bluuebunny/crossref_metadata_2025 huggingface dataset:
SO034A NEW MARKER OF RESISTANT HYPERTENSION IN CKD PATIENTS
Authors: Gembillo Guido , Siligato Rossella , Cernaro Valeria , Satta Ersilia , Conti Giovanni , Salvo Antonino , Romeo Adolfo , Calabrese Vincenzo , Sposito Giovanna , Ferlazzo Guido , Santoro Domenico
Published: June 2020

Background and Aims

Monocytes -HDL ratio (MHR), has emerged as a possible marker of inflammation and oxidative stress (OS), demonstrating its possible use in the population with Chronic Kidney Disease (CKD). These effects seem to be modulated by an increased lipid production, by reduced cellular catabolism of fatty acids and by the alteration of the antioxidant, anti-inflammatory mechanisms and the reverse cholesterol transport of HDL. The latter to exert favorable effects on inflammatory and oxidative pathway. The purpose of our research is to evaluate the link between MHR and resistant hypertension (RH) which, together with inflammation, OS and atherosclerosis, represents a widespread feature in the population with CKD and carries a greater risk of premature death due to cardiovascular disease.

Method

A retrospective study has been performed on 251 hypertensive patients, admitted in the last 6 months to the Unit of Nephrology and Dialysis of the Policlinic G. Martino of Messina, Italy. 80 patients were diagnosed with RH, defined as blood pressure that remains above 140/90 mmHg despite use of three different classes of antihypertensive medications (one of which must be a diuretic) at the maximum tolerated doses.

We evaluated the distribution of data with Kolmogorov-Smirnov test and, considering that MHR had a non-normal distribution, we expressed the values as medians and interquartile ranges (IQR). Moreover, differences between groups with Mann-Whitney test, correlations with Rank Correlation and Spearman's Rho coefficient were also considered in the analysis. Finally, we assessed the differences of variables between the means of different groups with ANOVA test using multiple regression to valuate independent relations between variables.

Results

MHR appeared to be positively correlated with serum creatinine levels (ρ=0.24; P=0.0001) (Figure 1). MHR correlated with the number of antihypertensive drugs per patient in the entire cohort of patients (F = 18.23; P <0.001) (Figure 2). Patients with RH had a significantly higher MHR than patients without resistant hypertension (0.1493 [IQR 0.12 - 0.18] versus 0.11 [IQR 0.0 - 0.13], P <0.0001) (Figure 3).

Conclusion

MHR has proven to be an accurate tool in quantifying inflammatory status and OS, whose effectiveness lies in the close correlation that exists between HDL and monocytes. HDL prevent and reverse the recruitment of monocytes in the arterial wall and their activation through a decrease in their F-actin content, thereby reducing the expression of CD11b on monocytes, and modulating their adhesion to the endothelium. Our study showed that MHR could be a useful and immediate tool to evaluate OS and inflammatory status in order to select high-risk patients and identify earlier and appropriate treatment strategies.
SO036THE EFFECT OF DAPAGLIFLOZIN ON AMBULATORY AORTIC BLOOD PRESSURE AND ARTERIAL STIFFNESS PARAMETERS IN PATIENTS WITH TYPE-2 DIABETES MELLITUS: A DOUBLE-BLIND RANDOMIZED CLINICAL TRIAL
Authors: Papadopoulou Eirini , Loutradis Charalampos , Kotsa Kalliopi , Karras Spiros , Sambanis Christos , Tzatzagou Glyceria , Karakozoglou Anastasios , Didangelos Triantafillos , Theodorakopoulou Marieta , Minopoulou Ioanna , Tsapas Apostolos , Karagiannis Asterios , Sarafidis Pantelis
Published: June 2020

Background and Aims

Arterial stiffness is a prominent risk factor for heart failure and overall mortality in patients with type-2 diabetes mellitus (DM). Sodium-glucose co-transporter 2 (SGLT-2) inhibitors reduce the incidence of heart failure and death in these patients. The aim of this study is to evaluate the effects of dapagliflozin on ambulatory central blood pressure (BP) levels and arterial stiffness parameters in patients with type-2 DM.

Method

This is a double-blind, randomized, placebo-controlled clinical trial including 85 adult patients with type-2 DM on monotherapy or combination therapy with two of: metformin, sulphonylurea, DDP-4 inhibitor, or insulin. Patients were randomized in a 1:1 ratio to oral dapagliflozin 10 mg per day or placebo for 12 weeks. Study participants underwent 24-h ambulatory BP monitoring with the Mobil-O-Graph NG monitor at baseline and study-end.

Results

Baseline demographic, clinical and laboratory parameters were similar in the two groups (age 61.74±6.73 vs 60.64±9.35; p=0.534). During follow-up, 24-hour central SBP/DBP significantly decreased in dapagliflozin (117.41±10.52/78.88±7.25 vs 113.30±8.75/77.25±6.54; p=0.002/p=0.047), but not in the placebo group. Corresponding reductions of 24-hour central SBP (-4.12±8.00 vs -0.65±7.77; p=0.046) were greater with dapagliflozin than placebo. Aortic pulse pressure (PP) decreased only in the dapagliflozin group (38.53±7.44 vs 36.05±6.59 mmHg; p=0.004). 24-hour heart-rate adjusted augmentation-index significantly decreased with dapagliflozin. Importantly, there was a significant difference in the change of 24-hour PWV (-0.16±0.32 vs 0.02±0.27; p=0.007) favoring dapagliflozin.

Conclusion

Treatment with dapagliflozin significantly reduces ambulatory central BP and PWV levels in type-2 diabetics. Improvement in these parameters may substantially contribute to the cardiovascular benefits of SGLT-2 inhibitors.
SO038A TRANSLATIONAL KIDNEY ORGANOID SYSTEM BOLSTERS HUMAN RELEVANCE OF CLINICAL DEVELOPMENT CANDIDATE
Authors: Westerling-Bui Amy , Soare Thomas , Venkatachalan Srinivasan , DeRan Michael , Fast Eva , Fanelli Alyssa , Kyrychenko Sergii , Hoang Hien , Corriea Grinal , Zhang Wei , Yu Maolin , Malojcic Goran , Pan-Zhou Xin-Ru , Ledeboer Mark , Harmange Jean-Christophe , Emani Maheswarareddy , Tibbitts Thomas T , Reilly John , Mundel Peter
Published: June 2020

Background and Aims

A major challenge in drug discovery is gaining confidence in the human relevance of pre-clinical animal studies. While human iPSC-derived organoids offer exciting opportunities to address this, concerns about applicability and scalability remain. Here, we report a high-throughput human organoid platform for assessment of kidney disease targeting compounds.

