Publications by authors named "Kyrill S Rogacev"

39 Publications

[Lipid management 2020 - medical therapy and lipid apheresis in context].

Dtsch Med Wochenschr 2020 04 1;145(7):464-469. Epub 2020 Apr 1.

Klinik und Poliklinik für Kardiologie, Universitätsklinikum Leipzig.

The recently updated 2019 European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidaemias set new, ambitious goals for lipid lowering based on recently generated evidence from large outcome trials. Noninvasive imaging as well as measurement of lipoprotein(a) as a non-traditional risk factor is advocated for the refinement of risk stratification. A highly potent statin - defined as a drug that lowers LDL-cholesterol by 50 % from baseline - is recommended as the standard choice of treatment, whenever medical lipid lowering is indicated. Combining different therapeutic strategies such as a statin with ezetimibe and/or a Proproteinkonvertase Subtilisin Kexin Type 9 inhibitor allows to achieve the new treatment targets. If needed, lipid apheresis can complement the medical armamentarium. Moreover, lipid apheresis remains the only approved treatment modality for lowering lipoprotein(a), however medical treatments are under current investigation.
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http://dx.doi.org/10.1055/a-0887-0595DOI Listing
April 2020

Lipid-modifying therapy in chronic kidney disease: Pathophysiological and clinical considerations.

Pharmacol Ther 2020 03 18;207:107459. Epub 2019 Dec 18.

Division of Pharmacology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Austria. Electronic address:

Chronic kidney disease (CKD), which affects >10% of the population worldwide, is associated with a dramatically increased rate of cardiovascular disease (CVD). More people with CKD will die from CVD than develop end-stage renal disease with dialysis-dependency. However, the contribution of classical atherosclerotic cardiovascular risk factors is less evident than in the general population. Particularly, the relationship between dyslipidemia and CVD morbidity and mortality in CKD patients is not as evident as in the general population. While LDL cholesterol-lowering drugs such as statins significantly reduce the rate of cardiovascular events in the general population, their role in patients with end-stage renal disease has been questioned. This could be caused by a shift from atherosclerotic to non-atherosclerotic CVD in patients with advanced CKD, which cannot be effectively prevented by lipid-lowering drugs. In addition, many lines of evidence suggest that impaired renal function directly affects the metabolism, composition and functionality of lipoproteins, which may affect their responsiveness to pharmacological interventions. In this review, we highlight the challenges for the therapeutic application of lipid-lowering treatment strategies in CKD and discuss why treatment strategies used in the general population cannot be applied uncritically to CKD patients.
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http://dx.doi.org/10.1016/j.pharmthera.2019.107459DOI Listing
March 2020

Still a reasonable goal: Targeting cholesterol in dialysis and advanced chronic kidney disease patients.

Semin Dial 2017 09 19;30(5):390-394. Epub 2017 Jun 19.

Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Graz, Austria.

Chronic kidney disease (CKD) patients have a high burden of cardiovascular disease. In the general population, lipid metabolism disorders, which cause the initiation and progression of atherosclerotic vascular changes, are major targets for preventive and therapeutic strategies in cardiovascular medicine. However, data from large cohort studies and from clinical trials suggest that the treatment guidelines on cardiovascular disease prevention and therapy cannot uncritically be transferred from individuals with intact renal function to CKD patients. Thus, unlike in the general population, neither plasma levels of HDL-cholesterol, nor the key parameter of HDL-cholesterol function-that is, cholesterol efflux capacity-predicts future cardiovascular events. Therefore, HDL-cholesterol should presently not be considered as therapeutic target in CKD patients. In contrast, lowering of LDL-cholesterol has been shown to reduce cardiovascular events at least among nondialysis CKD patients. The cardiovascular benefit of targeting LDL-cholesterol among dialysis CKD patients is less evident. We strongly believe that at least some subgroups of dialysis patients may profit from such treatment, particularly those with highest baseline LDL-cholesterol. Finally, as CKD patients have been characterized to have rather high intestinal cholesterol absorption, and relatively low hepatic cholesterol synthesis, substituting combined statin/ezetimibe treatment for statin monotherapy may be of particular benefit for nephrologic patients.
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http://dx.doi.org/10.1111/sdi.12621DOI Listing
September 2017

Reprint of: MicroRNA profiling of human intermediate monocytes.

Immunobiology 2017 06 31;222(6):831-840. Epub 2017 May 31.

Department of Internal Medicine IV, Saarland University Medical Center, Homburg, Germany. Electronic address:

Among the three human monocyte subsets, intermediate CD14++CD16+ monocytes have been characterized as particularly proinflammatory cells in experimental studies and as potential biomarkers of cardiovascular risk in clinical cohorts. To further substantiate the distinct role of intermediate monocytes within human monocyte heterogeneity, we assessed subset-specific expression of miRNAs as central epigenetic regulators of gene expression. We hypothesized that intermediate monocytes have a distinct miRNA profile compared to classical and non-classical monocytes. By using small RNA-seq we analyzed 662 miRNAs in the three monocyte subsets. We identified 38 miRNAs that are differentially expressed in intermediate monocytes compared to both classical and non-classical monocytes with a p value of <10, of which two miRNAs - miR-6087 (upregulated) and miR-150-5p (downregulated) - differed in their expression more than ten-fold. Pathway analysis of the 38 differentially expressed miRNAs linked intermediate monocytes to distinct biological processes such as gene regulation, cell differentiation, toll-like receptor signaling as well as antigen processing and presentation. Moreover, differentially expressed miRNAs were connected to those genes that we previously identified as markers of intermediate monocytes. In aggregation, we provide first genome-wide miRNA data in the context of monocyte heterogeneity, which substantiate the concept of monocyte trichotomy in human immunity. The identification of miRNAs that are specific for intermediate monocytes may allow to develop strategies, which particularly target this cell population while sparing the other two subsets.
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http://dx.doi.org/10.1016/j.imbio.2017.05.003DOI Listing
June 2017

MicroRNA profiling of human intermediate monocytes.

Immunobiology 2017 03 13;222(3):587-596. Epub 2016 Nov 13.

