Sarah Seiler-Mußler

External Validation of the Kidney Failure Risk Equation and Re-Calibration with Addition of Ultrasound Parameters

BACKGROUND AND OBJECTIVES Progression of CKD toward ESRD is heterogeneous. The Kidney Failure Risk Equation (KFRE) was developed to identify CKD patients at high risk of ESRD. We aimed to externally validate KFRE and to test whether the addition of predefined Duplex ultrasound markers - renal resistive index (RRI) or difference of resistive indices in spleen and kidney (DI-RISK) - improved ESRD prediction. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The prospective Cardiovascular and Renal Outcome in CKD 2-4 Patients-The Fourth Homburg evaluation (CARE FOR HOMe) study recruits CKD stage G2-G4 patients referred to a tertiary referral center for nephrologic care. Four hundred three CARE FOR HOMe participants enrolled between 2008 and 2012 had available RRI measurements at study inclusion; they were subsequently followed for a mean of 4.4±1.6 years. This subcohort was used to validate KFRE and to assess the added value of the ultrasound markers (new models KFRE+RRI and KFRE+DI-RISK). Model performance was assessed by log-likelihood ratio test, c-statistic, integrated discrimination improvement metrics (for study participants without subsequent ESRD [IDI No ESRD] and for patients with ESRD [IDI ESRD]), and calibration plots. If either new model improved on KFRE, we determined to validate it in an independent cohort of 162 CKD patients. RESULTS KFRE predicted ESRD in CARE FOR HOMe participants with a c-statistic of 0.91 (95% confidence interval, 0.83 to 0.99). Adding RRI improved the KFRE model (P<0.001), and the KFRE+RRI model was well calibrated; however, the c-statistic (0.91 [0.83-1.00]) was similar, and overall sensitivity (IDI No ESRD=0.05 [0.00-0.10]) or overall specificity (IDI ESRD=0.00 [0.00-0.01]) did not improve. Adding DI-RISK did not improve the KRFE model. In the external validation cohort, we confirmed that the KFRE+RRI model did not outperform KFRE. CONCLUSIONS Routine Duplex examinations among CKD patients did not improve risk prediction for progression to ESRD beyond a validated equation.

Impact of individual intravenous iron preparations on the differentiation of monocytes towards macrophages and dendritic cells

Background Treatment of iron deficiency with intravenous (i.v.) iron is a first-line strategy to improve anaemia of chronic kidney disease. Previous in vitro experiments demonstrated that different i.v. iron preparations inhibit differentiation of haematopoietic stem cells to monocytes, but their effect on monocyte differentiation to macrophages and mature dendritic cells (mDCs) has not been assessed. We investigated substance-specific effects of iron sucrose (IS), sodium ferric gluconate (SFG), ferric carboxymaltose (FCM) and iron isomaltoside 1000 (IIM) on monocytic differentiation to M1/M2 macrophages and mDCs. Methods Via flow cytometry and microRNA (miRNA) expression analysis, we morphologically and functionally characterized monocyte differentiation to M1/M2 macrophages and mDCs after monocyte stimulation with IS, SFG, FCM and IIM (0.133, 0.266 and 0.533 mg/mL, respectively). To assess potential clinical implications, we compared monocytic phagocytosis capacity in dialysis patients who received either 500 mg IS or IIM. Results Phenotypically, IS and SFG dysregulated the expression of macrophage (e.g. CD40, CD163) and mDC (e.g. CD1c, CD141) surface markers. Functionally, IS and SFG impaired macrophage phagocytosis capacity. Phenotypic and functional alterations were less pronounced with FCM, and virtually absent with IIM. In miRNA expression analysis of mDCs, IS dysregulated miRNAs such as miR-146b-5p and miR-155-5p, which are linked to Toll-like receptor and mitogen-activated protein kinase signalling pathways. In vivo, IS reduced monocytic phagocytosis capacity within 1 h after infusion, while IIM did not. Conclusions This study demonstrates that less stable i.v. iron preparations specifically affect monocyte differentiation towards macrophages and mDCs.

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

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.

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

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.

MP32-11 PERCUTANEOUS TRANSLUMINAL ANGIOPLASTY FOR TREATMENT OF TRANSPLANT RENAL ARTERY STENOSIS

Donor blood sampling performed once prior to transplant. Recipient blood sampling performed daily while inpatient and processed in MDC as per protocol Institution review board approved study RESULTS: 1 or more informative INDELs detected in 9 of 10 recipients post transplant. Where the informative INDEL was multiplexed with an INDEL present in both donor and recipient DNA, percentages of the former can be calculated The cfdDNA levels rose sharply to peak at post operative Day 1-2 and decreased to a trough by Day 3-6(refer to chart) CONCLUSIONS: INDEL polymorphism is a plausible mechanism to detect cfdDNA in recipient plasma post renal transplant cfdDNA has been shown to spike with insults to donor graft. Current results have achieved a proof of concept and demonstrate ability of the this novel technique to potentially monitor graft health Future directions include correlation of cfDNA with long term graft outcome and peak level with various graft insults