Method

In vitro & in vivo transplanted under athymic rat kidney capsule, differentiated organoids were characterized using single cell RNA sequencing (scRNA-Seq), NanoString, & immunofluorescence techniques. Immunofluorescence quantitative analysis of aggregated actin per in vitro organoid in a protamine sulfate (PS) podocyte injury model was used to evaluate efficacy of GFB-887, a sub-type selective, small molecule transient receptor potential canonical 5 (TRPC5) inhibitor. In pharmacokinetic studies, GFB-887 was orally administered into rats, then the presentation of GFB-887 was measured in rat plasma, rat kidney, & in vivo transplanted human organoids. In pharmacodynamic studies of transplanted human organoids, rats were co-perfused with GFB-887 & PS or orally dosed with GFB-887 prior to PS, then immunofluorescence quantitative analysis of mean synaptopodin intensity in podocytes of the in vivo transplanted organoids was used to evaluate efficacy of GFB-887.

Results

We confirmed platform reproducibility by scRNA-Seq and derived a NanoString panel for efficient quality control. Organoid transplantation in rats for 2 to 4 weeks promoted organoid maturation and vascularization. In functional studies, cyclosporine A (CsA), a calcineurin inhibitor clinically utilized for the treatment of nephrotic syndrome, and GFB-887, a novel sub-type selective TRPC5 inhibitor currently in clinical development, protected in vitro kidney organoids from injury. Pharmacodynamic studies with GFB-887 delivered orally to rats were also successfully performed in human transplanted organoids.

Conclusion

These data show how human organoids can deliver confidence in taking development candidate compounds to the clinic, fulfilling their promise to revolutionize drug discovery.
SO045DOES MALNUTRITION INFLAMMATION SCORE MAINTAINS ITS PREDICTIVE RISK ASSESSMENT IN THE MODERN HEMODIALYSIS ERA?
Authors: Sá Martins Vitor , Adragao Teresa , Aguiar Leila , Dias Catarina , Lourenço Pedro , Figueiredo Rita , Pascoal Tania , Pereira Juliana , Pinheiro Tatiana , Ramião Inês , Velez Brígida , Papoila Ana Luisa , Pinto Iola , Borges Nuno , Calhau Conceição , Macário Fernando
Published: June 2020

Background and Aims

Malnutrition Inflammation score (MIS) is a risk score published in 2001 (Kalantar-Zadeh, 2001) and validated in 2008 (Rambod, 2009). It is associated with a high mortality and morbidity risk in hemodialysis (HD) patients (pts).

Currently, HD pts population is composed of much older individuals, submitted to a high efficient treatment with access to pharmacological and nutritional therapy, assured by a bundled payment, when comparing with the validation study population.

The objective of this study is to evaluate if MIS maintain its predictive risk assessment.

Method

Cross sectional analysis of HD pts from 25 outpatient clinics. MIS was evaluated at the study baseline. Univariable and multivariable Cox additive regression models were used to analyze the data. C-index was estimated to assess the performance of the final model. A level of significance of α= 0.05 was considered.

Results

A total of 2444 pts were analyzed (59.0% males; 32.0% diabetic) during a median period of 48 months (P25=31; P75=48), 875 patients registered MIS<5, corresponding to 35.8%. All-cause mortality was observed in 860 pts (35.2%). There were 202 (35.8%) events in the group of patients with MIS<5, while in the group with MIS≥5, the number of deaths was higher (658 pts, 41.9%).

In univariable analysis using Cox additive model, the main results were:

In multivariable analysis, adjusting for age, nPNA, IDWG, Kt/V and diabetes, a MIS ≥ 5 and ≥ 7 showed, respectively, a HR of 1.761 (IC 95%, p<0.001) and 1.822 (IC 95%, p<0.001).

Conclusion

The findings of this analysis confirms that MIS maintains a discriminative power to identify higher risk of mortality. In this model, age and diabetes also correlate with mortality risk increase, while nPNA, IDWG and Kt/V have the opposite effect.
SO059ASSOCIATION OF ALL-CAUSE MORTALITY WITH PRE-HEMODIALYSIS PULSE PRESSURE IN CHRONIC HEMODIALYSIS PATIENTS
Authors: Zhang Hanjie , Cherif Alhaji , Kotanko Peter
Published: June 2020

Background and Aims

Chronic and end-stage kidney disease patients experience significantly increased risk of cardiovascular morbidity and mortality due to multitude of interlinked pathophysiological processes inducing metabolic and inflammatory conditions. Pulse pressure (PP) reports cardiac and vascular conditions, where consistently high PP values are associated with atrial fibrillation, aortic insufficiency, arterial stiffness or arteriovenous malformation, and low PP values may be associated with aortic valve stenosis, cardiac insufficiency or cardiac tamponade. However, the association of pre-hemodialysis (pre-HD) PP with mortality among hemodialysis patients is not well understood. In this study, we aim to explore the extent to which PP is associated with mortality.

Method

We analyzed pre-HD PP (calculated as pre-HD SBP minus pre-HD DBP) between 1/2001 and 12/2012 in hemodialysis patients treated in U.S. Fresenius Medical Care facilities. A 3-months baseline period was defined as months 4 to 6 after hemodialysis initiation, all-cause mortality was noted during follow-up. Only patients who survived baseline were included. Censoring events were renal transplantation, modality change, or study end. We built Cox proportional hazards models with spline terms, allowing us to model nonlinear effects of pre-HD PP as a continuous variable and its relationship with all-cause mortality.

Results

We included 152,625 patients. Mean age was 60.8 years, 59% were white and 56% were male. During a median follow-up of 26.0 months 40.4% patients died. We found that for patients with pre-HD PP between 49.2 mmHg and 74.7 mmHg, were associated with better survival. In contrast, a PP below 49.2 mmHg and above 74.7 mmHg were associated with higher mortality. Similar nonlinear effects are seen in SBP for a given pre-HD PP value (see Fig. 1).