Department of Internal Medicine IV, Saarland University Medical Center, Homburg, Germany. Electronic address:

Among the three human monocyte subsets, intermediate CD14++CD16+ monocytes have been characterized as particularly proinflammatory cells in experimental studies and as potential biomarkers of cardiovascular risk in clinical cohorts. To further substantiate the distinct role of intermediate monocytes within human monocyte heterogeneity, we assessed subset-specific expression of miRNAs as central epigenetic regulators of gene expression. We hypothesized that intermediate monocytes have a distinct miRNA profile compared to classical and non-classical monocytes. By using small RNA-seq we analyzed 662 miRNAs in the three monocyte subsets. We identified 38 miRNAs that are differentially expressed in intermediate monocytes compared to both classical and non-classical monocytes with a p value of <10, of which two miRNAs - miR-6087 (upregulated) and miR-150-5p (downregulated) - differed in their expression more than ten-fold. Pathway analysis of the 38 differentially expressed miRNAs linked intermediate monocytes to distinct biological processes such as gene regulation, cell differentiation, toll-like receptor signaling as well as antigen processing and presentation. Moreover, differentially expressed miRNAs were connected to those genes that we previously identified as markers of intermediate monocytes. In aggregation, we provide first genome-wide miRNA data in the context of monocyte heterogeneity, which substantiate the concept of monocyte trichotomy in human immunity. The identification of miRNAs that are specific for intermediate monocytes may allow to develop strategies, which particularly target this cell population while sparing the other two subsets.
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http://dx.doi.org/10.1016/j.imbio.2016.11.006DOI Listing
March 2017

NT-proBNP and Echocardiographic Parameters for Prediction of Cardiovascular Outcomes in Patients with CKD Stages G2-G4.

Clin J Am Soc Nephrol 2016 11 11;11(11):1978-1988. Epub 2016 Aug 11.

Internal Medicine IV, Nephrology and Hypertension, Saarland University Medical Center, Homburg, Germany;

Background And Objectives: Natriuretic peptides and echocardiographic parameters both predict cardiovascular events in patients with CKD. However, it is unknown whether simultaneous assessment of amino-terminal probrain natriuretic peptide (NT-proBNP) and echocardiographic parameters provides complementary or redundant predictive information; in the latter case, one of these two might be dispensable. We aimed to analyze the implications of using NT-proBNP alone, echocardiographic parameters alone, or a combination of both for prediction of adverse cardiovascular outcome.

Design, Setting, Participants, & Measurements: Within the longitudinal Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Fourth Homburg Evaluation Study, we prospectively studied 496 patients with CKD stages G2-G4, in whom we measured NT-proBNP. Left ventricular mass index, left atrial volume index, diastolic left ventricular function, and systolic left ventricular function were assessed echocardiographically. During 4.5±2.0 years of follow-up, the occurrence of (1) decompensated heart failure or all-cause mortality and (2) atherosclerotic events or all-cause mortality was recorded. We assessed the association of NT-proBNP and echocardiographic parameters with outcome (using Cox models) and evaluated the increased discriminative value associated with the addition of echocardiographic parameters and NT-proBNP (using integrated discrimination improvement and net reclassification improvement).

Results: During follow-up, 104 patients suffered decompensated heart failure or all-cause mortality, and 127 patents had atherosclerotic events or all-cause mortality. In univariable analyses, NT-proBNP and echocardiographic parameters predicted cardiovascular events. NT-proBNP remained an independent predictor for both end points in multivariate analysis, whereas left ventricular mass index, left atrial volume index, and diastolic left ventricular function did not. The addition of NT-proBNP on top of clinical and various echocardiographic variables was associated with improvements in reclassification for decompensated heart failure or all-cause mortality (integrated discrimination improvement =6.5%-8.3%; net reclassification improvement =23.1%-27.0%; all P≤0.03). Adding echocardiographic variables on top of clinical variables and NT-proBNP was not associated with significant net reclassification improvement (all P>0.05).

Conclusions: Our data confirm NT-proBNP is an independent predictor of adverse outcomes in patients with CKD. The additional use of echocardiography for improvement of risk stratification is not supported by our results.
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http://dx.doi.org/10.2215/CJN.01660216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5108187PMC
November 2016

Best Albuminuria Measurement to Predict Cardiovascular and Renal Events.

Am J Nephrol 2016 18;43(5):383-8. Epub 2016 May 18.

Internal Medicine IV - Nephrology and Hypertension, Saarland University Medical Center, Homburg, Germany.

Background: Kidney Disease Improving Global Outcomes (KDIGO) guidelines encourage clinicians to estimate 24-hour albuminuria as albumin to creatinine ratio (ACR) from spot urine samples. However, ACR underestimates 24-hour albumin excretion in muscular individuals. Equations that adjust ACR for surrogates of muscle mass to yield an estimated albumin excretion rate (eAER) were developed. We hypothesised that eAER is a better predictor of cardiovascular and renal outcomes than ACR.

Methods: We determined ACR and eAER among 443 patients with chronic kidney disease G2-G4 recruited into the CARE FOR HOMe study. Patients were classified into KDIGO albuminuria categories, and followed for cardiovascular and renal events. The primary analysis was the net reclassification improvement (NRI) for those with and without events within 3 years of follow-up.

Results: Eighty five patients experienced cardiovascular events during 3 years of follow-up, 13 of whom were reclassified to a more advanced albuminuria category, and 1 patient to a less advanced category by eAER compared to ACR (NRIevent: 14.1% (95% CI 5.8-22.4)). Among 358 patients without a cardiovascular event, 17 patients were reclassified to a more advanced albuminuria category, and 2 patients to a less advanced category by eAER (NRIno event: -4.2%, 95% CI -8.5 to -1.8). Sixty patients went through renal events, and 383 patients had event-free 3-year follow-up. NRIevent was 6.7% (95% CI -1.2 to 14.5), and NRIno event was -6.0% (95% CI -10.6 to 3.4) for renal events.

Conclusion: Compared to ACR albuminuria categories, eAER categories are better associated with future cardiovascular events, but not with renal events.
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http://dx.doi.org/10.1159/000446483DOI Listing
January 2018

DNA methylation profiling reveals differences in the 3 human monocyte subsets and identifies uremia to induce DNA methylation changes during differentiation.

Epigenetics 2016 04 28;11(4):259-72. Epub 2016 Mar 28.

a Department of Internal Medicine IV , Saarland University Medical Center , Homburg , Germany.

