality: findings from the USA, Japan and European Dialysis Outcomes and Practice Patterns Study.

Nephrol Dial Transplant 2018 12;33(12):2234-2244

Arbor Research Collaborative for Health, Ann Arbor, MI, USA.

Background: The Kidney Disease: Improving Global Outcomes guidelines have cautioned against administering intravenous (IV) iron to hemodialysis patients with high serum ferritin levels due to safety concerns, but prior research has shown that the association between high ferritin and mortality could be attributed to confounding by malnutrition and inflammation. Our goal was to better understand the ferritin-mortality association and relative influence of IV iron and inflammation in the USA, where ferritin levels have recently increased dramatically, and in Europe and Japan, where ferritin levels are lower and anemia management practices differ.

Methods: Data from 18 261 patients in Phases 4 and 5 (2009-15) of the international Dialysis Outcomes and Practice Patterns Study, a prospective cohort study, were analyzed. Using Cox regression, we modeled the association between baseline ferritin and 1-year mortality with restricted cubic splines and assessed the impact of potential confounders.

Results: Median ferritin levels were 718 ng/mL in the USA, 405 in Europe and 83 in Japan. High ferritin levels were associated with elevated mortality (relative to region-specific medians) in all three regions. The strength of this association was attenuated more by adjustment for malnutrition and inflammation than by IV iron and erythropoiesis-stimulating agent dose in each region.

Conclusion: The utility of high ferritin as a biomarker for clinical risk due to excess iron stores may be limited, although caution regarding IV iron dosing to higher upper ferritin targets remains warranted. Research to resolve biomarker criteria for iron dosing, and whether optimal anemia management strategies differ internationally, is still needed.
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http://dx.doi.org/10.1093/ndt/gfy190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6275147PMC
December 2018

Associations of Fibroblast Growth Factor 23 with Markers of Inflammation and Leukocyte Transmigration in Chronic Kidney Disease.

Nephron 2018 4;138(4):287-295. Epub 2018 Jan 4.

Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

Background: Patients with chronic kidney disease (CKD) show elevated levels of inflammatory markers and have an increased risk of infections as well as cardiovascular morbidity. Recent studies have implied effects of fibroblast growth factor 23 (FGF23) on inflammation in CKD. We analyzed potential correlations between levels of FGF23 with pro-inflammatory chemokines and markers of leukocyte transmigration in CKD patients.

Methods: One hundred three patients with CKD 2-5ND and 54 healthy controls, had biochemical markers in blood and urine analyzed according to routine protocol. Pro-inflammatory cytokines were analyzed by Milliplex technique and leukocyte CD11b adhesion molecule expression was measured by flow cytometry. FGF23 levels were measured with ELISA technique. Treatment of leukocytes from healthy blood donors with FGF23 was performed in vitro and effects analyzed by flow cytometry.

Results: Tumor necrosis factor-alpha, RANTES and interleukin (IL)-12 levels were significantly higher (p = 0.001, p < 0.001, and p < 0.001) in patients with CKD. Elevated FGF23 levels in the CKD group correlated to glomerular filtration rate, parathyroid hormone, urinary albumin excretion and phosphate as well as to IL-12 and RANTES. CD11b expression on resting granulocytes and monocytes, and on activated monocytes, was associated with FGF23. In vitro treatment of leukocytes with FGF23 reduced CD11b expression in resting as well as in formyl-methyinoyl-leucyl-phenylalanine-stimulated granulocytes (p = 0.03).

Conclusion: FGF23 levels are associated with various inflammatory markers such as pro-inflammatory cytokines and adhesion molecules on innate immune cells. However, further studies are warranted to define the direct role of FGF23 in modulation of the innate immune system in CKD.
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http://dx.doi.org/10.1159/000485472DOI Listing
September 2019

Mortality risk in patients on hemodiafiltration versus hemodialysis: a 'real-world' comparison from the DOPPS.

Nephrol Dial Transplant 2018 04;33(4):683-689

Arbor Research Collaborative for Health, Ann Arbor, MI, USA.

Background: With its convective component, hemodiafiltration (HDF) provides better middle molecule clearance compared with hemodialysis (HD) and is postulated to improve survival. A previous analysis of Dialysis Outcomes and Practice Patterns Study (DOPPS) data in 1998-2001 found lower mortality rates for high replacement fluid volume HDF versus HD. Randomized controlled trials have not shown uniform survival advantage for HDF; in secondary (non-randomized) analyses, better outcomes were observed in patients receiving the highest convection volumes.

