bluuebunny/crossref_metadata_2025 huggingface dataset:
FC 005DEPOSITION OF PLATELET-DERIVED MICRO-PARTICLES IN PODOCYTES CONTRIBUTES TO DIABETIC NEPHROPATHY
Authors: Huang Sijia , Lu Jian , Chen Pei Pei , Zhang Jia Xiu , Li Xue Qi , Liu Bicheng , Ma Kun Ling
Published: May 2021

Background and Aims

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the developed world. Podocyte injury has been shown to be a critical cellular event in the progression of DN. Our previous studies demonstrated that platelet-derived microparticles (PMPs) mediated endothelial injury in diabetic rats. Therefore, this study aimed to investigate whether the PMPs deposit in podocytes and its potential effects on podocyte injury in DN.

Method

Deposition of PMPs in podocytes was checked by immunofluorescent staining and electron microscopy. Renal pathological change and ultra-microstructure were respectively checked by periodic acid-schiff staining and electron microscopy. The protein expression of inflammatory cytokines and extracellular matrix was measured by immunohistochemical staining and Western blot.

Results

The PMPs were found to be widely deposited in podocytes of glomeruli in diabetic patients and animal models and closely associated with progression of DN. Interestingly, aspirin treatment significantly inhibited accumulation of PMPs in glomeruli of diabetic rats, accompanied with alleviated mesangial matrix expansion, fusion of foot processes, decreased protein expression of inflammatory cytokines and extracellular matrix secretion. The in vitro study further confirmed the deposition of PMPs in podocytes. Moreover, PMPs stimulation induced phenotype transition of podocytes through decreased protein expression of podocin and increased protein expression of α-SMA and fibronectin, which was correlated with increased production of inflammatory cytokines.

Conclusion

Our findings for the first time demonstrated that deposition of PMPs in podocytes contributed to the development of DN.
FC 006PP2A PHOSPHATASE INHIBITION IS ANTI-FIBROTIC THROUGH SER77 PHOSPHORYLATION-MEDIATED ARNT/ARNT HOMODIMER FORMATION
Authors: Nyamsuren Gunsmaa , Rapp Gregor Christof , Tampe Björn , Zeisberg Michael
Published: May 2021

Background and Aims

Aryl hydrocarbon receptor nuclear translocator (ARNT) mediates anti-fibrotic activity in kidney and liver through induction of ALK3-receptor expression and subsequently increased Smad1/5/8 signaling. While expression of ARNT can be pharmacologically induced by sub-immunosuppressive doses of FK506 or by GPI1046, its anti-fibrotic activity is only realized when ARNT-ARNT homodimers form, as opposed to formation of ARNT-AHR or ARNT-HIF1α heterodimers. Mechanisms underlying ARNTs dimerization decision to specifically form ARNT-ARNT homodimers and possible cues to specifically induce ARNT homodimerization have been previously unknown. We here aimed to elucidate the molecular mechanisms underlying control of ARNT dimerization decision and to explore its therapeutic potential.

Method

We analyzed dimerization of recombinant and native ARNT by immunoprecipitation, MALDI-TOF mass spectrometry, and LS-MS/MS analysis and proximity ligation assay. Phosphorylation sites were mapped through generation of phosphorylation site mutants and through pharmacological inhibition. For in vivo analysis we challenged mice with model of unilateral ureter obstruction and carbon tetrachloride to induce fibrosis in kidney and liver.

Results

Here we report that inhibition of PP2A phosphatase activity increases intracellular accumulation of ARNT-ARNT homodimers. This effect is dependent on enhanced ARNT-ARNT homodimerization and decreased ARNT proteolytic degradation, but independent of ARNT transcription (which remains unchanged upon PP2A inhibition). We further identify that Ser77 phosphorylation plays a critical role in ARNT homodimerization, as ARNT-ARNT homodimers do not form with Ser77/Asp-mutant ARNT proteins. In light of previous studies which identified anti-fibrotic activity upon increased ARNT expression, we further demonstrate attenuated fibrosis upon monotherapy with the PP2A inhibitor LB100, and additive anti-fibrotic activities upon combination with pharmacological inducers of ARNT expression FK506 or GPI1046 in murine models of kidney and liver fibrosis.

Conclusion

Our study provides additional evidence for the anti-fibrotic activity of ARNT and reveals Ser77 phosphorylation as a novel pharmacological target to realize the therapeutic potential of increased ARNT transactivation activity.
FC 116WEIGHT CHANGE AS A PREDICTOR OF MORTALITY IN CHRONIC HEMODIALYSIS PATIENTS
Authors: Moromizato Takuhiro , Iseki Kunitoshi
Published: May 2021

Background and Aims

Serial decrease in body weight can be a prognostic marker reflecting Protein Energy Wasting (PEW) condition in haemodialysis patients. However, the impact of longitudinal body weight changes on mortality have rarely been evaluated. Therefore, we applied landmark analysis and time-scale mixed regression analyses to clarify the impact of long-term changes in body weight on all-cause mortality.

Method

This study is a post-hoc analysis of the participants in the Olmesartan Clinical Trial in Okinawan Patients Under OKIDS (OCTOPUS) conducted between June 2006 and June 2011. We additionally followed up with the participants until 31 July, 2018. During the OCTOPUS trial, the body weight of surviving participants was repeatedly measured every 6 months. The primary aim of the study was to clarify the association of serial change in body weights and all-cause mortality. The participants were categorized into 4 groups based on weight change slope during the first 2 years (bottom to highest group correspond with the first quartile to the fourth quartile group). We conducted a landmark analysis to evaluate the influence of weight change slope on the subsequent survival with Cox-proportional hazard regression. We also conducted time-scale multilevel regression analyses to draw marginal plots of body weight with a backward time scale to describe the difference in trajectories of body weight between deceased and surviving patients.