Human monocytes are a heterogeneous cell population consisting of 3 subsets: classical CD14++CD16-, intermediate CD14++CD16+ and nonclassical CD14+CD16++ monocytes. Via poorly characterized mechanisms, intermediate monocyte counts rise in chronic inflammatory diseases, among which chronic kidney disease is of particular epidemiologic importance. DNA methylation is a central epigenetic feature that controls hematopoiesis. By applying next-generation Methyl-Sequencing we now tested how far the 3 monocyte subsets differ in their DNA methylome and whether uremia induces DNA methylation changes in differentiating monocytes. We found that each monocyte subset displays a unique phenotype with regards to DNA methylation. Genes with differentially methylated promoter regions in intermediate monocytes were linked to distinct immunological processes, which is in line with results from recent gene expression analyses. In vitro, uremia induced dysregulation of DNA methylation in differentiating monocytes, which affected several transcription regulators important for monocyte differentiation (e.g., FLT3, HDAC1, MNT) and led to enhanced generation of intermediate monocytes. As potential mediator, the uremic toxin and methylation inhibitor S-adenosylhomocysteine induced shifts in monocyte subsets in vitro, and associated with monocyte subset counts in vivo. Our data support the concept of monocyte trichotomy and the distinct role of intermediate monocytes in human immunity. The shift in monocyte subsets that occurs in chronic kidney disease, a proinflammatory condition of substantial epidemiological impact, may be induced by accumulation of uremic toxins that mediate epigenetic dysregulation.
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http://dx.doi.org/10.1080/15592294.2016.1158363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889294PMC
April 2016

PCSK9 Plasma Concentrations Are Independent of GFR and Do Not Predict Cardiovascular Events in Patients with Decreased GFR.

PLoS One 2016 22;11(1):e0146920. Epub 2016 Jan 22.

Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine, Saarland University Medical Center, Homburg, Germany.

Background: Impaired renal function causes dyslipidemia that contributes to elevated cardiovascular risk in patients with chronic kidney disease (CKD). The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of the LDL receptor and plasma cholesterol concentrations. Its relationship to kidney function and cardiovascular events in patients with reduced glomerular filtration rate (GFR) has not been explored.

Methods: Lipid parameters including PCSK9 were measured in two independent cohorts. CARE FOR HOMe (Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Forth Homburg evaluation) enrolled 443 patients with reduced GFR (between 90 and 15 ml/min/1.73 m2) referred for nephrological care that were prospectively followed for the occurrence of a composite cardiovascular endpoint. As a replication cohort, PCSK9 was quantitated in 1450 patients with GFR between 90 and 15 ml/min/1.73 m2 enrolled in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) that were prospectively followed for cardiovascular deaths.

Results: PCSK9 concentrations did not correlate with baseline GFR (CARE FOR HOMe: r = -0.034; p = 0.479; LURIC: r = -0.017; p = 0.512). 91 patients in CARE FOR HOMe and 335 patients in LURIC reached an endpoint during a median follow-up of 3.0 [1.8-4.1] years and 10.0 [7.3-10.6] years, respectively. Kaplan-Meier analyses showed that PCSK9 concentrations did not predict cardiovascular events in either cohort [CARE FOR HOMe (p = 0.622); LURIC (p = 0.729)]. Sensitivity analyses according to statin intake yielded similar results.

Conclusion: In two well characterized independent cohort studies, PCSK9 plasma levels did not correlate with kidney function. Furthermore, PCSK9 plasma concentrations were not associated with cardiovascular events in patients with reduced renal function.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146920PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4723078PMC
August 2016

Comparison of two different strategies for human monocyte subsets gating within the large-scale prospective CARE FOR HOMe Study.

Cytometry A 2015 Aug 9;87(8):750-8. Epub 2015 Jun 9.

Department of Internal Medicine IV - Nephrology and Hypertension, Saarland University Medical Center, Homburg, Germany.

Monocytes are heterogeneous cells consisting of (at least) three subsets: classical, intermediate, and nonclassical monocytes. Correct enumeration of cell counts necessitates well-defined gating strategies, which are essentially based upon CD14 and CD16 expression. For the delineation of intermediate from nonclassical monocytes, a "rectangular gating (RG) strategy" and a "trapezoid gating (TG) strategy" have been proposed. We compared the two gating strategies in a well-defined clinical cohort of patients with chronic kidney disease (CKD). Within the ongoing CARE FOR HOMe study, monocyte subsets were reanalyzed in 416 CKD patients, who were followed 3.6 ± 1.6 years for the occurrence of a cardiovascular event. Gating was performed by either RG or TG. We analyzed the expression of surface markers, and compared the predictive role of cell counts of monocyte subsets, as defined by RG and TG, respectively. With both gating strategies, higher intermediate monocyte counts predicted the cardiovascular endpoint in Kaplan-Meier analyses (P < 0.001 with RG; P < 0.001 with TG). After correction for confounders, intermediate monocyte counts remained independent predictors in Cox-Regression analyses (HR = 1.013 [95% CI: 1.006-1.020; P < 0.001] with RG; HR = 1.015 [95% CI: 1.006-1.024; P = 0.001] with TG). NRI was 3.9% when reclassifying patients from quartiles of intermediate monocyte counts with RG strategy toward quartiles of intermediate monocytes counts with TG strategy. In expression analysis, those monocytes which are defined as intermediate monocytes by the RG strategy and as nonclassical monocytes by the TG strategy share characteristics of both subsets. In conclusion, intermediate monocytes were independent predictors of cardiovascular outcome irrespective of the applied gating strategy. Future studies should aim to identify markers that allow for an unequivocal definition of intermediate monocytes, which may further improve their power to predict cardiovascular events.
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http://dx.doi.org/10.1002/cyto.a.22703DOI Listing
August 2015

Immunosuppression and monocyte subsets.

Nephrol Dial Transplant 2015 Jan 13;30(1):143-53. Epub 2014 Oct 13.

Department of Internal Medicine IV, Saarland University Medical Center, Homburg, Germany.

Background: Monocytes are critical in innate immunity and transplantation. Three monocyte subsets exist, CD14(++)CD16(-), CD14(++)CD16(+) and CD14(+)CD16(++) monocytes; cell counts of CD14(++)CD16(+) and CD14(+)CD16(++) monocytes are increased in pre-transplant chronic kidney disease. Interestingly, the effect of immunosuppressants on monocyte heterogeneity has not been well studied.

Methods: The impact of immunosuppressants on monocyte subsets was studied: (i) in 152 kidney transplant (KTx) recipients to characterize subset distribution in the steady state, (ii) in patients after autologous (n = 10) versus allogenic (n = 9) haematopoietic stem cell transplantation (HSCT) to analyse monocyte subset development and (iii) in an in vitro model to compare the effect of immunosuppressants on monocyte subset biology.

