bluuebunny/crossref_metadata_2025 huggingface dataset:
FC 108BASELINE AND CORONARY ARTERY CALCIFICATION PROGRESSION MODULATES THE RISK OF DEATH IN INCIDENT TO DIALYSIS PATIENTS
Authors: Bellasi Antonio , Di Lullo Luca , Russo Domenico , Ratti Carlo , Cozzolino Mario Gennaro , Di iorio Biagio Raffaele
Published: May 2021

Background and Aims

It is estimated that Chronic Kidney Disease (CKD) accounts for 5 to 10 million deaths annually, mainly due to cardiovascular (CV) diseases. Although traditional CV risk factors are prevalent, other non-traditional CV risk factors such as vascular calcification (VC) are believed to contribute to this disproportionate CV risk burden in CKD subjects. We sought to investigate the association of Coronary Artery Calcification (CAC) progression with all-cause mortality in a cohort of patients new to hemodialysis (HD).

Method

This is a post hoc analysis of the Independent study (NCT00710788) originally designed to test the impact of 2 different phosphate binder regimens on various hard as well as surrogate endpoint in HD subjects. A total of 412 (88.4% of the Independent study cohort) underwent repeated CAC quantification according to the Agatston methods at study inception as well as after 12 months of follow-up. The square root method was used to assess CAC progression (CACP) and survival analyses were used to check the association of CACP and all-cause mortality.

Results

412 middle age (65 years) men and women (51.2%) were considered. Detectable CAC was present in about 2 out 3 patients (68.2%) at study inception. At 12 months of follow-up completion, about 1 out of 3 subjects (33.1%) experience a significant CACP. CACP was associated with older age and use of calcium-based phosphate binders. At study completion (median follow-up: 36 months) 106 patients expired of all-cause. Age, diabetes mellitus, atherosclerotic CV events, baseline CAC extension were predictors of unfavorable outcome. Multivariable adjusted analysis confirmed an independent association of both baseline CAC (Hazard Ratio 1.29; 95% Confidence Interval: 1.17-1.44) and CACP (HR: 5.16; 95%CI: 2.61-10.21) with all-cause mortality. However, CACP diminished the risk associated with baseline CAC (p for interaction term 0.002) and use of calcium-free phosphate binders significantly weakened the link between CACP (HR. 1.95; 95%CI: 0.92-4.16) and mortality

Conclusion

Baseline CAC as well as CACP predict mortality in incident to HD individuals. Nevertheless, CACP mitigates the risk associated with baseline CAC and calcium-free phosphate binders attenuates the association of CACP and mortality, suggesting that CACP modulation may impact survival in this population
FC 110PTH INDCUED ENDMT VIA MIR-29A-5P/GSAP/NOTCH1 PATHWAY CONTRIBUTED TO VALVULAR CALCIFICATION IN RATS WITH CKD
Authors: Wang Liting , Zhang Yuxia , Tang Rining
Published: May 2021

Background and Aims

Endothelial-to-mesenchymal transition (EndMT) of valvular endothelial cells is the common pathophysiology of valvular calcification (VC) among the patients of non-chronic kidney disease (CKD). However, there are few studies of valvular calcification in CKD. In our previous work, parathyroid hormone (PTH) was considered as an important player of EndMT in vascular diseases. Meanwhile, the increasing serum level of PTH in CKD patients is closely related to VC, so whether PTH could induce valvular EndMT and the mechanism involved are worthy of further study.

Method

5/6 nephroectomy (5/6Nx) with high phosphorus diet was used to construct a VC model in rats with CKD. miRNA sequencing was used to find the changes of miRNA in human umbilical vein endothelial cells (HUVECs) intervened by PTH. The expression levels of miR-29a-5p, markers of EndMT and Notch1 pathway were determined by PCR, western blot and immunofluorescence. The activity of γ-secretase was determined by ELISA. VC was observed by VonKossa staining and scanning electron microscope.

Results

Firstly, we found PTH could induce valvular EndMT in VC among the rat with CKD, and VC could be alleviated by cinacalcet. As for the contribution of PTH on EndMT, in vitro, global microRNA(miRNA) expression profiling of HUVECs was examined in PTH versus control and miR-29a-5p was identified as the miRNA that was most notably decreased under PTH stimulation, which could be resumed by PTHrP(7-34) (PTHR1 inhibitor). Overexpressing miR-29a-5p could inhibit PTH-induced EndMT in vitro and valvular EndMT in vivo. The dual luciferase assay was verified that γ-secretase activating protein (GASP) is the target of miR-29a-5p. miR-29a-5p-mimics, si-GSAP and DAPT (γ-secretase inhibitor) could inhibit PTH-induced γ-secretase activation thus blocking Notch1 pathway activation to inhibit PTH-induced EndMT in vitro. In vivo, Notch1 pathway activation was observed in VC among the rats with CKD. Blocking Notch1 pathway activation by AAV-miR-29a and DAPT could inhibit vavular EndMT in rats with CKD. In addition, blocking Notch1 pathway activation could also alleviate VC among the rats with CKD.

Conclusion

PTH could activate valvular EndMT via miR-29a-5p/GSAP./Notch1 pathway, and that could contributed to VC in rats with CKD.
FC 115HIGHER VARIABILITY OF SERUM PHOSPHATE IS ASSOCIATED WITH INCREASED MORTALITY RISK ONLY WHEN ASSOCIATED WITH HYPOALBUMINEMIA
Authors: Ter Meulen Karlien , Ye Xiaoling (Janice) , Usvyat Len A , Van Der Sande Frank , Konings Constantijn , Kotanko Peter , Kooman Jeroen , Maddux Frank
Published: May 2021

Background and Aims

Both hypophosphatemia and hypoalbuminemia are established risk factors for mortality in hemodialysis (HD) patients. Evidence indicates that higher variability of serum phosphate (P) is associated with higher risk of mortality. However, little is known about to what extent of this association is influenced by other risk factors, most importantly nutritional or inflammatory state. The aim of this study was to analyze the variability of serum P with all-cause mortality taking into account the interaction with the levels of albumin (Alb)

Method

All adult incident HD patients treated in Fresenius Medical Care North America (FMCNA) clinics between 01/2010 and 10/2018 were included. Serum P and Alb levels were averaged from month 1 to 6 after the start of dialysis (baseline). Baseline variability of P was described by coefficient of variation (CV). All-cause mortality was recorded between months 7 and 18. Cox proportional hazards models with spline terms were applied to explore the association between variability of P and Alb and all-cause mortality. Additionally, tensor product smoothing splines were computed to study the interactions of Alb and P variability and their associations with outcomes respectively.

