bluuebunny/crossref_metadata_2025_split huggingface dataset:
P0679LOSARTAN REDUCES INFLAMMATION INDUCED BY TERTIARY LYMPHOID TISSUES IN ENSUING CKD AFTER ACUTE KIDNEY INJURY
Authors: SHAO YU-HAN , Chou Yu-Hsiang , CHENG SHUN-YANG , LIN SHUEI-LIONG 
Published: June 2020

Abstract

Background and Aims
Chronic inflammation and renin-angiotensin system (RAS) overactivation have been demonstrated as a central mechanism that results in the development of progressive chronic kidney disease (CKD). Evidences have indicated that tertiary lymphoid tissues (TLT) form after acute kidney injury (AKI), especially in old-aged mice. Heterogeneous fibroblasts which appear and secret proinflammatory cytokines after AKI underlie TLT formation. There is an association between TLT sizes and impaired renal function along with increase of proinflammatory cytokines, suggesting a probable cause of persistent inflammation after AKI. In this study, we explored the relationship between TLT development and RAS activity. The phenotypes of heterogeneous fibroblasts diversified after AKI is also investigated.

Method
Here we utilized ischemia-reperfusion injury to cause ensuing CKD both in a CD-1 and C57BL6J mice model. We also used staining of CD3 and B220 to label and confirm multiple TLTs which represents T and B lymphocytes respectively.

Results
Administration of losartan, a kind of RAS inhibitor, offered protection against subsequent CKD development and attenuated number and size of TLT besides blood pressure reduction. Moreover, heterogeneous fibroblasts diminished and proinflammatory cytokines such as CXCL13, CCL21 and CCL19 which trigger the initiation of TLT were downregulated. In experiments of several fibroblast cell lines, angiotensin II (Ang II) administration could induce differentiation of fibroblasts with distinct phenotypes expressing p75 neurotrophin receptor and retinaldehyde dehydrogenase 2 which contribute to TLT formation. These fibroblasts expressing PDGFRβ stimulated production of aforementioned proinflammatory cytokines and expression of pro-fibrotic genes.

Conclusion
Our data demonstrates that TLT plays an important role in AKI-CKD transition. We also verify that Ang II causes phenotypic change of fibroblasts which constitute TLT. Losartan can ameliorate TLT formation through inhibition of these distinctive fibroblasts. It is a plausible mechanism to reduce ensuing CKD.
P0680A POST-HOC ANALYSIS OF EFFICACY AND SAFETY OF TOLVAPTAN (TOL) IN DECREASING RATE OF RENAL FUNCTION DECLINE IN PATIENTS WITH VERY LATE-STAGE AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (ADPKD)
Authors: Torres Vicente , Gansevoort Ronald , Perrone Ron , Chapman Arlene , Ouyang John , Lee Jennifer , Japes Hina , Wang Tao 
Published: June 2020

Abstract

Background and Aims
ADPKD is a progressive inherited disease that causes end-stage renal disease (ESRD) in ∼50% of the affected individuals by 60 years of age. TOL, a selective vasopressin V2-receptor antagonist, has been shown in randomized, placebo-controlled trials to slow the progression of renal function decline in ADPKD subjects with an eGFR of 25 mL/min/1.73m2 or higher. The efficacy and safety of TOL in subjects with lower eGFR remain understudied. This post-hoc analysis evaluated the efficacy and safety of TOL in subjects with stage 4 ADPKD (eGFR of &lt;30 mL/min/1.73m2).

Method
This is a retrospective analysis of a subgroup of ADPKD subjects who enrolled in the TOL long-term open-label extension (OLE) trial (NCT02251275). Included subjects had a baseline eGFR of &lt;30 mL/min/1.73m2, received ≥ 1 TOL dose, and were randomized to the placebo group in the REPRISE trial (NCT02160145). Two subgroups of subjects were analyzed, one with baseline eGFR of 25-30 (Subgroup 1) and one with &lt;25 (Subgroup 2). The variables evaluated included: 1) demographics, 2) adverse event (AE) profile, 3) intra-subject comparison of change in annualized eGFR decline during the open-label study (treatment period) to that during placebo use in the REPRISE trial (control period). Annualized eGFR change slopes in the treatment period were calculated using eGFR values between Month 1 and 12 visits to compensate for the acute hemodynamic effect of tolvaptan. Comparison was made by linear mixed model.

