bluuebunny/crossref_metadata_2025 huggingface dataset:
MO039THE 24-WEEK INTERIM ANALYSIS RESULTS OF A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED PHASE II STUDY OF ATACICEPT IN PATIENTS WITH IGA NEPHROPATHY AND PERSISTENT PROTEINURIA
Authors: Barratt Jonathan , Tumlin James A , Suzuki Yusuke , Kao Amy , Aydemir Aida , Zima Yulia , Appel Gerald
Published: June 2020

Background and Aims

IgA nephropathy (IgAN) is the most common primary glomerulonephritis in the world. Despite being described over 50 years ago, there remains no approved therapy for this common global cause of kidney failure. The central pathogenic feature in IgAN is the formation of circulating IgA containing immune complexes which have the propensity to deposit in the kidneys and trigger glomerular inflammation and tubulointerstitial scarring. The primary substrate for immune complex formation is an excess of poorly O-galactosylated polymeric IgA1 (Gd-IgA1) in the circulation. These IgA1 O-glycoforms are thought to trigger the formation of IgA and IgG autoantibodies. Atacicept is a human TACI-Ig fusion protein that inhibits B cell-stimulating factors, BLyS and APRIL, and has been associated with reductions in levels of serum IgA and IgG, as well as reductions in mature B cells and plasma cells. A number of studies have shown elevated levels of BLyS, APRIL and Gd-IgA1 in IgAN patients which have been linked to worse clinical outcomes. IgAN patients with persistent proteinuria >1 g/day are at increased risk of progression to end-stage renal disease. This Phase II study examines the safety and efficacy of atacicept in reducing pathogenic Gd-IgA1 levels and measures of renal activity in IgAN.

Method

This Phase II study (NCT02808429) enrolled patients with IgAN and proteinuria ≥1 g/day or 0.75 mg/mg on 24-hour urine protein-creatinine ratio (UPCR) despite maximal standard of care therapy (angiotensin converting enzyme inhibitor and/or angiotensin receptor blocker). Enrolled patients were randomized 1:1:1 to receive placebo or atacicept 25mg or 75mg once weekly by subcutaneous injection. The primary endpoint was a change in proteinuria by 24-hour UPCR at Week 48; key secondary endpoints included change in eGFR, serum immunoglobulin and Gd-IgA1 levels.

Results

Data from the 24-week interim analysis are reported here for enrolled patients (placebo=5; atacicept 25mg=6; atacicept 75mg=5). A consistent, dose-dependent reduction in serum immunoglobulins (IgA, IgG and IgM) and, in particular, Gd-IgA1 (Figure) were observed through Week 24. In parallel, proteinuria (24-hour UPCR) showed a higher median % reduction from baseline with atacicept at Week 24: -18.67% and -25.34% with atacicept 25 mg and 75 mg, respectively, vs +0.098% with placebo (Figure). eGFR remained stable over time. TEAEs were reported by 81% of the subjects. TEAEs were mild or moderate in severity, with no severe TEAEs reported. No serious related events, events with severe hypogammaglobulinemia or fatal outcome were reported.

Conclusion

These 24-week interim analysis results provide early proof of concept for the potential treatment of atacicept in patients with IgAN and persistent proteinuria.
MO049EFFECT OF VITAMIN D ON ENDOTHELIAL FUNCTION IN EARLY DIABETIC NEPHROPATHY
Authors: Mahapatra Himansu , Kumar Adarsh , Kulshreshtha Bindu , Chirkara Anubhuti
Published: June 2020

Background and Aims

Diabetic Nephropathy is associated with endothelial dysfunction at an early stage. The benefit of Vitamin D supplementation on endothelial function is supported by a few studies in non-diabetic chronic kidney disease (CKD). However, studies on its effect in early DN is scarce. Hence, the present study was planned to assess the effect of vitamin D supplementation on endothelial function by measuring Flow mediated dilation (FMD) in patient of early DN.

Method

A total of 730 Diabetic subjects were screened for early DN based on Inclusion criteria (eGFR ≥ 120ml/min/1.73m2 with unrestricted ACR value eGFR of 60- 120 mL/min/1.73m2 and ACR 30-300mg) and Exclusion criteria (on ACE I or ARB, eGFR<60ml/min/1.73m2, Hypercalcemia (>11.5mg%), UTI, Pregnancy, Hypertension, HbA1c (>8.0 %), vitamin D supplementation during the last 6 month). Of them 103 included subjects were underwent randomization to receive either Cholecalciferol (54) or matching Placebo (49) in a double blind method. All were subjected to routine investigations, urinary albumin: creatinine (UACR), C reactive protein (CRP), serum 25(OH)vitamin D, intact parathyroid hormone (iPTH) and Flow mediated dilatation at the zero and six months. All subjects were subjected. Comparative results at zero and six months of both groups were compared and analyzed.

Results

There was no significant difference between cholecalciferol and placebo group with respect to CRP, iPTH, 25-hydroxyvitamin D (25(OH) D), UACR, FMD at baseline. Median FMD after 6 month was significantly higher in cholecalciferol as compared to placebo group [Median (IQR): 24 % (21.75-26.0) and 22% (18-24) respectively, p= 0.01]. After 6 month UACR was significantly lower in the cholecalciferol group as compared to placebo group (p= 0.04). Significant association of vitamin D level was observed with CRP level. In 25(OH) D < 20 ng/ml subgroup there was significant decrease in CRP level in comparison to 25(OH) D ≥20 ng/ml subgroup (p=0.04).

Conclusion

There was significant improvement in endothelial function as assessed by FMD% following vitamin D supplementation. Vitamin D supplementation given to early diabetic nephropathy patients may have favourable effects on cardiovascular outcome as reflected by improvement in FMD% and decrease in CRP level.
MO060ACUTE KIDNEY INJURY PROMOTES DEVELOPMENT OF A PAPILLARY RENAL CELL ADENOMA-CARCINOMA SEQUENCE FROM RENAL PROGENITORS
Authors: Peired Anna Julie , Allinovi Marco , Antonelli Giulia , Angelotti Maria Lucia , Guzzi Francesco , Romagnani Paola
Published: June 2020

Background and Aims

Renal cell carcinoma (RCC) accounts for 2% of all cancers, with about 190,000 new cases per year worldwide. Risk factors for RCC include obesity, diabetes, hypertension and genetic factors, but the majority of cancers occur in apparent absence of clear risk factors. Acute tissue injury (AKI) causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. We proposed to verify whether AKI plays a role in RCC development, and to identify the cellular origin of RCC.