Results

We enrolled 353,142 patients. The average age was 62.7 years, 58% were male, 64% were diabetic. Baseline P was 4.98 mg/dL, median serum P CV was 0.19. Baseline Alb was 3.61 g/dL. While we studied the joint effect of P variability with Alb on outcome, the association between P variability and outcomes appeared to be predominant in patients with low serum Alb levels (Fig. 1).

Conclusion

Higher P variability is associated with adverse outcomes but predominantly in patients with hypoalbuminemia. This suggests a major role for malnutrition and/or inflammation as explanatory factors for the association between P variability in outcome. A high P variability in this patient group can be interpreted as an additional risk factor. When studying the relation between the variability of a single parameter with outcome, the possible underlying role of “third factors” should be explored, for which the methodology used in this abstract might provide an example.
FC 117TIME TRENDS IN PROBABILITY OF STARTING HOME DIALYSIS OVER A 20 YEAR PERIOD: A DUTCH REGISTRY STUDY
Authors: Bonenkamp Anna , Hoekstra Tiny , Hemmelder Marc , Van Eck van der Sluijs Anita , Abrahams Alferso C , Van Ittersum Frans J , Van Jaarsveld Brigit
Published: May 2021

Background and Aims

A growing number of patients suffers from End Stage Kidney Disease(ESKD), causing a logistical and economic burden to the healthcare system. Utilization of home dialysis is low in many countries worldwide, although home dialysis has several advantages including higher quality of life and possibly lower costs. The aim of this study is to explore time trends in the use of home dialysis in the Netherlands.

Method

Anonymized registry data from the Dutch Renal Registry (RENINE) were used for this study. All dialysis episodes of adult patients who started dialysis treatment between 1997 through 2016 in the Netherlands were included, including those who previously underwent kidney transplantation. Dialysis episodes shorter than 90 days were excluded. The probability of starting home dialysis between 1997 through 2016 was evaluated in time periods of 5 years, using logistic regression analysis. Home dialysis was defined as start with peritoneal dialysis or home haemodialysis, or transfer to either within 2 years after dialysis start. A logistic multilevel model was used to adjust for clustering at patient level. The cumulative incidence function of start of home dialysis in incident patients was estimated with a competing risk model with recovery of kidney function, kidney transplantations, and all-cause mortality as competing events. All analyses were stratified for age categories at dialysis start: 20-44 years, 45-64 years, 65-74 years and ≥75 years.

Results

A total of 33,340 dialysis episodes in 31,569 patients were evaluated. Between 1997 and 2016, mean age at start of dialysis treatment increased from 62.5±14.0 to 65.5±14.5 years in in-centre haemodialysis patients, whereas it increased from 51.9±15.1 to 62.5±14.6 years in home dialysis patients. In patients < 65 years, the probability of starting home dialysis was significantly lower during each 5-year period compared to the previous period, and kidney transplantation occurred more often. In patients ≥ 65 years, incidence of home dialysis remained constant, whereas mortality decreased.

Conclusion

In patients < 65 years, the overall probability of starting home dialysis declined consistently over the past 20 years. The age of home dialysis patients increased more rapidly than that of in-centre dialysis patients, implying that pre-dialysis education and organization of home dialysis must be adapted to the needs of the elderly patient. These developments have a significant impact on the organisation of home dialysis for patients with ESKD.
FC 118DIALYSIS WITHDRAWAL IN THE NETHERLANDS BETWEEN 2000-2020: TIME TRENDS AND CENTRE VARIATION
Authors: Van Oevelen Mathijs , Abrahams Alferso C , Bos Willem Jan W , Hoekstra Tiny , Van Buren Marjolijn
Published: May 2021

Background and Aims

Treatment withdrawal is an important cause of death among dialysis-dependent patients. Widely variable withdrawal rates were reported in studies using varying designs and definitions in culturally different regions of the world, limiting comparability of individual studies. Cessation of life-prolonging treatment is a well-accepted option in the Netherlands, however it is unclear if these premises result in higher dialysis withdrawal rates and if this effect is generalisable. This study aims to describe dialysis withdrawal practice in the Netherlands, focussing on time trends and practice variation between centres.

Method

Patient data was retrieved from RENINE, the Dutch national registration which includes nearly all patients requiring dialysis for at least 28 days. All patients who initiated maintenance dialysis from January 1, 2000, to December 31, 2020, and died within this period were included for analysis. Since the primary aim of this study concerned cause of death on dialysis, data of patients in whom dialysis was stopped due to kidney transplantation or recovery of kidney function, were excluded. Main outcome was death by dialysis withdrawal, as registered by the treating physician using ERA-EDTA codes. Other causes of death were used as comparison. Time trends for dialysis withdrawal were first analysed as unadjusted data (proportion per year). Univariable logistic regression analyses were then used to identify factors associated with dialysis withdrawal, including year of death in five-year strata. A multivariable model was subsequently used to determine risks, adjusting for factors associated with dialysis withdrawal. Centre variation was compared visually by using funnel plots.

Results

A total of 34.692 patients commenced maintenance dialysis of which 20.389 died. After applying exclusion criteria, a cohort of 18.412 patients was used for analysis. Dialysis withdrawal was an increasingly common cause of death, increasing from 13.5% in 2000 to 31.2% in 2019 (22.1% overall). In multivariable analysis, increasing age, female sex, increasing dialysis vintage, haemodialysis as treatment modality, and year of death were independent factors associated with death by dialysis withdrawal. Centre variation was large, even after correction for confounding factors (36.6% outside 95% control limits).

