bluuebunny/crossref_metadata_2025_split huggingface dataset:
FC 069CHRONIC KIDNEY DISEASE AND ATRIAL FIBRILLATION: A DANGEROUS COMBINATION
Authors: Ocak Gurbey , Khairoun Meriem , Khairoun Othman , Bos Willem Jan , Fu Edouard , Cramer Maarten J , Westerink Jan , Verhaar Marianne , Visseren Frank L J 
Published: May 2021

Abstract

Background and Aims
Chronic kidney disease (CKD) and atrial fibrillation (AF) are both risk factors for bleeding, stroke and mortality. Whether the combination of CKD and AF leads to higher risks of bleeding, stroke and mortality than CKD or AF alone is not known. The aim of our study was to investigate the interaction between CKD and AF and outcomes.

Method
We included 12,394 subjects referred to the University Medical Center Utrecht (the Netherlands) from September 1996 to February 2018f for an out-patient visit with classical risk factors for arterial disease or with symptomatic arterial disease (Utrecht Cardiovascular Cohort Second Manifestation of Arterial disease (UCC-SMART) cohort). Hazard ratios (HRs) with 95% confidence intervals (CIs) for bleeding, ischemic stroke or mortality were calculated with Cox proportional hazards analyses. Presence of additive interaction between AF and CKD was examined by calculating the relative excess risk due to interaction (RERI), the attributable proportion (AP) due to interaction and the synergy index (S).

Results
Of the 12,394 patients, 699 patients had AF, 2,752 patients had CKD and 325 patients had both AF and CKD. Overall, 382 patients developed a first bleeding event, 421 patients had a first ischemic stroke and 2203 patients died. Patients with both CKD and AF had a 3.0-fold (95% CI 2.0-4.4) increased risk for bleeding, a 4.2-fold (95% CI 3.0-6.0) increased ischemic stroke risk and a 2.2-fold (95% CI 1.9-2.6) increased mortality risk after adjustment as compared with subjects without AF and CKD (Table 1). Although bleeding and mortality risks were highest for the combination of AF and CKD, we did not find interaction between AF and CKD. However, we found an interaction between AF and CKD for ischemic stroke risk (RERI 1.88 (95% CI 0.31-3.46), AP 0.45 (95% CI 0.17-0.72) and S 2.40 (95% CI 1.08-5.32)) (Table 1).

Conclusion
The combination of CKD and AF is associated with high risks for bleeding, ischemic stroke and mortality. There is a positive interaction between AF and CKD for ischemic stroke risk, but not for bleeding or mortality.
FC 076DIAGNOSTIC ACCURACY OF BONE TURNOVER MARKERS IN RENAL OSTEODYSTROPHY
Authors: Jørgensen Hanne Skou , Behets Geert , Cavalier Etienne , D'Haese Patrick , Evenepoel Pieter 
Published: May 2021

Abstract

Background and Aims
A transiliac bone biopsy is the gold standard for diagnosing renal osteodystrophy, but is not recommended as part of routine clinical workup due to its invasive nature. Suitable non-invasive alternatives have yet to be established. The aim of this study was to investigate the diagnostic accuracy novel biochemical markers of bone remodeling compared to that of biointact parathyroid hormone (PTH) for bone turnover as evaluated by histomorphometry.

Method
Protocolled bone biopsies were performed in end-stage kidney disease patients (ESKD, n = 80) and kidney transplant recipients (n = 119). Full-length (1-84) PTH, bone-specific alkaline phosphatase (BsAP), intact N-terminal propeptide of type I collagen (P1NP), and tartrate-resistant acid phosphatase isoform 5b (TRAP5b) were measured. Diagnostic performance was evaluated by area under the receiver operator characteristics curve (AUC). Optimal diagnostic cutoffs were established in an exploration cohort (n=100), and subsequently validated in a separate subset of patients (n=99).