Method

We used the following techniques: 1. observational, retrospective clinical trial to identify a possible association of AKI with RCC. 2. Experimental AKI induction in wild-type mice to study tumor development over 36 weeks. 3. Analysis of TCGA Research Network dataset on human papillary RCC (pRCC) molecular characterization, focusing on AKI-driven pathways. 4. Development of mouse models in which the intracellular domain of Notch 1 (NICD1), a molecule modulated during AKI, is expressed constitutively by all Pax8+ tubular epithelial cells (Pax8/NICD1) or only by Pax2+ renal progenitors (Pax2/NICD1) upon induction in adult mice. The mice were sacrificed at 36 weeks or 4 weeks after AKI. 5. Clonal analysis of tumoral lesions with Confetti reporter. 6. Examination of single cell RNA sequencing (RNAseq) data from pRCC patients.

Results

We observed that an AKI episode is a major risk factor for pRCC development and recurrence in patients. Wild-type mice subjected to AKI developed pRCC over time in an adenoma-carcinoma sequence, corroborating our human findings. Among AKI-related pathways, Notch1 overexpression in human pRCC associated with worse outcome, prompting us to generate Notch1-overexpressing mice. At 36 weeks o at 4 weeks following AKI, Pax8/NICD1 mice presented a significant decline of renal excretory function as well as type 2 pRCCs. Confetti lineage tracing showed that most of the pRCCs were monoclonal or biclonal, suggesting that they could originate from a local stem cell/progenitor population. Pax2/NICD1 mice presented type 2 pRCCs, and lineage tracing identified single Pax2+ tubular progenitors as the source of pRCCs. Single cell RNAseq analysis confirmed that the molecular signature of the pRCC cell of origin matched the one of human tubular progenitors.

Conclusion

This study expose the link between AKI and pRCC development in patients, with important clinical implications. In mice, AKI promotes long-term development of type 2 papillary tumors by activating the AKI-associated Notch1 pathway. Additionally, pRCC originates from clonal proliferation of renal progenitors in a classical adenoma-carcinoma sequence leading to invasive pRCC growth and metastatization in mice.
MO062CHRONIC KIDNEY DISEASE, INFLAMMATION, AND HEART FAILURE WITH PRESERVED EJECTION FRACTION: A RENAL-CARDIO AXIS?
Authors: Chade Alejandro , Williams Maxx , Engel Jason , Bidwell Gene
Published: June 2020

Background and Aims

Inflammation contributes to progressive renal dysfunction and increases cardiovascular mortality of patients with chronic kidney disease (CKD). The association of CKD and heart failure with preserved ejection fraction (HFpEF) is observed in up to 50%, suggesting the possibility of a shared pathophysiology. CKD and HFpEF are commonly associated with inflammation. Using a novel swine model of CKD and HFpEF, we propose that a renal-cardio inflammatory axis drives diastolic dysfunction and HFpEF in CKD and that targeting renal inflammation will improve cardiac health and reduce cardiovascular risk.

Methods

We developed a biopolymer-fused peptide of nuclear-factor kappa (NFk)B (ELP-p50i) that we show it blocks its activity in vitro and in vivo. NFkB is a key pro-inflammatory transcription factor that is upregulated in CKD. To test our hypothesis, we induced CKD in 10 pigs via bilateral renovascular disease and dyslipidemia. Pigs were observed for 6 weeks, renal hemodynamics quantified (multi-detector CT), then randomized to single intra-renal ELP-p50i or placebo (n=5 each), and studies repeated 8 weeks later accompanied by echocardiographic assessment. Blood pressure was continuously measured (telemetry). Blood was collected to measure circulating TNF-α and biomarkers of HF (ANP, BNP). Furthermore, kidneys and hearts were used to quantify expression of factors involved in NFkB signaling.

Results

CKD led to a significant loss of renal function, accompanied by left ventricular hypertrophy and diastolic dysfunction with pEF, increased renal mRNA expression of TNF-α and canonical and non-canonical mediators of NFkB signaling, and elevated systemic TNF-α, ANP, and BNP, indicating renal and cardiac dysfunction. Most of these changes were improved after intra-renal ELP-p50i, although cardiac inflammatory signaling was unchanged (Figure) suggesting the kidney as a source of inflammation that can target the heart in CKD.

Conclusion

We show that a renal anti-inflammatory strategy via targeted inhibition of renal NFkB improves renal and cardiac function in CKD, suggesting an inflammatory renal-cardio axis. The translational pathological features of CKD and HFpEF combined with the predictive power of the model may contribute to advance the field towards new treatments targeting renal inflammation to reduce cardiovascular risk in CKD.
MO064TISSUE-RESIDENT B CELLS DETERMINE SUSCEPTIBILITY TO URINARY TRACT INFECTION BY ORCHESTRATING MACROPHAGE POLARISATION
Authors: Suchanek Ondrej , Wijeyesinghe Sathi , Ferdinand John , Tuong Zewen K , Chandra Anita , Clare Simon , Bashford-Rogers Rachael , Lawley Trevor , Okkenhaug Klaus , Masopust David , Clatworthy Menna
Published: June 2020

Background

Urinary tract infection (UTI) is an important clinical problem. More than half of women and 1 in 10 men will be affected during their lifetime. Many of these affect the lower urinary tract but recurrent pyelonephritis can lead to scarring and chronic kidney disease. There is an increasing appreciation that tissue-resident immune cells, such as macrophages, play an important role in defence against infection, but only little is known about B lymphocytes in this context. Here we sought to address the question of whether B cells reside in the kidney and bladder in homeostasis and to determine their phenotype and contribution to local organ immunity.