Results
Of the 1,803 subjects enrolled, 159 (8.8%) subjects (76 in Subgroup 1 and 83 in Subgroup 2) met the selection criteria for analysis. Annualized eGFR change slopes for all subjects (n=148) were -5.28 (SE 0.27) in the control period and -3.16 (SE 0.30) in the treatment period with a treatment effect of 2.11 mL/min/1.73m2/year (95% CI 1.56, 2.66), p&lt;0.0001). Demographic information, baseline eGFR, treatment duration and effects in the 2 subgroups are shown in the Table below. Treatment-emergent AEs were observed in 95% and 90% of the subjects in the 2 subgroups, respectively. Discontinuation due to AEs occurred in 15% and 17% of the 2 subgroups, respectively. The 5 most common AEs for all subjects were thirst (32%), polyuria (30%), renal pain (25%), blood creatinine increase (23%) and nocturia (22%); the rates were similar between the 2 subgroups. One incidence of hepatic enzyme increase, hemodialysis and death (unrelated to TOL) was observed in Subgroup 2, but not in Subgroup 1.

Conclusion
This post-hoc analysis demonstrated that TOL significantly decreases the rate of eGFR decline in ADPKD subjects with stage 4 CKD, including those with an eGFR of &lt;25 mL/min/1.73m2.
P0683PATTERNS OF HYPERKALAEMIA RECURRENCE AMONG CHRONIC KIDNEY DISEASE PATIENTS IN UK CLINICAL PRACTICE
Authors: Hurst Michael , Hoskin Louise , Badora Karolina , Tafesse Eskinder , Sugrue Daniel , Qin Lei , James Glen , McEwan Phil 
Published: June 2020

Abstract

Background and Aims
Patients with chronic kidney disease (CKD) are at increased risk of hyperkalaemia, HK (high serum potassium concentration) due to impaired renal function. This medical condition is potentially life threatening if untreated or poorly managed. This study describes the characteristics of CKD patients in the UK who experience HK and assessed the frequency of recurrent HK and time between first (index) and subsequent events.

Method
A retrospective cohort study was conducted using linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) data from 01 January 2008 to 30 June 2018, with a five-year lookback period (2003-2007).
Patients were included if they were diagnosed with CKD stage 3+ (READ code or eGFR &lt;60 mL/min/1.73m2 without prior dialysis) during the study or lookback periods and aged &gt;18 years at diagnosis (index).
Patient demographics, clinical history and baseline medication use were described. HK was defined as serum K+ ≥5.0 mmol/L. HK events occurring during the study period, but after diagnosis of CKD, were assessed. Recurrent HK was defined as any event subsequent to the first event. Time to recurrence was calculated using Kaplan-Meier.

Results
In total, 297,702 CKD patients (mean age 74.7 years [standard deviation: 11.3], male [41.4%]) met eligibility criteria. At time of CKD diagnosis, 30.6% of the population had resistant hypertension. Other prominent comorbidities included diabetes (22.24%), CKD (7.9%) and cancer (7.8%). Approximately half of patients were in receipt of diuretics at baseline (49.2%), while 32.5% and 32.0% were in receipt of beta blockers and calcium channel blockers, respectively. During follow up, 67.0% of patients received a renin-angiotensin aldosterone system inhibitor (RAASi).
147,215 patients (49.5%) experienced at least one HK event, of which 53,695 (36.5%) had only one HK event, 93,250 (63.5%) had two or more HK events and 29,413 (20.0%) had six or more events. HK event incidence was predictive of subsequent events, with the probability of experiencing a HK event increasing from 49.5% to 63.5%, 70.7%, 74.1%, 76.5% and 78.6% for patients experiencing 2-6 events, respectively. There was an inverse relationship between the number of recurrent events and time to next event, with less time between the next event for those experiencing multiple events (Figure 1).

