Publications by authors named "Gunnar H Heine"

124 Publications

[SARS-CoV-2 vaccines - what the nephrologist should know].

Dtsch Med Wochenschr 2021 Apr 29;146(7):466-470. Epub 2021 Mar 29.

Universität des Saarlandes, Homburg.

Only fifteen months after the beginning of the COVID-19 pandemic, several vaccines are already available for clinical use. While the spike protein of SARS-CoV-2 constitutes the main target of all predominant SARS-CoV-2 vaccines, they work by different mechanisms (mRNA-based vaccines vs. vector-based vaccines vs. protein-based vaccines).Though there are slight differences regarding the level of protection against mild COVID-19, all five vaccines that have been through phase 3 trials were nearly 100 % effective in preventing severe or fatal cases of COVID-19. The side effects were of short duration.Patients with chronic kidney disease (or other significant comorbidities) were largely excluded from Phase 3 trials, which makes definite recommendations concerning their vaccination difficult. The vaccine's effectiveness may be reduced in that population due to a uremic immune defect and/or immunosuppressive medication. However, these patients have an increased risk for severe or fatal COVID-19, so that they may particularly benefit from the vaccine.
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http://dx.doi.org/10.1055/a-1375-4471DOI Listing
April 2021

Increase of plasma erythroferrone levels during high-altitude exposure: A sub-analysis of the TOP OF HOMe study.

Am J Hematol 2021 05 9;96(5):E179-E181. Epub 2021 Mar 9.

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

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http://dx.doi.org/10.1002/ajh.26130DOI Listing
May 2021

[Anemia and iron deficiency - treatment options in chronic kidney disease and in chronic heart failure].

Dtsch Med Wochenschr 2020 12 30;145(24):1775-1780. Epub 2020 Nov 30.

Agaplesion Markus-Krankenhaus, Medizinische Klinik II, Frankfurt am Main.

Anemia and iron deficiency are highly prevalent in chronic kidney disease (CKD) and in chronic heart failure. Both may epidemiologically predict future renal and/or cardiovascular events. However, anemia treatment with either erythropoietin or erythropoiesis-stimulating agents failed to induce a prognostic benefit in either CKD or chronic heart failure. Instead, in the subgroup of chronic dialysis patients, liberal intravenous iron supplementation was beneficial, and ongoing clinical trials are testing the prognostic implication of intravenous iron supplementation in chronic heart failure. Finally, HIF stabilizers are a new treatment option for anemia in chronic kidney disease, and safety studies are currently ongoing in CKD patients. Whether patients suffering from chronic heart failure might also benefit from this treatment is currently unknown.
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http://dx.doi.org/10.1055/a-1133-7849DOI Listing
December 2020

Current Understanding of the Relationship of HDL Composition, Structure and Function to Their Cardioprotective Properties in Chronic Kidney Disease.

Biomolecules 2020 09 21;10(9). Epub 2020 Sep 21.

Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, 8010 Graz, Austria.

In the general population, the ability of high-density lipoproteins (HDLs) to promote cholesterol efflux is a predictor of cardiovascular events, independently of HDL cholesterol levels. Although patients with chronic kidney disease (CKD) have a high burden of cardiovascular morbidity and mortality, neither serum levels of HDL cholesterol, nor cholesterol efflux capacity associate with cardiovascular events. Important for the following discussion on the role of HDL in CKD is the notion that traditional atherosclerotic cardiovascular risk factors only partially account for this increased incidence of cardiovascular disease in CKD. As a potential explanation, across the spectrum of cardiovascular disease, the relative contribution of atherosclerotic cardiovascular disease becomes less important with advanced CKD. Impaired renal function directly affects the metabolism, composition and functionality of HDL particles. HDLs themselves are a heterogeneous population of particles with distinct sizes and protein composition, all of them affecting the functionality of HDL. Therefore, a more specific approach investigating the functional and compositional features of HDL subclasses might be a valuable strategy to decipher the potential link between HDL, cardiovascular disease and CKD. This review summarizes the current understanding of the relationship of HDL composition, metabolism and function to their cardio-protective properties in CKD, with a focus on CKD-induced changes in the HDL proteome and reverse cholesterol transport capacity. We also will highlight the gaps in the current knowledge regarding important aspects of HDL biology.
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http://dx.doi.org/10.3390/biom10091348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564231PMC
September 2020

[Dilemma situation: Oral anticoagulation in dialysis patients with non-valvular atrial fibrillation].

Dtsch Med Wochenschr 2020 08 24;145(17):1277-1279. Epub 2020 Aug 24.