Results
Mean age was 55±13 years, two-thirds were men (67%), and 23% had diabetes mellitus. Post-transplant eGFR was 49 [IQR 39, 59] ml/min/1.73m². Bone turnover was low in 47 (24%), normal in 119 (60%), and high in 33 (17%) patients. All biomarkers differed significantly across categories of bone turnover (p &lt; 0.001). The AUC of biointact PTH for high turnover was 0.82 (0.73, 0.91), which was not significantly different from AUC values for BsAP, Intact P1NP, and TRAP5b (0.87, 0.90, and 0.86, respectively). AUC of biointact PTH for low turnover was 0.71 (0.63, 0.78), which was significantly lower than the values for BsAP, Intact P1NP, and TRAP5b (0.79, 0.83, and 0.79, respectively; p &lt; 0.05, all). Calculated optimal diagnostic cutoffs in the exploration cohort are shown in Table 1. Applying these cutoffs in the validation cohort revealed high negative predictive values for both high (92 - 96%) and low (82 - 90%) bone turnover. Positive predictive values were consistently low.

Conclusion
The diagnostic accuracies of BsAP, Intact P1NP and TRAP5b are sufficient to rule out both high and low bone turnover in CKD. Biointact PTH shows inferior performance, particularly in kidney transplant recipients.
FC 077LONG-TERM SAFETY OF TENAPANOR FOR THE CONTROL OF SERUM PHOSPHORUS IN PATIENTS WITH CKD ON DIALYSIS
Authors: Weiner Daniel , Fishbane Steven , Lynn Robert , Yang Yang , Rosenbaum David 
Published: May 2021

Abstract

Background and Aims
Tenapanor, a first-in-class, phosphate absorption inhibitor blocks the paracellular absorption of phosphate in the GI tract by local inhibition of the sodium-hydrogen exchanger (NHE3). It therefore provides a novel, non-binder approach for managing hyperphosphatemia. Tenapanor is dosed as one small pill twice daily. In three pivotal trials, tenapanor met its primary phosphorus-lowering outcome. This report evaluates long-term safety data from the longest of these trials.

Method
This 52-week study consisted of a 26-week, open-label, randomized treatment period with a 12-week placebo-controlled randomized withdrawal period, followed by a 14-week open label safety extension period. Maintenance dialysis patients with serum phosphorus ≥ 6.0 mg/dL and a 1.5 mg/dL increase in serum phosphorus following phosphate binder washout were randomized 3:1 to receive tenapanor 30 mg twice daily or sevelamer carbonate, dosed per package insert. At end of the randomized treatment period all patients in the tenapanor arm were re-randomized 1:1 to either tenapanor or placebo for the randomized withdrawal period followed by tenapanor for the safety extension period. Sevelamer was used as a safety control for comparisons of serious adverse events/hospitalizations to tenapanor.

Results
Tenapanor was generally well tolerated, with diarrhea the only adverse event reported by &gt;5% of patients during the randomized treatment period. Diarrhea was typically mild-to-moderate in severity, transient, and occurred more commonly during the randomized treatment period than the randomized withdrawal or safety extension periods. Rates of serious adverse events leading to hospitalization were higher in patients treated with sevelamer than tenapanor (35.8% vs 24.6%). The highest reported percentages of serious adverse events were infections and infestations (16.1% vs 9.3%) cardiac disorders (8.0% vs 5.7%), respiratory, thoracic and mediastinal disorders (8.8% vs 5.5%), and metabolism and nutritional disorders (7.3% vs 3.6%) for sevelamer and tenapanor, respectively. Adverse events leading to death were higher in patients treated with sevelamer than tenapanor (3.6% vs 2.9%).