Conclusion

Treatment withdrawal has become the main cause of death in the Netherlands among dialysis-dependent patients during 2000-2020. Large practice variations were observed between centres, even after correction for confounding factors. These findings emphasize the need for timely advance care planning and urge treating health care professionals to better inform their patients when choosing to start dialysis or not.
FC 020SINGLE CELL SEQUENCING REVEALS TRANSCRIPTIONAL SIGNATURES AND CELL CROSSTALK IN PATIENTS WITH HYPERTENSIVE NEPHROPATHY
Authors: Tang Rong , Meng Ting , Lin Wei , Zhong Yong
Published: May 2021

Background and Aims

Hypertensive nephropathy (HTN) is one of the leading causes of end-stage renal disease (ESRD). HTN is characterized by injury to the glomerulus, arterioles and tubulointerstitium, yet the precise mechanisms and cell-specific gene expression changes are still unknown. This study used single-cell RNA sequencing (scRNA-seq) to explore novel molecular mechanisms and the gene targets for HTN.

Method

The gene expression profiles of human renal biospsy samples obtained from subjects with HTN and pre-transplant healthy living controls were determined by scRNA-seq technology. Then the differentially expressed genes (DEGs) and their functions were identified. Gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted, and the ligand-receptor interaction among different cell populations were anlyzed.

Results

18 distinct cell clusters were identified in kidney from HTN patients. Endothelial cells overexpressed LRG1, a pleiotropic factor linked to apoptosis and inflammation, which was validated at proteome level in kidney from HTN, providing a potential novel molecular target. In HTN patients, mesangial cells highly expressed proliferation related signatures (MGST1, TMSB10, EPS8 and IER2) not detected in renal diseases before. The upregualted genes in tubules of HTN were mainly participating in inflammatory signatures including IFN-γ signature, IL-17 signaling and TLR signaling. Specific gene expression of kidney-resident immune cells including dendritic cells and CD8+ T cells revealed abnormal regulation associated with cell adhesion and inflammation. Furthermore, the receptor-ligand interactions analysis indicated cell-cell crosstalks in kidney contribute to recruitment and infiltration of inflammatory cells into kidneys, and fibrotic process in hypertensive renal injury.

Conclusion

In brief, our data identifies distinct cell-specific gene expression profile, pathogenic signaling pathways and potential cell-cell communication in pathogenesis of HTN. These findings will provide a promising novel landscape for mechanisms and treatment of HTN.
FC 133HEMODIAFILTRATION IS ASSOCIATED WITH REDUCED INFLAMMATION AND INCREASED BONE TURNOVER COMPARED TO CONVENTIONAL HEMODIALYSIS IN CHILDREN - THE HDF, HEART AND HEIGHT (3H) STUDY
Authors: Fischer Dagmar-Christiane , Smith Colette , De Zan Francesca , Askiti Varvara , Bayazit Aysun Karabay , Canpolat Nur , Litwin Mieczyslaw , Paglialonga Fabio , Schaefer Franz , Schmitt Claus , Shroff Rukshana
Published: May 2021

Background and Aims

Children on dialysis have a high burden of bone related comorbidities and fractures. We report a post-hoc analysis of the HDF-Hearts-Height study to determine the prevalence and risk factors for mineral bone disease in children on hemodiafiltration (HDF) and conventional hemodialysis (HD).

Method

144 children were included in baseline cross-sectional analysis, of which 103 (61 HD, 42 HDF) completed 12-month follow-up. Biomarkers of bone formation and resorption, inflammatory markers, fibroblast growth factor-23 (FGF23) and klotho were measured.

Results

Inflammatory markers interleukin-6 [IL-6], tumor necrosis factor-alfa [TNF-α], and high-sensitivity CRP [hsCRP] were lower in the HDF compared to HD cohorts at baseline and 12 months (p<0.001). Concentrations of bone formation (bone-specific alkaline phosphatase, BAP) and resorption (tartrate-resistant acid phosphatase 5b [TRAP5b]) markers were comparable between cohorts at baseline, but after 12-months the BAP/TRAP5b ratio increased in HDF (p=0.004) and was unchanged in HD (p=0.44). On adjusted analysis the BAP/TRAP5b ratio was 2.66-fold lower (95%CI -3.91, -1.41; p<0.0001) in HD compared to HDF. FGF23 was comparable between groups at baseline (p=0.52) but increased in HD (p<0.0001) and remained static in HDF (p=0.34) at 12-months. Klotho levels were similar between groups and unchanged during follow-up. The FGF23/klotho ratio was 3.86-fold higher (95% CI 2.15, 6.93; p<0.0001) in HD compared to HDF.

Conclusion

We conclude that children on HDF have increased bone turnover, an attenuated inflammatory profile and lower FGF23/klotho ratios compared to those on HD. Long-term studies are required to determine the effect, if any, of an improved bone biomarker profile on fracture risk and growth.
FC 062OBESITY AS A CAUSE OF KIDNEY DISEASE - INSIGHTS FROM MENDELIAN RANDOMISATION STUDIES
Authors: Xu Xiaoguang , Eales James , Jiang Xiao , Sanderson Eleanor , Scannali David , Morris Andrew , Guzik Tomasz , Charchar Fadi , Holmes Michael , Tomaszewski Maciej
Published: May 2021

Background and Aims

Obesity and kidney diseases are common complex disorders with an increasing clinical and economic impact on healthcare around the globe. We aim to examine if modifiable anthropometric indices of obesity exert putatively causal effects on different measures of kidney health and disease.

Method

We performed conventional observational and Mendelian randomisation (MR) study to examine if modifiable anthropometric indices of obesity exert putatively causal effects on different kidney health and disease-related phenotypes. These analyses were conducted using approximately 300,000 participants of white-British ancestry from UK Biobank and up to 480,000 participants of predominantly European ancestry from genome-wide association studies.