In patients with intact kidney function and in patients with mild to moderate chronic kidney disease (CKD), strong evidence suggests the use of non-vitamin K dependent oral anticoagulants (NOAC) for preventing ischemic strokes and systemic thromboembolic events in patients with non-valvular atrial fibrillation (nvAF) and elevated thromboembolic risk. In contrast, less evidence is available on the risk-benefit ratio of oral anticoagulation (OAC) in patients with nvAF and severe CKD, particularly in dialysis patients. No large randomised study has tested whether OAC will reduce the risk of thromboembolic events in nvAF without prohibitively high bleeding risk, and whether NOACs or vitamin K antagonists are the superior strategy for OAC. Considering absence of strong evidence, the authors suggest that in dialysis patients with nvAF, in whom the treatment team sees the clear need to prevent thromboembolic events, the use of NOACs or left atrial appendage occlusion should be preferred over treatment with vitamin K antagonists. Any OAC treatment for dialysis patients with nvAF is not in-label in most European countries.
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http://dx.doi.org/10.1055/a-1124-2404DOI Listing
August 2020

Sharp rises in FGF23 and hypophosphatemia after intravenous iron administration do not cause myocardial damage.

Clin Res Cardiol 2020 10 25;109(10):1316-1318. Epub 2020 Mar 25.

Department of Internal Medicine I, University Hospital RWTH Aachen, Pauwelstrasse 30, 52074, Aachen, Germany.

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http://dx.doi.org/10.1007/s00392-020-01630-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515940PMC
October 2020

Limited role for fibroblast growth factor 23 in assessing prognosis in heart failure patients: data from the TIME-CHF trial.

Eur J Heart Fail 2020 04 5;22(4):701-709. Epub 2020 Feb 5.

Department of Cardiology, University Hospital Basel, Basel, Switzerland.

Aim: Fibroblast growth factor 23 (FGF23) is an intensively studied biomarker at the crossroads of cardiovascular disease, heart failure (HF) and chronic kidney disease. Independent associations between increasing FGF23 levels and cardiovascular events were found in many, but not all studies. By analysing data from the TIME-CHF cohort, we sought to investigate the prognostic value of FGF23 in an elderly, multimorbid HF patient cohort. We determined differences between intact (iFGF23) and C-terminal FGF23 (cFGF23) regarding their prognostic value and their levels over time in different HF subgroups according to left ventricular ejection fraction (LVEF).

Methods And Results: In this multicentre trial of 622 patients with symptomatic HF aged ≥60 years, we determined iFGF23 and cFGF23 at baseline, 3, 6 and 12-month follow-up. In unadjusted analyses, cFGF23 significantly predicted all HF-related outcomes at all time points. The predictive value of iFGF23 was less and not statistically significant at baseline. After multivariable adjustments, the association between both cFGF23 and iFGF23 and outcome lost statistical significance apart from cFGF23 at month 3. Overall, patients with preserved and mid-range LVEF had higher levels of iFGF23 and cFGF23 than those with reduced LVEF. Levels decreased significantly during the first 3 months in mid-range and reduced LVEF patients, but did not significantly change over time in those with preserved LVEF.

Conclusions: Fibroblast growth factor 23 is of limited value regarding risk prediction in this elderly HF population. Potentially heterogeneous roles of FGF23 in different LVEF groups deserve further investigation.
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http://dx.doi.org/10.1002/ejhf.1749DOI 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

Does a rise in plasma erythropoietin after high-altitude exposure affect FGF23 in healthy volunteers on a normal or low-phosphorus diet?

Nutr Metab Cardiovasc Dis 2019 12 9;29(12):1361-1367. Epub 2019 Sep 9.

Saarland University Medical Center, Internal Medicine IV - Nephrology and Hypertension, Homburg, Germany; Agaplesion Markus Krankenhaus, Frankfurt (Main), Germany.

Background And Aims: Data of experimental rodent models suggest that hypoxia with subsequent increase in erythropoietin stimulates the expression of the phosphaturic hormone fibroblast growth factor 23 (FGF23).

Methods And Results: To translate the findings of animal studies into human physiology, herein we exposed eight healthy volunteers to high altitude (2656 m above sea level) for four days. The volunteers were randomized on a low-phosphorous diet (n = 4) or a normal phosphorus diet (n = 4). Although high-altitude exposure caused a significant increase in plasma erythropoietin (EPO) (before high-altitude exposure: low phosphorus: median EPO 6.6 mIU/ml [interquartile range (IQR) 6.0; 8.2], normal phosphorus: median EPO 9.0 mIU/ml [IQR 7.9; 11.5]; at day 2: low phosphorus: median EPO 21.3 mIU/ml [IQR 19.5; 23.8], normal phosphorus: median EPO 19.4 mIU/ml [IQR 18.0; 20.8]), there was no consistent increase in plasma c-terminal FGF23 or plasma intact FGF23. We observed only a single, intermittent peak in c-terminal FGF23 levels after 5 h of maximal aerobic exercise.

Conclusion: These data do not support a substantial effect of moderate hypoxia alone on the expression of FGF23, but they suggest that combined exercise and high-altitude exposure may temporarily induce FGF23 expression.
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http://dx.doi.org/10.1016/j.numecd.2019.09.002DOI Listing
December 2019

Low serum lathosterol levels associate with fatal cardiovascular disease and excess all-cause mortality: a prospective cohort study.