Conclusion
Among maintenance dialysis patients with hyperphosphatemia, tenapanor, a novel, non-binder, phosphate absorption inhibitor that blocks paracellular absorption of phosphorus with a one tablet twice daily dose, has an acceptable safety profile, and, if approved, may offer a new approach to the treatment of hyperphosphatemia.
FC 080VARIABILITY IN SERUM PHOSPHATE ASSESSED BY DIRECTIONAL CHANGE IS ASSOCIATED WITH INCREASED MORTALITY
Authors: Ye Xiaoling (Janice) , Ter Meulen Karlien , Usvyat Len A , Van Der Sande Frank , Konings Constantijn , Kooman Jeroen , Kotanko Peter , Maddux Frank 
Published: May 2021

Abstract

Background and Aims
Prior studies showed that there is a wide variability between serial pre-dialysis measurements of serum phosphate (P). Serum P vary can be due to changes in nutritional intake, underlying bone disorders, medication use or inflammation. Various variability markers have been investigated to study the association between P variability and its association with outcomes, however, the directional trends have not been studied in depth. We aimed to study directional changes and investigated its association with outcomes.

Method
All adult incident HD patients treated in Fresenius Medical Care North America (FMCNA) clinics between 01/2010 and 10/2018 were included in this retrospective cohort study. Serum P levels were averaged from month 1 to 6 after the initiation of dialysis (baseline). Baseline absolute and directional range (DR) of serum P were calculated. DR of P was calculated as: P min/max (t2) – P max/min (t1), with P (t1) and P (t2) represents the timepoint when either the min P value or max P value was measured, whichever comes first, and with t2 happened after t1. It is positive when the minimum antedates the maximum, otherwise negative. All-cause mortality was recorded between months 7 and 18. Cox proportional hazards models with spline terms were applied to explore the association between absolute and DR of P and all-cause mortality. Additionally, tensor product smoothing splines were computed to study the interactions of P with absolute P and DR of P and their joint associations with outcomes, respectably.

Results
We studied 353,142 patients. The average age was 62.7 years, 58% were male, 64% were diabetic. Baseline P was 4.98 mg/dL, median absolute range was 2.40 mg/dL, median DR was 1.1 mg/dL. Across different levels of P, both higher levels of absolute range and DR of P were associated with higher risk of mortality (Figure 1, Figure 2). The associations even seemed stronger in patients with lower levels of serum P and with negative DR (Figure 1).

Conclusion
Lower levels of serum P are independently associated with an increased risk of all-cause mortality. Whereas both a positive and negative DR of P are in general associated with increased mortality, the effects of an increase are most predominant in patients with higher levels of serum P, whereas a negative directional range are most predominant in patients with low serum P. This could be explained by the fact that patients with lower levels of P are generally malnourished or inflamed, where a further reduction indicates nutritional deterioration.
FC 008INTERDEPENDENT REGULATION OF POLYCYSTIN EXPRESSION INFLUENCES STARVATION-INDUCED AUTOPHAGY AND CELL DEATH
Authors: Decuypere Jean-Paul , Van Giel Dorien , Janssens Peter , Dong Ke , Somlo Stefan , Cai Yiqiang , Mekahli Djalila , Vennekens Rudi 
Published: May 2021

Abstract

Background and Aims
Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by mutations in either PKD1 (ca. 78%) or PKD2 (ca. 15%), encoding for the proteins polycystin-1 (PC1) or polycystin-2 (PC2), respectively. Mutations in PKD1 generally lead to a more severe disease progression compared to PKD2 patients. The exact function of the polycystins in cyst formation remains unclear, but it is clear that the levels of PC1 and PC2 are inversely correlated to cyst formation. Moreover, renal stress has been proposed to enhance cystogenesis. We therefore aimed to investigate the cellular response towards nutritional stress in mouse inner medullary collecting duct cells (mIMCDs), either wild-type (WT) or lacking PC1 or PC2 (PC1KO or PC2KO), and unique human urine-derived proximal tubular epithelial cells (PTECs) of early-stage ADPKD patients with truncating PKD1 mutations versus healthy individuals, with a focus on cell survival (autophagy) and cell death.