Results

The Mendelian randomisation analysis indicated that increasing values of genetically predicted BMI and waist circumference were causally linked to changes in renal function indices including reduced estimated glomerular filtration (PeGFRcystatineC=5.96 × 10-59 for BMI and PeGFRcystatineC=1.72 × 10-69 for waist circumference) and increased blood urea nitrogen (PBUN=2.01 × 10-10 for BMI and PBUN=4.54 × 10-12 for waist circumference) in UK Biobank individuals. These associations were replicated using data from CKDGen Consortium individuals (PeGFRcystatineC=1.47 × 10-5 for BMI and PeGFRcystatineC=7.63 × 10-5 for waist circumference; PBUN=1.96 × 10-4 for BMI and PBUN=3.10 × 10-3 for waist circumference). One standard deviation increase in genetically-predicted BMI and waist circumference decreased the relative odds of kidney health index by 14% and 18% (OR=0.86; 95%CI: 0.82-0.92; P=9.18 × 10-6 for BMI and OR=0.82; 95%CI: 0.75-0.90; P=2.12 × 10-5 for waist circumference). Approximately 13-16% of the causal effect of obesity indices on kidney health was mediated by blood pressure. Obesity increased the risk of both acute and chronic kidney disease of several aetiologies including hypertensive renal disease (OR=1.79; 95%CI: 1.14-2.82; P=1.15 × 10-2 for BMI and OR=2.41; 95%CI: 1.30-4.45; P=5.03 × 10-3 for waist circumference), renal failure (OR=1.51; 95%CI: 1.25-1.83; P=2.60 × 10-5 for BMI and OR=1.86; 95%CI: 1.43-2.42; P=4.16 × 10-6 for waist circumference) and CKD (OR=1.50; 95%CI: 1.16-1.96; P=2.44 × 10-3 for BMI and OR=1.83; 95%CI: 1.28-2.63; P=9.49 × 10-4 for waist circumference) and diabetic nephropathy (OR=1.92; 95%CI: 1.44-2.54; P=6.86 × 10-6 for BMI).

Conclusion

These findings indicate that obesity is causally linked to indices of renal health and the risk of different kidney diseases. This evidence substantiates the value of weight loss as a strategy of preventing and/or counteracting a decline in kidney health as well as decreasing the risk of renal disease.
FC 063DAPAGLIFLOZIN DECREASES ALBUMINURIA IN PATIENTS WITH CHRONIC KIDNEY DISEASE WITH AND WITHOUT TYPE 2 DIABETES: INSIGHTS FROM THE DAPA-CKD TRIAL
Authors: Jong Niels , Chertow Glenn , Hou Fan Fan , McMurray John , Correa-Rotter Ricardo , Rossing Peter , Sjöström David , Stefansson Bergur , Toto Robert , Langkilde Anna Maria , Wheeler David C , Lambers Heerspink Hiddo
Published: May 2021

Background and Aims

Reductions in albuminuria are consistently associated with a subsequent lower risk of kidney failure. The sodium glucose co-transporter 2 inhibitor dapagliflozin significantly reduced albuminuria in patients with type 2 diabetes. Whether this effect persist in patients with chronic kidney disease (CKD) with and without diabetes is unknown. We therefore assessed and compared the effects of dapagliflozin on albuminuria in patients with CKD with and without type 2 diabetes from the DAPA-CKD trial.

Method

We randomized 4304 patients with CKD and an eGFR of 25-75 ml/min/1.73m2 and urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g to dapagliflozin (10 mg once daily) or placebo. Change in albuminuria was a pre-specified exploratory outcome. We used regression in UACR stage, defined as a transition from macroalbuminuria (≥300 mg/g) to micro- or normoalbuminuria (<300 mg/g), and progression in UACR stage, defined as a transition from non-nephrotic (<3000 mg/g) to nephrotic range albuminuria (≥3000 mg/g), as additional endpoints. Subgroup analyses were performed according to baseline type 2 diabetes status.

Results

Median (25th to 75th Percentile) UACR was 949 (477-1885) mg/g. In patients with and without type 2 diabetes baseline median UACR was 1017 mg/g and 861 mg/g, respectively. Dapagliflozin, compared to placebo, reduced UACR by 29.3% (95% confidence interval [CI] 25.2, 33.1; p<0.001), with a 35.1% (95%CI 30.6, 39.4) reduction in patients with type 2 diabetes and 14.8% (95%CI 5.9, 22.9) reduction in patients without type 2 diabetes (p for interaction <0.001). Among 3860 patients with UACR ≥300 mg/g at baseline, dapagliflozin significantly increased the likelihood of regression in UACR stage (hazard ratio [HR] 1.81; 95%CI 1.60, 2.05). The corresponding HRs for patients with and without type 2 diabetes were 2.06 (95%CI 1.78, 2.39) and 1.33 (95%CI 1.07, 1.66), respectively (p for interaction 0.001). Among 3820 patients with UACR <3000 mg/g at baseline, dapagliflozin significantly decreased the risk of nephrotic range albuminuria (HR 0.41; 95%CI 0.32, 0.52). The corresponding HRs for patients with and without type 2 diabetes were 0.39 (95%CI 0.29, 0.51) and 0.50 (95%CI 0.30, 0.82), respectively (p for interaction 0.401).