Methods: In a 'real-world' setting, we analyzed patients on dialysis >90 days from seven European countries in DOPPS Phases 4 and 5 (2009-15). Adjusted Cox regression was used to study HDF (versus HD) and mortality, overall and by replacement fluid volume.

Results: Among 8567 eligible patients, 2012 (23%) were on HDF, ranging from 42% in Sweden to 12% in Germany. Median follow-up was 1.5 years during which 1988 patients died. The adjusted mortality hazard ratio (95% confidence interval) was 1.14 (1.00-1.29) for any HDF versus HD and 1.08 (0.92-1.28) for HDF >20 L replacement fluid volume versus HD. Similar results were found for cardiovascular and infection-related mortality. In an additional analysis aiming to avoid treatment-by-indication bias, we did not observe lower mortality rates in facilities using more HDF (versus HD).

Conclusions: Our results do not support the notion that HDF provides superior patient survival. Further trials designed to test the effect of high-volume HDF (versus lower volume HDF versus HD) on clinical outcomes are needed to adequately inform clinical practices.
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http://dx.doi.org/10.1093/ndt/gfx277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5888924PMC
April 2018

Altered basophil function in patients with chronic kidney disease on hemodialysis
.

Clin Nephrol 2017 Aug;88(8):86-96

Aims: Chronic kidney disease (CKD) leads to impairment of immune cell function. Given the potential role of basophils in the pathogenesis of CKD, we aimed to study the basophil responsiveness towards microbial antigen exposure, judged as adhesion molecule expression and degranulation, in CKD patients on hemodialysis.

Materials And Methods: We selected markers linked to two crucial biological phases: the transmigration and degranulation processes, respectively. For the transmigration process, we selected the adhesion molecules CD11b, active CD11b epitope, and CD62L and for the degranulation process CD203c (piecemeal degranulation marker), CD63 (degranulation marker), and CD300a (inhibitory marker of degranulation). We measured basophil responsiveness after stimulation of different activation pathways in basophils using lipopolysaccharide (LPS), peptidoglycan (PGN), formyl-methyinoyl-leucyl-phenylalanine (fMLP), and anti-FcεRI-ab.

Results: The expression of CD63 in basophils following activation by fMLP was significantly higher in the patient group compared to matched healthy controls, but no differences were observed after activation by anti-FcɛI. CD300a expression was significantly higher in patients following activation by fMLP and anti-FcɛI, and the active epitope CD11b expression was significantly higher in patients after LPS activation. In addition, we found that CD62L was not shed from the cell surface after activation with LPS and fMLP. A slight downregulation was noted after activation with anti-FcɛI in healthy controls.

Conclusion: Together, these data demonstrate that basophil functions related to adhesion and degranulation are altered in CKD patients on hemodialysis, which indicates a potential role for the basophil in the pathogenesis of complications related to infections.
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http://dx.doi.org/10.5414/CN108992DOI Listing
August 2017

Vitamin D receptor activation reduces inflammatory cytokines and plasma MicroRNAs in moderate chronic kidney disease - a randomized trial.

BMC Nephrol 2017 May 16;18(1):161. Epub 2017 May 16.

Department of Clinical Sciences, Karolinska Institutet, Danderyd University Hospital, Stockholm, Sweden.

Background: Chronic kidney disease (CKD) is a major risk factor for cardiovascular disease (CVD), partly due to endothelial dysfunction and chronic inflammation. Vitamin D treatment in end stage renal disease is suggested to modulate the immune system and lead to improved outcomes. We and others have demonstrated that treatment with vitamin D or activated vitamin D analogues protects the endothelial function in less severe renal disease as well. Since the endothelial protection might be mediated by vitamin D effects on inflammation, we assessed levels of pro-inflammatory cytokines and micro RNAs (miRs) in patients with moderate CKD, treated with an active vitamin D analogue (paricalcitol).

Methods: Thirty-six patients with moderate CKD were randomized to 12 weeks treatment with placebo, 1 μg, or 2 μg paricalcitol daily. Cytokines were measured by Milliplex 26-plex. Total RNA was isolated from plasma and miRs were determined by quantitative reverse transcription PCR analysis.

Results: Selected pro-inflammatory cytokines decreased significantly following treatment, while no change was observed in the placebo group. The micro RNAs; miR 432-5p, miR 495-3p, and miR 576-5p were significantly downregulated in the active treated groups, compared to the placebo group.