Conclusion

The association of pre-HD PP with mortality is nonlinear, and a better understanding of the nonlinearity will provide further insights into disentangling the associated mediators affecting its dynamics. Our findings may aid risk stratification in HD patients.
SO093LONGITUDINAL DATA ON TREATMENT DURATION AND COMPLIANCE FROM AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE CLINICAL TRIALS WITH TOLVAPTAN
Authors: Zhou Xiaolei , Garbinsky Diana , Ouyang John , Davenport Eric , Agarwal Indra , Oberdhan Dorothee
Published: June 2020

Background and Aims : Observation of impactful clinical outcomes in a clinical trial setting for ADPKD is challenging due to the life-long progressive nature of ADPKD and longer-term associated outcomes of interest in this population (e.g., renal function decline, cardiovascular events, and mortality). Since 2004, the tolvaptan (TOL) clinical trial program enrolled subjects in multiple clinical studies with the opportunity to enroll in subsequent clinical trials for treatment and outcomes evaluation.

Method : Data from 6 ADPKD studies (protocols 156-04-250, 156-04-251, 156-06-260, 156-09-284, 156-09-290, 156-08-271) were pooled and evaluated over time for overall treatment duration, treatment time, and treatment gaps. Treatment duration for the individual clinical trials ranged from 1 week to up to 3 years.

Results : Overall, 1,437 subjects received TOL in these ADPKD clinical trials. For these subjects, the mean overall treatment duration was 4.1 years (3.8 years on treatment) with a maximum of 9.7 years (9.0 years on treatment). In this cohort, 513 subjects (35.7%) received TOL treatment for more than 5 years. Mean treatment compliance was 94.1%. Overall, 723 subjects (50.3%) received TOL treatment in ≥2 trials, with a median treatment gap duration between trials of 0.1 years (maximum, 5.6 years). At least 7 years of follow-up data are available for estimated glomerular filtration rate in 241 subjects (mean at baseline, 78.6 mL/min/1.73m2) and for total kidney volume in 130 subjects (mean at baseline, 1,816.9 mL).

Conclusion : This analysis provides longitudinal follow-up over an extended timeframe in a large number of subjects treated with TOL, with the greatest number of subjects being enrolled in clinical trials enriched for rapidly progressing ADPKD. Treatment compliance over years was reasonably good despite treatment gaps.
MO006INFLAMMASOME ACTIVATOR NLRP3 HYPOMETHYLATION IS ASSOCIATED WITH GLUCOCORTICOID RESISTANCE IN PATIENTS WITH IDIOPATHIC NEPHROTIC SYNDROME
Authors: Granata Simona , Stocco Gabriele , Lucafò Marianna , Bonten Erik , McCorkle Robert , Decorti Giuliana , Gambaro Giovanni , Evans William E , Zaza Gianluigi
Published: June 2020

Background and Aims

We have previously shown that the Nod-like receptor protein-3 (NLRP3) gene is over-expressed in leukocytes of many patients with chronic kidney disease, and studies have also shown that hypomethylation and overexpression of NLRP3 are associated with glucocorticoid resistance in acute lymphoblastic leukemia. Therefore, we hypothesized that hypomethylation of the NLRP3 promoter my cause glucocorticoid resistance in patients with Idiopathic Nephrotic Syndrome (INS) associated with minimal change disease (MCD) or focal glomerulosclerosis (FSGS).

Method

We assessed NLRP3 and Caspase 1 (CASP1) promoter methylation by SNuPE reaction in germline DNA from leukocytes of 14 glucocorticoid-resistant and 18 glucocorticoid-sensitive adult INS patients (discovery cohort) and 7 glucocorticoid-resistant and 14 glucocorticoid-sensitive pediatric INS patients with MCD/FSGS (validation cohort). The effects of NLRP3 inflammasome on glucocorticoid resistance were validated in vitro in human monocytic cell lines (THP-1 and U937).

Results

Methylation of CpG islands in the CASP1 promoter was undetectable in both groups whereas NLRP3 promoter methylation was significantly lower in glucocorticoid-resistant compared to glucocorticoid-sensitive in both adults and children.

The AUROC curve was 81.2% (p=0.0003) in adults and 73.5% (p=0.0002) in children demonstrating the capability of NLRP3 methylation to discriminate glucocorticoid-resistant versus glucocorticoid-sensitive.

Activation of the NLRP3 inflammasome by LPS/ATP reduced glucocorticoid receptor expression and increased glucocorticoid resistance in U937. Consistently, knockdown of NLRP3 in THP-1 increased sensitivity to glucocorticoids.

Conclusion

Our findings demonstrate a novel mechanism whereby INS patients develop resistance to glucocorticoids via leukocyte epigenetic changes of NLRP3 and reveal a new potential clinical biomarker to early detect this condition.
MO012IS IT SAFE TO USE INTERLEUKIN-2 RECEPTOR ANTAGONIST INDUCTION THERAPY IN 2DR MISMATCH RENAL TRANSPLANTS IN TACROLIMUS ERA?
Authors: Ali Hatem Kaies Ibrahim Elsayed , Daoud Ahmed , Mohamed Mahmoud , Soliman Karim
Published: June 2020

Background and Aims

2DR HLA mismatch indicates high immunological risk renal transplant. Induction therapy with rabbit Anti-thymocyte Globulin (r-ATG) and IL-2 Receptor Antagonist (IL-2RA) resulted in marked reduction of acute allograft rejection rate and improved graft survival. However, the outcomes in 2DR (HLA-DR) mismatched renal transplant recipients (RTRs) in the era tacrolimus-mycophenolate mofetil maintenance immunosuppression remains understudied.