Methods and Results

Using intravenous labelling and parabiosis, we identified a population of bona-fide self-renewing, tissue-resident B cells that included non-naïve and innate-like CD5+ B-1 cells, in murine kidneys and urinary bladder (but also in liver and lung). The size and phenotype of this B cell subset was influenced by genetic background, age, and microbiome, with an expanded population evident after co-housing with pet-store mice. Although kidney B cells had less diverse Igh repertoire compared to blood, their seeding was largely independent of their B-cell receptor specificity. In human kidneys we found a similar enrichment for non-naïve B cells compared to blood and spleen.

Using two strains of genetically modified mice with higher (PI3KδE1020K-B) or lower (μMT-) numbers of tissue-resident B cells, we tested the function of these cells during UTI. Surprisingly, the number of tissue-resident B cells inversely correlated with bacterial clearance. We found that these B cells were spatially co-localised with kidney macrophages and skewed their polarization towards an anti-inflammatory M2 phenotype, leading to reduced anti-microbial responses. This effect was, at least in part, driven via IL-10.

Conclusion

In conclusion, our data identify a critical role for tissue-resident B cells in modulating local immunity in the urinary tract, determining the inflammatory ‘set-point’ of resident and recruited myeloid cells, with important clinical implications for the use of B-cell depleting therapies and conditions such as infection, transplant rejection, fibrosis or autoimmunity.

Graphical Abstract
MO065TUBULAR EPITHELIAL CELL POLYPLOIDIZATION IS REQUIRED TO SURVIVE AKI BUT PROMOTES CKD DEVELOPMENT
Authors: De Chiara Letizia , Lazzeri Elena , Angelotti Maria Lucia , Conte Carolina , Peired Anna Julie , Antonelli Giulia , Melica Maria Elena , Mazzinghi Benedetta , Lasagni Laura , Romagnani Paola
Published: June 2020

Background and Aims

Acute kidney injury (AKI) is a global health concern. If not lethal in the acute phase, AKI is considered reversible based on the capacity of surviving tubular cells (TECs) to re-enter cell cycle. However, even mild AKI episodes carry a substantial risk of developing chronic kidney disease (CKD). The pathophysiological basis for this phenomenon remains unclear. Recently, we demonstrated that tubular epithelial cells (TECs) can undergo endoreplication-mediated hypertrophy after AKI. Endoreplications are incomplete cell cycles that lead to the formation of polyploid cells. As polyploid cells can provide increased cell function without restoring tissue integrity, we hypothesized that this mechanism is essential to survive AKI but it can be potentially maladaptive.

Method

To address this hypothesis, we employed a series of in vitro and in vivo transgenic models based on the Fluorescence Ubiquitin Cell Cycle Indicator (FUCCI) technology to monitor cell cycle phasing in combination with YAP1 overexpression or downregulation. In the in vivo models, YAP1 overexpressing mice and YAP1 knock-out mice were subjected to unilateral ischemia reperfusion injury (IRI) or glycerol-induced rhabdomyolysis to induce AKI. Polyploid cells have been then characterized by microarray analysis, cell sorting, super-resolution STED microscopy and transmission electron microscopy.

Results

In vitro, human renal tubular cells undergo polyploidization. The fraction of polyploid cells significantly decreases when YAP1 nuclear translocation is blocked, suggesting a possible involvement of YAP1 in regulating TEC polyploidization. After AKI in mice, the inhibition of YAP1 significantly reduces the number of polyploid cells and worsens kidney function resulting in a dramatic decrease of mouse survival. In contrast, YAP1 overexpression leads to an increase in the number of polyploid cells up to 20% of all TECs, further confirming the role of YAP1 in controlling TEC polyploidization. In YAP1 overexpressing mice, electron microscopy and STED analysis revealed the presence of both mononucleated and binucleated polyploid cells. Strikingly, these mice appear to be more prone to develop tubulointerstitial fibrosis acquiring a marked senescent phenotype along with significant decline in renal function thus suggesting an association between polyploidization and CKD development. Indeed, isolation of polyploid cells proved that these cells actively transcribe and secrete pro-fibrotic and senescent factors confirming their role in CKD progression.

Conclusion

These data suggest that: 1) polyploidization after AKI is required to preserve renal function in the acute phase of damage and it is essential for survival 2) polyploid cells are pro-fibrotic and senescent leading in the long run to the progression of AKI to CKD.
MO066GASDERMIND MUTATION IS PROTECTIVE AGAINST RENAL ISCHEMIA REPERFUSION INJURY
Authors: Rogers Natasha , Li Jennifer , Alexander Stephen
Published: June 2020

Background and Aims

Ischemia reperfusion injury (IRI) is an important contributor to acute kidney injury (AKI) and manifests as delayed graft function following kidney transplantation. Limiting the damage of IRI has implications on graft outcomes and has driven further exploration of the underlying pathophysiology. We hypothesize that pyroptosis, a pro-inflammatory form of cell death, has an important role in IRI and AKI. The pyroptosis pathway converges to the cleavage and release of N-terminal of the Gasdermin-D protein, leading to pore formation in the cell membrane and cell death. We examined the effects of Gasdermin-D mutation on inflammation in acute kidney injury.

Method

Male C57BL/6 mice were exposed to ethyl-N-nitrosourea mutagenesis, leading to a loss-of-function, single nucleotide polymorphism (isoleucine to asparagine mutation, I105N) in the Gasdermin-D gene. Age- and gender-matched littermate control wild-type, heterozygous and homozygous Gasdermin-DI105N mice were subjected to bilateral renal IRI (36°C, 22mins) and sacrificed 24-hours post-reperfusion for analysis of renal function, histology and biomolecular phenotyping. To delineate if the GasderminD mutation in renal parenchymal or hematopoietic cells were key drivers of IRI, we generated chimeric mice with whole body irradiation and infusion of syngeneic donor bone marrow. Following 8 weeks of engraftment, bilateral renal IRI was performed with analysis at 24 h reperfusion.