Conclusion

In patients with CKD with and without type 2 diabetes dapagliflozin significantly reduced albuminuria, with a larger reduction in patients with type 2 diabetes. The similar effects of dapagliflozin on clinical outcomes in patients with or without type 2 diabetes, but different effects on UACR suggest that part of dapagliflozin’s protective effect in patients without diabetes is mediated through pathways unrelated to UACR reduction.
FC 064A RENAL-CARDIO INFLAMMATORY AXIS MEDIATES CARDIAC DYSFUNCTION IN CKD VIA IL-33-ST2: A NOVEL MECHANISM
Authors: Chade Alejandro , Hall Michael , Fortenberry Deandra , Bossier Drew , Bidwell Gene
Published: May 2021

Background and Aims

We developed a swine model of chronic kidney disease (CKD) that also display cardiac abnormalities associated with heart failure (HF). Inflammation contributes to progressive renal dysfunction and increases cardiovascular mortality of patients with CKD. Interleukin (IL)-33 is a tissue-derived nuclear cytokine from the IL family. IL-33 constitutively expressed but upregulated and released after cellular damage or necrotic cell death, acting as a pro-inflammatory cytokine. We hypothesize that IL-33 plays a prominent mechanistic role in renal-cardio pathophysiology in CKD.

Method

We induced CKD in 10 pigs via bilateral renovascular disease and dyslipidemia. We developed a renally-targeted biopolymer-fused peptide inhibitor of nuclear-factor kappa (NF-k)B (ELP-p50i) and show it blocks NFkB activity in vitro and in vivo. NF-kB is a key pro-inflammatory transcription factor upregulated in CKD and closely interacts with IL-33. Pigs were observed for 6 weeks, renal (multi-detector CT) and cardiac structure and function (echo) were quantified, then randomized to single intra-renal ELP-p50i or placebo (n=5 each), and studies repeated 8 weeks later. Blood was collected to measure circulating TNF-α, IL-33 and its specific decoy receptor soluble (s) ST2 (ELISA). Heart weights were measured after euthanasia, and renal and cardiac expression of ST2 and morphometric analyses were performed.

Results

Loss of renal function in CKD was accompanied by increased heart weight, left ventricular (LV) hypertrophy, diastolic dysfunction, abnormal LV strain, renal/cardiac fibrosis, circulating TNF-α, IL-33 but unchanged sST2, and increased renal/cardiac ST2 expression. Most of these changes were improved after intra-renal ELP-p50i and accompanied by augmented sST2, suggesting that inhibition of renal inflammation can attenuate cardiac abnormalities via augmented clearance of IL-33 (Figure).

Conclusion

Our study supports a prominent role for renal inflammation as a driving force for precursors of HF in CKD, proposing a renal-cardio inflammatory axis possibly mediated by NF-kB-TNF-α-IL-33/ST2 interactions. TNF-α can stimulate IL-33 as IL33 can activate NF-kB and TNF-α, extending this inflammatory loop in both the kidney and heart. We show that a translational renal anti-inflammatory strategy via targeted inhibition of renal NFkB inhibits this axis and improves renal and cardiac function, which may guide to new treatments targeting renal inflammation in CKD.
FC 134WATER SAVING COMPARISON AT DIFFERENT DIALYSATE FLOWS IN EXPANDED HEMODIALYSIS
Authors: Molano-Triviño Alejandra , Vesga Jasmin , Romero Gregorio , Ronco Claudio
Published: May 2021

Background and Aims

Expanded hemodialysis (HDx) improves clearance of middle molecules as a target for uremia treatment. According to previously published results, high cut off filters have high enough clearance to allow diminishing of dialysate flow (Qd) without detrimental in HD adequacy outcomes with less water waste.

According to World Health Organization (WHO), globally, almost 800 million people lack access to safe water and 2.5 billion lack access to optimal sanitation. Is our duty to search for ways to avoid water waste.

Our aim is to describe the differences in water use between HDX patients receiving Qd 400 mL/min (Group 1) vs 500 ml/min (group 2) in HD patients from 10 renal clinics in Colombia as an alternative to reduce water waste in chronic HD as a strategy from Blue Planet Dialysis initiatives.

Method

We performed a Sub-analysis of CORHEX Study: We calculated water use at different Qd from our database: prospective, multicentre, observational cohort study of 992 adult patients undergoing chronic HD from 12 renal clinics in Colombia who were switched from high-flux HD to MCO therapy and observed for 12 months. All patients were prescribed with HDX three times a week for a minimum of 4 hours.

We analysed patients with weight lower than 70 Kg at different Qd prescriptions to calculate water use at different Qd prescriptions and performed a prediction analysis, adjusting to Qd 400 mL/min, the whole potential population with weight lower than 70 Kg.

Results

462 patients with weight lower than 70 Kg were analysed, 127 patients received Qd 400 mL/min.

When diminishing Qd from 500 to 400 mL/min, 24 litres were saved per session per patient without detriment of middle molecule clearance. There were no differences in adequacy HD parameters between Qd prescriptions (Table 1 and 2).

Conclusion

HDX allows lowering of Qd to 400 mL/min without harm for patients and with remarkable savings of potable water: 24 Litres were saved in each session per patient that can be translated in almost 3500 Litres of water each year by patient which is enough for one year for 47 adults. (Based on the WHO minimum for basic health protection of at least 20 L per person/day) (2).

We consider our results especially relevant since the World Health Organization estimates that within the next 5 years, over 50% of world population could reside in geographies lacking sufficient access to water.

We hope that our results from the Blue Planet dialysis research group, alongside with Dr. Agar`s and Dr. Barraclough`s green nephrology initiatives, can help educate the nephrology community on the ecological impact of dialysis and can present an innovative solution to offer HD therapy even in countries suffering from limited access to potable water.
FC 081ULTRA-PROCESSED FOOD CONSUMPTION AND RISK OF INCIDENT CHRONIC KIDNEY DISEASE: THE LIFELINES COHORT
Authors: Cai Qingqing , Duan Minjie , Dekker Louise H , Bakker Stephan , De Borst Martin , Navis Gerjan
Published: May 2021

Background and Aims

Ultra-processed foods (UPF), that are widespread in Western-style diet, are risk factors for the development of cardiovascular disease, diabetes, obesity, hypertension, and all-cause mortality. The role of UPF in kidney function decline, however, is still unknown. The aim of this study was to investigate the associations of UPF consumption with incident CKD and estimated glomerular filtration rate (eGFR) decline. Additionally, we considered the heterogeneity of UPF by identifying different patterns of UPF consumption.