Results: In KTx, steroid intake was associated with higher total, CD14(++)CD16(-) and CD14(++)CD16(+) monocyte counts, but fewer CD14(+)CD16(++) monocytes, whereas intake of mycophenolate, calcineurin inhibitors (CNI) and mammalian target of rapamycin inhibitors (mTORI) did not affect monocyte (subset) counts. In linear regression analysis, only steroid intake was a significant determinant of monocyte (subset) counts: total monocytes (β = 0.331; P < 0.001), CD14(++)CD16(-) monocytes (β = 0.374; P < 0.001), CD14(++)CD16(+) monocytes (β = 0.221; P = 0.010) and CD14(+)CD16(++) monocytes (β = -0.169; P = 0.049). After HSCT, CD14(++)CD16(-) monocytes were the first to arise, followed by CD14(++)CD16(+) and later by CD14(+)CD16(++) monocytes. Monocyte subset distribution did not differ significantly in patients after allogenic compared with autologous transplantation. CNI, mycophenolate and methotrexate did not influence monocyte subset development, but modified surface receptor expression (CCR2, HLA-DR, ENG, TEK and TLR4) in allogenic HSCT.

Conclusion: Chronic low-dose steroids are associated with monocytosis and higher counts of CD14(++)CD16(-) and of proinflammatory CD14(++)CD16(+) monocytes.
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http://dx.doi.org/10.1093/ndt/gfu315DOI Listing
January 2015

Association of vascular endothelial factors with cardiovascular outcome and mortality in chronic kidney disease patients: a 4-year cohort study.

Atherosclerosis 2014 Oct 12;236(2):360-5. Epub 2014 Aug 12.

Division of Renal Diseases and Hypertension, The George Washington University School of Medicine, Washington, DC, USA. Electronic address:

Background: Angiogenic cytokines fms-like tyrosine kinase-1(sFlt-1) and placental growth factor (PlGF) are associated with increased risk for cardiovascular disease (CVD) in the general population. In this study we examine the association between these vascular endothelial factors and atherosclerosis, cardiovascular outcome, and mortality in chronic kidney disease (CKD) patients.

Methods: Serum level of PlGF and sFlt-1 were measured in 301 patients with CKD, who were followed for up to 4 years. Primary outcomes were CV events and all-cause mortality. Carotid-intima media thickness (CIMT) was used as marker of atherosclerosis. Kaplan-Meier survival curves and the Cox proportional hazard model were used to assess the association of biomarkers and clinical outcomes.

Results: Mean (SD) PlGF and sFlt-1 were 5.45 ng/ml (3.76) and 68.6 (28.0) pg/ml, respectively. During the follow up time, 60 patients (19.9%) experienced CV events and 22 patients (7.3%) died. Compared with low PlGF, patients with PlGF above median level had higher CV events (12.7% vs. 27.2%, p = 0.002) and mortality (2.0% vs. 12.6%, p < 0.001). The associations of PlGF and sFlt-1 with CV events were not statistically significant in the fully adjusted model. Higher PlGF was associated with greater death risk (HR = 5.22, 95% CI: 1.49-18.33, p = 0.01), which was robust to adjustment for sFlt-1 and other risk factors. Elevated sFlt-1 level was also an independent predictor of mortality (HR 3.41, 95% CI: 1.49-9.51, p = 0.019).

Conclusion: In CKD patients not yet on dialysis, higher serum level of PlGF and sFlt-1 are associated with increased mortality, but not CV events.
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http://dx.doi.org/10.1016/j.atherosclerosis.2014.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4327843PMC
October 2014

Lower Apo A-I and lower HDL-C levels are associated with higher intermediate CD14++CD16+ monocyte counts that predict cardiovascular events in chronic kidney disease.

Arterioscler Thromb Vasc Biol 2014 Sep 24;34(9):2120-7. Epub 2014 Jul 24.

From the Department of Internal Medicine III, Cardiology, Angiology and Intensive Care Medicine (K.S.R., M.B) and Department of Internal Medicine IV, Nephrology and Hypertension (K.S.R., A.M.Z., I.E., S.S., D.F., G.H.H.), Saarland University Medical Center, Homburg, Germany; and Department of Medicine, Imperial College London, London, United Kingdom (K.J.W.).

Objective: Patients with chronic kidney disease (CKD) display impaired cholesterol efflux capacity and elevated CD14(++)CD16(+) monocyte counts. In mice, dysfunctional cholesterol efflux causes monocytosis. It is unknown whether cholesterol efflux capacity and monocyte subsets are associated in CKD.

Approach And Results: In 438 patients with CKD, mediators of cholesterol efflux capacity (high-density lipoprotein cholesterol/apolipoprotein A-I) and monocyte subsets were analyzed as predictors of cardiovascular events. Monocyte subset-specific intracellular lipid content, CD36, CD68, and ABCA1 were measured in a subgroup. Experimentally, we analyzed subset-specific cholesterol efflux capacity and response to oxidized low-density lipoprotein cholesterol stimulation in CKD. Epidemiologically, both low Apo-I and low high-density lipoprotein cholesterol were associated with high CD14(++)CD16(+) monocyte counts in linear regression analyses (apolipoprotein A-I: β=-0.171; P<0.001; high-density lipoprotein cholesterol: β=-0.138; P=0.005), but not with counts of other monocyte subsets. In contrast to apolipoprotein A-I or high-density lipoprotein cholesterol, higher CD14(++)CD16(+) monocyte counts independently predicted cardiovascular events (hazard ratio per increase of 1 cell/μL: 1.011 [1.003-1.020]; P=0.007). Experimentally, CD14(++)CD16(+) monocytes demonstrated preferential lipid accumulation, high CD36, CD68, and low ABCA1 expression and, consequently, displayed low cholesterol efflux capacity, avid oxidized low-density lipoprotein cholesterol uptake, and potent intracellular interleukin-6, interleukin-1β, and tumor necrosis factor-α production.

Conclusions: Taken together, mediators of cholesterol efflux are associated with CD14(++)CD16(+) monocyte counts, which independently predict adverse outcome in CKD.
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http://dx.doi.org/10.1161/ATVBAHA.114.304172DOI Listing
September 2014

Associations of FGF-23 and sKlotho with cardiovascular outcomes among patients with CKD stages 2-4.

Clin J Am Soc Nephrol 2014 Jun 27;9(6):1049-58. Epub 2014 Mar 27.

Department of Internal Medicine IV-Nephrology and Hypertension, Saarland University Medical Centre, Homburg, Germany;

Background And Objectives: CKD-mineral and bone disorders (CKD-MBD) measures contribute to cardiovascular morbidity in patients with CKD. Among these, fibroblast growth factor (FGF)-23 and its coreceptor Klotho may exert direct effects on vascular and myocardial tissues. Klotho exists in a membrane-bound and a soluble form (sKlotho). Recent experimental evidence suggests sKlotho has vasculoprotective functions.