Results

Out of 461 patients in the cohort, 404 participants were analysed in the landmark analysis. Of the participants, 168 (41.6%) were deceased, and 236 participants (58.4%) survived. Although baseline body weights and indices about body components such as a creatinine index were similar among the 4 groups, multivariate Cox-proportional hazard regression showed that the higher rate of body weight loss was associated with higher mortality. Hazard ratios were 2.02 (1.28–3.20), 1.77 (1.10–2.85), 1.00 (Reference), and 1.11 (0.67–1.83) for first quartile, second quartile, third quartile (Reference), and fourth quartile group, respectively (P for trend was <0.001). The association was also described using Kaplan-Meier plots, with the P-value of general Log-rank test being 0.015 (Fig 1a). Marginal plots drawn with a multivariate adjusted time-scale multilevel regression model, which included all 461 participants, with a backward time-scale, showed that body weight constantly decreased in deceased patients, while body weight was longitudinally stable in surviving patients (Fig 1b). These trends of weight change have been soundly observed in sensitivity analyses.

Conclusion

In chronic haemodialysis patients, the higher rate of body weight loss, such as a decrease in body weight by 1 kg (1.7%) per 6 months, was significantly associated with higher mortality. Persistent loss of body weight is a significant predictor of death among chronic dialysis patients.
FC 093EFFICACY OF EXPANDED HEMODIALYSIS AT DIFFERENT DIALYSATE FLOWS
Authors: Molano-Triviño Alejandra , Vesga Jasmin , Zuñiga Eduardo , Gutiérrez Juan Felipe , Ramos Carolina , Ronco Claudio
Published: May 2021

Background and Aims

Expanded hemodialysis (HDx) is based on hollow fibre dialyzer focused on improving the clearance of middle molecules as a target for uremia treatment. According to in vitro and in vivo results, High cut off filters have high enough clearance to allow diminishing of dialysate flow. Our aim is to compare clearance of middle molecules at different dialysate flow (Qd) in HDx with TheranovaMR membranes.

Our aim was to Evaluate efficacy of MCO dialyzer in terms of Kt/V and phosphorus levels at different prescribed dialysate flows (Qd) 400 vs 500 ml/min in HD patients from 10 renal clinics in Colombia.

Method

We performed a Prospective, observational, multicenter cohort study.

Prevalent adult HD patients (>90 days), with weight lower or equal to 70 Kg, were included between September to November 2017 and prospectively followed for one year with routine monthly blood tests for HD adequacy and registered at both Qd groups at 1, 3, 6, 9 and 12 months. A mixed-model repeated measures analysis (MMRM) was performed to identify statistical differences over time. Socio-demographic and clinical characteristics of all patients were summarized descriptively by Qd.

Results

462 patients were included: 127 with Qd 400 mL/min. We did not find statistically significative differences in serum levels of albumin, hemoglobin, calcium or phosphorus when comparing Qd 400ml/min vs 500 ml/min. We found statistically higher Kt/V in Qd 400 mL/min patients. (Table 2).

In a sustainability analysis, part of Blue Planet dialysis research group, we calculated important savings in water waste in Qd 400 mL/min group.

Conclusion

MCO dialyzers are at least as effective in reaching HD adequacy parameters (Kt/V, PO4) at Qd 400 as 500 mL/min with interesting savings of potable water: 24 Liters were saved in each session per patient.
FC 094THREE VERSUS TWICE-WEEKLY HEMODIALYSIS SESSIONS: A COMMUNITY EXPERIENCE
Authors: Bonagiri Paavan , Owen Meagan , Mohandas Shreya , Sharma Simrun , Ejaz Abutaleb
Published: May 2021

Background and Aims

We investigated the feasibilty of converting stable end stage renal disease (ESRD) patients from three to twice weekly hemodialysis (HD) sessions based on published criteria.

Method

ESRD patients on three times weekly (3xwkly) HD sessions for at least 3 months duration were screened for eligibility for conversion to twice weekly (2xwkly) maintenace HD schedule in a university-affiliated community dialysis program. Eligibility criteria were: residual renal function > 3ml/min; urine output >500mL/day; intradialytic weight gain <2.5kg; hemoglobin >8gm/dL; manageable phosphorus and potasium levels. Clinical parameters on 3xwkly vs. 2xwkly HD sessions were then performed in the eligible patients.

Results

7/71 (9.8%) of the patients met criteria for conversion to 2xwkly HD sessions. Baseline patient characteristics are shown in Table 1. Major indication for HD initiation was symptomatic progression of disease. Less than 50% of patients had a functioning arteriovenous fistula at initiation of HD. In the current cohort, residual renal function > 3mL/min was maintainedfor >200 days after initiation of HD. There were no significant changes in electrolytes, hemoglobin, nutrition staus or adequacy of dialysis. PTH levels were not significantly different: 3xwkly, 625.7 + 546.2pg/mL vs. 2xwkly, 399 + 344.2pg/mL; p=0.374). Karnofsky Performance Status Scale improved post conversion but did not achieve statistical significance (3xwkly, 57.1 vs. 2xwkly, 70; p=0.316). There were no hospital admissions since conversion to 2xwkly schedule during the study period.

Conclusion

In a community-based dialysis program, 10% of total HD patients qualified for conversion from 3xwkly to 2xwkly maintenance HD without significant changes to their laboratory or clinical performance measures. These observations stimulate discussion regarding increased application of incremental dialysis initiation strategies to preserve residual renal function, increase dialysis-free days and alleviate transportation and care provider-related burden to patients and families.
FC 096THE EFFECT OF INCREMENTAL START OF HAEMODIALYSIS ON BLOOD PRESSURE AND INTERDIALYTIC WEIGHT GAIN: PRELIMINARY FINDINGS FROM THE ENDURE STUDY
Authors: Hazara Adil , Allgar Victoria , Twiddy Maureen , Bhandari Sunil
Published: May 2021

Background and Aims

Mortality rates are high in patients starting haemodialysis/haemodiafiltration (HD) therapy. Incremental HD may help reduce this risk by reducing the burden of early treatment whilst patients are still adapting to long-term HD therapy. A feasibility study (ENDURE study – Clinical trials ID: NCT04268264) is being conducted with the primary objectives of evaluating the acceptability and tolerance of a new incremental HD regime. Its secondary aims are to evaluate the impact of this form of incremental HD on indicators of patient safety and wellbeing. These indicators include blood pressure (BP) control and interdialytic weight gains (IDWG) which are independently associated with adverse cardiovascular outcomes in patients on long-term HD. We present preliminary findings from the study related to systolic BP and IDWG.