Method

Using data from the United States organ procurement and transplantation network, all 2 DR mismatched RTRs with panel reactive antibodies <20% maintained on tacrolimus and mycophenolate mofetil immunotherapy between 2000 and 2017 were retrospectively reviewed. Data including age, sex, gender, ethnicity, functional status, diabetes, body mass index, cold ischemia time, number of previous transplants, panel reactive antibodies, donor type, donor age, HLA-mismatches, number of acute rejection episodes, induction therapies, maintenance immunotherapy, recipients and graft survival were collected. Based on induction therapies administered, RTRs were divided into 2 groups: (r-ATG) and IL-2RA groups. Poisson regression analysis was used to assess effect of induction therapies on acute rejection episodes. Cox hazard regression analysis was used to assess effect of different induction therapies on patient and graft survival

Results

3379 patients received IL2-RA while 3677 patients received ATG for induction. There were no significant differences between both groups in terms of acute rejection episodes (95% CI ranges from 0.95 to 1.068, P=0.805), graft survival (95% CI: 0.91 - 1.06, P=0.712), or patient survival (95% CI: -0.949 - 1.12, P=0.43) .

Conclusion

This study revealed no significant difference in acute rejection episodes, patient or graft survival when utilizing ATG vs IL-2RA in 2DR HLA mismatched renal transplant recipients with PRA<20%, in the tacrolimus-based maintenance immunosuppression era. Therefore, IL2-RA is a safe induction therapy in this group of patients and non-inferior to –ATG induction therapy.
MO013PATERNAL SAFETY OF THE USE OF MYCOPHENOLIC ACID BY KIDNEY TRANSPLANT RECIPIENTS. RESULTS OF THE EMVARON STUDY
Authors: Martin-Moreno Paloma Leticia , Sánchez-Fructuoso Ana I , Mazuecos Auxiliadora , Mir Marisa , López López Isabel , González-Rinne Ana , Coca Armando , Ridao Natalia , Rosalía Valero , Ventura Galiano Ana , Toapanta Néstor , Fernández-Tagarro Ernesto José , Pérez-Mir Mónica , Cruzado-Vega Leónidas , Jimenez Carlos
Published: June 2020

Background and Aims

Mycophenolic acid (MPA) is one of the most used immunosuppressive drugs. It is teratogenic in women with a typical embryopathy profile. Regarding its effect on the children of male kidney transplant recipients, although clinical evidence does not indicate a greater risk of malformations, the European Medicines Agency and the Spanish Agency for Medicines and Health Products introduced in 2015 the recommendation to use contraceptive methods because of their genotoxic potential.

For this reason, we propose to study the results of the Spanish Kidney Transplant Centers.

Method

Multicenter retrospective observational study in which 15 Kidney Transplant Centers have participated. Of 3934 men ≤ 60 years old that received a kidney transplant between 2000 and 2015, 3023 were contacted, and 159 men who fathered at least one post-transplant pregnancy (total 252 fetuses) were included. We compared the incidence of abortions and live births with malformations among those who received MPA at the time of conception vs. those who did not.

Results

In the 252 fetuses (characteristics in table 1) there was an exitus and no differences were detected in the incidence of abortions between the group exposed to MPA (n = 230) and the unexposed group (n = 22), 11.3% vs 18.2%, p = 0.31. Among the 221 live-born fetuses, no differences were found in congenital malformations between the group exposed to MPA (n = 203) and the unexposed (n = 18) 4.9% vs. 16.7%, p = 0.07. Among the malformations described, the typical embryopathy profile of the MPA was not found.

Conclusion

According to the data of this retrospective national multicenter study, the use of MPA in male kidney transplant recipients does not cause a greater number of abortions or congenital malformations.

For these reasons, and given the evidence also published by other groups, it seems necessary to reevaluate the recommendation given on contraception in men treated with MPA.
MO016MYOCARDIAL INFARCTION IN THE PIVOTAL STUDY OF IV IRON IN HAEMODIALYSIS: A PRE-SPECIFIED SECONDARY ANALYSIS
Authors: Petrie Mark , Jhund Pardeep , Robertson Michele , Mark Patrick , Connolly Eugene , Macdonald Michael , White Claire , Reid Chante , Anker Stefan D , Bhandari Sunil , Farrington Kenneth , Kalra Philip A , Tomson Charles R V , Wheeler David , Ford Ian , McMurray John , Macdougall Iain
Published: June 2020

Background and Aims

Coronary artery disease is prevalent in patients with CKD but how often a myocardial infarction (MI) occurs in patients on maintenance haemodialysis, and the prognostic importance of these MIs, is uncertain. The PIVOTAL trial investigated the effects of proactive high-dose versus reactive low-dose intravenous (IV) iron in incident haemodialysis patients. We now report the rates of MI, sub-types of MI, and the prognostic importance of these MIs, as well as the effect of high versus low dose iron on this event.

Method

This was a pre-specified secondary analysis of 2141 patients enrolled in the PIVOTAL trial. All potential endpoints in the trial, including MIs were adjudicated by a blinded Endpoint Adjudication Committee. The outcomes of time-to-first MI (type 1 or type 2 MI, STEMI or NSTEMI) and the composite outcome of MI and death due to MI were reported. In addition to time-to-first MI, we also analysed recurrent events, to account for the cumulative burden of events over time, as well as case-fatality related to MI. The time-to-event analyses of the primary, secondary and post hoc outcomes were performed in the intention-to-treat population using Cox proportional hazards regression, with treatment group as the only explanatory variable. The Kaplan–Meier method was used to estimate event rates. Recurrent events were analysed using the proportional-means model of Lin et al. and described in the form of mean frequency functions.

Results

8.4% of patients experienced a MI over a median of 2.1 years follow-up. Rates of type 1 MIs (3.2/100 patient years) were 2.5 times higher than type 2 MIs (1.3/100 patient years). NSTEMIs (3.3/100 patient years) were 6.6 times more common than STEMIs (0.5/100 patient years). Mortality was high after non-fatal MI (30-day and 1-year mortality were 11.3% and 39.8%, respectively). In time-to-first event analyses, proactive high-dose IV iron reduced the rate of non-fatal MI (HR 0.69, 95% CI 0.51-0.93; p=0.01) and the composite endpoint of non-fatal and fatal MI (HR 0.69, 95% CI 0.52-0.93, p=0.015) (Figure) when compared to low dose reactive IV iron. The benefits of a proactive high-dose IV iron strategy were seen in type 1 MIs but not type 2 MIs.