Results

Homozygote and heterozygote Gasdermin-DI105N mice were protected from renal IRI in a gene dose-dependent manner when compared to wild-type, with lower mean serum creatinine (15.7, 48.1 and 85.5µmol/L respectively, p<0.001), less histological tubular injury and cell death (1.8, 3.6 and 5.1 TUNEL+ cells/hpf, p<0.01) and significantly decreased expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, RANTES). Homozygote GasderminDI105N chimeric mice (reconstituted with wild-type donor bone marrow) were more susceptible to IRI, and serum creatinine was similar to that of wild-type chimeric control mice, indicating that hematopoietic cells rather than parenchymal cells, are likely predominant drivers of injury. Similarly, adoptive transfer of CpG-activated CD11c+ dendritic cells into homozygous Gasdermin-DI105N mice augmented renal injury compared to GpC-treated cells.

Conclusion

GasderminDI105N mice were protected from IRI and demonstrates the importance of the pyroptosis pathway on acute kidney injury. Manipulation of GasderminD is potentially an attractive target to mitigate inflammation and cellular death following injury.
MO078HEMODIAFILTRATION MAINTAINS A SUSTAINED IMPROVEMENT IN BP COMPARED TO CONVENTIONAL HEMODIALYSIS IN CHILDREN - THE HDF, HEART AND HEIGHT (3H) STUDY
Authors: De Zan Francesca , Bayazit Aysun Karabay , Azukaitis Karolis , Canpolat Nur , Bakkaloglu Sevcan , Krid Saoussen , Litwin Mieczysław , Paglialonga Fabio , Samaille Charlotte , Shenoy Mohan , Sinha Manish , Spasojevic Brankica , Schmitt Claus , Schaefer Franz , Vidal Enrico , Shroff Rukshana
Published: June 2020

Background and Aims

Hypertension is prevalent in children on dialysis and associated with left ventricular hypertrophy, cardiovascular disease and mortality. We studied the effect of different dialysis modalities (conventional hemodialysis [HD] vs hemodiafiltration [HDF]) on BP and risk factors affecting the evolution of BP over a one-year follow-up.

Method

This is a post-hoc analysis of the “3H - HDF-Hearts-Height” dataset, a multicenter, non-randomized, parallel-arm intervention study. The time–averaged 24-h mean arterial pressure (MAP) was used for the analyses and hypertension defined as 24-h MAP standard deviation score exceeding the 95th percentile.

Results

All 133 children who completed 12 months follow-up in the 3H study were included in this post - hoc analysis. 78 (74%) were on HD and 55 (77%) on HDF. At baseline MAP-SDS was > 95th percentile in 64 (82%) of children on HD and 23 (41.8%) patients on HDF, but these data are skewed by a high percentage of prevalent dialysis patients in the study. 43 (55%) of HD patients and 23 (42%) of HDF patients were on antihypertensive medications, and uncontrolled hypertension (BP>95th centile on medications) was present in 38 (88%) of HD patients and 6 (25%) of HDF patients. In the stepwise logistic regression at baseline, independent risk factors for hypertension were gender (OR 2.29; 95%CI 1.06–4.96; p=0.04) and inter-dialytic weight gain at baseline (OR 1.3; 95%CI 1.1–1.55; p=0.004). Over the one-year study period, MAP-SDS increased by 39% in HD patients and 12% in HDF patients (p< 0.001) (Figure). Significant risk factors for hypertension over time were dialysis modality (OR for HD compared to HDF 7.65; 95% CI 3.23 – 18.12; p< 0.001), inter-dialytic weight gain (OR 1.21; 95% CI 1.05 – 1.39; p=0.007), and dialysate sodium (for 1 mmol/L increase in dialysate sodium MAP-SDS increased by 1.1mmHg ; 95% CI 1.01 – 1.21; p=0.04).

Conclusion

Children on HD compared to HDF had a 7.6-fold higher 24-hr MAP-SDS and a sustained increase in BP over the one-year study period. Higher inter-dialytic weight gain and higher dialysate sodium levels were associated with a higher MAP-SDS in both groups.
TO001EFFECTS OF THE BET-INHIBITOR APABETALONE ON CARDIOVASCULAR EVENTS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS AND ACUTE CORONARY SYNDROME, ACCORDING TO PRESENCE OR ABSENCE OF CHRONIC KIDNEY DISEASE. A BETONMACE TRIAL REPORT
Authors: Kalantar-Zadeh Kam , Ray Kausik K , Nicholls Stephen J , Ginsburg Henry N , Buhr Kevin A , Johansson Jan , Kulikowski Ewelina , Toth Peter P , Sweeney Michael , Schwartz Gregory G
Published: June 2020

Background and Aims

Patients with type 2 diabetes (T2D) and acute coronary syndrome (ACS) are at high risk for recurrent cardiovascular (CV) events, particularly in the presence of chronic kidney disease (CKD). Apabetalone (APB) is a novel inhibitor of bromodomain and extraterminal (BET) proteins. Its cardiovascular efficacy and safety were evaluated in a phase 3 trial, BETonMACE.

Method

BETonMACE was a randomized, double-blind, comparison of effects of ABP or placebo (PBO) on major adverse CV events (MACE) defined as CV-death, non-fatal myocardial infarct or stroke, in 2425 pts with T2D and recent ACS. Here we report MACE plus CHF hospitalization in subjects with or without CKD Stage 3.

Results

Baseline characteristics: median age 62 years, 25.6% female, 87.6% white, 90% high intensity statin use, mean LDL-C 70.3 and HDL-C 33.3 mg/dl, median HbA1c 7.3%, and 11% with CKD Stage 3. Overall in the trial, MACE plus CHF hospitalization occurred in 139 (11.5%) patients with ABP and 173 (14.3%) with PBO (HR 0.78, 95% CI 0.63-0.98). In the subgroup with CKD, MACE plus CHF hospitalization occurred in 16 (12.9%) on APB and 41 (25%) on PBO (HR 0.48, 95% CI 0.26-0.89). In the subgroup without CKD, MACE plus CHF hospitalization occurred in 123 (11.3%) and 132 (12.7%) with APB or PBO, respectively (HR 0.89, 95% CI 0.70-1.

