Plasma Concentrations of Trimethylamine-N-Oxide, Choline, and Betaine in Patients With Moderate to Advanced Chronic Kidney Disease and Their Relation to Cardiovascular and Renal Outcomes.

OBJECTIVES: Trimethylamine N-oxide (TMAO) is a gut bacteria-mediated liver metabolite of dietary betaine, choline, and carnitine, which is excreted by glomerular filtration. We studied whether TMAO is excreted by cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). METHODS: Among 478 patients with CKD stage G2 (n = 104), G3a (n = 163), G3b (n = 123), and G4 (n = 88), we studied the association between fasting plasma concentrations of TMAO, choline, or betaine at baseline and kidney function, prevalent CVD, and future renal outcomes during a mean follow-up of 5.1 years. RESULTS: Decreased glomerular filtration rate was associated with higher plasma concentrations of TMAO, choline, and betaine. Baseline concentrations of TMAO were higher in participants with preexisting CVD compared to those without CVD (8.4 [10.1] vs. 7.8 [8.0] µmol/L; P = .047), but the difference was not significant after adjusting for confounders. During the follow-up, 147 participants experienced CVD or died, and 144 reached the predefined renal endpoint. In the adjusted regression analyses, TMAO or choline concentrations in the upper three quartiles (vs. the lowest quartile) were not associated with any of the study's clinical endpoints. In contrast, the adjusted hazard ratio of plasma betaine in the highest quartile versus the lowest quartile was 2.14 (1.32, 3.47) for the CVD endpoint and 1.64 (1.00, 2.67) for the renal endpoint. CONCLUSIONS: Elevated plasma TMAO concentrations were explained by impaired kidney function. Elevated plasma concentrations of betaine, but not those of TMAO or choline, constituted a risk factor for adverse outcomes. TMAO might not be an appropriate target to reduce CVD or renal outcomes in patients with preexisting CKD.

Chronic kidney disease and the global public health agenda: an international consensus.

Early detection is a key strategy to prevent kidney disease, its progression and related complications, but numerous studies show that awareness of kidney disease at the population level is low. Therefore, increasing knowledge and implementing sustainable solutions for early detection of kidney disease are public health priorities. Economic and epidemiological data underscore why kidney disease should be placed on the global public health agenda - kidney disease prevalence is increasing globally and it is now the seventh leading risk factor for mortality worldwide. Moreover, demographic trends, the obesity epidemic and the sequelae of climate change are all likely to increase kidney disease prevalence further, with serious implications for survival, quality of life and health care spending worldwide. Importantly, the burden of kidney disease is highest among historically disadvantaged populations that often have limited access to optimal kidney disease therapies, which greatly contributes to current socioeconomic disparities in health outcomes. This joint statement from the International Society of Nephrology, European Renal Association and American Society of Nephrology, supported by three other regional nephrology societies, advocates for the inclusion of kidney disease in the current WHO statement on major non-communicable disease drivers of premature mortality.

DKK3 as a potential novel biomarker in patients with autosomal polycystic kidney disease.