Design, Settings, Participants, & Measurements: Traditional and novel CKD-MBD variables were measured among 444 patients with CKD stages 2-4 recruited between September 2008 and November 2012 into the ongoing CARE FOR HOMe study. Across tertiles of baseline sKlotho and FGF-23, the incidence of two distinct combined end points was analyzed: (1) the first occurrence of an atherosclerotic event or death from any cause and (2) the time until hospital admission for decompensated heart failure or death from any cause.

Results: Patients were followed for 2.6 (interquartile range, 1.4-3.6) years. sKlotho tertiles predicted neither atherosclerotic events/death (fully adjusted Cox regression analysis: hazard ratio [HR] for third versus first sKlotho tertile, 0.75 [95% confidence interval (95% CI), 0.43-1.30]; P=0.30) nor the occurrence of decompensated heart failure/death (HR for third versus first sKlotho tertile, 0.81 [95% CI, 0.39-1.66]; P=0.56). In contrast, patients in the highest FGF-23 tertile had higher risk for both end points in univariate analysis. Adjustment for kidney function attenuated the association between FGF-23 and atherosclerotic events/death (HR for third versus first FGF-23 tertile, 1.23 [95% CI, 0.58-2.61]; P=0.59), whereas the association between FGF-23 and decompensated heart failure/death remained significant after adjustment for confounders (HR for third versus first FGF-23 tertile, 4.51 [95% CI, 1.33-15.21]; P=0.02).

Conclusions: In this prospective observational study of limited sample size, sKlotho was not significantly related to cardiovascular outcomes. FGF-23 was significantly associated with future decompensated heart failure but not incident atherosclerotic events.
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http://dx.doi.org/10.2215/CJN.07870713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4046724PMC
June 2014

S-adenosylhomocysteine is associated with subclinical atherosclerosis and renal function in a cardiovascular low-risk population.

Atherosclerosis 2014 May 18;234(1):17-22. Epub 2014 Feb 18.

Department of Internal Medicine IV, Saarland University Medical Center, Homburg, Germany. Electronic address:

Objective: Although homocysteine has been proposed as a cardiovascular risk factor, interventional trials lowering homocysteine have not consistently demonstrated clinical benefit. Recent evidence proposed the homocysteine metabolite S-adenosylhomocysteine (SAH) rather than homocysteine itself as the real culprit in cardiovascular disease. Of note, SAH is predominantly excreted by the kidneys, and cannot be lowered by vitamin supplementation. Due to its cumbersome measurement, data from large studies on the association between SAH, kidney function and cardiovascular disease are not available.

Methods: We recruited 420 apparently healthy subjects into our I Like HOMe FU study. Among all study participants, we assessed parameters of C1 metabolism (homocysteine, SAH and S-adenosylmethionine), renal function (estimated glomerular filtration rate [eGFR]) and subclinical atherosclerosis (common carotid intima-media-thickness [IMT]). eGFR was estimated by the CKD-EPIcreat-cys equation.

Results: Traditional cardiovascular risk factors and subclinical atherosclerosis were associated with SAH, but not with homocysteine (IMT vs SAH: r = 0.129; p = 0.010; IMT vs homocysteine: r = 0.009; p = 0.853). Moreover, renal function was more closely correlated with SAH than with homocysteine (eGFR vs SAH: r = -0.335; p < 0.001; eGFR vs homocysteine: r = -0.250; p < 0.001). The association between eGFR and SAH remained significant after adjustment for traditional cardiovascular risk factors.

Conclusion: In summary, cardiovascular risk factors, subclinical atherosclerosis and eGFR are more strongly associated with SAH than with homocysteine in apparently healthy subjects. Thus, SAH might represent a more promising target to prevent cardiovascular disease than homocysteine.
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http://dx.doi.org/10.1016/j.atherosclerosis.2014.02.002DOI Listing
May 2014

Distinct immunologic effects of different intravenous iron preparations on monocytes.

Nephrol Dial Transplant 2014 Apr 11;29(4):809-22. Epub 2014 Feb 11.

Department of Internal Medicine IV - Nephrology and Hypertension, Saarland University Medical Center, Homburg, Germany.

Background: Iron deficiency contributes to anaemia in patients with chronic kidney disease. I.v. iron is therefore widely used for anaemia treatment, although it may induce oxidative stress and activate monocytes. Different i.v. iron preparations are available, but interestingly their substance-specific immunologic effects are poorly studied.

Methods: We analysed the effect of iron sucrose, ferric carboxymaltose, iron isomaltoside 1000, low-molecular-weight iron dextran and ferumoxytol on classical, intermediate and nonclassical monocyte biology. We therefore stimulated in vitro mature monocytes and haematopoietic CD34(+) stem cells during their differentiation into monocytes with different concentrations (0.133, 0.266, 0.533 mg/mL) of i.v. iron preparations. Alterations of monocyte subset distribution, expression of surface markers (CD86, CCR5, CX3CR1), as well as production of pro-inflammatory cytokines (TNF-α, IL-1β) and reactive oxygen species were measured using flow cytometry. Additionally, we analysed phagocytosis and antigen presentation capacity.

Results: We found specific immunologic effects after stimulation with iron sucrose which were not induced by the other iron preparations. Iron sucrose activated monocyte subsets leading to significantly increased CD86 expression. Simultaneously CD16 and CX3CR1 expression and monocytic phagocytosis capacity were decreased. Additionally, differentiation of monocytes from haematopoietic CD34(+) stem cells was almost completely abolished after stimulation with iron sucrose.

Conclusions: Our findings demonstrate that specific immunologic effects of distinct i.v. iron preparations exist. The clinical relevance of these findings requires further investigation.
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http://dx.doi.org/10.1093/ndt/gft524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3967833PMC
April 2014

Massive analysis of cDNA Ends (MACE) and miRNA expression profiling identifies proatherogenic pathways in chronic kidney disease.

Epigenetics 2014 Jan 1;9(1):161-72. Epub 2013 Nov 1.

Department of Internal Medicine IV; Saarland University Medical Center; Homburg, Germany.