Method

The ENDURE study is being carried out at a tertiary care hospital in the United Kingdom. Patients aged > 18 years known to renal services for at least 90 days, referred for start of HD, were eligible for participation. Following approved consenting procedures, they are started on a new regime of incremental HD starting dialysis twice weekly with progressive increases in the duration and frequency of sessions over 15 weeks. This period is split in to four phases; phase 1 representing the first two days of dialysis (baseline) whereas phases 2 – 4 representing the pre-specified incremental steps. Propensity scores were calculated to match each participant (incremental HD group) with two controls from a database of patients who previously started HD at our centres using the standard protocol of 3 times weekly, 4hr long sessions. The matching criteria accounted for 14 key demographic, clinical and laboratory characteristics. Results were analysed as intention to treat. In comparing BP and IDWG between the two groups, only readings taken pre-dialysis at the first session of the week was considered. This study has been approved by the West of Scotland Research Ethics committee-4 (Ref: 19/WS/0019).

Results

Baseline characteristics of the first 15 participants (target 20) and their matched controls are presented in table 1. The proportion of females and duration of previous specialist input was higher in the incremental HD group.

Conclusion

The ENDURE study tests the feasibility of starting patients on a novel incremental HD regime. Early data suggest that control of systolic BP and IDWG are comparable to patients who start dialysis at 3 times weekly. Further work is needed to understand the impact of reducing dialysis frequency on BP control correlating the findings with changes residual renal function and objective measures of fluid overload.
FC 012PRIMARY KIDNEY DISEASE IMPACTS OUTCOME IN CKD PREGNANCIES: COMPLICATIONS IN COL4A3-5 RELATED DISEASE (ALPORT SYNDROME) VS OTHER CKD PREGNANCIES
Authors: Snoek Rozemarijn , Gosselink Margriet , Vogt Liffert , De Jong Margriet , Cerkauskaite Agne , Vollenberg Renee , Knoers Nine , Lely Titia , Van Eerde Albertien M
Published: May 2021

Background and Aims

Chronic kidney disease (CKD) affects approximately 3% of pregnant women. CKD increases the risk of pregnancy complications such as prematurity, low birthweight and pre-eclampsia. Also, kidney function can deteriorate more quickly due to pregnancy. There is limited knowledge on pregnancy outcomes in specific kidney diseases. The aim of the ALPART network is to study pregnancy outcomes differentiated by CKD aetiology. We have started with COLA3-5 related disease (Alport syndrome), which is one of the most prevalent monogenic kidney diseases. Comparing outcomes in COLA3-5 related disease to pregnancies with other CKD aetiologies allows us to investigate whether this specific diagnosis impacts outcome in CKD pregnancies.

Method

The ALPART network is an international 15-center network, which aims to include ∼200 COLA3-5 related disease pregnancies. In this intermediary analysis, we present data on 109 pregnancies from 68 women with COLA3-5 related disease. We compared outcomes to a cohort of 457 CKD stage 1-2 patients (a similar CKD stage as our cohort) of diverse aetiology from a 2015 Italian study and 159,924 women from the general Dutch population.

Results

The main pregnancy and kidney outcomes are presented in Figure 1. Foetal outcomes were better in COLA3-5 pregnancies than in pregnancies of women with CKD stage 1-2 of diverse aetiology. We saw less prematurity (17% vs 36% respectively) and a higher mean birthweight of 3216 ± 663 gram compared to 2768 ± 680 in the Italian cohort. Maternal kidney outcomes should be interpreted with caution (>30% missing data): proteinuria (73%) and hypertension (30%) were more frequent in COLA3-5 pregnancies than the Italian cohort. In the ALPART cohort, 10% developed severe hypertension. Median eGFR was not impacted by pregnancy and decline of eGFR before and after pregnancy were not significantly different between groups.

Conclusion

Fetal outcomes in pregnancies with COLA3-5 related disease seem to be more favorable than in a cohort with mixed cause of CKD. In this intermediary analysis, proteinuria levels and frequency of new-onset hypertension in pregnancy are higher. There is no significant eGFR loss during pregnancy or increased eGFR deterioration in the long-term. The differences between COLA3-5 and general CKD pregnancies underscore the importance of investigating pregnancy outcomes in specific kidney disease phenotypes to ensure adequate (pre-) pregnancy counselling and care.
FC 019PROTEOMIC PROFILING OF GLOMERULI FROM KIDNEYS WITH HYPERTENSIVE NEPHROPATHY REVEALS SIGNATURE OF DISEASE PROGRESSION
Authors: Mikkelsen Håvard , Vikse Bjørn Egil , Scherer Andreas , Finne Kenneth , Marti Hans-Peter
Published: May 2021

Background and Aims

Hypertensive nephropathy (HN) often represents an unspecific clinical diagnosis applied to non-diabetic, chronic kidney disease (CKD) patients with low-level proteinuria and elevated blood pressure. Kidney biopsy-based findings are the diagnostic gold standard, but they are not entirely specific and there is a need for prognostic markers. We aimed at defining candidate markers that predict disease progression based on protein signatures.

Method

We included adult patients (n=17) with an eGFR >30 ml/min/1.73m2 and proteinuria <3g/d from the Norwegian Kidney Biopsy Registry (NKBR). Subjects were divided into two groups: stable patients (n=9) and subjects with HN progression (n=8) leading to end-stage renal disease (ESRD) within 20 years of follow-up. Glomerular cross-sections were microdissected from 10 μm whole archival kidney biopsy sections and processed for protein extraction. Proteomic analyses were performed at our local facility PROBE in Bergen using a Q-exactive HF mass spectrometer. Abundances of glomerular proteins were compared between the two groups.