Clin Res Cardiol 2019 Dec 4;108(12):1381-1385. Epub 2019 Apr 4.

Klinik für Innere Medizin IV, Abteilung für Nieren-und Hochdruckkrankheiten, Universitätsklinikum des Saarlandes, Homburg, Saar, Germany.

Importance: A more precise identification of patients at "high cardiovascular risk" is preeminent in cardiovascular risk stratification.

Objective: To investigate the relationships between markers of cholesterol homeostasis, cardiovascular events and all-cause mortality.

Design, Setting And Participants: We quantified markers of cholesterol homeostasis by gas chromatography-mass spectrometry in 377 subjects with suspected coronary artery disease, who were not on lipid-lowering drugs at baseline. All patients were followed for occurrence of cardiovascular events and mortality over a period of 4.9 +/- 1.7 years. The standardized mortality ratio (SMR) was calculated as the ratio of the observed and the expected deaths based on the death rates of the Regional Databases Germany, and Poisson regression (rate ratio, RR) was used to compare subgroups. The SMR and RR were standardized for sex, age category and calendar period. In addition, Cox regression (Hazard ratio, HR) was used to determine the effect of co-variables on (cardiovascular) mortality within the cohort.

Main Outcomes: Cardiovascular events, cardiovascular mortality and all-cause mortality.

Results: A total of 42 deaths were observed in 1818 person-years corresponding with an SMR of 0.99 (95% CI 0.71-1.33; p = 0.556). A fatal cardiovascular event occurred in 26 patients. Lower levels of lathosterol were associated with increased cardiovascular mortality (HR 1.59; 95% CI: 1.16-2.17; p = 0.004) and excess all-cause mortality (HR 1.41; 95% CI: 1.09-1.85; p = 0.011). Lower lathosterol tertile compared to the adjacent higher tertile was associated with 1.6 times higher all-cause mortality risk (RR 1.60; 95% CI 1.07-2.40; p for trend = 0.022). This corresponded with a 2.3 times higher mortality risk of a lathosterol-LDL ratio equal to or below the median (RR 2.29; 95% CI 1.19-4.43; p = 0.013). None of the other cholesterol homeostasis markers were associated with cardiovascular and all-cause mortality.

Conclusions: In patients not on lipid-lowering agents, low serum lathosterol correlated with increased risk of cardiovascular events and excess all-cause mortality.
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http://dx.doi.org/10.1007/s00392-019-01474-2DOI Listing
December 2019

[The Cardiorenal Syndrome].

Dtsch Med Wochenschr 2019 03 28;144(6):e2. Epub 2019 Mar 28.

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http://dx.doi.org/10.1055/a-0884-5458DOI Listing
March 2019

[The Cardiorenal Syndrome].

Dtsch Med Wochenschr 2019 03 14;144(6):382-386. Epub 2019 Mar 14.

In patients with chronic cardio renal syndrome chronic heart disease coexists with chronic kidney disease and poses the patients to a specifically high risk for cardiovascular events and mortality. Treatment recommendations in this condition with a high level of evidence are sparse. Mainstay of therapy in cardiorenal syndrome is fluid metabolism control and stabilization of renal and cardiac function, which can basically been achieved by substances modifying the renin-angiotensin-aldosterone-system as well as diuretics. Noteworthy, despite inducing short-term decreases in renal function, inhibition of the RAAS and diuretic medication associate with the long-term improvements of outcome (so-called pseudo-worsening of renal function). The chronic cardiorenal syndrome calls for interdisciplinary care by both nephrologists and cardiologists in order to allow high-end patient care with a maximum of beneficial effect and a minimum of treatment-related side effects.
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http://dx.doi.org/10.1055/a-0661-4456DOI Listing
March 2019

Strength of Fibroblast Growth Factor 23 as a Cardiovascular Risk Predictor in Chronic Kidney Disease Weaken by ProBNP Adjustment.

Am J Nephrol 2019 26;49(3):203-211. Epub 2019 Feb 26.

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

Background: Various epidemiological studies linked high fibroblast growth factor 23 (FGF23) levels with cardiovascular events in chronic kidney disease (CKD). It remains enigmatic whether high FGF23 exerts adverse cardiovascular effects, or whether it reflects detrimental effects of residual confounders. Earlier studies adjusted for CKD-mineral bone disease (CKD-MBD) regulators of FGF23 rather than for recently discovered non-CKD-MBD regulators, among which iron deficiency and heart failure are of particular importance. Moreover, they used c-terminal FGF23 (cFGF23) assays rather than more specific intact FGF23 (iFGF23) assays.

Methods: The CARE FOR HOMe study analyzed plasma ferritin, iFGF23, cFGF23 and N-terminal proBNP (NT-proBNP) along with conventional risk factors, among 575 CKD G2-G4 patients to determine the interaction between FGF23, its non-CKD-MBD regulators, and incident cardiovascular events in CKD patients. The participants were followed up for 5.1 ± 2.1 years for the occurrence of atherosclerotic events and hospitalization for acute decompensated heart failure.