Backgound: Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, and leads to a steady loss of kidney function in adulthood. The variable course of the disease makes it necessary to identify the patients with rapid disease progression who will benefit the most from targeted therapies and interventions. Currently, magnetic resonance imaging-based volumetry of the kidney is the most commonly used tool for this purpose. Biomarkers that can be easily and quantitatively determined, which allow a prediction of the loss of kidney function, have not yet been established in clinical practice. The glycoprotein Dickkopf 3 (DKK3) which is secreted in the renal tubular epithelium upon stress and contributes to tubulointerstitial fibrosis via the Wnt signaling pathway, was recently described as a biomarker for estimating risk of kidney function loss, but has not been investigated for ADPKD. This study aimed to obtain a first insight into whether DKK3 may indeed improve outcome prediction in ADPKD in the future. Methods: In 184 ADPKD patients from the AD(H)PKD registry and 47 healthy controls, the urinary DKK3 (uDKK3) levels were determined using ELISA. Multiple linear regression was used to examine the potential of these values in outcome prediction. Results: ADPKD patients showed significantly higher uDKK3 values compared with the controls (mean 1970 ± 5287 vs 112 ± 134.7 pg/mg creatinine). Furthermore, there was a steady increase in uDKK3 with an increase in the Mayo class (A/B 1262 ± 2315 vs class D/E 3104 ± 7627 pg/mg creatinine), the best-established biomarker of progression in ADPKD. uDKK3 also correlated with estimated glomerular filtration rate (eGFR). Patients with PKD1 mutations show higher uDKK3 levels compared with PKD2 patients (PKD1: 2304 ± 5119; PKD2: 506.6 ± 526.8 pg/mg creatinine). Univariate linear regression showed uDKK3 as a significant predictor of future eGFR slope estimation. In multiple linear regression this effect was not significant in models also containing height-adjusted total kidney volume and/or eGFR. However, adding both copeptin levels and the interaction term between copeptin and uDKK3 to the model resulted in a significant predictive value of all these three variables and the highest R2 of all models examined (∼0.5). Conclusion: uDKK3 shows a clear correlation with the Mayo classification in patients with ADPKD. uDKK3 levels correlated with kidney function, which could indicate that uDKK3 also predicts a disproportionate loss of renal function in this collective. Interestingly, we found an interaction between copeptin and uDKK3 in our prediction models and the best model containing both variables and their interaction term resulted in a fairly good explanation of variance in eGFR slope compared with previous models. Considering the limited number of patients in these analyses, future studies will be required to confirm the results. Nonetheless, uDKK3 appears to be an attractive candidate to improve outcome prediction of ADPKD in the future.

Rapid and Effective Elimination of Myoglobin with CytoSorb® Hemoadsorber in Patients with Severe Rhabdomyolysis.

INTRODUCTION: Rhabdomyolysis is characterized by destruction of muscle fibers by various causes and is diagnosed by increased creatine kinase concentrations in the blood. Myoglobin released into the blood may cause acute kidney injury. In this randomized controlled study, we hypothesized that myoglobin elimination would be faster when a hemoadsorber was added to a continuous veno-venous hemodialysis (CVVHD). METHODS: Four patients in the control group received CVVHD with a high cut-off hemofilter using high blood and dialysate flows for 48 h. Four patients in the CytoSorb group received the same treatment, but in addition, the hemoadsorber CytoSorb® was inserted in front of the hemofilter and replaced once after 24 h. Blood samples were drawn simultaneously before (pre) and after (post) the hemofilter or else the hemoadsorber, after 5 and 30 min, as well as after 2, 4, 8, and 24 h. All measurements were repeated the next day after the hemoadsorber had been renewed in the CytoSorb group. Primary outcome was the area under the curve (AUC) of the relative myoglobin concentrations as percent of baseline. To evaluate the efficacy of myoglobin removal, relative reductions in myoglobin concentrations during one passage through each device at each time point were calculated. RESULTS: Patients in the CytoSorb group had a significantly lower AUC during the first 24 h (42 ± 10% vs. 63 ± 6%, p = 0.029) as well as during the observation period of 48 h (26 ± 7% vs. 51 ± 12%, p = 0.029). The relative reductions for myoglobin were considerably higher in the CytoSorb group compared to the control group during the first 8 h. CONCLUSION: Myoglobin concentrations declined considerably faster when CytoSorb was added to a CVVHD. When compared to a high-cut-off hemofilter, efficacy of CytoSorb in myoglobin elimination was much better. Because of saturation after 8-12 h an exchange may be necessary.

ELOVL2-methylation and renal and cardiovascular event in patients with chronic kidney disease.

BACKGROUND: Methylation of the Elongation Of Very Long Chain Fatty Acids-Like 2 (ELOVL2) gene promoter may predict premature ageing and cardiovascular risk. METHODS: We studied the cross-sectional associations between blood ELOVL2-methylation and cardiovascular risk factors in 350 patients with chronic kidney disease (CKD) stage G2-G4 aged between 22 and 90 years. In a follow-up study for a mean of 3.9 years, we investigated the association between baseline ELOVL2-methylation and renal or cardiovascular events including death. RESULTS: ELOVL2-methylation at seven CpG cites increased with age (the correlation coefficients between 0.67 and 0.87, p < 0.001). The ELOVL2-CpGs methylation was lower in patients with CKD stage G2 versus those in stage G3a, G3b and G4, but the differences were explained by age. ELOVL2-CpGs methylation showed no correlations with cardiovascular risk factors after adjusting for age. During the follow-up, 64 patients showed deterioration in renal function or died and 77 showed cardiovascular events or died. The hazard ratio and 95% confidence intervals for renal or cardiovascular events according to baseline ELOVL2-CpGs methylation were not significant after adjustment for covariates. CONCLUSIONS: ELOVL2-hypermethylation showed a strong association with age, but was not independently associated with cardiovascular risk factors or with future renal or cardiovascular events in patients with CKD. ELOVL2 gene methylation is not likely to be itself a cause for ageing or illnesses, but it could be rather influenced by other upstream processes that deserve investigation.