Results

Amongst a total of 1870 quality filtered proteins, we identified 58 proteins with absolute fold change (FC) ≥1.5, p≤0.05, including 17 proteins with absolute FC ≥2, indicative of HN progression (highest FC: Cadherin 16 and UDP-glucuronosyl-transferase 2B7). Hierarchical cluster and principal component analysis (PCA) with the 17 proteins showed clear separation of samples into these two disease clusters of HN progressors and non-progressors. To find proteins as biomarkers for the identification of progressors, we employed unsupervised K nearest neighbors validation algorithm coupled with leave-one-out internal cross-validation. Thereby, a set of five proteins (incl. cadherin 16) performed best and separated the two groups in a PCA, as shown in Figure 1. This classifier classified 16 of 17 samples correctly (AUC 0.993), misclassifying only one progressor sample. Applying Geneset Enrichment Analysis (GSEA; The Broad Institute, USA), in general metabolic pathways were up-regulated in progressors and structural cell pathways up-regulated in non-progressors. Ingenuity Pathway Analysis (IPA; Qiagen, USA) identified Epithelial Adherens Junction Signaling as the most affected canonical pathway (p=1.95E-06); five of six member proteins were down-regulated in progressors.

Conclusion

Glomerular proteomic profiling can be used to distinct progressors from non-progressors in HN.
FC 131OFATUMUMAB OR RITUXIMAB FOR CHILDREN WITH STEROID-DEPENDENT NEPHROTIC SYNDROME. A RANDOMIZED CONTROLLED TRIAL
Authors: Ravani Pietro , Colucci Manuela , Bruschi Maurizio , Vivarelli Marina , Cioni Michela , Di Donato Armando , Cravedi Paolo , Lugani Francesca , Emma Francesco , Angeletti Andrea , Ghiggeri Gian Marco
Published: May 2021

Background and Aims

The chimeric anti-CD20 monoclonal antibody rituximab has been successfully used in steroid-dependent forms of nephrotic syndrome (SDNS) to maintain oral-drug-free remission, but relapses at one year occur in almost half of the patients. Ofatumumab, a fully human anti-CD20 monoclonal antibody, may be superior to rituximab in maintaining remission of SDNS. We compared the efficacy and safety of ofatumumab vs. rituximab in children and young adults with SDNS (NCT02394119) and evaluated the risk of relapse following steroid and calcineurin-inhibitor tapering and withdrawal.

Method

We randomly assigned 140 children and younger adults (age 2-24 years) with SDNS maintained in remission with steroids and calcineurin-inhibitors to receive intravenous ofatumumab (1.500 mg/1.73 m2; intervention) or rituximab (375 mg/m2; control). Following infusions, oral drugs were tapered and withdrawn. Participants were followed for 24 months. The primary outcome was relapse at one year, defined by protein-creatinine ratio ≥2000 mg/g or >3+ protein on urine dipstick for 3 consecutive days. Cellular and safety data were also assessed.

Results

At 12 months, 36 patients (51.4%) relapsed in the rituximab arm and 37 (52.8%) in the ofatumumab arm (Odds Ratio [OR] 1.06; 95% confidence interval [CI] 0.55 to 2.06). At 24 months, 46 children relapsed in the rituximab arm (65.7%) and 53 in the ofatumumab arm (75.7%). In both arms, circulating B cell levels declined following treatment and recovered between 3 and 9 months. Higher pretreatment levels and faster recovery after decline of memory B cells predicted relapse.

Conclusion

In children and younger adults with SDNS, ofatumumab is not superior to the chimeric anti-CD20 antibody rituximab. Immune phenotyping data indicate that anti-CD20 therapies alter the course of the disease by interfering with memory B cell populations and can be used to predict response to anti-CD20 treatment.
FC 066DICKKOPF-3 (DKK3) LINKS RECIPROCAL LUNG AND KIDNEY INJURY IN MICE AND HUMANS
Authors: Schunk Stefan , Beisswenger Christoph , Sarah Triem , Hütter Gregor , Sarakpi Tamim , Boor Peter , Jörres Rudolf , Watz Henrik , Welte Tobias , Vogelmeier Claus , Gröne Hermann , Fliser Danilo , Bals Robert , Speer Thimoteus
Published: May 2021

Background and Aims

Chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD) represent global public health problems with high disease-related morbidity and mortality. However, the interaction between both diseases remains unclear.

Method

In a novel murine model, cigarette smoke (CS)-induced lung injury was combined with a CKD model (CS-CKD model). In 2,314 patients of the prospective multi-center COSYCONET study, urinary Dickkopf-3 (DKK3), a renal tubular stress marker, was quantified. The association between urinary DKK3 and trajectories of FEV1 and estimated glomerular filtration rate (eGFR), exercise capacity, risk of exacerbation, and mortality was determined (follow-up 37.1 months).

Results

In the CS-CKD model, CKD was associated with higher systemic and pulmonary inflammation, and the combination of CKD and CS significantly aggravated kidney inflammation as well as fibrosis and increased renal expression of DKK3. Abrogation of Dkk3 attenuated kidney injury and pulmonary inflammation alike. In COPD patients, higher urinary DKK3 was associated with rapidly declining FEV1 (OR 3.36, P<0.0001), higher risk for exacerbation, lower 6-minute walking distance, and higher all-cause mortality (HR 1.49, P=0.015). Importantly, higher urinary DKK3 was also associated with declining eGFR during follow-up (OR 2.23, P=0.0005). Neither eGFR nor proteinuria were associated with lung or kidney dysfunction during follow-up.