Conclusion

Patients with T2D, ACS, and Stage 3 CKD have a very high risk of subsequent MACE plus CHF hospitalization. The BET protein inhibitor ABP may reduce this risk.
TO002REDUCTION IN THE RATE OF EGFR DECLINE WITH SEMAGLUTIDE VS PLACEBO: A POST HOC POOLED ANALYSIS OF SUSTAIN 6 AND PIONEER 6
Authors: Tuttle Katherine , Cherney David , Hadjadj Samy , Idorn Thomas , Mosenzon Ofri , Perkovic Vlado , Rasmussen Søren , Wolthers Benjamin , Bain Stephen C
Published: June 2020

Background and Aims

The SUSTAIN 6 cardiovascular outcomes trial (CVOT) indicated that once-weekly (OW) subcutaneous (s.c.) semaglutide may have beneficial effects on kidney function. SUSTAIN 6 and the more recent PIONEER 6 CVOT (oral semaglutide) had similar designs and subject populations; both evaluated the effects of semaglutide compared with placebo on important macro- and microvascular outcomes. This post hoc analysis of pooled data from the two trials evaluated the effects of semaglutide vs placebo on kidney function, assessed by estimated glomerular filtration rate (eGFR) slope.

Method

Data for 6,480 subjects from SUSTAIN 6 (OW s.c. semaglutide 0.5 and 1.0 mg or placebo, n=3,297; median follow-up 2.1 years) and PIONEER 6 (oral semaglutide once-daily 14 mg or placebo, n=3,183; median follow-up 1.3 years) were pooled into two groups: semaglutide and placebo. Annual change in eGFR was compared between semaglutide and placebo in patients with eGFR data at baseline, both overall and by baseline eGFR subgroup (≥30–<60 or ≥60 mL/min/1.73 m2). Data were analysed using a linear random regression model with individual intercept and time slope. Estimated treatment difference (ETD) between annual rates of eGFR slope (from baseline to timepoint of interest) was calculated at Year 1 and Year 2 (Year 2 data predominantly from SUSTAIN 6); interaction p-values indicated differences between subgroups.

Results

In the overall treatment population, the annual rate of eGFR change was 0.60 mL/min/1.73 m2 (95% confidence interval [CI]: 0.31;0.90; p<0.0001) lower with semaglutide vs placebo in Year 1. In the subgroup with an eGFR ≥60 mL/min/1.73 m2 at baseline, the ETD for semaglutide vs placebo at Year 1 was 0.48 mL/min/1.73 m2/year (95% CI: 0.13;0.82). Whereas, at Year 1, the subgroup with eGFR ≥30–<60 mL/min/1.73 m2 had an ETD of 1.07 mL/min/1.73 m2/year (95% CI: 0.46;1.68) (Table). Accordingly, a numerically larger difference in ETD was observed in the eGFR ≥30–<60 mL/min/1.73 m2 vs the eGFR ≥60 mL/min/1.73 m2 subgroup (not statistically significant; pinteraction=0.21).  

Conclusion

Semaglutide was associated with a significantly smaller decline in renal function compared with placebo in subjects across stages of impaired kidney function at baseline. Although benefits were observed in the overall population, the findings indicate that the primary benefit may be observed in those with established chronic kidney disease.

Table

Annual eGFR change with semaglutide or placebo and ETD between semaglutide and placebo in pooled SUSTAIN 6 and PIONEER 6 trials
TO003CROSSTALK OF UREMIC TOXINS AND INFLAMMASOME IN CHRONIC KIDNEY DISEASE-RELATED COGNITIVE IMPAIRMENT
Authors: LI LUNG-CHIH , CHEN WEI-YU , Chen Jin Po , Lee Wen-Chin , YANG JENG-LIN
Published: June 2020

Background and Aims

Chronic kidney disease (CKD) is getting prevalent and causes big burden to the health care systems worldwide. CKD-associated cognitive impairment (CI) not only influences the behave function, but also results in longer hospitalization and higher risk of mortality. Inflammation is an important pathogenesis of CKD and plays a crucial role in progression of CKD. In this study, we hypothesized that accumulated uremic toxins, especially indoxyl sulfate (IS) and P-cresyl sulfate (PCS) induce neuroinflammation via activation of NLRP3 inflammasome in the brain tissue of CKD animals. This study aims to delineate the crosstalk between uremic toxins and inflammation in CKD-induced CI.

Method

Eight-week-old male C57B6 wildtype and NLRP3 knockout mice received sham and 5/6 nephrectomy to mimic CKD status. AST-120 (Kremezin), a spherical carbon adsorbent, was given orally to mice to neutralize the accumulated uremic toxins. The Y-maze and Morris water maze (MWM) testes were applied to evaluate cognitive function, including the spatial, short-term and long-term memory in shame, CKD, and AST-120 treated CKD mice. HPLC was used to examine the concentration of IS and PCS in the serum and brain tissues. Western blot and immunohistochemistry stain were used to identify the protein expression of target molecules in the brain tissue.

Results

CKD mice showed impaired spatial, short-term and long-term memory; however, 10% AST-120 attenuated CKD-induced memory impairment (Figure 1). IS, but not PCS, elevated in the brain tissues, especially in the frontal cortex and hippocampus. AST-120 reduced CKD-induced IS elevation in the brain tissue, and also ameliorated NLRP3 inflammasome activation in the astrocytes in the frontal and hippocampus. Finally, NLRP3 deficiency reversed the CKD-induced memory impairment (Figure 2).