Conclusion: Paricalcitol treatment for 12 weeks in patients with moderate CKD reduces cytokines and micro RNAs involved in atherosclerosis and inflammation. The potentially protective role of vitamin D receptor activation in the inflammatory processes regarding the long-term outcomes in CKD patients warrants further studies.

Trial Registration: SOLID study; NCT01204528 , April 27, 2010.
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http://dx.doi.org/10.1186/s12882-017-0576-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5434555PMC
May 2017

Aspects of carotid structure and function in health and different stages of chronic kidney disease.

Clin Physiol Funct Imaging 2018 May 16;38(3):402-408. Epub 2017 Apr 16.

Department of Clinical Physiology, Karolinska University Hospital, Stockholm, Sweden.

Introduction: Arterial remodelling and stiffening have been demonstrated in end-stage renal disease (ESRD). The presence of vascular alterations in earlier-stage chronic kidney disease (CKD) is less studied. We evaluated vascular structure and function in mild-to-moderate CKD (stages 2-3) compared with healthy subjects and advanced CKD (stages 4-5).

Methods: Carotid ultrasound was performed in 103 non-dialysis CKD patients and 54 healthy controls. Carotid intima-media thickness (CIMT) and common carotid artery (CCA) diameter were measured. Strain, stiffness and the pressure-strain elastic modulus (E ) of the right CCA were calculated.

Results: There was no significant difference in CCA diameter between CKD 2-3 and controls. The CCA diameter was larger in CKD 4-5 compared with CKD 2-3 and controls (CKD 4-5, 6·50 ± 0·79 mm versus CKD 2-3, 6·08 ± 0·56 mm, P = 0·003; and versus controls 5·97 ± 0·53 mm, P<0·001). However, after adjustments, the difference in CCA diameter was valid only for older ages and also dependent on systolic blood pressure (SBP). There were no significant differences in CIMT, strain or stiffness between the groups, but E was higher in CKD 4-5 compared with controls (P = 0·006).

Conclusion: In mild-to-moderate CKD, there were no significant differences in carotid artery structure or function compared with healthy subjects. Only patients with advanced CKD and older ages showed signs of arterial remodelling. Our study indicates that vascular alterations occur in advanced CKD, with SBP and age as important contributing factors.
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http://dx.doi.org/10.1111/cpf.12429DOI Listing
May 2018

Hemodialysis Patients Display a Declined Proportion of Th2 and Regulatory T Cells in Parallel with a High Interferon-γ Profile.

Nephron 2017 6;136(3):254-260. Epub 2017 Apr 6.

Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.

Background: A high prevalence of cardiovascular diseases (CVDs) and infections in patients with chronic kidney disease (CKD) arises partly due to a high inflammatory state and aberrations in immune cells function. Following in vitro stimulation of leukocytes with different T-cell mitogens, we observed a lower level of interleukin (IL)-2 and IL-10 production in CKD patients. To gain more knowledge as to whether this is the result of an alteration in T-cell function, we investigated the T-cell subsets profile and cytokine production in hemodialysis patients.

Methods: CD4+ cells were isolated from whole blood of 10 hemodialysis patients and 10 age- and gender-matched healthy controls. Following in vitro stimulation with an antigen-independent T-cell mitogen, Th1, Th2, and regulatory T (Treg) cell subsets were analyzed by flow cytometry through the expression of specific transcription factors. The levels of cytokines, interferon (IFN)-γ, IL-4, and IL-10 were analyzed by enzyme-linked immunosorbent assay in the supernatants.

Results: The proportion of CD4+CD25+FOXP3+ (Treg) and CD4+GATA3+ (Th2) cells was significantly lower in patients compared to healthy controls, while the proportion of CD4+T-bet+ (Th1) cells was similar. Moreover, levels of IL-4 were significantly lower in supernatants from patients, while IFN-γ levels were higher. IL-10 levels did not differ compared to those of the healthy controls.

Conclusions: Our findings indicate a diminished anti-inflammatory Treg, and Th2 cell profile in hemodialysis patients, accompanied by a high pro-inflammatory IFN-γ profile. Since this profile is characterized in CVDs, we propose that an imbalance between the inflammatory and anti-inflammatory responses may contribute to the pathogenesis of CVD in advanced CKD.
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http://dx.doi.org/10.1159/000471814DOI Listing
May 2018

Systematic underutilisation of secondary preventive drugs in patients with acute coronary syndrome and reduced renal function.