Conclusion

In summary, the present study identified a strong pathophysiological link between lung and kidney dysfunction, which is at least partially mediated by DKK3. Urinary DKK3 allows identification of COPD patients at increased risk for deteriorating pulmonary and kidney function as well as adverse outcomes. These patients might particularly benefit from preventive therapeutic strategies as a personalized-medicine approach.
FC 050THE PREDICTIVE ABILITY OF URINARY BIOMARKERS FOR PROGRESSION OF ACUTE KIDNEY INJURY IN CRITICAL ILLNESS
Authors: Duff Stephen , Irwin Ruairi , Cote Jean Maxime , Doran Peter , Murray Patrick
Published: May 2021

Background and Aims

Acute Kidney Injury (AKI) is a common hospital complication associated with high morbidity, mortality and the risk of progression to CKD. Despite globally increasing rates of AKI and a shortage of critical care beds, clinicians currently lack the tools to predict progression of early AKI. The Dublin Acute Biomarker Group Evaluation (DAMAGE) Study is a prospective multi-center observational study with a heterogenous cohort of critically ill patients (n= 717). We hypothesised that a panel of 14 novel urinary biomarkers would predict progression of AKI.

Method

Biomarker values were measured daily for 7 days from ICU admission, including on the day of Stage 1-2 AKI diagnoses occurring within 48 hours of ICU admission. The primary outcome was progression to the composite outcome of increased AKI KDIGO Stage, Renal Replacement Therapy (RRT) or Death within 7 days of ICU admission. AUC-ROC values and adjusted Odds Ratios were calculated using multivariate logistic regression, and the additional value of biomarkers over the clinical model (serum creatinine and urine output at time of diagnosis) was assessed. In a secondary analysis,all AKI events within 7 days (including those diagnosed at Stage 3, and/or on days 3-7) were included, with the endpoint of progression to RRT/Death within 30 days of ICU admission.

Results

AKI developed in 268 patients (37%) within 7 days of ICU admission. 95 patients were diagnosed with AKI at Stage 1or2 AKI within 48 hours, of whom 32 (33.7%) progressed to the primary outcome. Adjusted odds ratios for the prediction of AKI progression were significantly higher for the highest tertile, versus the lowest, of eight biomarkers including uCystatin C (OR 5.2, 95% CI; 1.3-23.6), uAlbumin (OR 4.9, 95% CI; 1.5-18.3), uNGAL (OR 4.6, 95% CI; 1.4-17.9) and uIGFBP-7 (OR 4.7, 95% CI; 1.2-21.5). LFABP-1, KIM-1, IL-18 and Alpha-1-M also significantly improved prediction (Table 1). In ROC analysis of the primary outcome, uCystatin C (AUC 0.75, 95% CI; 0.63-0.87), uNGAL (AUC 0.72, 95% CI;0.61-0.84), uAlbumin (AUC 0.70, 95% CI; 0.59-0.82) and IL-18 (AUC 0.70, 95% CI; 0.58-0.82) had moderate accuracy; the others did not.

Conclusion

In this cohort study of AKI progression within 7 days of ICU admission, eight novel urinary biomarkers improved the prediction of AKI progression after multivariate adjustment. Similarly, ROC analysis found that several biomarkers had moderate accuracy for the prediction of AKI progression in the ICU.
FC 098MESENCHYMAL STEM CELL EXOSOMES AMELIORATE MICE PERITONEAL FIBROSIS INDUCED BY HUMAN PERITONITIS DIALYSIS EFFLUENT
Authors: Chen Kehong , He Yani
Published: May 2021

Background and Aims

Peritoneal fibrosis is a severe complication of peritoneal dialysis, but there are few effective therapies for it. The purpose of this study was to investigate the protective effect of exosomes secreted by mouse bone marrow mesenchymal stem cells on peritoneal fibrosis and to reveal the mechanism.

Method

Forty-two male C57BL/6 mice were randomly divided into a normal group, a control group (2.5% glucose dialysate), a peritonitis-effluent group (The overnight 2.5% glucose dialysate of patients with peritonitis), a high glucose dialysate group (4.25% glucose concentration), a peritonitis-dialysate + exosome group, and a high glucose dialysate + exosome group. The mouse model of peritoneal fibrosis was constructed by intraperitoneal injection of human peritonitis effusion continuously for 42 days. The mice in the exosome treatment group received intraperitoneal injection of mesenchymal stem cell (MSC)-exosomes twice. The level of peritoneal structural and functional damage, inflammation, fibrosis and mesothelial cell damage of peritoneum were detected. Furthermore, the effect of MSC-exosomes was validated in vitro.

Results

Peritoneal transport was significantly impaired and peritoneal thickness was significantly increased in the peritonitis-effluent group and the high glucose dialysate group after 42 days. The degree of peritoneal inflammation and fibrosis in the two groups was significantly higher than the control group. The results suggested that human peritonitis dialysis effluent could be used to construct a mouse model of peritoneal fibrosis. Masson staining results showed that the fibrosis degree of peritonitis - effluent + exosome group was significantly less than the peritonitis - effluent group. Immunohistochemical analysis showed that the expression levels of mesothelial markers E-cadherin and ZO-1, neutrophil granulocytes (MPO) and macrophages (F4/80), and fibrosis markers collagen I and a-SMA in the peritonitis - effluent + exosome group were significantly lower than those in the peritonitis - effluent group. Similarly, the high glucose dialysate + exosome group mice showed significantly lower levels of peritoneal inflammation and fibrosis than the high glucose dialysate group mice. In vitro experiments showed that exosomes could down-regulate the secretion of IL-1, IL-6 and TGF- by renal tubular cells stimulated by high glucose dialysate, maintain the expression of mesenchymal cell marker (E-cadherin), and inhibit the mesenchymal marker (-SMA), suggesting that exosomes could inhibit the transdifferentiation of peritoneal mesenchymal cell-mesenchymal cells (MMT).