Conclusion

IS is the major uremic toxin that causes CI in CKD mice via activating NLRP3 inflammasome pathway in the brain tissue. However, AST-120 effectively ameliorates CKD-induced CI.
TO008COMPARATIVE TRANSCRIPTOME AND CO-EXPRESSION NETWORK ANALYSIS REVEALED A POTENTIAL ROLE OF C1QB AND INTERFERON TYPE 1 PATHWAY IN CIRCULATING IMMUNE CELLS OF KIDNEY TRANSPLANTS PATIENTS WITH CHRONIC ANTIBODY MEDIATED REJECTION
Authors: Santoro Gloria , Granata Simona , Pontrelli Paola , Rossi Mattia , Gambaro Giovanni , Grandaliano Giuseppe , Zaza Gianluigi
Published: June 2020

Background and Aims

Chronic antibody-mediated rejection (CAMR) is a multifactorial pathological condition that can affect more that 40-50% of kidney allografts. Its clinical evolution is often silent, and this can delay its diagnosis. Although many advances in understanding the biological mechanisms underlying its onset/development, at the moment, no reliable non-invasive diagnostic biomarkers are available in clinic.

Method

We enrolled 29 patients with biopsy-proven CAMR, 29 stable transplant recipients (controls). Subsequently, the microarray profile of mRNA isolated from peripheral blood mononuclear cells (PBMCs) from 10 randomly selected CAMR patients and 10 controls was evaluated by Agilent technology. For the bioinformatics analysis we employed several statistical algorithms (including ANOVA and Kruskal-Wallis tests adjusted for multiple-tests) and a Weighted Gene Correlation Network Analysis (WGCNA) to select genes biologically associated in co-expressed networks.

Results

935 genes resulted differentially expressed between the two study groups, demonstrating the large biological impact of this pathological condition on circulating immune-inflammatory cells. After WGCNA co-expression analysis, a group of genes (enclosed in a single co-expression module, 13 genes) resulted highly discriminating CAMR versus controls (p<.5.2 e-7, FDR<1%). This module included: Interferon-induced transmembrane proteins (IFITM) 2, 3, 4, confirming previous results by our group. However, the top discriminative gene was C1QB (Complement component 1, q subcomponent, B chain, p <000.1), a key element involved in the classical complement pathway. ELISA confirmed the microarray results on the entire patients’ cohort.

Conclusion

Our study confirmed the role of the type 1 interferon pathway in CAMR and underlined its capability to promote C1QB expression. These effects could contribute to better define the role of innate immunity in CAMR. Finally, C1QB, if validated in a large cohort of patients, could represent a new valuable molecular diagnostic biomarker for this complication.
TO010A NEW IMMUN-TOXICOLOGICAL TEST TO DETECT POLYSULFONE HYPERSENSITIVITY IN HEMODIALYSIS PATIENTS
Authors: Beige Joachim , Wendt Ralph , Rüssmann Despina , Ringel Karl-Peter
Published: June 2020

Background and Aims

Incompatibility of dialysis procedure due to hypersensitivity against dialyzer material which currently is mainly based on polysulfone and derivatives can not be assessed by routine laboratory tests. Although the frequency of such symptoms is suspected to be low (below 2%) such resembles an important clinical problem because dialysis procedures are frequently accompanied by symptoms of non-tolerability with reasons not being entirely clear while circulatory reasons are suspected to play a major role.

Method

To enlighten the role of polysulfone hypersensitivity, we adapted known standardized material immune-toxicological tests (lymphocyte transformation test, basophil degranulation test) to the specific conditions of dialysis and polysulfone material sensitivity. We developed a method of polysulfone micronisation and measured humoral immune response of isolated patient´s lymphocytes when incubated with polysulfone dispersion.

Results

39 samples from 103 patients with suspected polysulfone hypersensitivity showed positive results for type 1 (n=19), type 4 (n=18) or both type (n=2) reactions. There were no significant differences in the level of stimulation measured for DI, SI and lymphogenesis before and after dialysis (average delta -0.4; -0.28; - 1.74, p = 0.71; 0.34; 0.37) and with different dialyzer materials (Tab. 1). Patients with pos. type 4 results (LTT and lymphogenesis) showed highly correlated results in either LTT or lymphogenesis test (Fig. 1, R=0.87, p<0.0001). 8 out of 8 samples from patients with repeated test on different PS showed positive results on either PS. One patient tested positive on PS showed no hypersensitivity with another non-PS (PMMA) material.

Conclusion

This is the first methodological report showing plausible in-vitro results of patients samples concerning polysulfone intolerance. On the first superficial view, a “false-negative” rate of 60% looks rather disappointing, because all samples derived from patients with suspicion of PS hypersensitivity. However, due to the clinical variability of intolerance symptoms and the high prevalence of any problems after HD initiation, mainly of circulatory origin after initiating extracorporeal circuit, this rate may obviously express the true frequency of isolated PS material hypersensitivity in suspected patients. Alternative pathophysiological pathways of material sensitivity like complement activation, remain to be elucidated and incorporated into a comprehensive future testing panel. Further clinical and laboratory research is needed to define true polysulfone hypersensitivity and to enlighten the field of hypothetic subclinical material incompatibility in patients with impaired dialysis tolerability.
TO013ADSORPTION THERAPY AND SEPTIC SHOCK: A RETROSPECTIVE STUDY COMPARING COUPLED PLASMA FILTRATION-ADSORPTION AND CYTOSORB
Authors: Di Maso Vittorio , Grecò Domenico , Cozzi Martina , Bedina Elisa , Gerini Ugo , Olivo Elisa , Leonardi Sabina , Giudici Fabiola , Berlot Giorgio , Bianco Francesco
Published: June 2020

Background and Aims

Septic shock is a life-threatening organ dysfunction caused by a dysregulated host response to infection. Excessive release of cytokines and other inflammatory mediators is a key mechanism and cytokines adsorption therapies are applied in this context to restore a balanced immune homeostasis. Different adsorption techniques are available but there are no studies comparing these different adsorption approaches. The aim of this retrospective observational study was to compare Coupled Plasma Filtration Adsorption (CPFA) and CytoSorbTM in terms of hemodynamic and clinical response, mortality and renal function recovery.