Conclusion
This study shows that approximately half of CKD patients experienced a HK event. Furthermore, patients who experienced a HK event were at increased risk of subsequent events. Frequent monitoring of serum potassium may help reduce the burden of HK in patients with CKD.
P0706THE EFFECT OF NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS ON RENAL OUTCOMES IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION
Authors: Deeprom Siwaporn , Chirananthavat Thanit 
Published: June 2020

Abstract

Background and Aims
Lifelong oral anticoagulation (either with warfarin or a non–vitamin K antagonist oral anticoagulant (NOACs)) is indicated for stroke prevention in most patients with atrial fibrillation (AF). NOACs has been recommended for thromboembolism prophylaxis of nonvalvular AF. However, studies on the impact of NOACs on renal outcomes has been inconclusive.

Method
This retrospective cohort study compared 3 NOACs: apixaban, dabigatran and rivaroxaban to warfarin for their effects on renal outcomes in patients with nonvalvular AF who had been using these medications for at least 2 years as of 2017-2018. The primary outcome was either the incidence of &gt; 30% decline in estimated glomerular filtration rate (eGFR) or doubling of the serum creatinine levels compare to baseline values at 24 months, and the secondary outcome was the incident of primary outcomes in different baseline eGFR subgroups (&gt; 60 vs &lt; 60 ml/min/1.73 m2) and major bleeding as an adverse event.

Results
90 patients were enrolled in each group, totaling to 360 patients. The incidence of &gt; 30% decline in eGFR is significantly higher in rivaroxaban compared to warfarin (hazard ratio: 2.09; 95% confidence interval: 1.35 to 3.24; p = 0.001). After multivariate analysis (using age, stage of chronic kidney disease, eGFR, CHAD2VAS and HASBLED score), dabigatran was also shown to significantly increase the incidence of &gt; 30% decline in eGFR. In subgroup analysis, rivaroxaban resulted in higher incidence of &gt; 30% decline in eGFR, in eGFR &lt; 60 ml/min/1.73 m2 subgroup and higher incidence of doubling of the serum creatinine level in eGFR &gt; 60 ml/min/1.73 m2 subgroup. There was no occurrence of major bleeding.

Conclusion
NOACs, especially rivaroxaban, may increase adverse renal outcomes in patients with nonvalvular AF.
P0708ASSOCIATION OF OBESITY WITH KIDNEY CYST GROWTH IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE; RESULTS FROM KNOW-CKD COHORT DATA
Authors: Kim Chang Seong , Choi Hong Sang , Bae Eun hui , Ma Seong Kwon , Kim Soo Wan 
Published: June 2020

Abstract

Background and Aims
Overweight or obese patients with autosomal dominant polycystic kidney disease (ADPKD) are associated with the decline of glomerular filtration rate. However, little is known about the annual rate of change in total kidney volume (TKV) in patients with ADPKD according to the body mass index (BMI) corrected by TKV and total liver volume (TLV).

Method
We analyzed 364 patients with ADPKD from the KoreaN Cohort Study for Outcomes in Patients with Chronic Kidney Disease. We compared the changes in TKV in less than 1-year, 2-years and 4-year follow-up from patients by dividing baseline body mass index (BMI) by 18.5 to 22.9 (normal), 23 to 24.9 (overweight), and &gt; 25 kg/m2 (obesity).

Results
During the 4-year follow-up period, TKV tended to increase statistically with increasing BMI (P = 0.032). Similarly, higher BMI group showed higher TKV than lower BMI group (P = 0.016). Conventional BMI is affected by TKV and TLV in advanced ADPKD patients. Therefore, we reclassified patients by corrected BMI using the adjusted body weight (body weight – TKV – TLV). Although the statistical significances between absolute value of TKV and corrected BMI groups were disappeared during the follow-up, TKV% change/year showed significantly higher in ADPKD patients with obesity among corrected BMI groups (normal; 20.2%, overweight; 17.6% and obesity; 30.6%, P for trend = 0.022)