Conclusion

MSC-exosomes can alleviate peritoneal fibrosis by inhibiting peritoneal mesothelial cell-mesenchymal cell transdifferentiation.
FC 086GLOMERULI PROTEOME ANALYSIS REVEALS EARLY DIFFERENCES BETWEEN PRE-EXISTING AND DE-NOVO TYPE 2 DIABETES IN HUMAN RENAL ALLOGRAFTS
Authors: Kipp Anne , Marti Hans-Peter , Babickova Janka , Nakken Sigrid , Leh Sabine , Halden Thea A S , Jenssen Trond , Vikse Bjørn Egil , Åsberg Anders , Furriol Jessica
Published: May 2021

Background and Aims

Diabetes mellitus, either preexisting or developing after kidney transplantation remains a crucial clinical problem. The aim of this study is to compare the proteome of histologically normal glomeruli from normoglycemic (NG), T2DM, and PTDM patients one year after kidney transplantation to identify novel early biomarkers detectable prior to the development of histologically visible diabetic nephropathy.

Method

We comparatively analyzed the proteome of histologically normal glomeruli from normoglycemic (NG) recipients, and recipients with pre-existing type 2 diabetes mellitus (T2DM), or post-transplant diabetes mellitus (PTDM), in protocol biopsies obtained one year after kidney transplantation. Glomerular cross-sections were microdissected in core biopsies from 8 NG, 8 PTDM and 8 T2DM kidney transplant recipients. Proteome was determined by liquid chromatography-tandem mass spectrometry. Relative differences in protein abundance and significantly dysregulated pathways were analyzed.

Results

Proteins related to immune response and inflammation, transport regulation and cell organization and communication, including the nephrin family, were more abundant in NG, as compared to the combined groups of diabetic patients. Proteins involved in cell morphogenesis and adhesion were less abundant in PTDM, as compared to T2DM. In contrast, CCT3, CCT4 and CNDP2 diabetic nephropathy markers, LDHB and tacrolimus binding protein FKBP1A were significantly overrepresented in glomeruli from PTDM, as compared to T2DM patients.

Conclusion

These data suggest that glomerular proteome profile differentiates PTDM from NG and T2DM, and disruption of cell-cell interactions at molecular level represents an early event in PTDM development.
FC 088DUAL BLOCKADE OF ENDOTHELIN A RECEPTOR (ETA) AND SODIUM-GLUCOSE COTRANSPORTER 2 (SGLT2) TO PREVENT DIABETIC KIDNEY DISEASE PROGRESSION ON A TYPE 2 MURINE MODEL
Authors: Vergara Arana Ander , Molina Mireia , Jacobs Cachá Conxita , Dominguez Pamela , Benito Begoña , Agraz Irene , Seron Micas Daniel , Soler María José
Published: May 2021

Background and Aims

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and endothelin A receptor (ETA) antagonist have shown nephroprotective effects in diabetic kidney disease (DKD) through blood pressure and urinary albumin loss reduction. The protective impact and the pathways through which they exert this protection have not yet been elucidated. This study aimed to investigate the effects of the add-on therapy of SGLT2i and ETA antagonists on a type 2 diabetes murine model.

Method

12 weeks-old db/db mice were treated for 8 weeks with different combinations of empagliflozin 10 mg/Kg/day (SGLT2i), atrasentan 7 mg/Kg/day (ETA antagonist) or ramipril 8 mg/Kg/day. A group of non-diabetic mice (db/m) was included as negative control. In vivo variables were recorded during treatment, including transdermal measured glomerular filtration rate (GFR) and urinary albumin-to-creatinine ratio (UACR). After treatment kidneys were preserved for histopathological studies.

Results

After 8 weeks of treatment empagliflozin decreased fasting blood glucose alone or in combination with atrasentan or ramipril (234.2 mg/dL mean reduction in three treated groups when compared to db/db). Ramipril decreased blood pressure (BP) in monotherapy or in add-on therapy. Empagliflozin or atrasentan alone did not have any effect on blood pressure, but combination of atrasentan and ramipril had a synergistic effect and reduced both systolic (9.0 mmHg, CI 95%: -16.3 to -1.1; P=0.028) and diastolic BP (11.9 mmHg, CI 95%: -17.7 to -3.1; P=0.005) when compared to ramipril alone. The combination of atrasentan and ramipril significantly reduced UACR (1002 ug/mg, CI 95%: -2312.0 to -32.4; P=0.043). Empagliflozin treatment alone or in combination also reduced UACR (686.0 ug/mg mean reduction in three treated groups), although this reduction was not statistically significant. In the kidney, empagliflozin in monotherapy or combination reduced glomerular mesangial matrix expansion (4.85% mean mesangial reduction in three treated groups). Treatments with atrasentan and ramipril also reduced measangial matrix expansion.

Conclusion

Both empagliflozin and atrasentan demonstrated possible beneficial effects in DKD by reducing BP, UACR, and mesangial matrix expansion. The add-on therapy did not show greater protective effects in the analysed variables. Further studies are needed to characterize these protective effects and pathways involved.
FC 026COVID-19 IMPACT ON ELDERLY HEMODIALYSIS POPULATION: RESULTS FROM THE SPANISH COVID-19 CKD WORKING GROUP REGISTRY
Authors: Vergara Arana Ander , Molina Mireia , Villegas Andrés , Sã¡nchez Cã¡mara Luis Alberto , De Sequera Ortiz Patricia , Toapanta Néstor , Manrique Joaquín , Shabaka Amir , Aragoncillo Ines , Ruíz María Carmen , Benito Silvia , Sanchez-Alvarez Jose Emilio , Soler María José
Published: May 2021

Background and Aims

Age and chronic kidney disease have been described as mortality risk factors for coronavirus disease 2019 (COVID-19). Currently, an important percentage of patients in hemodialysis are elderly. This study aimed to investigate the impact of COVID-19 in this population and to determine risk factors associated with mortality.