Urinary DKK3 as a biomarker for short-term kidney function decline in children with chronic kidney disease: an observational cohort study.

BACKGROUND: Childhood-onset chronic kidney disease is a progressive condition that can have a major effect on life expectancy and quality. We evaluated the usefulness of the kidney tubular cell stress marker urinary Dickkopf-related protein 3 (DKK3) in determining the short-term risk of chronic kidney disease progression in children and identifying those who will benefit from specific nephroprotective interventions. METHODS: In this observational cohort study, we assessed the association between urinary DKK3 and the combined kidney endpoint (ie, the composite of 50% reduction of the estimated glomerular filtration rate [eGFR] or progression to end-stage kidney disease) or the risk of kidney replacement therapy (ie, dialysis or transplantation), and the interaction of the combined kidney endpoint with intensified blood pressure reduction in the randomised controlled ESCAPE trial. Moreover, urinary DKK3 and eGFR were quantified in children aged 3-18 years with chronic kidney disease and urine samples available enrolled in the prospective multicentre ESCAPE (NCT00221845; derivation cohort) and 4C (NCT01046448; validation cohort) studies at baseline and at 6-monthly follow-up visits. Analyses were adjusted for age, sex, hypertension, systolic blood pressure SD score (SDS), BMI SDS, albuminuria, and eGFR. FINDINGS: 659 children were included in the analysis (231 from ESCAPE and 428 from 4C), with 1173 half-year blocks in ESCAPE and 2762 in 4C. In both cohorts, urinary DKK3 above the median (ie, >1689 pg/mg creatinine) was associated with significantly greater 6-month eGFR decline than with urinary DKK3 at or below the median (-5·6% [95% CI -8·6 to -2·7] vs 1·0% [-1·9 to 3·9], p<0·0001, in ESCAPE; -6·2% [-7·3 to -5·0] vs -1·5% [-2·9 to -0·1], p<0·0001, in 4C), independently of diagnosis, eGFR, and albuminuria. In ESCAPE, the beneficial effect of intensified blood pressure control was limited to children with urinary DKK3 higher than 1689 pg/mg creatinine, in terms of the combined kidney endpoint (HR 0·27 [95% CI 0·14 to 0·55], p=0·0003, number needed to treat 4·0 [95% CI 3·7 to 4·4] vs 250·0 [66·9 to ∞]) and the need for kidney replacement therapy (HR 0·33 [0·13 to 0·85], p=0·021, number needed to treat 6·7 [6·1 to 7·2] vs 31·0 [27·4 to 35·9]). In 4C, inhibition of the renin-angiotensin-aldosterone system resulted in significantly lower urinary DKK3 concentrations (least-squares mean 12 235 pg/mg creatinine [95% CI 10 036 to 14 433] in patients not on angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers vs 6861 pg/mg creatinine [5616 to 8106] in those taking angiotensin-converting enzyme inhibitors or angiotensin 2 receptor blockers, p<0·0001). INTERPRETATION: Urinary DKK3 indicates short-term risk of declining kidney function in children with chronic kidney disease and might allow a personalised medicine approach by identifying those who benefit from pharmacological nephroprotection, such as intensified blood pressure lowering. FUNDING: None.

Real-Life Anemia Management Among Patients with Non-Dialysis-Dependent Chronic Kidney Disease in Three European Countries.