Conclusion
Even after correcting the TKV and TVL, obese patients showed a high of TKV% change/year compared to non-obese patients with ADPKD.
P0710DUAL GPR40/GPR84 FATTY ACID RECEPTOR DELETION IMPROVES ADENINE-INDUCED RENAL INJURY IN MICE
Authors: Cheff Véronique , Blais Amelie , Holterman Chet , Hébert Richard , Kennedy Chris , Thibodeau Jean-Francois 
Published: June 2020

Abstract

Background and Aims
Fatty acid receptors have recently been implicated in the progression of fibrotic disorders. GPR40 deletion predisposes to AKI and CKD-induced fibrosis, while deletion of the pro-inflammatory GPR84 receptor was beneficial in this context. PBI-4050, a novel therapeutic compound with excellent safety and efficacy profiles in both experimental and clinical settings, is a dual GPR40 agonist and GPR84 antagonist. In this study, we sought to determine which of these receptors had a predominant effect in adenine-induced CKD.

Method
Ten-week-old male GPR40/84 double knockout mice (40/84ko) and age/strain matched WT C57BL/6 mice were subjected to a regular or adenine-supplemented diet (0.25%) for 4 weeks (n=10 per group). Plasma samples were collected on a weekly basis for hematocrit assessment. At endpoint, mice were placed in metabolic cages for 24 hours for urine collection. Plasma minerals and electrolytes, urinalysis and a comprehensive blood count were performed at endpoint.

Results
Adenine feeding led to early and sustained weight-loss, which was significantly worse in WT mice compared to 40/84ko mice. At day 14, Hct was significantly decreased in adenine-fed WT mice, while unaffected in the 40/84ko group. Adenine-induced reductions in hemoglobin and red blood cells counts were also greatly improved in 40/84ko mice. Adenine-feeding led to increased circulating neutrophils and decreased lymphocyte in WT mice, which was not seen in 40/84ko mice. Importantly, renal function assessed by plasma creatinine, urea and creatinine-clearance and renal hypertrophy were significantly improved in Ad-fed 40/84ko mice. Moreover, fractional excretion for sodium, potassium and calcium were increased by adenine-feeding in WT, but not in 40/84ko mice.

Conclusion
Overall, the loss of both GPR40 and GPR84 led to major improvements in several key renal functional abnormalities associated with adenine-induced CKD including weight-loss, anemia and renal functional decline. These studies, along with our previous work highlight the potential of targeting fatty-acid GPCR’s, notably GPR84, for the treatment of inflammation/fibrosis related kidney diseases.
P0713DIFFERENTIAL PREDICTION OF DECLINE IN GFR IN PROTEINURIC VS NON-PROTEINURIC DIABETIC PATIENTS
Authors: Tanaka Hiroshi 
Published: June 2020

Abstract

Background and Aims
Diabetes mellitus (DM) is known to cause a progressive loss in renal function in at leaset 2 types of clinical presentation: classical diabetic nephropathy with overt proteinuria and non-proteinuric kidney diseases. The mechanisms of the progression should be multifactorial and are considered different at least in some ways in each patient. Now it is important to predict whether each diabetic patient has progressive renal disease or not, hopefully before overt proteinuria appears.

Method
A hospital-wide study with all the laboratory data for a period of 4 years and 2 months was conducted. A total of 2,804 non-dialysis patients with an age 18 or more in whom the eGFR slope was calculated over 731 days or more with HbA1c measured at least twice were retrieved. Medians were used for each laboratory datum, including dipstick proteinuria and haematuria (both changed to numeric variables, e.g. 1+ into 1.0), blood cell count, serum chemistry, and HbA1c. Medication class counts were defined as a total number of groups (DPP4, SGLT2, SU, .. ) where insulin was classified into 3 groups (rapid, mixed, and basal); the required prescription period was 3 months or more for each class. Statistical analysis was performed with R 3.6.0 on Ubuntu. For prediction, missing values were imputed by an R package {mice}.