Method

Data was obtained from the Spanish COVID-19 CKD Working Group Registry, that included patients in renal replacement therapy (dialysis and kidney transplantation) infected by COVID-19. From March 18, 2020, to August 27, 2020, 1165 patients on hemodialysis affected by COVID-19 were included in the Registry. A total of 328 patients were under 65 years-old and 837 were 65 years old or older (elderly group).

Results

Mortality was 18.6% higher (95% confidence interval (CI): 13.8%-23.4%) in the elderly hemodialysis patients compared to the non-elderly group (see figure). Death from COVID-19 infection was increased 5.5-fold in hemodialysis patients compared to mortality in the general population for a similar period, and there was an age-associated mortality increase in both populations (see figure 1). In multivariate Cox regression analysis, age (hazard ratio (HR) 1.58, 95% CI: 1.31-1.92), dyspnea at presentation (HR 1.61, 95% CI: 1.20-2.16), pneumonia (HR 1.76, 95% CI: 1.12-2.75) and admission to hospital (HR 4.13, 95% CI: 1.92-8.88) were identified as independent mortality risk factors in the elderly hemodialysis population. Treatment with glucocorticoids reduced the risk of death (HR 0.71, 95% CI: 0.51-0.98) in aged patients on hemodialysis.

Conclusion

Mortality is dramatically increased in elderly hemodialysis patients affected by COVID-19. Age, dyspnea at presentation, pneumonia or hospitalization are factors associated with a worse prognosis, after adjusting dialysis population to other confounding factors. Treatment with glucocorticoids could be a therapeutic option for this specific population.
FC 121THE UPTAKE OF PET RADIOTRACER 18 F-FLUORODEOXYGLUCOSE BY THE RENAL ALLOGRAFT SIGNIFICANTLY CORRELATES WITH THE ACUTE BANFF SCORES OF CORTEX INFLAMMATION
Authors: Weekers Laurent , Lovinfosse Pierre , Pottel Hans , Bouquegneau Antoine , Bonvoisin Catherine , Bovy Christophe , Grosch Stéphanie , Hustinx Roland , Jouret François
Published: May 2021

Background and Aims

Acute T-cell mediated rejection (TCMR) is associated with the recruitment of mononuclear leukocytes into the renal transplant, which corresponds to the core of the conventional Banff classification. The boosted metabolism of these inflammatory cells can be assessed by positron emission tomography (PET) quantifying the renal uptake of 18F-fluorodeoxyglucose (18FDG). The correlation of biopsy-based Banff versus PET-based scores of acute inflammation in the renal transplant is unknown.

Method

From January 2013 to December 2019, we prospectively performed 114 18FDG-PET/CT in 105 adult KTR who underwent per cause transplant biopsy for suspected TCMR. Biopsy-proven polyoma-BK nephropathies (n=7) and uninterpretable PET images (n=2) were excluded. PET/CT was performed 194±19 minutes after administration of 243±35 MBq of 18FDG, before any immunosuppression change. The mSUVs were measured in both upper and lower poles of the renal allograft. The acute Banff score was conventionally defined as the sum (from 0 to 15) of g (glomerulitis), ptc (peritubular capillaritis), t (tubulitis), i (inflammation in non-scarred cortex) and v (endarteritis). The Banff “total i” score (from 0 to 3) corresponds to the total cortical inflammation, including scarred and non-scarred cortex. Regression of mSUV against the acute Banff score was performed, and Pearson correlation coefficients were calculated. The distribution of mSUV between “total i” groups was assessed by the non-parametric Kruskal-Wallis test followed by Dunn’s post hoc test.

Results

The mean age of the cohort was 51.5±14.3 years, with M/F ratio of 67/38. The prevalence of biopsy-proven TCMR and borderline was 20.9% and 16.2%, respectively. The mean mSUV of the 105-case cohort was 1.82±0.45. The highest value of acute Banff score was 12, while 55.2% of biopsies were scored as 0. The distribution of “Total i” score was: 0 (58.8%); 1 (20.6%); 2 (8.8%); 3 (11.8%). Regression showed a significant correlation between mSUV and acute Banff score (p<0.0001), with adjusted R² of 0.38. The mSUV value was significantly different between subgroups of “Total i” (p, 0.0047), with 2.33±0.76 in score 3 versus 1.68±0.24 in score 1.

Conclusion

18FDG-PET/CT may help noninvasively assess the degree of allograft inflammation in KTR with suspected TCMR.
FC 125DIURETIC USE IS ASSOCIATED WITH INCREASED RISK FOR POSTTRANSPLANTATION DIABETES MELLITUS IN RENAL TRANSPLANT RECIPIENTS
Authors: Sokooti Oskooei Sara , Tye Sok Cin , M. Douwes Rianne , Lambers Heerspink Hiddo , Bakker Stephan
Published: May 2021

Background and Aims

Posttransplantation diabetes Mellitus (PTDM) is one of the major medical problems in renal transplant recipients (RTRs). Diuretic-induced hyperglycemia and diabetes have been described in the general population. We aimed to investigate whether diuretics also increase PTDM risk in RTRs.

Method

We included 486 stable outpatient RTRs (with a functioning graft ≥1 year) without diabetes from a prospective longitudinal study (the Transplantlines Food and Nutrition Study [NCT02811835]). Participants were classified as diuretic users and non-diuretic users based on their medication use recording at baseline. PTDM was defined according the American Diabetes Association’s diagnostic criteria for diabetes. Multivariable Cox proportional-hazards regression analyses were performed to assess the prospective association between diuretic use and the risk of PTDM development.