Conclusion

Most MIs in patients on HD were type 1 and NTEMIs. Patients randomised to the high-dose group of PIVOTAL had a substantial reduction in fatal and non-fatal MI compared to those in the low-dose group.
MO031EFFECTS OF PREDICTIVE MODELLING RISK DIRECTED INTERVENTIONS ON HOSPITALIZATION RATES IN HAEMODIALYSIS PATIENTS
Authors: Chaudhuri Sheetal , Rosen Sophia , Larkin John , Usvyat Len A , Sweet David , Vinson Allison , Johnstone Steinberg Stephanie , Maddux Franklin
Published: June 2020

Background and Aims

End Stage Kidney Disease (ESKD) patients have high hospitalization rates. We have developed and deployed a predictive model to identify in-centre haemodialysis (HD) patients at an increased risk for all-cause hospitalization within the next 12 months. The model was used in a pilot called Dialysis Hospitalization Reduction Program (DHRP) to identify patients predicted to be at risk of >=6 hospital admissions and provide additional interdisciplinary team intervention. We investigated the impact of the DHRP on hospitalization rates in HD patients.

Method

We used data from 45 clinics in South Alabama/Florida Panhandle regions of the United States who participated in DHRP pilot starting January 2016. The predictive model used more than 200 variables to stratify patients as high risk (>=6 admissions), medium high risk (>=3 admissions) and medium low risk (>=1 admission) and low risk (<1 admission). For patients identified at high risk of hospitalization, social workers assessed psychosocial barriers and offered additional psychosocial intervention to target those barriers. Dietitians utilized a high risk assessment looking at weight, nutrition, and access to food and supplements. Resident nurses assessed high risk patients focusing on anaemia, adequacy, access, blood pressure, fluid management, prior hospitalizations, glycaemic control and risk of skin ulcers and blood stream infection Data from patients at the participating clinics was collected and yearly hospital admission and day rates per patient year were calculated 2 years prior to (2014, 2015) and 3 years after (2016-2018) pilot start. Comparison clinics were chosen from neighbouring regions in South and North Florida (43 and 45 clinics respectively).

Results

Over the study period the number of patients ranged from 4661 to 5672 in the DHRP pilot clinics, 5416 to 5947 in South Florida control clinics, and 6087 to 7596 in North Florida control clinics. Hospitalization rates in pilot clinics during the first year of the DHRP remined similar to the rates during the two years preceding the pilot start. In the second and third years of the DHRP, pilot clinics showed reductions in hospital admission and day rates. At control clinics in both regions the hospital admissions and day rates showed increasing trends while DHRP clinics showed decreasing trends over the study period (Figures 1a and 1b).

Conclusion

These findings suggest predictive model risk directed interdisciplinary team interventions associate with lower hospitalization rates in HD patients, compared to controls. Further studies are needed to confirm these results.
MO048MULTICENTRE PROSPECTIVE VALIDATION OF THE URINARY PEPTIDOME-BASED CLASSIFIER CKD273 AS A PREDICTOR OF RENAL FUNCTION DECLINE IN SUBJECTS WITH TYPE 2 DIABETES
Authors: Lindhardt Morten , Tofte Nete , Currie Gemma , Frimodt-Moeller Marie , Von der Leyen Heiko , Delles Christian , Mischak Harald , Rossing Peter , For the PRIORITY Investigators
Published: June 2020

Background and Aims

In the PRIORITY study, it was recently demonstrated that the urinary peptidome-based classifier CKD273 was associated with increased risk for progression to microalbuminuria. As a prespecified secondary outcome, we aim to evaluate the classifier CKD273 as a determinant of relative reductions in eGFR (CKD-EPI) of 30% and 40% from baseline, at one timepoint without requirements of confirmation.

Method

The ‘Proteomic prediction and Renin angiotensin aldosterone system Inhibition prevention Of early diabetic nephRopathy In TYpe 2 diabetic patients with normoalbuminuria trial’ (PRIORITY) is the first prospective observational study to evaluate the early detection of diabetic kidney disease in subjects with type 2 diabetes (T2D) and normoalbuminuria using the CKD273 classifier.

Setting

1775 subjects from 15 European sites with a mean follow-up time of 2.6 years (minimum of 7 days and a maximum of 4.3 years).

Patients

Subjects with T2D, normoalbuminuria and estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73m2. Participants were stratified into high- or low-risk groups based on their CKD273 score in a urine sample at screening (high-risk defined as score > 0.154).

Results

In total, 12 % (n = 216) of the subjects had a high-risk proteomic pattern. Mean (SD) baseline eGFR was 88 (15) ml/min/1.73m2 in the low-risk group and 81 (17) ml/min/1.73m2 in the high-risk group (p < 0.01). Baseline median (interquartile range) urinary albumin to creatinine ratio (UACR) was 5 (3-8) mg/g and 7 (4-12) mg/g in the low-risk and high-risk groups, respectively (p < 0.01).

A 30 % reduction in eGFR from baseline was seen in 42 (19.4 %) subjects in the high-risk group as compared to 62 (3.9 %) in the low-risk group (p < 0.0001). In an unadjusted Cox-model the hazard ratio (HR) for the high-risk group was 5.7, 95 % confidence interval (CI) (3.9 to 8.5; p<0.0001). After adjustment for baseline eGFR and UACR, the HR was 5.2, 95 % CI (3.4 to 7.8; p<0.0001).

A 40 % reduction in eGFR was seen in 15 (6.9 %) subjects in the high-risk group whereas 22 (1.4 %) in the low-risk group developed this endpoint (p<0.0001). In an unadjusted Cox-model the HR for the high-risk group was 5.0, 95 % CI (2.6 to 9.6; p<0.0001). After adjustment for baseline eGFR and UACR, the HR was 4.8, 95 % CI (2.4 to 9.7; p<0.0001).

Conclusion

In normoalbuminuric subjects with T2D, the urinary proteomic classifier CKD273 predicts renal function decline of 30 % and 40 %, independent of baseline eGFR and albuminuria.
MO050GLYCEMIC CONTROL AND THE RISK OF AKI IN PATIENTS WITH DIABETES AND CKD: PARALLEL POPULATION-BASED COHORT STUDIES IN U.S. AND SWEDEN ROUTINE CARE
Authors: Xu Yang , Surapaneni Aditya , Alkas Jim , Chang Alexander , Grams Morgan , Carrero Juan Jesus
Published: June 2020

Background and Aims

Patients with diabetes and chronic kidney disease (CKD) have increased susceptibility to acute kidney injury (AKI), but the underlying mechanisms are not well known. We here explore the association between glycemic control and risk of AKI.