Background: Anemia is prevalent among patients with chronic kidney disease (CKD), yet current evidence indicates that treatment may not adhere to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. We aimed to document the management of patients with non-dialysis-dependent (NDD)-CKD receiving erythropoiesis-stimulating agent (ESA) therapy in Europe. Methods: This retrospective, observational study extracted information from medical records in Germany, Spain, and the UK. Eligible patients were adults with NDD-CKD stages 3b-5 who initiated ESA therapy for anemia between January and December 2015. Anemia was defined as hemoglobin (Hb) <13.0 g/dL (males) or <12.0 g/dL (females). Data regarding ESA treatment, treatment response, concomitant iron therapy and blood transfusions were extracted up to 24 months post-ESA initiation, and data on CKD progression until abstraction date. Results: Eight hundred and forty-eight medical records were abstracted. Approximately 40% received no iron therapy prior to ESA initiation. At ESA initiation, mean ± standard deviation Hb level was 9.8 ± 1.0 g/dL. Most patients received darbepoetin alfa, and switching between ESAs was rare (8.5% of patients). Concomitant intravenous and oral iron therapy was prescribed for 36% and 42% of patients, respectively, during initial ESA therapy. Mean Hb levels reached the target level (10-12 g/dL) within 3-6 months of ESA initiation. Hb, transferrin saturation, and ferritin levels were infrequently monitored from 3 months post-ESA initiation. Rates of blood transfusion, dialysis, and diagnosis of end-stage renal disease were 16.4%, 19.3%, and 24.6%, respectively. Rates of kidney transplant and death were 4.8% and 8.8%, respectively. Conclusion: Among ESA-treated patients, ESA initiation was in accordance with KDIGO guidelines, but subsequent monitoring of Hb and iron deficiency were suboptimal.

Patiromer utilization in patients with advanced chronic kidney disease under nephrology care in Germany.

Background: Hyperkalemia (HK) is a frequent condition in patients with chronic kidney disease (CKD) that is associated with high morbidity and mortality. Patiromer has recently been introduced as a potassium binder. Data on patiromer use in patients with CKD in the real-world setting in Europe are lacking. We describe time to discontinuation and changes in serum potassium levels among German CKD stage 3-5 patients starting patiromer. Methods: Duration of patiromer use was estimated by Kaplan-Meier curve, starting at patiromer initiation and censoring for death, dialysis, transplant or loss to follow-up. Serum potassium levels and renin-angiotensin-aldosterone system inhibitor (RAASi) use are described at baseline and during follow-up, restricted to patients remaining on patiromer. Results: We identified 140 patiromer users within our analysis sample [81% CKD stage 4/5, 83% receiving RAASi, and median K+ 5.7 (5.4, 6.3) mmol/L]. Thirty percent of patiromer users had prior history of polystyrene sulfonate use. Overall, 95% of patiromer users stayed on treatment past 1 month, with 53% continuing for over a year. Mean serum potassium levels decreased after patiromer initiation and remained stable under treatment during follow-up (up to 180 days). Among these patients, 73%-82% used RAASis during the time periods before and after patiromer initiation, with no obvious trend indicating discontinuation. Conclusion: Real-world evidence of patiromer use in Germany shows that, in line with what has been observed in clinical trials, patients on patiromer have a reduction in serum potassium when used long-term. Moreover, most patients on patiromer do not discontinue treatment prior to 1 year after initiation.

Kidney outcome after mild to moderate COVID-19.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a remarkable kidney tropism. While kidney effects are common in severe coronavirus disease 2019 (COVID-19), data on non-severe courses are limited. Here we provide a multilevel analysis of kidney outcomes after non-severe COVID-19 to test for eventual kidney sequela. METHODS: This cross-sectional study investigates individuals after COVID-19 and matched controls recruited from the Hamburg City Health Study (HCHS) and its COVID-19 program. The HCHS is a prospective population-based cohort study within the city of Hamburg, Germany. During the COVID-19 pandemic the study additionally recruited subjects after polymerase chain reaction-confirmed SARS-CoV-2 infections. Matching was performed by age, sex and education. Main outcomes were estimated glomerular filtration rate (eGFR), albuminuria, Dickkopf3, haematuria and pyuria. RESULTS: A total of 443 subjects in a median of 9 months after non-severe COVID-19 were compared with 1328 non-COVID-19 subjects. The mean eGFR was mildly lower in post-COVID-19 than non-COVID-19 subjects, even after adjusting for known risk factors {ß = -1.84 [95% confidence interval (CI) -3.16 to -0.52]}. However, chronic kidney disease [odds ratio (OR) 0.90 (95% CI 0.48-1.66)] or severely increased albuminuria [OR 0.76 (95% CI 0.49-1.09)] equally occurred in post-COVID-19 and non-COVID-19 subjects. Haematuria, pyuria and proteinuria were also similar between the two cohorts, suggesting no ongoing kidney injury after non-severe COVID-19. Further, Dickkopf3 was not increased in the post-COVID-19 cohort, indicating no systematic risk for ongoing GFR decline [ß = -72.19 (95% CI -130.0 to -14.4)]. CONCLUSION: While mean eGFR was slightly lower in subjects after non-severe COVID-19, there was no evidence for ongoing or progressive kidney sequela.