Results: cFGF23 correlated strongly with high iFGF23 (r = 0.607), fairly with high NT-proBNP (r = 0.453) and weakly with low ferritin (r = -0.207); correlation coefficients of iFGF23 with NT-proBNP and ferritin were numerically lower. In Kaplan-Meier analyses, both endpoints were predicted by cFGF23 and iFGF23. In Cox regression models, cFGF23 remained an outcome predictor after adjustment for conventional risk factors and ferritin. This prediction was largely eliminated when further adjusting for NT-proBNP. iFGF23 was less consistently associated with adverse outcome in partly adjusted models, and failed to predict outcome in fully adjusted models.

Conclusion: In summary, iron deficiency and heart failure affect plasma FGF23. As adjustment for NT-proBNP virtually eliminates the association between plasma FGF23 and predefined outcome, we speculate that high FGF23, rather than exerting detrimental cardiovascular effects, mirrors prevalent heart disease.
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http://dx.doi.org/10.1159/000497125DOI Listing
May 2020

Author Correction: Lipid management in patients with chronic kidney disease.

Nat Rev Nephrol 2019 Feb;15(2):121

CNR- IFC, Clinical Epidemiology and Pathophysiology of Hypertension and Renal Diseases, Ospedali Riuniti, Italy.

In the acknowledgements section of this article as originally published, information on the authors' roles as EURECAm members is missing. The correct acknowledgement is as follows: "This Review was planned as part of the activity of the European Renal and Cardiovascular Medicine working (EURECAm) group and all authors are EURECAm members. A.O.'s work was supported by Spanish Government ISCIII FEDER funds (PI16/02057, ISCIII-RETIC REDinREN RD16/0009) and Community of Madrid (B2017/BMD-3686 CIFRA2-CM). P.R.'s work is supported by a public grant overseen by the French National Research Agency (ANR) as part of the second "Investissements d'Avenir" program FIGHT-HF (reference: ANR-15-RHU-0004) and by the French PIA project "Lorraine Université d'Excellence", reference ANR-15-IDEX-04-LUE." The omission has been corrected in the PDF and HTML versions of the article.
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http://dx.doi.org/10.1038/s41581-018-0099-yDOI Listing
February 2019

Plasma levels of the oxyphytosterol 7α-hydroxycampesterol are associated with cardiovascular events.

Atherosclerosis 2018 12 17;279:17-22. Epub 2018 Oct 17.

Institut für Klinische Chemie und Klinische Pharmakologie, Universitätsklinikum Bonn, Germany. Electronic address:

Background And Aims: There are safety issues regarding plant sterol ester-enriched functional food. Oxidized plant sterols, also called oxyphytosterols, are supposed to contribute to plant sterol atherogenicity. This study aimed to analyze associations of plasma oxyphytosterol levels with cardiovascular events.

Methods: Plasma cholesterol was measured by gas chromatography-flame ionization detection. Plasma campesterol and sitosterol and their 7-oxygenated metabolites were analyzed by gas chromatography-mass selective detection.

Results: In 376 patients admitted for elective coronary angiography, who were not on lipid-lowering drugs, 82 cardiovascular events occurred during a follow-up period of 4.2 ± 1.8 years. Patients with cardiovascular events had significantly higher 7α-hydroxycampesterol plasma levels (median, 0.46; [interquartile range (IQR) 0.22-0.81] nmol/L vs. median, 0.25 [IQR, 0.17-0.61] nmol/L; p = 0.003) and 7α-hydroxycampesterol-to-cholesterol ratios (median 0.08 [IQR, 0.04-0.14] nmol/mmol vs. median, 0.05 [IQR 0.03-0.11] nmol/mmol; p = 0.005) than controls without such events. Patients above the median were characterized by higher cumulative event rates in Kaplan-Meier-analysis (Logrank-test p = 0.084 and p = 0.025) for absolute and cholesterol corrected 7α-hydroxycampesterol, respectively. After adjustment for influencing factors and related lipids, the hazard ratios per one standard deviation of the log-transformed variables (HR) were 1.19 [95% confidence interval (CI), 0.95-1.48], p = 0.132 for 7α-hydroxycampesterol and HR, 1.18 [95% CI, 0.94-1.48], p = 0.154 for 7α-hydroxycampesterol-to-cholesterol ratio. None of the other investigated oxyphytosterols showed an association with cardiovascular events.

Conclusions: In patients not on lipid-lowering drugs, absolute plasma levels of 7α-hydroxycampesterol and their ratios to cholesterol are associated with cardiovascular events. Further research is required to elucidate the role of OPS in cardiovascular diseases.
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http://dx.doi.org/10.1016/j.atherosclerosis.2018.10.010DOI Listing
December 2018

Lipid management in patients with chronic kidney disease.