Method

A retrospective observational study was designed enrolling all patients admitted to ICU with a diagnosis of septic shock treated with blood adsorption, either CPFA or CytoSorbTM, from January 2015 to December 2017. Primary endpoints of the study were the assessment of changes in NE dosage, MAP values, SOFA score and PCT levels before and after blood adsorption. Secondary endpoints ICU length of stay (LOS), mortality at 30, 60 and 90 days from adsorption initiation; renal outcome at 30 and 90 days from adsorption initiation.

Results

The study included 28 patients (14 CPFA, 14 CytosorbTM). Adsorption treatment was associated with a significant (p=0.03) improvement in hemodynamics with a Norepinephrine/Mean Arterial Pressure ratio (NE/MAP) of 0.64 (0.14-2.6) pre-treatment vs 0.11 (0.0-0.32) post-treatment regardless of the applied technique. Furthermore, a significant (p<0.001) procalcitonin (PCT) post treatment reduction was demonstrated with a comparable effect in the two groups (p=0.32) (Fig.1). No difference has been found in SOFA score changes (p=0.06) and again without any difference between groups (p=0.17). Overall Survival (OS) rate at 30 days was comparable between groups being 64.3% in CPFA and 78.6% in CytoSorbTM group (p=0.34). Finally, a complete recovery of kidney function at 30 and 90 days has been obtained in respectively 90% and 100% of survived patients without any difference between groups (p=1.00) (Fig.2).

Conclusion

These data confirmed the effectiveness of adsorption in terms of short-term clinical improvement independently from the applied technique, supporting the role of both these adjunctive therapies in septic shock treatment. CPFA and CytosorbTM have comparable effects in terms of hemodynamic improvement, clinical outcome, mortality and recovery of kidney function from septic shock AKI.
P0003ADHERENCE BENEFITS OF ADV7103, AN INNOVATIVE PROLONGED-RELEASE ORAL COMBINATION PRODUCT, IN PATIENTS WITH DISTAL RENAL TUBULAR ACIDOSIS
Authors: Bertholet-Thomas Aurélia , Guittet Catherine , Manso-Silván Maria Asunción , Navas Serrano Victor , Granier Luc André , Cochat Pierre
Published: June 2020

Background and Aims

Distal renal tubular acidosis (dRTA) is a rare disorder leading to impaired net acid excretion by the kidney inducing hyperchloremic metabolic acidosis and hypokalemia. The therapeutic effect of the standard of care is of short duration and requires multiple day and night administrations; it is also often accompanied by gastrointestinal discomfort and poor palatability impacting medication adherence. ADV7103, the first advanced therapy for dRTA, consists of a combination of prolonged-release potassium citrate and prolonged-release potassium bicarbonate granules providing round-the-clock alkali and potassium coverage with twice daily administration. Long-term adherence with ADV7103 is reported, along with acceptability of the product.

Method

B22CS is a multicentre, open-label long-term extension study, evaluating safety, tolerability, acceptability and efficacy of ADV7103 in adult and paediatric patients with dRTA. Adherence was assessed at each study visit up to 24 months, based on accountability of study drug retrieval, laboratory results, and interview of the patients in a diary and expressed as the proportion of patients that presented adherence lower than 50%, between 50% and 74%, between 75 and 90%, and higher than to 90%. Treatment acceptability as well as quality of life of the patients and their parents were assessed using a 100-mm visual analogue scales (VAS).

Results

Table 1 shows the evolution of compliance between Month 6 and Month 24. Overall, of the 29 patients remaining in the study after 24 months, 18 (62%) had adherence rates >90%, 5 (17%) had adherence rates of 75-90%, 6 (21%) had adherence rates of 50-74%, and there were no patients with adherence <50%. Adherence was good in all age groups, with rates of ≥75% in 100% of adults, 63% of adolescents 85% of children, and 67% of infants and toddlers.

Compared to the alkalising treatments they had before the study, more than 80% of the patients perceived both the improvement of the formulation and of the number of daily doses at scores ≥ 75 mm. The overall improvement of quality of life reported by the patients was of 89 ± 19 mm and that reported by their parents was of 90 ± 14 mm after 24 months of treatment.

Conclusion

Adherence to treatment was maintained at a high level throughout the 24 months of the study confirming the good acceptance of ADV7103 therapy.
P0004REDUCED EXPRESSION OF PROXIMAL ACID-BASE TRANSPORT PROTEINS IN KIDNEY TRANSPLANT PATIENTS WITH METABOLIC ACIDOSIS
Authors: Wiegand Anna , Daryadel Arezoo , Imenez da Silva Pedro Henrique , Gaspert Ariana , Wuthrich Rudolf Peter , Wagner Carsten , Mohebbi Nilufar
Published: June 2020

Background and Aims

Metabolic acidosis (MA) is a frequent complication of chronic kidney disease and an independent risk factor for kidney disease progression and mortality. MA is highly prevalent after kidney transplantation (12%-58%)(1). However, there are scarcely any data available on the underlying pathomechanisms and in particular molecular mechanisms involved in metabolic acidosis after kidney transplantation. Thus, we wanted to investigate the expression of key acid base transport proteins in kidney biopsies of kidney transplant recipients with and without metabolic acidosis.

Method

We evaluated 22 kidney transplant biopsies including 9 biopsies from kidney transplant recipients (KTR) with MA, nine biopsies from KTRs without MA (control) and four biopsies from KTRs with MA that were consequently subjected to alkali therapy (Alkali therapy). Immunofluorescence staining was used to identify key renal acid-base transport proteins. Additionally, six control kidneys were analyzed. Immunofluorescence staining was used to identify key renal acid-base transport proteins along the nephron. In addition, RNA extraction and full RNA sequencing analysis of all biopsies –where available- was performed.

Results

In the proximal tubule, we observed reduced immunostaining for the sodium bicarbonate cotransporter NBCe1 (SLC4A4) in the MA group compared to the control and alkali group, whereas the alkali group demonstrated the strongest staining of all three groups. In the distal nephron, expression of the chloride/bicarbonate exchanger Pendrin (SLC26A4) and the B1 subunit of the V-ATPase (ATP6V1B1) were markedly stronger in the alkali and control group compared to the MA group.