Method

The study was performed in a prospective general population-based cohort in the Northern Netherlands. A total of 78 346 participants who were free of CKD at baseline were included in this study. The dietary information was assessed at baseline using a 110-item food frequency questionnaire. The proportion (in weight) of UPF in the total diet was calculated and UPF consumption patterns were identified by principle component analysis (PCA). Multivariable logistic regression analyses were used to evaluated the associations of the proportion of UPF consumption and UPF patterns, respectively, with risk of incident CKD and a ≥20% eGFR decline.

Results

Average UPF consumption was 37.7% of total food intake in grams. After a mean (SD) follow-up of 7.9±1.1 years, 2 072 participants developed CKD and 7 611 had a ≥20% eGFR decline. The consumption of UPF was independently associated with a higher risk of incident CKD (OR for an absolute increment of 10 % of UPF in the diet 1.07 [95% CI 1.01-1.13], P=0.026) and with a higher risk of ≥20% eGFR decline (OR10% increment 1.07 [95% CI 1.05-1.10], P<0.001). PCA revealed four habitual UPF consumption patterns. The “warm savory snack” pattern was associated with both incident CKD (OR 1.13 [1.04-1.23], P=0.003) and a ≥20% eGFR decline (OR 1.08 [1.05-1.11], P<0.001). The “sweet snack” pattern was associated with eGFR decline (OR 1.06 [1.03-1.09], P<0.001) only, whereas the “Dutch traditional” and the “cold snack” were not associated with CKD or eGFR decline.

Conclusion

A higher UPF consumption was associated with higher risks of incident CKD and eGFR decline in the general population. Different UPF consumption patterns were identified, with different impact on renal risk. The “warm savory snack” pattern and the “sweet snack” pattern were associated with kidney function decline. Our findings suggest that UPF need to be considered in designing future dietary strategies for CKD prevention.
FC 083PROBIOTIC L.CASEI ZHANG SLOWS THE PROGRESSION OF ACUTE AND CHRONIC KIDNEY DISEASE
Authors: Zeng Rui
Published: May 2021

Background and Aims

The relationship between gut microbial dysbiosis and acute or chronic kidney disease is currently acknowledged to be a health concern which is characterized by immune dysregulation and metabolic disorder. However, the therapeutic strategies remain to be developed. In the present study, we examined the protective effects and mechanisms of action of probiotic Lactobacillus casei Zhang (L. casei Zhang) on bilateral renal ischemia-reperfusion (I/R)-induced injury in mice.

Method

We orally gavaged male C57BL/6 mice with or without L. casei Zhang and probiotic Lactobacillus acidophilus (L. acidophilus) for 4 weeks (1 × 109 CFU per day) prior to being subjected to ischemia-reperfusion (I/R)-induced injury. Serum, colons and renal samples were collected after 5 days and 28 days. The composition and abundance of gut microbiota was investigated by using 16S rRNA. LC-MS metabolomic analysis technology and GC-MS analysis technology were used to investigate the metabolic alterations. To define the intra-renal cell subsets that are involved in L. casei Zhang-induced renoprotection, we performed single-cell RNA-sequencing (scRNA-seq) of kidney samples dissected from L. casei Zhang pretreated mice at day 5 after I/R along with samples from non-treated controls.

Results

Compared to L.acidophilus, L. casei Zhang demonstrated superior capacity in restoring intestinal flora homeostasis, protecting intestinal mucosal barrier function and improving the disrupted metabolomic profile. L. casei Zhang not only elevated the short chain fatty acids (SCFAs) in serum and kidney, but also significantly increased nicotinamide, by which L. casei Zhang inhibited renal inflammatory response and alleviated the damage of renal tubular epithelial cells (TECs) via interacting with SCFAs receptors on macrophages and TECs, and activating NAD+ metabolism in injured kidneys.

Conclusion

These results show that oral administration of L. casei Zhang, by altering SCFAs and nicotinamide metabolism, is a potential therapy to mitigate kidney injury and slow the progression of renal decline.
FC 051PREDICTIVE VALUE OF PLASMA NGAL:HEPCIDIN-25 FOR MAJOR ADVERSE KIDNEY EVENTS AFTER CARDIAC SURGERY WITH CARDIOPULMONARY BYPASS: A PILOT STUDY
Authors: Elitok Saban , Haase-Fielitz Anja , Ernst Martin , Haase Michael
Published: May 2021

Background and Aims

Neutrophil gelatinase-associated lipocalin (NGAL) and hepcidin-25 appear to be involved in catalytic iron-related kidney injury after cardiac surgery with cardiopulmonary bypass. We aimed to explore the predictive value of plasma NGAL, plasma hepcidin-25, and the plasma NGAL:hepcidin-25 ratio for major adverse kidney events after cardiac surgery.

Method

We compared the predictive value of plasma NGAL, hepcidin-25, and NGAL:hepcidin-25 with those of serum creatinine (Cr), and urinary output and urinary protein for primary endpoint major adverse kidney events (MAKE; acute kidney injury [AKI] stages 2 and 3, persistent AKI > 48 hrs, acute dialysis, and in-hospital mortality) and secondary-endpoint AKI in 100 cardiac surgery patients at intensive care unit (ICU) admission. We performed ROC curve, logistic regression, and reclassification analyses.

Results

At ICU admission, plasma NGAL, plasma NGAL:hepcidin-25, and Cr predicted MAKE (area under the ROC curve [AUC]: 0.77 [95% confidence interval (CI) 0.60–0.94], 0.79 [0.63–0.95], 0.74 [0.51–0.97]) and AKI (0.73 [0.53–0.93], 0.89 [0.81–0.98], 0.70 [0.48–0.93]). For AKI prediction, NGAL:hepcidin-25 had a higher discriminatory power than Cr (AUC difference 0.26 [95% CI 0.00–0.53]). Urinary output and protein, plasma lactate, C-reactive protein, creatine kinase myocardial band, and brain natriuretic peptide did not predict MAKE or AKI (AUC < 0.70). Only plasma NGAL:hepcidin-25 correctly reclassified patients for MAKE or AKI (category-free net reclassification improvement: 0.82 [95% CI 0.12–1.52], 1.03 [0.29–1.77]). After adjustment to the Cleveland risk score, plasma NGAL:hepcidin-25 ≥ 0.9 independently predicted MAKE (adjusted odds ratio 16.34 [95% CI 1.77–150.49], P = 0.014), whereas Cr did not.