Eur J Prev Cardiol 2017 05 14;24(7):724-734. Epub 2017 Feb 14.

1 Division of Cardiovascular Medicine, Department of Clinical Sciences, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden.

Aims The high risk of recurrent events in patients with reduced renal function following an acute coronary syndrome (ACS) may in part be due to suboptimal secondary prevention. We aimed to describe the association between renal dysfunction and the prescription, initiation and persistent use of secondary prevention during the first year after a first ACS. Methods We identified all patients admitted to any Swedish coronary care unit for a first ACS between 2005 and 2010 ( n = 77,432). In 75,129 patients, creatinine levels were available in order to obtain the estimated glomerular filtration rate (eGFR). Persistent use of prescribed drugs was determined for 1 year using the National Prescription Registry, with complete coverage of all prescribed and dispensed drugs in Sweden. Results After adjustment for relative and absolute contraindications, compared to patients with eGFR ≥ 60 mL/min/1.73 m, patients with eGFR 30-59 had higher odds of not being prescribed acetylsalicylic acid (ASA; odds ratio [OR]: 1.56, 95% confidence interval [CI]: 1.47-1.67), statins (OR: 2.94, 95% CI: 2.86-3.13) or β-blockade (OR: 1.25, 95% CI: 1.18-1.32). Patients with eGFR 30-59 were more likely to discontinue treatment with ASA (hazard ratio [HR]: 1.59, 95% CI: 1.42-1.56), statins (HR: 1.35, 95% CI: 1.29-1.41), angiotensin-converting enzyme inhibitors and angiotensin-II receptor blockers (HR: 1.37, 95% CI: 1.31-1.43) or β-blockade (HR: 1.22, 95% CI: 1.18-1.27). Patients with eGFR < 30 showed a similar pattern in both prescription and discontinuation. Conclusion High-risk ACS patients with reduced renal function are less likely to be prescribed secondary prevention drugs at discharge, are less likely to initiate treatment when being prescribed these drugs, are less likely to be persistent in the use of these drugs and more often discontinue treatment.
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http://dx.doi.org/10.1177/2047487317693950DOI Listing
May 2017

Healthcare costs in chronic kidney disease and renal replacement therapy: a population-based cohort study in Sweden.

BMJ Open 2016 10 7;6(10):e012062. Epub 2016 Oct 7.

Unit of Renal Medicine, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

Objective: To compare healthcare costs in chronic kidney disease (CKD) stage 4 or 5 not on dialysis (estimated glomerular filtration rate <30 mL/min/1.73m), peritoneal dialysis, haemodialysis and in transplanted patients with matched general population comparators.

Design: Population-based cohort study.

Setting: Swedish national healthcare system.

Participants: Prevalent adult patients with CKD 4 or 5 (n=1046, mean age 68 years), on peritoneal dialysis (n=101; 64 years), on haemodialysis (n=460; 65 years) and with renal transplants (n=825; 52 years) were identified in Stockholm County clinical quality registers for renal disease on 1 January 2010. 5 general population comparators from the same county were matched to each patient by age, sex and index year.

Primary And Secondary Outcome Measures: Annual healthcare costs in 2009 incurred through inpatient and hospital-based outpatient care and dispensed prescription drugs ascertained from nationwide healthcare registers. Secondary outcomes were annual number of hospital days and outpatient care visits.

Results: Patients on haemodialysis had the highest mean annual cost (€87 600), which was 1.49 (95% CI 1.38 to 1.60) times that observed in peritoneal dialysis (€58 600). The mean annual cost was considerably lower in transplanted patients (€15 500) and in the CKD group (€9600). In patients on haemodialysis, outpatient care costs made up more than two-thirds (€62 500) of the total, while costs related to fluids ($29 900) was the largest cost component in patients on peritoneal dialysis (51%). Compared with their matched general population comparators, the mean annual cost (95% CI) in patients on haemodialysis, peritoneal dialysis, transplanted patients and patients with CKD was 45 (39 to 51), 29 (22 to 37), 11 (10 to 13) and 4.0 (3.6 to 4.5) times higher, respectively.