Expression of other acid base proteins such as Renal ammonia transporter RhCG (SLC42A3), Carbonic Anhydrase II, Glutamate dehydrogenase, anion exchanger AE1 (SLC4A1) and the B2 subunit of the V-ATPase (ATP6V1B2) showed no difference among all groups. Interestingly, the B2 subunit was absent in the proximal tubule in transplant biopsies of all groups.

In kidney biopsies of transplant recipients with metabolic acidosis RNA abundance of NBCe1, CAII and Pendrin was lower while RhCG and B1 RNA counts were not different when compared to recipients without metabolic acidosis.

Conclusion

Our data demonstrate altered protein and mRNA expression of several key acid base transporters in kidney biopsies of transplant recipients with metabolic acidosis. Treatment with alkali may have the potential to reverse or prevent these changes in renal allografts after transplantation.
P0031AURINE METABOLOMICS: AN EMERGING TOOL FOR DISSECTING BIOLOGICAL ABERRATIONS UNDERLYING RENAL DYSFUNCTION IN BARDET-BIEDL SYNDROME
Authors: Zacchia Miriam , Marchese Emanuela , Caterino Marianna , Ruoppolo Margherita , Capasso Giovambattista
Published: June 2020

Background and Aims

Bardet Biedl Syndrome (BBS) is a rare genetic disorder characterized by a wide range of organ dysfunction, including kidney disease. The severity of renal dysfunction is highly variable in this setting, ranging from tubular defects to the end stage renal disease, with poor genotype-phenotype correlation. Proteomics and metabolomics are powerful tools able to contribute to the better understanding of molecular basis of disease conditions. Our previous studies demonstrated that the urinary proteomic pattern of BBS patients differed from that of healthy subjects, with a set of deregulated proteins including cell adhesion and extracellular matrix organization proteins (1). The present study aims to characterize urine metabolomic profile of BBS patients, in order to identify both 1) potential disease biomarkers and 2) aberrant metabolic pathways underlying renal disease

Method

To this end, in the pilot study urine samples have been collected from 14 adult BBS patients and have been compared with healthy volunteers, using an untargeted strategy. In the confirmation study, 24 BBS patients with wide range of kidney dysfunction have been enrolled, and additional control groups, besides healthy subjects, were included: 1) age-gender-matched chronic kidney disease patients by other causes and 2) obese individuals.

Results

Several metabolites were de-regulated in BBS patients compared with normal subjects (lactic acid, glycolic acid,3-Hydroxypropionic acid, pyruvic acid, 3-hydroxyisobutyric acid, 2-ethyl-3-hydroxy-propionic acid, succinic acid, fumaric acid, erythropentonic acid, 2-hydroxyglutaric acid, 4-hydroxyphenyllactic acid, 3,4-pyridinedicarboxylic acid, retinoic acid, 4-hydroxyphenylacetic acid, palmitic acid, 9-Hexadecenoic acid, oleic acid and 9-Octadecenoic acid). The clusterization performed by MetaboAnalyst tool, revealed a possible deregulation of different metabolic pathways, including glycolysis, TCA cycle, pyruvate metabolism, lipids biosynthesis and glutamate metabolism (p-value <0.01) (figure 1); some of these pathways were described as de-regulated in other ciliopathies (2). In the confirmation study (on-going studies) some metabolites, including lactic acid and intermediates of Krebs cycle, correlated with kidney dysfunction only in the BBS group.

Conclusion

These findings suggest that urine metabolomic fingerprint of BBS patients is different from that of healthy subjects and indicate a possible deregulation of several metabolic pathways; some urinary molecules correlated with kidney dysfunction only in BBS patients, suggesting the specificity of these results.
P0040BASELINE CHARACTERISTICS AND ASSOCIATIONS WITH RENAL FUNCTION IN A GREEK COHORT OF POLYCYSTIC KIDNEY DISEASE
Authors: Kostopoulou Myrto , Louka Michaela , Kanellopoulou Konstantina , Gkika Vasiliki , Fokas Stavros , Koutsogianni Anastasia , Lymperopoulos Konstantinos , Tsirpanlis George
Published: June 2020

Background and Aims

Recent advances in the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) highlight the interplay between the clinical and the laboratory profile of the disease. This study aims to present the baseline characteristics of patients followed in a large ADPKD cohort from a single center in Greece, and explore possible associations between demographic, clinical and laboratory parameters.

Method

Patients followed in a specialized outpatient PKD clinic from December 2018 up to December 2019 were recruited in this study. At enrollment, demographics, medical and family history and laboratory data were recorded using a standardized form. Estimated glomerular filtration rate (eGFR) was calculated and Magnetic Resonance Imagining for total kidney volume (TKV) measurement was performed.

Results

One-hundred three females and 83 males with a mean age±SD of 41.4 ± 13 years (18.8 % < 30 years) were enrolled. Overall, 60.8% of them were classified as Chronic Kidney Disease, (CKD) stage 1 and 2. The ADPKD was diagnosed at a mean age±SD of 26.5±12.5 years. Thirty four percent out of 186 patients were diagnosed before the age of 20 and 9% of them before the age of 10. A positive family history was present in 89% of patients. In this subgroup, the median age of the affected parent that reached end stage renal disease (ESRD) was 55 (range 28-87) years. Hypertension was diagnosed in 89% at a mean± SD age of 37.2 ± 10.5 years. Hepatic cysts were present in 79.3% of patients, urinary tract infections, nephrolithiasis, macroscopic hematuria and pain in 44.3%, 42.5%, 24.8% and 54.4% respectively. A history of intracranial bleeding in family was positive in 21.5%. In multivariable analysis, lower eGFR was associated with younger age at the time of APKD diagnosis (p < 0.002), younger age at hypertension diagnosis (p < 0.08) and greater values of TKV (p < 0.001), height adjusted TKV (p < 0.001) and Body Mass Index (BMI) (p = 0.02).

Conclusion

In this study, patients with ADPKD were diagnosed at a young age and hypertension developed early on the course of the disease. Both these factors together with higher values of BMI and TKV were independently associated with low eGFR.