Conclusion

NGAL:hepcidin-25 is a promising plasma marker for predicting postoperative MAKE.
FC 052ACID-BASE BALANCE DURING IN-SERIES EXTRACORPOREAL CARBON DIOXIDE REMOVAL AND CONTINUOUS VENOVENOUS HEMOFILTRATION: PREDICTIONS FROM A MATHEMATICAL MODEL
Authors: Leypoldt John (Ken) , Kurz Joerg , Echeverri Jorge , Storr Markus , Harenski Kai
Published: May 2021

Background and Aims

Critically ill acute kidney injury (AKI) patients may require treatment by extracorporeal carbon dioxide removal (ECCO2R) devices to allow protective or ultraprotective mechanical ventilation and avoid hypercapnic acidosis. Continuous venovenous hemofiltration (CVVH) and ECCO2R devices can be arranged in series to form a single extracorporeal circuit; such a circuit has been proposed to be optimal, based carbon dioxide removal efficacy, if the ECCO2R device is placed proximal to the CVVH device (Allardet-Servent et al, Crit Care Med 43:2570-2581, 2015).

Method

We developed a mathematical model of whole-body, acid-base balance during extracorporeal therapy using in-series ECCO2R and CVVH devices for treatment of mechanically ventilated AKI patients. Equilibrium acid-base chemistry in blood was assumed as reported previously (Rees and Andreassen, Crit Rev Biomed Eng 33:209-264, 2005). Published clinical data from Allardet-Servent et al of mechanically ventilated (6 mL/kg predicted body weight or PBW) AKI patients treated by CVVH without ECCO2R were used to adjust model parameters to fit plasma levels of arterial partial pressure of carbon dioxide (PaCO2) and arterial plasma bicarbonate concentration ([HCO3]). The effects of applying ECCO2R at an unchanged tidal volume and a reduced tidal volume (4 mL/kg PBW) on PaCO2 and [HCO3] were then simulated assuming carbon dioxide removal rates from the ECCO2R device measured in the clinical study (91 mL of CO2/min when ECCO2R was proximal and 72 mL of CO2/min when CVVH was proximal).

Results

Agreement of model predictions with the clinical data was good, and model predictions were relatively independent of the in-series position of the devices (see Table). Total carbon dioxide removal from the CVVH device via ultrafiltration predicted by the model was lower after applying ECCO2R at both the unchanged tidal volume (25 mL of CO2/min when ECCO2R was proximal and 39 mL of CO2/min when CVVH was proximal) and the reduced tidal volume (30 mL of CO2/min when ECCO2R was proximal and 44 mL of CO2/min when CVVH was proximal). The reduced removal of total carbon dioxide via ultrafiltration when ECCO2R was proximal resulted from the lower total carbon dioxide concentration in blood entering the CVVH device. Thus, independent of the in-series position of the devices, the magnitude of this difference in total carbon dioxide removal by the CVVH device (14 mL of CO2/min) approximately cancels out the relative greater efficacy of the ECCO2R device (19 mL of CO2/min).

Conclusion

The described mathematical model has quantitative accuracy. It suggests that overall acid-base balance when using ECCO2R and CVVH devices in a single, combined extracorporeal circuit will be similar, independent of their in-series position.
FC 084LIPOTOXICITY MEDIATED BY GPR43 ACTIVATION CONTRIBUTES TO PODOCYTE INJURY IN DIABETIC NEPHROPATHY THROUGH MODULATING ERK/EGR1 PATHWAY
Authors: Lu Jian , Zhang Jia Xiu , Chen Pei Pei , Li Xue Qi , Liu Bicheng , Ma Kun Ling
Published: May 2021

Background and Aims

The G-protein-coupled receptor 43 (GPR43) is a post-transcriptional regulator involved in cholesterol metabolism. Our previous studies demonstrated that intracellular cholesterol accumulation contributed to podocyte injury in diabetic nephropathy (DN). This study aimed to investigate possible roles of GPR43 activation in lipid nephrotoxicity in DN and to explore its potential mechanisms.

Method

The experiments were conducted by using diabetic GPR43 knockout mice and cell culture model of podocytes. Renal pathological changes were checked by periodic acid schiff staining, immunohistochemical staining and transmission electron microscopy (TEM). The lipid deposition and free cholesterol contents in kidney tissues were detected by Oil Red O staining, BODIPY staining, and cholesterol quantitative assay. The protein expressions of GPR43, LC3II, p62 and related molecules of LDLR pathway in kidney tissues and podocytes were detected by real-time PCR, immunofluorescent staining, and Western blotting.

Results

There were decreased plasma level of LDL-cholesterol and cholesterol accumulation in kidney tissues of diabetic GPR43 knockout mice. In vitro study demonstrated that acetate, a stimulator of GPR43, increased LDLR-mediated cholesterol uptake in podocytes, accompanied with reduced cholesterol autophagic degeneration, characterized by inhibited LC3 maturation, p62 degradation, and autophagosome formation. These may evoke synergistic effects attributing to cellular cholesterol accumulation in podocytes. While genetic knockdown or pharmacological inhibition of GPR43 inhibited this effect in podocytes. Furthermore, the activation of GPR43 led to the activation of ERK1/2/EGR1 pathway in podocytes, whereas blocking ERK1/2 activity or reducing EGR1 expression reversed cholesterol influx and the inhibition of autophagy mediated by GPR43 activation in podocytes. Meanwhile, deletion of the GPR43 improved autophagy and inhibited the ERK1/2-EGR1 pathway of podocyte in diabetic mice in vivo.