Results
A total of 2,804 patients (M:F = 1375:1429, age 66.9+-13.6 (18--101, median 68) years) were analyzed whose median HbA1c was 6.14+-0.79 (3.6-11.6, median 5.95)%.
This population was further divided into a proteinuric group (the median of dipstick proteinuria of 1+ or more, n=296) and a non-proteinuric group (the median of dipstick proteinuria of +- or less, n=2508). In the multivariate analysis, the proteinuric DM patients had the eGFR slope associated with initial eGFR, proteinuria, uric acid, and the number of classes of the anti-diabetic medications; higher uric acid and less number of DM medication were significantly associated with faster decline in eGFR. The non-proteinuric DM patients had eGFR slope associated with age, initial GFR, uric acid, chloride, and haemoglobin, but not with proteinuria; the patients with higher uric acid with lower haemoglobin had significantly faster decline in eGFR (-1.86 vs -1.34, P = 0.013). Prediction of faster eGFR decline was analyzed with machine learning technologies, ie, {ranger} and {randomForest}, where precision was 68.9%/67.9% (proteinuric group, ranger/randomForest) vs 76.8%/75.9% (non-proteinuric group, ranger/randomForest).

Conclusion
Propensity to lose kidney function is different in each diabetic patient, which should to be ideally predicted in individual basis.
P0731LOW BIRTH WEIGHT IS ASSOCIATED WITH LOWER MEASURED GLOMERULAR FILTRATION RATE IN ADULT AGE
Authors: Lillås Bjørn Steinar , Tã¸ndel Camilla , Vikse Bjørn Egil 
Published: June 2020

Abstract

Background and Aims
Low birth weight (LBW) has been shown to increase the risk of severe kidney disease. Studies have also shown that LBW is associated with lower estimated glomerular filtration rate (eGFR) or creatinine clearance in young adults. In the present study we investigated whether LBW associate with measured glomerular filtration rate (mGFR) in 40-50 year old adults.

Method
Retrospective longitudinal cohort study using the Medical Birth Registry of Norway to invite 200 individuals with LBW (birth weight ≤ 2300 gram) and 200 individuals with normal birth weight (NBW, 3500 – 4000 grams). All participants were aged 41 – 52 at time of examination. GFR was measured using plasma clearance of iohexol. Birth weight and gestational age were reported from the Medical Birth Registry. Main outcome was difference in measured GFR.

Results
We included 105 individuals – 57 LBW and 48 NBW – 55% females. Mean GFR was 94.8 ± 14.2 ml/min/1.73m2 in the LBW group and 100.2 ± 12.5 ml/min/1.73m2 in the NBW group (p=0.043). In females the mean GFR was 90.4 ± 12.2 ml/min/1.73m2 in the LBW group and 100.5 ± 14.0 ml/min/1.73m2 in the NBW group (p=0.005). In males the mean GFR was 101.4 ± 14.5 and 100 ± 11.2 ml/min/1.73m2 in the LBW and NBW groups respectively (p=0.7). In a multi-regression model adjusting for age, maternal age and maternal civil status, we found an increase in mGFR of 4.5 ml/min/1.73m2 for an increase of 1 kg in birth weight (p= 0.02) for women. For men there was a non-significant decrease of 1.2 ml/min/1.73m2 for an increase of 1 kg in birth weight (p=0.6).

Conclusion
Women aged 41-52 years with low birth weight had significantly lower measured GFR as compared with participants with normal birth weight, there was no difference for men.
P0734THE DELETION OF AKT1 PROMOTES THE RENAL FIBROSIS IN THE MURINE MODEL OF UNILATERAL URETERAL OBSTRUCTION
Authors: Kim Il Young , Ye Byung Min , Kim Min Jeong , Lee Dong Won , Lee Soo Bong , Song Sang Heon , Seong Eun Young 
Published: June 2020

Abstract

Background and Aims
Previous studies have found the increased Akt activity in experimental renal fibrosis. We investigated the role of Akt1, one of the three Akt isoforms, in renal fibrosis using the murine model of unilateral ureteral obstruction (UUO).