Targeting innate immunity-driven inflammation in CKD and cardiovascular disease.

Mortality among patients with chronic kidney disease (CKD) is largely a consequence of cardiovascular disease (CVD) and is a particular concern given the increasing prevalence of CKD. Sterile inflammation triggered by activation of the innate immune system is an important driver of both CKD and associated CVD. Several endogenous mediators, including lipoproteins, crystals such as silica, urate and cholesterol crystals, or compounds released from dying cells interact with pattern recognition receptors expressed on a variety of different cell types, leading to the release of pro-inflammatory cytokines. Disturbed regulation of the haematopoietic system by damage-associated molecular patterns, or as a consequence of clonal haematopoiesis or trained innate immunity, also contributes to the development of inflammation. In observational and genetic association studies, inflammation is linked to the progression of CKD and cardiovascular events. In 2017, the CANTOS trial of canakinumab provided evidence that inhibiting inflammation driven by NLRP3-IL-1-IL-6-mediated signalling significantly reduced cardiovascular event rates in individuals with and without CKD. Other approaches to target innate immune pathways are now under investigation for their ability to reduce cardiovascular events and slow disease progression among patients with atherosclerosis and stage 3 and 4 CKD. This Review summarizes current understanding of the role of inflammation in the pathogenesis of CKD and its associated CVD, and how this knowledge may translate into novel therapeutics.

Plasma biomarkers outperform echocardiographic measurements for cardiovascular risk prediction in kidney transplant recipients: results of the HOME ALONE study.

Background: Since kidney transplant recipients (KTRs) have a high cardiovascular disease burden, adequate risk prediction is of importance. Whether echocardiographic parameters and plasma biomarkers, natriuretic peptides [N-terminal pro-B-type natriuretic peptide (NT-proBNP)] and troponin T provide complementary or overlapping prognostic information on cardiovascular events remains uncertain. Methods: The prospective Heterogeneity of Monocytes and Echocardiography Among Allograft Recipients in Nephrology (HOME ALONE) study followed 177 KTRs for 5.4 ± 1.7 years. Predefined endpoints were hospitalization for acute decompensated heart failure or all-cause death (HF/D) and major atherosclerotic cardiovascular events or all-cause death (MACE/D). At baseline, plasma NT-proBNP, plasma troponin T and echocardiographic parameters [left atrial volume index, left ventricular (LV) mass index, LV ejection fraction, and LV filling pressure] were assessed. Results: Among all echocardiographic and plasma biomarkers measured, only NT-proBNP was consistently associated with HF/D in univariate and multivariate {third versus first tertile: hazard ratio [HR] 4.20 [95% confidence interval (CI) 1.02-17.27]} analysis, and only troponin T was consistently associated with MACE/D in univariate and multivariate [third versus first tertile: HR 8.15 (95% CI 2.75-24.18)] analysis. Conclusion: Our data suggest that plasma biomarkers are robust and independent predictors of heart failure and atherosclerotic cardiovascular events after kidney transplantation, whereas standard echocardiographic follow-up does not add to risk prediction.

Potential Surrogate Outcomes for Kidney Failure in Advanced CKD: Evaluation of Power and Predictive Ability in CKDopps.