Conclusion

Activation of the GPR43 mediated lipid nephrotoxicity contributes to podocyte injury in DN, which was mainly through the activation of ERK/EGR1 pathways. These findings suggested that the GPR43 receptor could be a potential therapeutic target for the prevention of DN progression.
FC 027COVID-19 IN PATIENTS ON KIDNEY REPLACEMENT THERAPY - CLINICAL CHARACTERISTICS AT TRIAGE ASSOCIATED WITH ADMISSION, READMISSION AND SHORT-TERM OUTCOMES
Authors: Mitra Sandip , Jayanti Anu , Vart Priya , Coca Armando , Gallieni Maurizio , Altern Øvrehus Marius , Midtvedt Karsten , Abd ElHafeez Samar , Gandolfini Ilaria , Büttner Stefan , Franssen Casper , Hemmelder Marc
Published: May 2021

Background and Aims

Patients on kidney replacement therapy (KRT) are at high risk of developing severe COVID-19 illness and often require high intensity care and utilisation of hospital resources. During the ongoing pandemic, the optimal care pathway and triage for KRT patients presenting with varying severity of COVID-19 illness is unknown. We studied clinical factors and outcomes associated with admission, readmission and short-term outcomes.

Method

Data from the European Renal Association COVID-19 Database (ERACODA) was analysed. This database includes granular data on dialysis patients and kidney transplant recipients with COVID-19 from all over Europe. The clinical and laboratory features at first presentation of hospitalized and non-hospitalized patients and those who returned for second presentation were studied. In addition, possible predictors of outcome in those who were not hospitalized at first presentation were identified.

Results

Among 1,423 KRT patients (haemodialysis; 1017/kidney transplant; 406) with COVID-19, 25% (n=355) were not hospitalized at first presentation. Of them, only 10% (n=36), presented for a second time in the hospital. The median interval between the first and second presentation was 5 days (Interquartile interval: 2-7 days). Patients who re-presented had worsening of pulmonary symptoms, a fall in oxygen saturation (97% to 90%), and an increase in C-reactive protein (26 mg/L to 73 mg/L) between their attendances. Patients who re-presented after initial assessment were older (72 vs. 63 years) and initially more often had pulmonary symptoms and abnormalities on lung imaging compared with those who did not present for a second time. The 28-day mortality rate of patients admitted at the second presentation was similar to that of patients admitted at first presentation (26.5% vs. 29.7%, p=0. 61). Among patients who were not hospitalized at first presentation (mortality 6%), age, prior smoking, clinical frailty scale, and shortness of breath at first presentation were identified as predictors of mortality.

Conclusion

KRT patients with COVID-19 and mild pulmonary abnormalities and no signs of pulmonary insufficiency can be safely returned without hospitalization. These patients should be advised to seek immediate contact when they develop respiratory distress. Our findings provide support for a risk-stratified clinical approach to admissions of KRT patients presenting with COVID-19. The study findings may be valuable for clinical triage and optimising hospital capacity utilisation during the ongoing pandemic.
FC 028COVID-19 RELATED MORTALITY IN KIDNEY TRANSPLANT AND DIALYSIS PATIENTS: A COMPARATIVE, PROSPECTIVE REGISTRY BASED STUDY
Authors: Candellier Alexandre , Goffin Eric Jean , Vart Priya , Noordzij Marlies , Arnol Miha , Covic Adrian , Lentini Paolo , Malik Shafi , Reichert Louis , Sever Mehmet Sukru , Watschinger Bruno , Jager Kitty J , Gansevoort Ronald
Published: May 2021

Background and Aims

Studies examining kidney failure patients with COVID-19 reported higher mortality in hemodialysis patients than in kidney transplant recipients. However, hemodialysis patients are often older and have more comorbidities. This study investigated the association of type of kidney replacement therapy with COVID-19 severity adjusting for differences in characteristics.

Method

Data were retrieved from the European Renal Association COVID-19 Database (ERACODA), which includes kidney replacement therapy patients diagnosed with COVID-19 from all over Europe. We included all kidney transplant recipients and hemodialysis patients who presented between February 1st and December 1st 2020 and had complete information reason for COVID-19 screening and vital status at day 28. The diagnosis of COVID-19 was made based on a PCR of a nasal or pharyngeal swab specimens and/or COVID-19 compatible findings on a lung CT scan. The association of kidney transplantation or hemodialysis with 28-day mortality was examined using Cox proportional-hazards regression models adjusted for age, sex, frailty and comorbidities. Additionally, this association was investigated in the subsets of patients that were screened because of symptoms or have had routine screening.

Results

A total of 1,670 patients (496 functional kidney transplant recipients and 1,174 hemodialysis patients) were examined. 16.9% of kidney transplant recipients and 23.9% of hemodialysis patients died within 28 days of presentation. In an unadjusted model, the risk of 28-day mortality was 33% lower in kidney transplant recipients compared with hemodialysis patients (hazard ratio (HR): 0.67, 95% CI: 0.52, 0.85). However, in an age, sex and frailty adjusted model, the risk of 28-day mortality was 29% higher in kidney transplant recipients (HR=1.29, 95% CI: 1.00, 1.68), whereas in a fully adjusted model the risk was even 43% higher (HR=1.43, 95% CI: 1.06, 1.93). This association in patients who were screened because of symptoms (n=1,145) was similar (fully adjusted model HR=1.46, 95% CI: 1.05, 2.04). Results were similar when other endpoints were studied (e.g. risk for hospitalization, ICU admission or mortality beyond 28 days) as well as across subgroups. Only age was found to interact significantly, suggesting that the increased mortality risk associated with kidney transplantation was especially present in elderly subjects.

Conclusion

In this study, kidney transplant recipients had a greater risk of a more severe course of COVID-19 compared with hemodialysis patients when adjusted for age, sex and comorbidities.