Nat Rev Nephrol 2018 12;14(12):727-749

CNR-IFC, Clinical Epidemiology and Pathophysiology of Hypertension and Renal Diseases, Ospedali Riuniti, Italy.

An increased risk of cardiovascular disease, independent of conventional risk factors, is present even at minor levels of renal impairment and is highest in patients with end-stage renal disease (ESRD) requiring dialysis. Renal dysfunction changes the level, composition and quality of blood lipids in favour of a more atherogenic profile. Patients with advanced chronic kidney disease (CKD) or ESRD have a characteristic lipid pattern of hypertriglyceridaemia and low HDL cholesterol levels but normal LDL cholesterol levels. In the general population, a clear relationship exists between LDL cholesterol and major atherosclerotic events. However, in patients with ESRD, LDL cholesterol shows a negative association with these outcomes at below average LDL cholesterol levels and a flat or weakly positive association with mortality at higher LDL cholesterol levels. Overall, the available data suggest that lowering of LDL cholesterol is beneficial for prevention of major atherosclerotic events in patients with CKD and in kidney transplant recipients but is not beneficial in patients requiring dialysis. The 2013 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Lipid Management in CKD provides simple recommendations for the management of dyslipidaemia in patients with CKD and ESRD. However, emerging data and novel lipid-lowering therapies warrant some reappraisal of these recommendations.
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http://dx.doi.org/10.1038/s41581-018-0072-9DOI Listing
December 2018

Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium.

Am J Kidney Dis 2019 02 19;73(2):206-217. Epub 2018 Oct 19.

BC Provincial Renal Agency and University of British Columbia, Canada.

Rationale & Objective: Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework.

Study Design: Cross-sectional individual participant-level analyses in a global consortium.

Setting & Study Populations: 17 CKD and 38 general population and high-risk cohorts.

Selection Criteria For Studies: Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension.

Data Extraction: Data were obtained and analyzed between July 2015 and January 2018.

Analytical Approach: We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses.

Results: The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g).

Limitations: Variations in study era, health care delivery system, typical diet, and laboratory assays.

Conclusions: Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD.
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http://dx.doi.org/10.1053/j.ajkd.2018.08.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348050PMC
February 2019

In Reply.

Authors:
Gunnar H Heine

Dtsch Arztebl Int 2018 09;155(37):606-607

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http://dx.doi.org/10.3238/arztebl.2018.0606bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6206395PMC
September 2018

Dickkopf-3 (DKK3) in Urine Identifies Patients with Short-Term Risk of eGFR Loss.

J Am Soc Nephrol 2018 11 2;29(11):2722-2733. Epub 2018 Oct 2.

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

Background: The individual course of CKD may vary, and improved methods for identifying which patients will experience short-term eGFR loss are needed. Assessing urinary Dickkopf-3 (DKK3), a stress-induced tubular epithelia-derived profibrotic glycoprotein, may provide information about ongoing tubulointerstitial fibrosis and short-term eGFR loss.

Methods: To investigate urinary DKK3's potential as a biomarker of short-term eGFR loss (over 12 months), we prospectively assessed eGFR and urinary DKK3 levels in patients with CKD of various etiologies at baseline and annual follow-ups. We also measured urinary DKK3 in a general population sample and patients with diagnostic kidney biopsies or IgA nephropathy under treatment.

Results: Median urinary DKK3-to-creatinine concentration at baseline was significantly higher in patients with CKD than the general population sample (431 versus 33 pg/mg). In the CKD cohort, having a urinary DKK3-to-creatinine level >4000 pg/mg was independently and significantly associated after multiple adjustments with mean annual decline in eGFR of 7.6% over 12 months. Urinary DKK3 significantly improved prediction of kidney function decline compared with eGFR or albuminuria alone. Urinary DKK3-to-creatinine levels were related to the extent of tubulointerstitial fibrosis in kidney biopsies. In patients with IgA nephropathy, a rise in urinary DKK3 was associated with significant eGFR decline within 6 months, whereas stable or decreasing urinary DKK3 indicated a more favorable course.

Conclusions: Urinary DKK3 levels identify patients at high risk for eGFR decline over the next 12 months regardless of the cause of kidney injury and beyond established biomarkers, potentially providing a tool to monitor CKD progression and assess effects of interventions.
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http://dx.doi.org/10.1681/ASN.2018040405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218861PMC
November 2018

Plasma FGF23 does not rise during physical exercise as a physiological model of sympathetic activation.

Clin Res Cardiol 2019 Mar 8;108(3):341-343. Epub 2018 Aug 8.

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

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http://dx.doi.org/10.1007/s00392-018-1347-7DOI Listing
March 2019

Corrigendum: FGF23 in Cardiovascular Disease: Innocent Bystander or Active Mediator?

Front Endocrinol (Lausanne) 2018 18;9:422. Epub 2018 Jul 18.

Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany.