RATIONALE & OBJECTIVE: Potential surrogate end points for kidney failure have been proposed in chronic kidney disease (CKD); however, they must be evaluated to ensure accurate, powerful, and harmonized research, particularly among patients with advanced CKD. The aim of the current study was to investigate the power and predictive ability of surrogate kidney failure end points in a population with moderate-to-advanced CKD. STUDY DESIGN: Analysis of longitudinal data of a large multinational CKD observational study (Chronic Kidney Disease Outcomes and Practice Patterns Study). SETTING & PARTICIPANTS: CKD stage 3-5 patients from Brazil, France, Germany, and the United States. OUTCOMES: Reaching an estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2 or eGFR decline of ≥40%, and composite end points of these individual end points. ANALYTICAL APPROACH: Each end point was used as a time-varying indicator in the Cox model to predict the time to kidney replacement therapy (KRT; dialysis or transplant) and was compared by the number of events and prediction accuracy. RESULTS: 8,211 patients had a median baseline eGFR of 27 mL/min/1.73 m2 (interquartile range, 21-36 mL/min/1.73 m2) and 1,448 KRT events over a median follow-up of 2.7 years (interquartile range, 1.2-3.0 years). Among CKD stage 4 patients, the eGFR < 15 mL/min/1.73 m2 end point had higher prognostic ability than 40% eGFR decline, but the end points were similar for CKD stage 3 patients. The combination of eGFR < 15 mL/min/1.73 m2 and 40% eGFR decline had the highest prognostic ability for predicting KRT, regardless of the CKD stage. Including KRT in the composite can increase the number of events and, therefore, the power. LIMITATIONS: Variable visit frequency resulted in variable eGFR measurement frequency. CONCLUSIONS: The composite end point can be useful for CKD progression studies among patients with advanced CKD. Harmonized use of this approach has the potential to accelerate the translation of new discoveries to clinical practice by identifying risk factors and treatments for kidney failure.

EDTAKI: a Nephrology and Public Policy Committee platform call for more European involvement in acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is an often neglected but crucial element of clinical nephrology. The aim of the Nephrology and Public Policy Committee (NPPC) of the European Renal Association-European Dialysis and Transplant Association is to promote several key aspects of European nephrology. One of the targets proposed by the NPPC was to advance European nephrology involvement in AKI. METHODS: We undertook a literature analysis to define the current position of European nephrology in the field of AKI compared with other regions and to determine how different European countries compare with each other. RESULTS: It appeared that vis-à-vis countries with a comparable socio-economic status (the USA, Australia, New Zealand and Canada), the European contribution was almost 50% less. Within Europe, Central and Eastern Europe and countries with a lower gross domestic product showed lower scientific output. Nephrologists contributed to less than half of the output. There was no trend of a change over the last decade. CONCLUSIONS: There is room to improve the contribution of European nephrology in the field of AKI. We propose a model on how to promote clinical collaboration on AKI across Europe and the creation of a pan-European nephrology network of interested units to improve clinical outcomes, increase nephrologist involvement and awareness outside nephrology and stimulate research on AKI in Europe. Accordingly, we also propose a list of research priorities and stress the need for more European funding of AKI research.

FGFR4 and Klotho Polymorphisms Are Not Associated with Cardiovascular Outcomes in Chronic Kidney Disease.

INTRODUCTION: High plasma fibroblast growth factor 23 (FGF-23) predicts cardiovascular events in chronic kidney disease (CKD) patients. Experimental evidence suggests FGF receptor 4 (FGFR4) activation by FGF-23, and deficiency of the soluble form of its co-receptor Klotho promotes left-ventricular hypertrophy (LVH). To evaluate the clinical relevance of these findings, a Mendelian randomization study analyzed the association of genetic variants of FGFR4 and Klotho with echocardiographic parameters and cardiac events in CKD patients. METHODS: The prospective Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Fourth Homburg Evaluation study recruited CKD G2-G4 patients, of whom 519 consented to SNP genotyping (FGFR4: rs351855; Klotho: rs9536314). Echocardiographic examinations at baseline and 5 years later assessed prevalence of LVH by measurement of left-ventricular mass index (LVMI). Patients were followed for 5.1 ± 2.1 years for the primary endpoints of cardiac decompensation and atherosclerotic cardiovascular disease (ASCVD). RESULTS: Carriers of the different alleles did neither differ in baseline LVMI (rs351855: p = 0.861; rs9536314: p = 0.379) nor in LVMI changes between baseline and follow-up (rs351855: p = 0.181; rs9536314: p = 0.995). Hundred and four patients suffered cardiac decompensation, and 144 patients had ASCVD. Time to cardiac decompensation (rs351855: p = 0.316; rs9536314: p = 0.765) and ASCVD (p = 0.508 and p = 0.800, respectively) did not differ between carriers of different alleles. DISCUSSION/CONCLUSION: rs351855 and rs9536314 were not associated with LVMI or cardiac events. These findings do not provide evidence for a relevant clinical role of either FGFR4 stimulation or soluble form of Klotho deficiency in LVH development.