Conclusions: The mean annual costs were ∼50% higher in patients on haemodialysis than in those on peritoneal dialysis. Compared with the general population, costs were substantially elevated in all groups, from 4-fold in patients with CKD to 11, 29 and 45 times higher in transplanted patients and patients on peritoneal dialysis and haemodialysis, respectively.
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http://dx.doi.org/10.1136/bmjopen-2016-012062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073563PMC
October 2016

Early Changes in Monocyte Adhesion Molecule Expression and Tumor Necrosis Factor-α Levels in Chronic Kidney Disease - A 5-Year Prospective Study.

Am J Nephrol 2016 8;44(4):268-275. Epub 2016 Sep 8.

Department of Nephrology, Karolinska Institutet, and Karolinska University Hospital, Stockholm, Sweden.

Background: Despite the absence of clinical symptoms, patients with chronic kidney disease (CKD) exhibit elevated levels of pro-inflammatory markers. To investigate whether it is possible to detect inflammatory activity and altered monocyte function at an early stage of renal disease, we studied patients with CKD stages 2-3 over 5 years.

Methods: The expression of adhesion molecules on monocytes at resting state and after stimulation with formyl-methionyl-leucyl-phenylalanine (fMLP), as well as oxidative metabolism capacity was measured with flow cytometry in 108 CKD patients and healthy controls. Soluble markers of inflammation, such as cytokines, were analyzed using the Milliplex technique.

Results: Patients showed significantly lower CD11b expression after stimulation during the 3rd (p = 0.002) and the 5th year (p < 0.001), together with a lower oxidative burst in response to fMLP over time (p = 0.02). The expression of CD62L on resting monocytes was lower during the 3rd (p = 0.001) and the 5th (p = 0.001) year in patients. Levels of tumor necrosis factor-α and RANTES were significantly increased (p = 0.001, p = 0.006) and interleukin-12 levels were also higher in CKD patients during the 5th year (p = 0.007).

Conclusion: Monocytes in CKD stages 2-3 show emerging functional abrasions, with altered adhesion molecule expression and impaired fMLP response. These findings suggest that a transformation of monocyte function occurs at an early phase of renal impairment and may together with increased plasma levels of pro-inflammatory cytokines contribute to the higher vulnerability of CKD patients to comorbidities, such as infections and cardiovascular disease.
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http://dx.doi.org/10.1159/000449290DOI Listing
January 2018

Initiation of erythropoiesis-stimulating agents and outcomes: a nationwide observational cohort study in anaemic chronic kidney disease patients.

Nephrol Dial Transplant 2017 Nov;32(11):1892-1901

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

Background: In 2012, new clinical guidelines were introduced for use of erythropoiesis-stimulating agents (ESA) in chronic kidney disease (CKD) patients, recommending lower haemoglobin (Hb) target levels and thresholds for ESA initiation. These changes resulted in lower blood levels in these patients. However, there is limited evidence on just when ESA should be initiated and the safety of a low Hb initiation policy.

Methods: In this observational inception cohort study, Swedish, nephology-referred, ESA-naïve CKD patients (n = 6348) were enrolled when their Hb dropped below 12.0 g/L, and they were followed for mortality and cardiovascular events. Four different ESA treatments were evaluated applying dynamic marginal structural models: (i) begin ESA immediately, (ii) begin ESA when Hb <11.0 g/dL, (iii) begin ESA when Hb <10.0 g/dL and (iv) never begin ESA in comparison with 'current practice' [the observed (factual) survival of the entire study cohort]. The adjusted 3-year survival following ESA begun over a range of Hb (from <9.0 to 12.0 g/dL) was evaluated, after adjustment for covariates at baseline and during follow-up.

Results: Overall, 36% were treated with ESA. Mortality during follow-up was 33.4% of the ESA-treated and 27.9% of the non-treated subjects. The adjusted 3-year survival associated with ESA initiation improved for subjects with initial Hb <9.0 to 11 g/dL and then decreased again for those with Hb above 11.5 g/dL. Initiating ESA at Hb <11.0 g/dL and <10.0 g/dL was associated with improved survival compared with 'current practice' [hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.79-0.89 and 0.90; 95% CI 0.86-0.94, respectively] and did not increase the risk of a cardiovascular event (HR 0.93; 95% CI 0.87-1.00).

Conclusion: In non-dialysis patients with CKD, ESA initiation at Hb < 10.0-11.0 g/dL is associated with improved survival in patients otherwise treated according to guidelines.
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http://dx.doi.org/10.1093/ndt/gfw328DOI Listing
November 2017

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Myocardial Infarction Patients With Renal Dysfunction.