Epigenetic dysregulation contributes to the high cardiovascular disease burden in chronic kidney disease (CKD) patients. Although microRNAs (miRNAs) are central epigenetic regulators, which substantially affect the development and progression of cardiovascular disease (CVD), no data on miRNA dysregulation in CKD-associated CVD are available until now. We now performed high-throughput miRNA sequencing of peripheral blood mononuclear cells from ten clinically stable hemodialysis (HD) patients and ten healthy controls, which allowed us to identify 182 differentially expressed miRNAs (e.g., miR-21, miR-26b, miR-146b, miR-155). To test biological relevance, we aimed to connect miRNA dysregulation to differential gene expression. Genome-wide gene expression profiling by MACE (Massive Analysis of cDNA Ends) identified 80 genes to be differentially expressed between HD patients and controls, which could be linked to cardiovascular disease (e.g., KLF6, DUSP6, KLF4), to infection / immune disease (e.g., ZFP36, SOCS3, JUND), and to distinct proatherogenic pathways such as the Toll-like receptor signaling pathway (e.g., IL1B, MYD88, TICAM2), the MAPK signaling pathway (e.g., DUSP1, FOS, HSPA1A), and the chemokine signaling pathway (e.g., RHOA, PAK1, CXCL5). Formal interaction network analysis proved biological relevance of miRNA dysregulation, as 68 differentially expressed miRNAs could be connected to 47 reciprocally expressed target genes. Our study is the first comprehensive miRNA analysis in CKD that links dysregulated miRNA expression with differential expression of genes connected to inflammation and CVD. After recent animal data suggested that targeting miRNAs is beneficial in experimental CVD, our data may now spur further research in the field of CKD-associated human CVD.
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http://dx.doi.org/10.4161/epi.26931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3928179PMC
January 2014

The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation incorporating both cystatin C and creatinine best predicts individual risk: a cohort study in 444 patients with chronic kidney disease.

Nephrol Dial Transplant 2014 Feb 28;29(2):348-55. Epub 2013 Oct 28.

Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University Medical Centre, Homburg, Germany.

Background: The recently introduced CKD-EPIcreat-cys equation surpassed creatinine-based equations for GFR estimation in a large cross-sectional analysis. However, its performance to predict individual risk of CKD progression and death in patients with various underlying CKD etiologies is unknown.

Methods: We recruited 444 patients with CKD GFR categories 2-4 (eGFR 15-89 mL/min/1.73 m2); baseline eGFR was estimated by the established MDRD and CKD-EPIcreat equations and by the novel CKD-EPIcreat-cys equation.

Results: Patients were followed for 2.7±1.2 years for the occurrence of the combined predefined endpoint event: death, need for renal replacement therapy or halving of eGFR. The endpoint occurred in 62 patients. Reclassification from MDRD determined categories to CKD-EPIcreat-cys categories yielded net reclassification improvements for those with the endpoint event (NRIevents) of 27.4% (95% CI: 16.7-40.0%) and for those without the event (NRInon-events) of -3.1% (-8.2 to 1.6%). Similarly, reclassification from CKD-EPIcreat categories to CKD-EPIcreat-cys categories yielded an NRIevents of 22.6% (10.2-34.3%) and NRInon-events of -11.3% (-15.9 to -6.5%). Addition of albuminuria to each eGFR equation increased the calculated risk of the outcome for a net 26-32% of those who subsequently reached the endpoint, and reduced the calculated risk in a net 21-23% in non-event patients, but only minimally.

Conclusions: The CKD-EPIcreat-cys equation assigned patients who went on to have the event to more appropriate CKD risk categories than MDRD and CKD-EPIcreat, but patients without the event to less appropriate categories than CKD-EPIcreat. Addition of albuminuria marginally improved risk classification for those who had the event.
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http://dx.doi.org/10.1093/ndt/gft422DOI Listing
February 2014

Single FGF-23 measurement and time-averaged plasma phosphate levels in hemodialysis patients.

Clin J Am Soc Nephrol 2013 Oct 11;8(10):1764-72. Epub 2013 Jul 11.

Department for Internal Medicine IV-Nephrology and Hypertension, Saarland University Medical Center, Homburg, Germany, †Psychological Institute, Humboldt-Universität zu Berlin, Berlin, Germany.

Background And Objectives: Plasma phosphate levels display considerable intraindividual variability. The phosphatonin fibroblast growth factor 23 is a central regulator of plasma phosphate levels, and it has been postulated to be a more stable marker than conventional CKD-mineral and bone disorder parameters. Thus, fibroblast growth factor 23 has been hypothesized to reflect time-averaged plasma phosphate levels in CKD patients.

Design, Setting, Participants, & Measurements: Among 40 patients from the outpatient dialysis center, serial measurements of plasma calcium and phosphate (before every dialysis session) as well as C-terminal fibroblast growth factor 23, parathyroid hormone, and alkaline phosphatase (one time weekly) were performed over a study period of 4 weeks in November and December of 2011. Intraindividual variability of repeated plasma fibroblast growth factor 23 measurements compared with other CKD-mineral and bone disorder markers was tested, and the association of a single plasma fibroblast growth factor 23 measurement with time-averaged plasma phosphate levels was analyzed.

Results: Against expectations, intraindividual variability of fibroblast growth factor 23 (median coefficient of variation=27%; interquartile range=20-35) was not lower than variability of plasma phosphate (median coefficient of variation=15%; interquartile range=10-20), parathyroid hormone (median coefficient of variation=24%; interquartile range=15-39), plasma calcium (median coefficient of variation=3%; interquartile range=2-4), or alkaline phosphatase (median coefficient of variation=5%; interquartile range=3-10). Moreover, the correlation between the last fibroblast growth factor 23 measurement after 4 weeks and time-averaged plasma phosphate did not surpass the correlation between the last fibroblast growth factor 23 measurement and a single plasma phosphate value (r=0.67, P<0.001; r=0.76, P<0.001, respectively).

Conclusions: Surprisingly, fibroblast growth factor 23 was not more closely associated to time-averaged plasma phosphate levels than a single plasma phosphate value, and it did not show a lower intraindividual variability than other tested markers of CKD-mineral and bone disorder. Thus, fibroblast growth factor 23 should not be used in clinical practice as a reflector of time-averaged plasma phosphate levels.
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http://dx.doi.org/10.2215/CJN.13021212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789357PMC
October 2013

Clinical relevance of epigenetic dysregulation in chronic kidney disease-associated cardiovascular disease.

Nephrol Dial Transplant 2013 Jul 19;28(7):1663-71. Epub 2013 Mar 19.

Department of Internal Medicine IV, Saarland University Medical Center, D-66421 Homburg, Germany.