[This corrects the article DOI: 10.3389/fendo.2018.00351.].
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http://dx.doi.org/10.3389/fendo.2018.00422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6058598PMC
July 2018

FGF23 in Cardiovascular Disease: Innocent Bystander or Active Mediator?

Front Endocrinol (Lausanne) 2018 27;9:351. Epub 2018 Jun 27.

Department of Cardiology, University Hospital of the RWTH Aachen, Aachen, Germany.

Fibroblast growth factor-23 (FGF23) is a mainly osteocytic hormone which increases renal phosphate excretion and reduces calcitriol synthesis. These renal actions are mediated via alpha-klotho as the obligate co-receptor. Beyond these canonical "mineral metabolism" actions, FGF23 has been identified as an independent marker for cardiovascular risk in various patient populations. Previous research has linked elevated FGF23 predominantly to left-ventricular dysfunction and consecutive morbidity and mortality. Moreover, some experimental data suggest FGF23 as a direct and causal stimulator for cardiac hypertrophy via specific myocardial FGF23-receptor activation, independent from alpha-klotho. This hypothesis offers fascinating prospects in terms of therapeutic interventions, specifically in patients with chronic kidney disease (CKD) in whom the FGF23 system is strongly stimulated and in whom left-ventricular dysfunction is a major disease burden. However, novel data challenges the previous stand-alone hypothesis about a one-way road which guides unidirectionally skeletal FGF23 toward cardiotoxic effects. In fact, recent data point toward local myocardial production and release of FGF23 in cases where (acute) myocardial damage occurs. The effects of this local production and the physiological meaning are under current examination. Moreover, epidemiologic studies suggest that high FGF-23 may follow, rather than induce, myocardial disease in certain conditions. In summary, while FGF23 is an interesting link between mineral metabolism and cardiac function underlining the meaning of the bone-heart axis, more research is needed before therapeutic interventions may be considered.
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http://dx.doi.org/10.3389/fendo.2018.00351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6036253PMC
June 2018

L-Homoarginine and its AGXT2-metabolite GOCA in chronic kidney disease as markers for clinical status and prognosis.

Amino Acids 2018 Oct 7;50(10):1347-1356. Epub 2018 Jul 7.

Institute of Clinical Pharmacology, Otto-von-Guericke University, Leipziger Str. 44, 39120, Magdeburg, Germany.

Plasma concentrations of L-homoarginine (hArg) are an emerging marker for clinical status and prognosis in renal and cardiovascular disease. Lowered hArg concentrations are associated with higher risk for these conditions, although a clear pathophysiological explanation for this association has not been established. Baseline plasma samples of patients with different stages of chronic kidney disease (CKD) (n = 527) were obtained from the CARE FOR HOMe study and were analyzed for hArg and, for the first time, its metabolite 6-guanidino-2-oxocaproic acid (GOCA) by isotope dilution LC-MS/MS methods. GOCA is converted from hArg by the enzyme alanine:glyoxylate aminotransferase 2 (AGXT2), which is also in the focus of current cardiovascular research. hArg levels ranged from 0.20-4.01 µmol/L with a median of 1.42 µmol/L, whereas GOCA levels were 0.08-25.82 nmol/L with a median of 1.45 nmol/L. hArg levels in the highest tertile (≥ 1.71 µmol/L) were associated with significantly lower risk for reaching the renal (hazard ratio 0.369, 95% confidence interval 0.028-0.655) or cardiovascular (HR 0.458, CI 0.295-0.712) endpoints in univariate Cox regression analysis. Inversely, GOCA levels in the highest tertile (≥ 2.13 nmol/L) were associated with increased renal (HR 3.807, CI 1.963-7.381) and cardiovascular (HR 1.611, CI 1.041-2.495) risk. A decreased ratio between hArg and GOCA predicted even more pronounced the risks for renal (HR 0.178, CI 0.087-0.363) and cardiovascular (HR 0.447, CI 0.281-0.709) events. However, adjustment for the confounders eGFR and albuminuria attenuated these findings. A pathophysiological role of an increased activity of AGXT2 in CKD should be evaluated in future clinical studies.
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http://dx.doi.org/10.1007/s00726-018-2610-yDOI Listing
October 2018

HDL functionality and cardiovascular outcome among nondialysis chronic kidney disease patients.

J Lipid Res 2018 07 22;59(7):1256-1265. Epub 2018 May 22.

Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Graz, Austria

CVD remains the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). CKD profoundly affects HDL composition and functionality, but whether abnormal HDL independently contributes to cardiovascular events in CKD patients remains elusive. In the present study, we assessed whether compositional and functional properties of HDL predict cardiovascular outcome among 526 nondialysis CKD patients who participate in the CARE FOR HOMe study. We measured HDL cholesterol, the content of HDL-associated proinflammatory serum amyloid A (SAA), and activities of the HDL enzymes paraoxonase and lipoprotein-associated phospholipase A2 (Lp-PLA). In addition, we assessed the antioxidative activity of apoB-depleted serum. During a mean follow-up of 5.1 ± 2.1 years, 153 patients reached the predefined primary endpoint, a composite of atherosclerotic cardiovascular events including cardiovascular mortality and death of any cause. In univariate Cox regression analyses, lower HDL-cholesterol levels, higher HDL-associated SAA content, and lower paraoxonase activity predicted cardiovascular outcome, while Lp-PLA activity and antioxidative capacity did not. HDL-cholesterol and HDL-paraoxonase activity lost their association with cardiovascular outcome after adjustment for traditional cardiovascular and renal risk factors, while SAA lost its association after further adjustment for C-reactive protein. In conclusion, our data suggest that neither HDL quantity nor HDL composition or function independently predict cardiovascular outcome among nondialysis CKD patients.
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http://dx.doi.org/10.1194/jlr.P085076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027904PMC
July 2018

Oral Anticoagulation in Chronic Kidney Disease and Atrial Fibrillation.

Dtsch Arztebl Int 2018 04;115(17):287-294

Saarland University Medical Center, Saarland University Faculty of Medicine, Internal Medicine IV - Nephrology and Hypertension, Homburg; Department of Cardiology, University Hospital RWTH Aachen; Saarland University Medical Center, Saarland University Faculty of Medicine, Internal Medicine III - Cardiology, Angiology, Intensive Care Medicine, Homburg.

Background: Cardiological societies recommend, in their guidelines, that patients with atrial fibrillation and an intermediate (or higher) risk of stroke and systemic embolization should be treated with oral anticoagulant drugs. For patients who do not have mitral valve stenosis or a mechanical valve prosthesis, non-vitamin-K dependent oral anticoagulants (NOAC) are preferred over vitamin K antagonists (VKA) for this purpose. It is unclear, however, whether patients with chronic kidney disease and atrial fibrillation benefit from oral anticoagulation to the same extent as those with normal kidney function. It is also unclear which of the two types of anti - coagulant drug is preferable for patients with chronic kidney disease; NOAC are, in part, renally eliminated.

Methods: This review is based on pertinent publications retrieved by a selective literature search, and on international guidelines.

Results: Current evidence suggests that patients with atrial fibrillation who have chronic kidney disease with a glomerular filtration rate (GFR) above 15 mL/ min/1.73 m² should be treated with an oral anticoagulant drug if they have an at least intermediate risk of embolization, as assessed with the CHA2DS2-VASc score. For patients with advanced chronic kidney disease (GFR from 15 to 29 mL/ min/1.73 m²), however, this recommendation is based only on registry studies. For dialysis patients with atrial fibrillation, decisions whether to give oral anticoagulant drugs should be taken on an individual basis, in view of the elevated risk of hemorrhage and the unclear efficacy of such drugs in these patients. The subgroup analyses of the NOAC approval studies show that, for patients with atrial fibrillation and chronic kidney disease with a creatinine clearance of >25-30 mL/min, NOAC should be given in preference to VKA, as long as the patient does not have mitral valve stenosis or a mechanical valve prosthesis. For those whose creatinine clearance is less than 25 mL/min, the relative merits of NOAC versus VKA are still debated.

Conclusion: The cardiological societies' recommendation that patients with atrial fibrillation should be given oral anticoagulant drugs applies to the majority of such patients who also have chronic kidney disease.
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http://dx.doi.org/10.3238/arztebl.2018.0287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974258PMC
April 2018

Do plasma neprilysin activity and plasma neprilysin concentration predict cardiac events in chronic kidney disease patients?

Nephrol Dial Transplant 2019 01;34(1):100-108

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

Background: Since the introduction of sacubitril/valsartan in clinical cardiology, neprilysin has become a major target for heart failure treatment. Plasma neprilysin concentration has been discussed as a novel biomarker that predicts cardiac events. Natriuretic peptides may inhibit plasma neprilysin. As they accumulate in chronic kidney disease (CKD), we hypothesized that high plasma neprilysin loses its predictive role in CKD patients.

Methods: We measured plasma levels of neprilysin concentration, neprilysin activity and brain natriuretic peptide (BNP) in 542 CKD G2-G4 patients within the CARE FOR HOMe study. Patients were followed for predefined endpoints of hospitalization for acute decompensated heart failure and incident atherosclerotic cardiovascular events.

Results: During 5.1 ± 2.1 years, 63 patients had acute decompensated heart failure and 125 patients had incident atherosclerotic cardiovascular events. In both Kaplan-Meier and multivariate Cox regression analyses, high plasma BNP and low, rather than elevated, neprilysin activity predicted future hospitalization for acute decompensated heart failure; neprilysin concentration was not predictive. Furthermore, only BNP was an independent predictor of incident atherosclerotic cardiovascular events.