Method

We created two parallel observational cohort studies of Swedish (SCREAM project, Stockholm, 2006-2011) and U.S. (Geisinger Heath system, Pennsylvania, 1996-2018) adult patients with diabetes mellitus and confirmed CKD stages G3-G5. Glycemic control was evaluated through repeated HbA1c measurements, which were categorized into 5 levels of glycemic control intensity, with HbA1c 6-6.9% as referent category, and continuously using cubic splines. We evaluated the association between baseline and time-varying HbA1c levels with AKI (defined as increase in creatinine >=0.3 mg/d over 48 hours or 1.5x creatinine over 7 days) using Cox proportional hazards regression and, in sensitivity analyses, Fine and Gray competing risk models accounting for death.

Results

In the Swedish cohort, there were 13932 patients with median age 76 years, 51% women, median eGFR 50.8 (Interquartile Range (IQR) 41.4-57.1) ml/min/1.73. In the U.S. cohort, there were 26520 patients with median age 71 years, 55% women and 52.1 (IQR 43.4-57.5) ml/min/1.73 m2. During a median of 2.3 and 3.1 years of follow up, 3172 and 8671 AKI events were recorded in the Swedish and US cohorts, respectively. The adjusted association between baseline HbA1c and AKI was similar in both cohorts, with the lowest risk between 6-6.9% and higher risk at higher levels of HbA1c. Compared to baseline HbA1c 6-6.9%, baseline HbA1c>9% associated with a 1.28 fold (95% CI 1.11-1.47) higher risk of AKI in the Swedish cohort, and a 1.14 (95% CI 1.04-1.25) higher risk in the U.S. cohort. Conversely, baseline HbA1c<6% did not associate with AKI. When using time-varying HbA1c, AKI risk was higher for HbA1c>9% (HR 1.18, 95% CI 1.03-1.37 in Swedish cohort and 1.27, 1.17-1.37 in U.S. cohort); AKI risk was also higher for HbA1c<6% in the U.S. cohort (1.12, 1.04-1.19), but not in the Swedish cohort (1.06, 0.97-1.16)).

Conclusion

Higher A1c was associated with AKI in adults with diabetes and CKD, suggesting that better glycemic control may also reduce risk of AKI.
MO052BIOPSY PROVEN KIDEY DISEASES IN TYPE 2 DIABETIC PATIENTS WITH IMPAIRED RENAL FUNCTION
Authors: Paek Jin Hyuk , Kwon Ohyun , Kim Yaerim , Park Woo Yeong , Han Seungyeup , Yoon Jeongsoo , Jin Kyubok
Published: June 2020

Background and Aims

Diabetic nephropathy (DN) is a major microvascular complication of diabetes mellitus (DM) and the most common cause of end stage of renal disease worldwide. The nature of kidney disease in type 2 DM is more complex than type 1 DM. However, the usefulness of kidney biopsy in type 2 DM is still controversial and there are few reports about the biopsy proven kidney disease, especially in patients with impaired renal function.

Method

We retrospectively reviewed 1454 patients who received native kidney biopsy at Keimyung university Dongsan medical center between 2005 and 2018. Among 1454 patients, 92 patients were diagnosed with type 2 DM before kidney biopsy. Fifty-three patients with impaired renal function (estimated glomerular filtration rate < 60 mL/min/1.73 m2 using Modification of Diet in Renal Disease formula) were finally enrolled in this study. We categorized the pathologic diagnoses as DN, non-diabetic renal disease (NDRD), and NDRD mixed with DN (Mixed).

Results

The mean age at kidney biopsy was 58.4 ± 11.2 and mean eGFR was 28.6 ± 14.6 mL/min/1.73 m2. Nineteen patients (35.8%) had diabetic retinopathy and mean duration of DM before kidney biopsy was 102.1 ± 82.2 months. Of the 53 patients, there were 28 NDRD (52.8%), 18 DN (34.0%), and 7 Mixed (13.2%). Diabetic retinopathy was more common in DN, following Mixed and NDRD (72.2%, 42.9%, and 10.7%, respectively, p < 0.001). Multivariable logistic regression analysis revealed that diabetic retinopathy was significantly associated with DN (OR, 23.672; 95% CI, 4.290-130.609; p < 0.001). In multivariable cox proportional hazard models, creatinine level (HR, 1.779; 95% CI, 1.404-2.255; p < 0.001) and dipstick albuminuria ≥ 2+ (HR, 22.721; 95% CI, 4.670-110.542; p < 0.001) were identified as independent prognostic factors for renal survival.

Conclusion

Kidney disease of type 2 diabetic patients were various and clinical parameters could not completely predict. Kidney biopsy is an important tool for the definite diagnosis and the proper treatment of kidney disease in diabetic patients with impaired renal function.
MO053INHIBITION OF SODIUM PHOSPHATE TRANSPORTER NPT2A IMPROVES EXPERIMENTAL VASCULAR CALCIFICATION AND PHOSPHATE HOMEOSTASIS IN RATS
Authors: Klar Juergen , Anja Giese , Ehrmann Alexander , Thiel Christoph , Riedl Bernd , Eitner Frank
Published: June 2020

Background and Aims

A dysregulated phosphate homeostasis is strongly associated with mortality, cardiovascular events and vascular calcification, particularly in patients suffering from CKD. Inhibition of the tubular phosphate transporter Npt2a provides a novel and unique mechanism to address phosphate homeostasis imbalance and vascular calcification.

Method

Npt2a activity was measured in a cell-based assay, using a stable CHO cell line with inducible Npt2a expression. Male Wistar rats were used for all experiments. Healthy rats were treated orally with BAY 767, a potent Npt2a inhibitor developed at Bayer AG to assess urinary phosphate excretion. Vascular calcification was induced by administration of a pan-FGFR inh. (25mg/kg) for 10 days. Calcium content in the aorta was measured as surrogate for vascular calcification. Blood samples were withdrawn at the end of the study to determine the plasma levels of FGF-23, parathyroid hormone and phosphate with commercially available assay systems according to the manufactures protocols (FGF-23 and PTH: ELISA Kit, Immuntopics; phosphate: Pentra400 system).