Results

Median time since transplantation was 5.4 (2.0-12.2) years and 168 (35%) RTRs were taking diuretics. After 5.2 (IQR, 4.0 5.9) years of follow up, 54 (11%) RTRs developed PTDM. In Kaplan-Meier (log-rank test, p<0.001) and Cox regression analyses, diuretic use was found to be associated with incident PTDM after adjustment for age, sex, fasting plasma glucose (FPG), and HbA1c (hazard ratio[HR] 3.28, 95% CI 1.84-5.83; p<0.001). The association remained independent of further adjustment for potential confounders, including lifestyle, use of other medication, kidney function, transplantation-specific parameters, BMI, lipids, and blood pressure. Exploratory analyses further indicates that, in Cox regression analyses, both thiazide (n=74) and loop diuretics (n=76) as two main types of diuretics used among RTRs appeared to be associated with the development of PTDM, independent of age, sex, FPG, and HbA1c ([HR 2.70, 95% CI 1.24-5.29; p=0.012], and [HR 5.08, 95% CI 2.49-10.34; p<0.001], respectively).

Conclusion

This study demonstrates that diuretics overall, associated with the risk of developing PTDM in RTRs, independent of established risk factors for PTDM development. The association was consistent for thiazide and loop diuretics.
FC 128NON-HLA ANTIBODIES AND EPLET MISMATCHES IN KIDNEY TRANSPLANT RECIPIENTS WITH A HISTOLOGICAL PICTURE OF ANTIBODY-MEDIATED REJECTION WITH AND WITHOUT HLA DONOR-SPECIFIC ANTIBODIES
Authors: Crespo Marta , Llinas Laura , Redondo Pachon Dolores , Butler Carrie L , Gimeno Javier , Perez-Saez Maria Jose , Buxeda Anna , Arias-Cabrales Carlos , Folgueiras Montserrat , Sanz Sara , Valenzuela Nicole M , Reed Elaine F , Pascual Santos Julio
Published: May 2021

Background and Aims

Correlation between antibody-mediated rejection (ABMR) and HLA donor-specific antibodies (DSA) is strong but imperfect in kidney transplant (KT) recipients, raising the possibility of other detrimental antibodies contributing to ABMR. The role of non-HLA antibodies on outcomes is not well known.

Method

We retrospectively assessed KT biopsies scored according to Banff’15 classification. Pre- and post-KT serum samples were checked for HLA and non-HLA antibodies (MICA-Ab, angiotensin II type 1 receptor (AT1R)-Ab, endothelin-1 type A receptor (ETAR)-Ab and crossmatches with primary aortic endothelial cells (EC-XM)). We also analyzed HLA epitope mismatches between donors and recipients.

Results

One-hundred eighteen patients with normal (n=19), ABMR histology (n=52) or IFTA (n=47) in their biopsy were studied. Graft survival was worse in ABMR patients (p=0.003). Pre-KT HLA-DSA were more frequent in ABMR cases (p=0.006). At biopsy, 73% ABMR patients had HLA-DSA (p<0.001). Pre-KT AT1R-Ab were more frequent in ABMR compared with IFTA and normal cases (p=0.003), without differences in other non-HLA antibodies. Fourteen patients with histological ABMR (27%) had no detectable HLA-DSA post-KT and only 3 had non-HLA Ab. However, these ABMR-DSA- cases showed similar biopsy changes and graft survival compared with ABMR-DSA+. Pre- or post-KT non-HLA antibodies other than AT1R-Ab were detected similarly in ABMR and in normal or IFTA cases. Both total class II and DRB1 epitope mismatches were associated with postransplant DSA and ABMR-DSA+. Multivariate analysis showed that both pre-KT HLA-DSA and AT1R-Ab (DSA: OR: 3.39 [1.20-9.59], p=0.021; AT1R-Ab: OR: 5.31 [1.75-16.10], p=0.003) were strong independent predictors of postransplant ABMR-DSA+ (Table 1).

Conclusion

Despite highly prevalent HLA-DSA before and after transplantation in KT with histological ABMR, 27% of cases did not show circulating HLA-DSA. Pre-KT AT1R-Ab associated with ABMR-DSA+, but not MICA-Ab, ETAR-Ab or EC-XM+. Any of them associated significantly with ABMR-DSA-. Epitope mismatch predicted both postransplant DRB-DSA and ABMR-DSA+. Detection of pre-KT HLA-DSA and/or AT1R-Ab, together with HLA epitope mismatch assessment, are valuable tools for better DSA and ABMR prediction in KT patients.
High immunogenicity of a messenger RNA-based vaccine against SARS-CoV-2 in chronic dialysis patients
Authors: Longlune Nathalie , Nogier Marie Béatrice , Miedougé Marcel , Gabilan Charlotte , Cartou Charles , Seigneuric Bruno , Del Bello Arnaud , Marion Olivier , Faguer Stanislas , Izopet Jacques , Kamar Nassim
Published: May 2021

Background

Patients with chronic kidney disease, dialysis patients and kidney transplant patients are at high risk of developing severe coronavirus disease 2019 (COVID-19). Data regarding the immunogenicity of anti-severe acute respiratory syndrome coronavirus 2 messenger RNA (anti-SARS-CoV-2 mRNA) vaccines in dialysis patients were published recently. We assessed the immunogenicity of anti-SARS-CoV-2 mRNA vaccine in dialysis patients.

Patients and methods

One hundred and nine patients on haemodialysis (n = 85) or peritoneal dialysis (n = 24) have received two injections of 30-μg doses of BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech) that were administered intramuscularly 28 days apart. Those who were still seronegative after the second dose were given a third dose 1 month later. Anti-SARS-CoV-2 antibodies were tested before and after vaccination.

Results

Ninety-one out of the 102 patients who had at least a 1-month follow-up after the second (n = 97) or the third (n = 5) vaccine doses had anti-SARS-CoV-2 antibodies. The seroconversion rate was 88.7% (86 out of 97 patients) among SARS-CoV-2 seronegative patients at the initiation of vaccination. Receiving immunosuppressive therapy was an independent predictive factor for non-response to vaccination.

Conclusion

Due to high immunogenicity and safety of mRNA vaccines, we strongly recommend prioritizing a two-dose vaccination of dialysis patients. A third dose can be required in non-responders to two doses. When possible, patients waiting for a kidney transplantation should be offered the vaccine before transplantation.