Conclusions: In line with experimental studies, high natriuretic peptides may inhibit neprilysin activity in CKD. Therefore, high neprilysin activity and concentrations are not predictors of adverse cardiovascular outcome in CKD patients. Thus neprilysin inhibitors should be implemented with caution in patients with advanced CKD.
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http://dx.doi.org/10.1093/ndt/gfy066DOI Listing
January 2019

Association of Nonoxidized Parathyroid Hormone with Cardiovascular and Kidney Disease Outcomes in Chronic Kidney Disease.

Clin J Am Soc Nephrol 2018 04 5;13(4):569-576. Epub 2018 Mar 5.

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

Background And Objectives: In patients with CKD, elevated plasma parathyroid hormone (PTH) levels are associated with greater cardiovascular morbidity and mortality. However, the reference method for PTH measurement is disputed. It has been argued that measurement of nonoxidized PTH better reflects biologically active PTH than measurements with conventional assays.

Design, Setting, Participants, & Measurements: PTH and nonoxidized PTH levels were measured at study baseline in 535 patients with CKD with an eGFR range between 89 and 15 ml/min per 1.73 m. Patients were followed over 5.1 years for the occurrence of acute heart failure, atherosclerotic events, CKD progression (doubling of serum creatinine or initiation of RRT), or all-cause death.

Results: Atherosclerotic events, acute heart failure, CKD progression, and deaths from any cause occurred in 116, 58, 73, and 85 patients, respectively. In Kaplan-Meier analyses, patients at the highest PTH and nonoxidized-PTH tertile (79-543 and 12-172 pg/ml, respectively) showed a higher rate of atherosclerotic events, acute heart failure, CKD progression, and death from any cause. After adjustment for eGFR and albuminuria, nonoxidized PTH was no longer associated with atherosclerotic events (hazard ratio third versus first tertile, 1.04 [95% confidence intervals, 0.62-1.75]), acute heart failure (hazard ratio third versus first tertile, 1.24 [95% confidence intervals, 0.59-2.62]), CKD progression (hazard ratio third versus first tertile, 0.93 [95% confidence intervals, 0.46-1.90]), and death from any cause (hazard ratio third versus first tertile, 1.23 [95% confidence intervals, 0.66-2.31]), and PTH lost its association with atherosclerotic events (hazard ratio third versus first tertile, 0.80 [95% confidence intervals, 0.46-1.38]) and CKD progression (hazard ratio third versus first tertile, 0.99 [95% confidence intervals, 0.46-2.10]), although it remained associated with acute heart failure (hazard ratio third versus first tertile, 2.76 [95% confidence intervals, 1.11-6.89]) and all-cause death (hazard ratio third versus first tertile, 2.35 [95% confidence intervals, 1.13-4.89]). After further adjustment for cardiovascular and kidney risk factors, PTH remained associated with all-cause death (hazard ratio third versus first tertile, 2.79 [95% confidence intervals, 1.32-5.89]), but with no other end point.

Conclusions: In a cohort of patients with CKD, PTH was associated with all-cause mortality; there was no association of nonoxidized PTH with any of the clinical outcomes examined.
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http://dx.doi.org/10.2215/CJN.06620617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5968904PMC
April 2018

Validation of echocardiographic criteria for the clinical diagnosis of heart failure in chronic kidney disease.

Nephrol Dial Transplant 2018 04;33(4):653-660

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

Background: The Acute Dialysis Quality Initiative (ADQI) XI Workgroup has suggested defining heart failure (HF) in patients with end-stage renal disease by the presence of at least one out of eight predefined echocardiographic criteria. Given the high prevalence of echocardiographic alterations in chronic kidney disease (CKD) patients, we hypothesized that application of echocardiographic ADQI criteria will result in overdiagnosis of HF, without providing substantial prognostic information.

Methods: Among 472 CKD stage G2-G4 patients recruited in the CARE FOR HOMe study, we assessed the presence of left-ventricular (LV) hypertrophy, valvular dysfunction, high left-atrial volume index (LAVI), systolic and diastolic LV dysfunction, enlarged LV diameter, and altered regional LV wall contractility. According to the ADQI proposal, presence of one or more of these alterations defined HF. We followed all patients for the occurrence of cardiac decompensation, defined as hospital admission for decompensated HF.

Results: A total of 313 (66%) out of 472 patients fulfilled at least one ADQI echocardiographic criterion for HF. Echocardiographic alterations were more common in advanced (G3b/G4: 80%) than in milder (G2/G3a: 56%) CKD. Within subcategories of echocardiographic criteria, an increased LAVI (50%) and diastolic dysfunction (30%) were the most frequent findings. During follow-up of 4.3 ± 2.0 years, the majority (87%) of all 313 patients who fulfilled ADQI echocardiographic criteria were not hospitalized for cardiac decompensation.

Conclusions: Echocardiographic criteria proposed by ADQI as a precondition for the clinical staging of HF are virtually omnipresent among CKD patients. By labelling a majority of CKD patients as having HF, application of ADQI criteria fails to specifically identify patients at high risk for future cardiac events.
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http://dx.doi.org/10.1093/ndt/gfx197DOI Listing
April 2018