Method
Cell death was assessed with Cytotox green-based live cell imaging in the Incucyte, by trypane blue exclusion and by analyzing the levels of cleaved Caspase 3. Autophagy was measured by LC3 immunoblotting and by counting GFP-LC3 punctae. Autophagy was blocked with Bafilomycin A1. To modulate the levels of PC1 and PC2, transient overexpression of human PC1 or siRNA-mediated knockdown of PC2 was performed.

Results
During chronic starvation, cell death was reduced and autophagy was increased in mouse PC1- and PC2-deficient mIMCDs. This was validated in human cells from early-stage ADPKD patients. Autophagy inhibition restored cell death resistance in KO cells, implying that decrease in cell death was caused by autophagy upregulation in PC1- and PC2KO cells. Interestingly, PC2 expression was increased in PC1KO cells, while PC2KO displayed a downregulation of PC1. Although PC2 is known to regulate autophagy, PC2 knockdown did not reduce autophagy in PC1KO cells, while the effect in PC2KO could be reversed by overexpression of PC1.

Conclusion
These findings indicate that PC1 levels determine the transition from renal cell survival to death, leading to enhanced survival of ADPKD cells during nutritional stress. Moreover, PC1 also indirectly influences this process by regulating PC1 levels during starvation. Our findings imply that in early stage ADPKD, cells with the lowest polycystin levels (which are most prone to form cysts) are more resistant to stress by autophagy upregulation. This is important, as renal stress is inherent to the cystic environment and has been proposed as an additional trigger in cystogenesis.
FC 0104-WEEK ANTIBIOTIC THERAPY PREVENTS RECURRENT RENAL CYST INFECTIONS IN AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE
Authors: Dang Julien , Knebelmann Bertrand , Charlier Caroline 
Published: May 2021

Abstract

Background and Aims
Renal cyst infection (CI) is a major complication of autosomal dominant polycystic kidney disease (ADPKD), associated with frequent hospitalization, worsening of kidney function and significant mortality. Data regarding treatment are scarce and recommendations only expert-based, with low level of evidence. Prolonged treatment duration and use of lipid-soluble antibiotics may increase antibiotic concentration in infected kidney cysts. However, benefits of this strategy have never been investigated in clinical practice.

Method
We undertook a monocentric retrospective study of CI in ADPKD patients from 2000 to 2018. CI were classified as “definite” (microbiologically proven), “probable” (clinical/biological and radiological signs) or possible (clinical/biological signs). Determinants of treatment failure and recurrences were studied.

Results
139 CI (11 “definite”, 74 “probable”, 54 “possible”) were compiled among 90 patients. Median age was 53 years. 28/90 (31%) were kidney transplant recipients. Escherichia coli was identified in 89/106 (84%) episodes. Treatment failure was reported in 22/139 (16%), and found associated with cyst diameter &gt;5cm (80% vs 36%, P&lt;0.01), cyst wall thickening (53% vs 12%, P&lt;0.001), cyst septations (18% vs 1%, P&lt;0.01), intracystic gas (18% vs 1%, P&lt;0.01), kidney abscess (35% vs 1%, P&lt;0.001), higher C-reactive protein level (210 [140-358] vs 145 [99-213] mg/L, P&lt;0.01) or documentation of Staphylococcus aureus and lugdunensis (P&lt;0.001). Recurrence was reported in 20/139 (14%) cases within 1-year follow-up. Recurrence rate was lower in patients treated with lipid soluble antibiotics than with non-lipid soluble antibiotics (HR=0.34 [0.12-0.97], p=0.045). Most importantly, cases with definite and probable CI experienced significantly fewer recurrences when treated with longer treatment duration: 81% for treatment &lt;21 days, 47% for 21-27 days, but only 2% for ≥28 days (p&lt;0.0001).

Conclusion
Treatment of kidney CI should last ≥28 days and include when possible lipid soluble antibiotics.
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

Abstract

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

Abstract

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

Abstract

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.