Results

BAY 767 was identified as potent Npt2a inhibitor, with an IC50 of 2.9/6 nM on rat/ human Npt2a, respectively, selective over Npt2b, Npt2c and Pit-1. Single dose treatments of healthy rats resulted in a significant, dose-dependent increase in urinary phosphate excretion within 16h. In an experimental vascular calcification model, massive vascular calcification and hyperphosphatemia was induced by daily oral administration of a FGFR inh. Simultaneous treatment with the Npt2a inhibitor BAY 767 significantly inhibited vascular calcification in comparison to untreated rats. In this set-up the plasma phosphate level was increased after 10 days up to 3.7 mmol/L in the FGFR inh. treated group compared to 1.9 mmol/L in control animals, whilst treatment with BAY 767 reduced plasma levels to 2.7 mmol/L. In addition, FGF-23 and PTH were also reduced under compound BAY 767 treatment. However, in the same model 2.2% lanthanum carbonate was not beneficial with respect to vascular calcification.

Conclusion

Our results show for the first time that treatment with a Npt2a inhibitor improves vascular calcification by addressing urinary phosphate excretion and phosphate homeostasis in rats.

Npt2a inhibition may provide a new therapeutic principle for patients suffering from disbalanced phosphate homeostasis and vascular calcifications, including CKD patients.
MO055STABLE CALCIUM ISOTOPES: A NOVEL BIOMARKER OF BONE MINERAL CONTENT IN PATIENTS WITH CHRONIC KIDNEY DISEASE
Authors: Shroff Rukshana , Heuser Alex , Lalayiannis Alex , Karabay Bayazit Aysun , Jankauskiene Augustina , BACCHETTA JUSTINE , Askiti Varvara , Schmitt Claus , Mitsioni Andromachi , Crabtree Nicola , Fewtrell Mary , Biassoni Lorenzo , Fischer Dagmar-Christiane , Eisenhauer Anton
Published: June 2020

Background and Aims

In CKD dysregulated calcium (Ca) homeostasis is common and causally associated with reduced bone mineral density (BMD) and vascular calcification. Currently available radiological measures and biomarkers do not allow accurate evaluation of BMD.

The aim of our study was to determine the sensitivity and specificity of stable Ca isotopes in determining bone mineral content.

Method

We measured stable Ca isotopes 44Ca and 42Ca by plasma-ionization mass-spectrometry in blood and urine. The relationship between bone Ca gain and loss is calculated using a compartment model based on Ca kinetics, and expressed as δ44/42Ca. Ca absorption from bones increases δ44/42CaBlood and δ44/42CaUrine, and resorption decreases these fractions.

104 children in CKD4-5 and on dialysis (CKD4-5D), 40 matched controls and 100 adults underwent Ca isotope measurement, bone biomarkers, dual energy x-ray absorptiometry (DXA) and tibial peripheral quantitative CT scan (pQCT), an accurate measure of cortical BMD.

Results

In healthy children the δ44/42CaBlood and δ44/42CaUrine were higher than in adults (p<0.0001), reflecting avid Ca uptake during bone formation. Since urinary Ca excretion is impaired in CKD, δ44/42CaBlood was higher and δ44/42CaUrine lower in children with CKD4-5D compared to controls (p<0.001 for both); Figure 1.

In CKD2-5D δ44/42CaBlood positively correlated with cholecalciferol (p=0.01) and alfacalcidol (p=0.002) doses, implying increased bone Ca uptake when Ca bioavailability is increased. δ44/42CaBlood positively correlated with biomarkers of bone formation (alkaline phosphatase, p=0.05) and negatively with bone resorption markers (PTH, p=0.013; TRAP5b, p<0.001 and CTX, p=0.006). δ44/42CaBlood positively correlated with tibial cortical BMD-Z-score (p=0.006, R2=0.39), and DXA hip BMD-Z-score (p=0.02). On multivariable linear regression analysis significant and independent predictors of tibial cortical BMD-Z-score were δ44/42CaBlood (β=0.68, p=0.006) and PTH (β-0.39, p=0.04), together predicting 67% of the variability in BMD.

Conclusion

Ca isotope ratios provide a novel, non-invasive method of assessing bone mineralization. Further studies are in progress to define optimal levels of δ44/42CaBlood that can guide safe and effective treatment to prevent Ca deficiency or overload.
MO058INHIBITION OF OSTEOCLAST DIFFERENTIATION BY 1.25-D AND THE CALCIMIMETIC KP2326 REVEALS 1.25-D RESISTANCE IN ADVANCED CKD
Authors: Bernardor Julie , Flammier Sacha , Ranchin Bruno , Gaillard Segolene , Platel Diane , Peyruchaud Olivier , Machuca-Gayet Irma , Bacchetta Justine
Published: June 2020

Background and Aims

Active vitamin D analogs and calcimimetics are cornerstones for managing secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). Their direct effects on bone cells remain to be determined.

Method

Peripheral blood mononuclear cells (PBMCs) of 19 pediatric CKD patients and 6 healthy donors (HD) were differentiated into osteoclasts in presence of M-CSF and RANKL. Effect of combined or single treatment with active vitamin D (1.25-D) and/or the calcimimetic KP2326 were evaluated onto osteoclast differentiation and osteoclast mediated bone resorption.

Results

1.25-D inhibited osteoclastic differentiation, a significant resistance to 1.25-D was observed when CKD worsens. A significant albeit less important inhibitory effect of KP2326 on osteoclastic differentiation was also found both in cells derived from HD and CKD patients, through an activation of the Erk pathway. This inhibitory effect was not modified by CKD stage. Combinatorial treatment with 1.25-D and KP2326 did not result in synergistic effects. Last, KP2326 significantly inhibited human osteoclast-mediated bone resorption.