Across the spectrum of clinical medicine, the field of epigenetics has gained substantial scientific interest in recent years. Epigenetics refers to modifications in gene expression which are not explained by changes in DNA sequence. Classical components of epigenetic regulation comprise DNA methylation, histone modifications and RNA interference. In chronic kidney disease (CKD), several features of uraemia, such as hyperhomocysteinemia and inflammation, may contribute to changes in epigenetic gene regulation. It has been suggested that these changes may affect genes related to cardiovascular disease. Thereby, a uraemia-associated disturbance in epigenetic regulation may contribute to the substantial increase in cardiovascular morbidity in CKD patients. The present review aims to summarize current knowledge of epigenetic dysregulation in cardiovascular disease from a nephrological perspective, with a special focus on DNA methylation. We first describe the impact of altered epigenetic regulation in non-CKD-associated arteriosclerosis, and next characterize uraemic features which may affect epigenetic gene regulation in the context of cardiovascular disease. Finally, we conclude that substantial additional work is needed before epigenetic regulatory mechanisms may become therapeutic targets in CKD-associated cardiovascular disease.
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http://dx.doi.org/10.1093/ndt/gft042DOI Listing
July 2013

SuperTAG methylation-specific digital karyotyping reveals uremia-induced epigenetic dysregulation of atherosclerosis-related genes.

Circ Cardiovasc Genet 2012 Dec 16;5(6):611-20. Epub 2012 Oct 16.

Department of Internal Medicine IV, Saarland University Medical Center, Homburg, Germany.

Background: Accelerated atherosclerosis is a hallmark of chronic kidney disease (CKD). Although the role of epigenetic dysregulation in atherosclerosis is increasingly appreciated, only a few studies focused on epigenetics in CKD-associated cardiovascular disease, virtually all of which assessed epigenetic dysregulation globally. We hypothesized that gene-specific epigenetic dysregulation in CKD exists, affecting genes pertinent to inflammation and atherosclerosis.

Methods And Results: Ten clinically stable patients undergoing hemodialysis therapy and 10 healthy age- and sex-matched controls were recruited. Genome-wide analysis of DNA methylation was performed by SuperTAG methylation-specific digital karyotyping, in order to identify genes differentially methylated in CKD. Analysis of 27 043 436 tags revealed 4288 genomic loci with differential DNA methylation (P<10(-10)) between hemodialysis patients and control subjects. Annotation of UniTags to promoter databases allowed us to identify 52 candidate genes associated with cardiovascular disease and 97 candidate genes associated with immune/infection diseases. These candidate genes could be classified to distinct proatherogenic processes, including lipid metabolism and transport (eg, HMGCR, SREBF1, LRP5, EPHX2, and FDPS), cell proliferation and cell-cycle regulation (eg, MIK67, TP53, and ALOX12), angiogenesis (eg, ANGPT2, ADAMTS10, and FLT4), and inflammation (eg, TNFSF10, LY96, IFNGR1, HSPA1A, and IL12RB1).

Conclusions: We provide a comprehensive analysis of genome-wide epigenetic alterations in CKD, identifying candidate genes associated with proatherogenic and inflammatory processes. These results may spur further research in the field of epigenetics in kidney disease and point to new therapeutic strategies in CKD-associated atherosclerotic disease.
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http://dx.doi.org/10.1161/CIRCGENETICS.112.963207DOI Listing
December 2012

CD14++CD16+ monocytes independently predict cardiovascular events: a cohort study of 951 patients referred for elective coronary angiography.

J Am Coll Cardiol 2012 Oct 19;60(16):1512-20. Epub 2012 Sep 19.

Department of Internal Medicine IV, Saarland University Medical Center, Homburg/Saar, Germany.

Objectives: The aim of this study was to analyze the yet ill-defined relationship of distinct human monocyte subsets with cardiovascular outcomes in a broad patient population at cardiovascular risk.

Background: Monocytes, the most abundant immune cell type found in atherosclerotic plaques, are crucial promoters of atherogenesis. Three distinct human monocyte subsets exist: classical CD14++CD16-, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes. Immunomodulation of distinct monocyte subsets has recently been discussed as a new therapeutic avenue in atherosclerosis.

Methods: Cardiovascular events in 951 subjects referred for elective coronary angiography were prospectively analyzed. Monocyte subset analysis was performed using flow cytometry, blinded to patients' clinical characteristics, and patients were categorized according to quartiles of total monocyte and monocyte subset counts. The primary endpoint was defined a priori as the first occurrence of cardiovascular death, acute myocardial infarction, or nonhemorrhagic stroke. Endpoint adjudication was done blinded to monocyte subset distribution.

Results: During a mean follow-up period of 2.6 ± 1.0 years, 93 patients experienced the primary endpoint. In univariate Kaplan-Meier analysis, counts of total (p = 0.010), classical CD14++CD16- (p = 0.024), and intermediate CD14++CD16+ (p < 0.001) monocytes predicted the primary endpoint, whereas nonclassical monocytes did not (p = 0.158). After full adjustment for confounders, CD14++CD16+ monocytes remained the only monocyte subset independently related to cardiovascular events (fourth vs. first quartile: hazard ratio: 3.019; 95% confidence interval: 1.315 to 6.928; p = 0.009).

Conclusions: CD14++CD16+ monocytes independently predicted cardiovascular events in subjects referred for elective coronary angiography. Future studies will be needed to elucidate whether CD14++CD16+ monocytes may become a target cell population for new therapeutic strategies in atherosclerosis.
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http://dx.doi.org/10.1016/j.jacc.2012.07.019DOI Listing
October 2012

Monocyte heterogeneity in human cardiovascular disease.

Immunobiology 2012 Dec 25;217(12):1273-84. Epub 2012 Jul 25.

Department of Internal Medicine IV, Saarland University Medical Center, Homburg, Germany.

Atherosclerosis has been characterized as an inflammatory process, in which monocytes and monocyte-derived macrophages are of paramount importance. Contrasting with their established role in atherosclerosis, monocytes have not unanimously been found to predict cardiovascular events in large epidemiological studies. However, in these studies human monocyte heterogeneity has been largely overlooked so far. Three human monocyte subsets can be distinguished: classical CD14(++)CD16(-), intermediate CD14(++)CD16(+) and nonclassical CD14(+)CD16(++) monocytes. Of note, correct enumeration of subset counts requires appropriate staining and gating strategies that encompass a pan-monocytic marker (e.g. HLA-DR or CD86). In experimental studies on murine atherogenesis a monocyte subset-specific contribution to atherosclerosis has been established. However, major interspecies differences in atherogenesis itself, as well as in the immune system (including monocyte subset phenotype and distribution) preclude a direct extrapolation to human pathology. Experimental and pilot clinical studies point to a prominent involvement of intermediate CD14(++)CD16(+) monocytes in human atherosclerosis. Future clinical studies should analyze monocyte heterogeneity in cardiovascular disease. If a specific contribution of intermediate monocytes should be confirmed, immunomodulation of this monocyte subset could represent a future therapeutic target in atherosclerosis.
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http://dx.doi.org/10.1016/j.imbio.2012.07.001DOI Listing
December 2012

Does the measurement of the difference of resistive indexes in spleen and kidney allow a selective assessment of chronic kidney injury?