Method
In vivo, we subjected the wild type and Akt1−/− mice to UUO. In vitro, gene silencing of Akt1 was achieved using the short hairpin RNA delivered by the lentiviral vector in immortalized human proximal tubular cells (HK2 cells) and rat kidney fibroblasts (NRK-49F cells).

Results
In immunohistochemical stain, the expression of Akt1 was significantly higher in obstructed kidneys of wild type mice compared with control sham kidneys and increased gradually as UUO progressed. The fibronectin, type I collagen, and heat shock protein 47 (HSP47) were markedly more expressed in obstructed kidneys of Akt1−/− mice than in those of the wild type mice. Transforming growth factor β1 (TGFβ1) was highly induced within 1 day of UUO in obstructed kidneys of Akt1−/− mice and the expression of TGFβ1 was significantly higher in the Akt1−/− mice than in the wild type mice as UUO progressed. Western blot showed that silencing of Akt1 increased the expression of TGFβ1, which was enhanced by angiotensin II stimulation in HK2 cells, but not in NRK-49F cells. Immunohistochemical stain demonstrated that the expression of cleaved caspase-3 in renal tubules was significantly higher in the Akt1−/− mice than in the wild type mice. Western blot showed that silencing of Akt1 increased the expression of cleaved caspase-3 in HK2 cells, but not in NRK-49F cells.

Conclusion
Our findings suggest that the deletion of Akt1 might contribute to tubulointerstitial fibrosis and tubular apoptosis via TGFβ1 induction. We also showed that TGFβ1 upregulation by genetic deletion of Akt1 is associated with activation of STAT3 independently of the TGFβ1/Smad signaling pathway.
P0736A NOVEL MODEL OF CHRONIC KIDNEY DISEASE AND HEART FAILURE WITH PRESERVED EJECTION FRACTION
Authors: Chade Alejandro , Williams Maxx , Engel Jason , Hall Michael 
Published: June 2020

Abstract

Background and Aims
Patients with chronic kidney disease (CKD) have a significantly higher cardiovascular risk that non-CKD patients, and over 50% of CKD patients die of cardiovascular events. We recently developed a model of CKD that displays major pathological features of clinical CKD: GFR of about 60 ml/min (stage 2-3a), significant renal inflammation, fibrosis, microvascular dysfunction and remodeling, and hypertension. The current study aims to define the cardiac phenotype of this model and, if cardiac abnormalities are present, the potential pathological traits involved.

Method
CKD was induced in 6 pigs via bilateral renovascular disease and dyslipidemia and observed for 14 weeks. After 14 weeks, renal hemodynamics (RBF, GFR) were quantified using multi-detector CT and echocardiographic assessment (morphology and function) performed using ultrasound-doppler. Mean arterial pressure (MAP) was continuously measured by telemetry. Blood was collected to measure circulating inflammatory cytokines (TNF-α, MCP-1, IL-6) and biomarkers of heart failure (ANP, BNP, NT-proBNP). Animals were then euthanized and kidneys and hearts collected for ex vivo studies. Normal pigs were used as time-matched controls.

Results
Loss of renal function in CKD was accompanied by left ventricular hypertrophy, left atrial dilatation, diastolic dysfunction (E/A ratio) with preserved ejection fraction (pEF), elevated ANP, BNP, and NT-proBNP, and hypertension (average MAP of 131.2 mm/Hg, p&lt;0.05 vs. normal). CKD also increased renal (but not cardiac) mRNA expression of TNF-α, MCP-1, IL-6, accompanied by increased circulating inflammatory cytokines (Figure).

Conclusion
This study shows that CKD in the swine model leads to cardiac hypertrophy and diastolic dysfunction (with pEF) and increased biomarkers of heart failure, meeting the criteria for a potential novel model of heart failure with pEF (HFpEF). Our data also suggest that hypertension and inflammatory mediators (possibly originated in the kidney) target the heart and may contribute to HFpEF pathophysiology. HFpEF is considered the largest unmet need in cardiology with no specific treatments and associates with CKD in about 50% of cases. Thus, our study offers a promising new experimental platform to increase our understanding of CKD-HFpEF and to test new treatments in a translational fashion.