Prevention of vascular calcification by the endogenous chromogranin A-derived mediator that inhibits osteogenic transdifferentiation.

The adrenal glands participate in cardiovascular (CV) physiology and the pathophysiology of CV diseases through their effects on sodium and water metabolism, vascular tone and cardiac function. In the present study, we identified a new adrenal compound controlling mesenchymal cell differentiation that regulates osteoblastic differentiation in the context of vascular calcification. This peptide was named the "calcification blocking factor" (CBF) due to its protective effect against vascular calcification and is released from chromogranin A via enzymatic cleavage by calpain 1 and kallikrein. CBF reduced the calcium content of cells and thoracic aortic rings under calcifying culture conditions, as well as in aortas from animals treated with vitamin D and nicotine (VDN animals). Furthermore, CBF prevented vascular smooth muscle cell (VSMC) transdifferentiation into osteoblast-like cells within the vascular wall via the sodium-dependent phosphate transporter PIT-1 and by inhibition of NF-κB activation and the subsequent BMP2/p-SMAD pathway. Pulse pressure, a marker of arterial stiffness, was significantly decreased in VDN animals treated with CBF. In line with our preclinical data, CBF concentration is significantly reduced in diseases characterized by increased calcification, as shown in patients with chronic kidney disease. In preparation for clinical translation, the active site of the native 19-AS long native CBF was identified as EGQEEEED. In conclusion, we have identified the new peptide CBF, which is secreted from the adrenal glands and might prevent vascular calcification by inhibition of osteogenic transdifferentiation. The anti-calcific effects of CBF and short active site may therefore promote the development of new tools for the prevention and/or treatment of vascular calcification.

Guanidinylated Apolipoprotein C3 (ApoC3) Associates with Kidney and Vascular Injury.

BACKGROUND: Coexistent CKD and cardiovascular diseases are highly prevalent in Western populations and account for substantial mortality. We recently found that apolipoprotein C-3 (ApoC3), a major constituent of triglyceride-rich lipoproteins, induces sterile systemic inflammation by activating the NOD-like receptor protein-3 (NLRP3) inflammasome in human monocytes via an alternative pathway. METHODS: To identify posttranslational modifications of ApoC3 in patients with CKD, we used mass spectrometry to analyze ApoC3 from such patients and from healthy individuals. We determined the effects of posttranslationally modified ApoC3 on monocyte inflammatory response in vitro, as well as in humanized mice subjected to unilateral ureter ligation (a kidney fibrosis model) and in a humanized mouse model for vascular injury and regeneration. Finally, we conducted a prospective observational trial of 543 patients with CKD to explore the association of posttranslationally modified ApoC3 with renal and cardiovascular events in such patients. RESULTS: We identified significant posttranslational guanidinylation of ApoC3 (gApoC3) in patients with CKD. We also found that mechanistically, guanidine and urea induce guanidinylation of ApoC3. A 2D-proteomic analysis revealed that gApoC3 accumulated in kidneys and plasma in a CKD mouse model (mice fed an adenine-rich diet). In addition, gApoC3 augmented the proinflammatory effects of ApoC3 in monocytes in vitro . In humanized mice, gApoC3 promoted kidney tissue fibrosis and impeded vascular regeneration. In CKD patients, higher gApoC3 plasma levels (as determined by mass spectrometry) were associated with increased mortality as well as with renal and cardiovascular events. CONCLUSIONS: Guanidinylation of ApoC3 represents a novel pathogenic mechanism in CKD and CKD-associated vascular injury, pointing to gApoC3 as a potential therapeutic target.