J Am Coll Cardiol 2016 Apr;67(14):1687-97

Department of Medicine, Huddinge, Section of Cardiology, Karolinska Institutet, and Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.

Background: There is no consensus whether angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) should be used for secondary prevention in all or in only high-risk patients after an acute myocardial infarction (AMI).

Objectives: This study sought to investigate whether ACEI/ARB treatment after AMI is associated with better outcomes across different risk profiles, including the entire spectrum of estimated glomerular filtration rates.

Methods: This study evaluated discharge and continuous follow-up data on ACEI/ARB use among AMI survivors (2006 to 2009) included in a large Swedish registry. The association between ACEI/ARB treatment and outcomes (mortality, myocardial infarction, stroke, and acute kidney injury [AKI]) was studied using Cox proportional hazards models (intention-to-treat and as treated).

Results: In total, 45,697 patients (71%) were treated with ACEI/ARB. The 3-year mortality was 19.8% (17.4% of ACEI/ARB users and 25.4% of nonusers). In adjusted analysis, significantly better survival was observed for patients treated with ACEI/ARB (3-year hazard ratio: 0.80; 95% confidence interval: 0.77 to 0.83). The survival benefit was consistent through all kidney function strata, including dialysis patients. Overall, those treated with ACEI/ARB also had lower 3-year risk for myocardial infarction (hazard ratio: 0.91; 95% confidence interval: 0.87 to 0.95), whereas treatment had no significant effect on stroke risk. The crude risk for AKI was in general low (2.5% and 2.0% for treated and nontreated, respectively) and similar across estimated glomerular filtration rate categories but was significantly higher with ACEI/ARB treatment. However, the composite outcome of AKI and mortality favored ACEI/ARB treatment.

Conclusions: Treatment with ACEI/ARB after AMI was associated with improved long-term survival, regardless of underlying renal function, and was accompanied by low rates of adverse renal events.
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http://dx.doi.org/10.1016/j.jacc.2016.01.050DOI Listing
April 2016

Increased fibrin formation and impaired fibrinolytic capacity in severe chronic kidney disease.

Blood Coagul Fibrinolysis 2016 Jun;27(4):401-7

aDepartment of Clinical Sciences, Division of NephrologybDepartment of Molecular Medicine and Surgery, Division of Clinical Chemistry/Coagulation ResearchcDepartment of Clinical Sciences, Division of Cardiovascular Medicine, Danderyd University Hospital, Karolinska Institutet, Stockholm, Sweden.

Chronic kidney disease (CKD) is associated with a concurrent increased risk of thrombosis and bleeding. We aimed to investigate whether CKD is associated with increased fibrin formation, impaired fibrin degradation, or both. Twenty-one patients with CKD stage 4 (CKD 4), 15 haemodialysis patients, and 13 controls (C) without kidney disease were studied. We used a global assay to determine fibrin formation and degradation in plasma. Fibrin turbidity was measured over time to obtain a value of the coagulation activation profile (Cp) and the fibrinolysis activation profile (Fp), and the amount of fibrin formed, termed fibrin optical density sum (fibrin OD-sum). We used scanning electron microscopy (SEM) to visualize the fibrin network. Plasminogen activator inhibitor type-1 antigen, thrombin-activatable fibrinolysis inhibitor activity, fibrinogen, von Willebrand factor, antithrombin, albumin, and C-reactive protein were measured in plasma. Fibrin OD-sum was significantly elevated in haemodialysis patients [312 a.u.; 278-435 (median; interquartile range); P < 0.0013] and in CKD 4 (293 a.u.; 169-434; P = 0.0119) compared with controls (115 a.u.; 82-234). SEM showed a tight fibrin network in haemodialysis and CKD 4 patients. Fp was lower in the haemodialysis group than in controls (P = 0.030). Plasminogen activator inhibitor type-1 was lower in haemodialysis patients (P = 0.034). Thrombin-activatable fibrinolysis inhibitor activity, Cp, antithrombin, and C-reactive protein did not differ between groups. Fibrinogen was significantly elevated and albumin decreased in both haemodialysis and CKD 4 patients compared with controls. Von Willebrand factor was elevated in haemodialysis patients compared with controls (P = 0.010). The prothrombotic state in severe CKD is characterized by impaired fibrinolysis in association with increased fibrin formation despite normal levels of endogenous fibrinolysis inhibitors.
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http://dx.doi.org/10.1097/MBC.0000000000000462DOI Listing
June 2016
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