Radiology 2012 Sep 6;264(3):894-902. Epub 2012 Jul 6.

Department of Internal Medicine IV-Nephrology and Hypertension, Saarland University Hospital, Kirrberger Strasse, 66421 Homburg/Saar, Germany.

Purpose: To determine whether the difference of resistive indexes (RIs) in spleen and kidney (DI-RISK) is a more specific ultrasonographic (US) marker of intrarenal parenchymal damage than intrarenal RI alone.

Materials And Methods: The study was approved by the local ethics committee. All study participants provided informed consent. The authors defined standard values for renal RI, splenic RI, and DI-RISK in 152 healthy subjects; carotid intima media thickness (IMT) was assessed as a marker of systemic vascular disease. Next, the authors measured these US parameters and collected echocardiographic data in 290 patients with chronic kidney disease (stage 2-4) recruited between September 2008 and February 2011 to evaluate the DI-RISK across the spectrum of stages of kidney function. Correlation coefficients were calculated with the Spearman test, and multivariate linear regression was used to analyze independent predictors of renal RI, splenic RI, and DI-RISK.

Results: Healthy subjects had a mean age of 34.3 years ± 8.7, and patients with chronic kidney disease had a mean age of 65.0 years ± 12.3 (P < .001). In healthy subjects, both renal and splenic RIs were associated with IMT (renal RI: r = 0.19, P = .022; splenic RI: r = 0.23, P = .005); there was no correlation between DI-RISK and IMT (r = -0.10, P = .215). Similarly, in patients with chronic kidney disease, renal and splenic RIs correlated with IMT (renal RI: r = 0.33, P < .001; splenic RI: r = 0.30, P = .001). DI-RISK was associated with the estimated glomerular filtration rate (eGFR; r = -0.19, P = .001) but not with IMT (r = 0.08, P = .174). At multivariate regression analysis, DI-RISK was independently associated with eGFR but not with extrarenal factors.

Conclusion: In patients with chronic kidney disease, renal RIs do not selectively indicate organ damage, but also mirror systemic vascular disease. The authors introduced DI-RISK as a potential US marker that may more specifically reflect kidney damage.
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http://dx.doi.org/10.1148/radiol.12111533DOI Listing
September 2012

Cholesterol synthesis, cholesterol absorption, and mortality in hemodialysis patients.

Clin J Am Soc Nephrol 2012 Jun 29;7(6):943-8. Epub 2012 Mar 29.

Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University Medical Center, Homburg, Germany.

Background And Objectives: Recent clinical trials on cholesterol-lowering in patients with CKD yielded conflicting results, which might have resulted from different treatment strategies. Serum cholesterol levels are determined by endogenous synthesis and intestinal absorption, which are differentially influenced by various classes of cholesterol-lowering agents. Assessing markers of cholesterol metabolism has thus been proposed for guidance of lipid-lowering therapy. This study analyzed surrogate markers of cholesterol absorption and synthesis in hemodialysis (HD) patients.

Design, Setting, Participants, & Measurements: In 113 HD patients, lathosterol was measured as a marker of cholesterol synthesis and cholestanol was measured as a marker of cholesterol absorption via gas chromatography. Controls were 229 healthy persons. Overall survival in HD patients was recorded over 3.4-year follow-up.

Results: Compared with controls, HD patients had lower lathosterol and higher cholestanol levels (P<0.001 for both). During follow-up, 58 patients died; higher cholestanol (indicating higher cholesterol absorption) predicted poor outcome among HD patients in multivariate Cox regression analysis after adjustment for potential confounders (hazard ratio for cholestanol above median, 2.24 [95% confidence interval (CI), 1.29-3.89]; P=0.004), whereas lower lathosterol (indicating lower cholesterol synthesis) did not (hazard ratio for lathosterol below median, 1.43 [95% CI, 0.81-2.50]; P=0.22).

Conclusions: This analysis of markers of cholesterol metabolism characterizes HD patients as cholesterol absorbers. In longitudinal analysis, higher levels of cholestanol were associated with all-cause mortality.
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http://dx.doi.org/10.2215/CJN.05170511DOI Listing
June 2012

CKD-associated atherosclerosis and monocyte heterogeneity.

Kidney Int 2012 Mar;81(6):599; author reply 599-600

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http://dx.doi.org/10.1038/ki.2011.433DOI Listing
March 2012

Ultrasound renal resistive index is not an organ-specific predictor of allograft outcome.

Nephrol Dial Transplant 2012 Aug 30;27(8):3315-20. Epub 2012 Jan 30.

Department of Internal Medicine IV, Saarland University Hospital, Homburg, Germany.

Background: Ultrasound-measured renal resistive index (RRI) has been suggested to predict allograft survival in renal transplant recipients. Based on experimental and clinical data, we objected to the theory that RRI specifically mirrors allograft characteristics. Instead, we hypothesized that RRI rather represents a marker of systemic vascular damage than an organ-specific marker. In order to refute this hypothesis, RRI should override the resistive index measured in other abdominal parenchymatous organs-such as the spleen-as predictor of allograft outcome. We therefore set out to simultaneously measure renal and splenic ultrasound resistive index in kidney allograft recipients.

Methods: Eighty-seven stable transplant recipients were recruited. We measured RRI, splenic resistive index (SRI) and an established marker of systemic vascular damage, namely common carotid intima-media thickness (IMT). During a follow-up of 4.9 ± 0.5 years, the occurrence of the combined primary end point, defined as a decrease of ≥ 50% in estimated glomerular filtration rate (eGFR), need for dialysis treatment or death, was recorded.

Results: At baseline, both RRI and SRI correlated with common carotid IMT [RRI: r = 0.203 (P = 0.006); SRI: r = 0.315 (P < 0.001)], but not with allograft-specific markers such as eGFR or proteinuria. Elevated RRI was a weak non-significant predictor of the combined primary end point. Notably, RRI did not surpass SRI as outcome predictor. When analysing individual components of the combined primary end point separately, elevated RRI failed to predict strictly renal events (decrease of ≥ 50% in eGFR/need for dialysis treatment), while it predicted total mortality.

Conclusions: Our findings support the notion that RRI is not a specific indicator of allograft damage. Similar to SRI, RRI is rather associated with systemic vascular damage markers and mortality.
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http://dx.doi.org/10.1093/ndt/gfr805DOI Listing
August 2012