Conclusion

Both 1.25-D and KP2326 inhibit osteoclastic differentiation, however to a different extent. Whilst 1.25-D has no significant effect on bone resorption, KP2326 inhibits bone resorption. Recent data showed that calcimimetics also have a direct anabolic effect on bone, through the stimulation of osteoblastic differentiation and mineralization in human mesenchymal stem cells in vitro. All these results provide a strong rationale for a global positive effect of calcimimetics on bone remodeling. Calcimimetics also significantly decrease FGF23 levels. In the setting of global systematic deleterious effects of high FGF23 levels in CKD, and keeping in mind that active vitamin D analogs stimulate FGF 23 production, all these data could favor the use of decreased doses of 1.25-D with low-doses of calcimimetics in SHPT in dialysis, the combination of these two therapies already being proposed in the 2017 K-DIGO guidelines.
MO063CHRONIC INTERSTITIAL NEPHRITIS IN AGRICULTURAL COMMUNITIES IS A TOXIN-INDUCED PROXIMAL TUBULAR NEPHROPATHY
Authors: Vervaet Benjamin , Nast Cynthia , Jayasumana Channa , Schreurs Gerd , Roels Frank , Herath Chula , Kojc Nika , Samaee Vahid , Rodrigo Sonali , Gowrishankar Swarnalata , Mousson Christiane , Dassanayake Rajeewa , Orantes Carlos , Vuiblet Vincent , Rigothier Claire , D'Haese Patrick , De Broe Marc
Published: June 2020

Background and Aims

30 years after the detection of CINAC, there is no consensus on its etiology. Heat stress/dehydration and toxic exposure are the two most likely etiologies. There are no diagnostic criteria that can directly identify CINAC patients.

Method

Renal biopsies (RB) (18 Sri Lanka, 10 El Salvador, 1 India, 3 France) of patients with CINAC (CKD2-3) were examined by light (LM) and electron microscopy (EM) in comparison to RB of normal kidneys at implantation and 6 and 12 months of calcineurin inhibitor (CNI) therapy, transplant patients on CNI with indication biopsies (n=24), proteinuric nephropathies (n=15), light chain disease (n=4), cases on nephrotoxic drugs (lomustine, clomiphene, lithium, tenofovir, cisplatinum) and CKD of various causes (n=20). A rat study was conducted comparing histopathology of heat stress/dehydration with cyclosporine nephrotoxicity.

Results

In addition to previously described histopathological changes, there was a unique constellation of proximal tubular cell (PTC) findings: cellular/tubular atrophy, cell fragment shedding, weak to non-proliferative capacity of the PTC and dysmorphic lysosomes increased in size and number with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound “aggregates”. Identical renal lesions were observed in 55-80% of renal transplant protocol biopsies taken after 6 and 12 months of calcineurin inhibitor (CNI) therapy and in indication biopsies, in implantation biopsies the prevalence was 6%. Several cases of nephrotoxic drugs (lomustine, clomiphene, lithium) and a subset of patients with light chain disease, all conditions that can be linked to CNI, presented the same lesion. Control RBs (n=66) of normal kidney, toxic nephropathies (tenofovir, cisplatinum), and overt proteinuric patients of different etiology to some extent could demonstrate the tubular cell changes observed by LM, but not or very rarely those that were observed by EM. Rats treated with cyclosporine for 4 weeks developed similar PTC lysosomal alterations, absent in a dehydration group.

Conclusion

A sensitive constellation of renal PTC lesions was detected associated with CINAC and CNI nephrotoxicity in several countries, suggesting a common new paradigm where CINAC patients are experiencing a tubulotoxic mechanism similar to CNI nephrotoxicity, the latter also being known as a direct or suggested indirect effect of pesticides.
MO070APPROPRIATE INTERVAL BETWEEN TWO EGFR MEASUREMENTS FOR THE EVALUATION OF THE ASSOCIATION OF EGFR SLOPE WITH INCIDENCE OF RENAL EVENTS
Authors: Kokubu Maiko , MATSUI MASARU , Uemura Takayuki , Tsuruya Kazuhiko
Published: June 2020

Background and Aims

In recent years, growing evidence has shown the prognostic utility of eGFR slope for the risk of end-staging renal disease (ESRD). Previous observational studies have assessed the association between renal events and eGFR slopes estimated by two measurements of eGFR but had great differences in the interval between two eGFR measurements. In this study, we thus aimed to determine the appropriate interval between two eGFR measurements to evaluate the association of eGFR slope with incidence of renal events.

Method

This is a retrospective cohort study in 203 chronic kidney disease (CKD) patients who visited Nara Prefecture General Medical Center, Japan between 1 January 2013 and 31 December 2016 and in whom two or more than two measurements of eGFR levels were confirmed in medical records. eGFR slopes were estimated by using two measurements of eGFR at baseline and 0.5, 1, 1.5, 2, or 3 years. We excluded patients with acute kidney injury, urologic malignancies, nephrotic syndrome with steroid treatment or collagen diseases. Outcome was renal events defined as a composite of ESRD and eGFR decline of > 30%. C statistics were used to evaluate the association between eGFR slope and incidence of renal events.

Results

The median (interquartile range) age of study participants was 67 (56-77) years and 71 (37%) were male. The median (interquartile range) levels of baseline eGFR were 34 (21-48) mL/min/1.73m2 and diabetes was present in 80 (39%) participants. During the median follow-up period of 38 months, renal events occurred in 52 participants. Medial levels of eGFR slopes0.5, 1, 1,5, 2 and 3yr were -7.8, -3.6, -2.9, -0.9, -1.5 mL/min/1.73m2, respectively. C-statistics of eGFR slopes0.5, 1, 1,5, 2 and 3yr for renal events were 0.622, 0.691, 0.797, 0.858, 0.806, respectively (shown in Figure 1), and that of eGFR slope1.5yr was significantly higher than that of eGFR slope0.5yr and eGFR slope1yr (p<0.001 and p=0.001, respectively). In stratified analysis, eGFR slope1.5yr had higher prognostic ability of renal events in patients with versus without diabetes, advanced CKD and proteinuria. C-statistics of renal events when considering baseline eGFR alone was 0.853 but combination use of baseline eGFR and eGFR slope1.5yr significantly increased c-statistics, to 0.913 (p=0.01).

Conclusion

eGFR slope for high prognostic ability of renal events may be needed to be calculated by at least 1.5-year interval between two eGFR measurements.