bluuebunny/crossref_metadata_2025_split huggingface dataset:
P0008CASE REPORT: METABOLIC ALKALOSIS RESULTING IN RESPIRATORY COMPROMISE IN A PATIENT UNDERGOING HIGH DOSE METHOTREXATE THERAPY
Authors: O'Donoghue Darragh , Truong Heather , Finnes Heidi , McDonald Jennifer , Leung Nelson 
Published: June 2020

Abstract

Background and Aims
High dose Methotrexate (HDMTX) is an important component of several modern oncological/haematological treatment protocols due to its central nervous system penetrance. Nephrotoxicity represents a significant adverse effect and can limit therapeutic options. Therefore, strategies to prevent this are paramount. Urinary alkalinisation and large volume resuscitation to maintain adequate hydration and urine output are the typical strategies. Urinary alkalinisation prevents tubular precipitation of methotrexate and therefore, a strict urinary pH target of 7 is maintained via a continuous bicarbonate infusion.

Method
We describe a case report, of Iatrogenic metabolic alkalosis leading to respiratory compromise in a patient receiving HDMTX from Mayo Clinic, Rochester.

Results
We present the case of a 76-year-old woman with a Diffuse Large B-Cell Lymphoma with CNS involvement who presented for elective admission for her 1st cycle of HDMTX. She received 7g of Methotrexate at dosing of 8 g/m2. She received the standard urinary alkalinisation with pre- and post-hydration. Her baseline HCO3- was 28 mEq/L. Her 48 hour MTX level was elevated at 1.2 so the urinary alkalinisation protocol was continued until &lt;0.1 mcmol/L. On day 4, she developed frequent episodes of apnoea. Her ABG demonstrated a metabolic alkalaemia pH 7.54, pCO 53, pO2 91, HCO3 45. She was transferred to the ICU for close monitoring. Her bicarbonate infusion was discontinued and she received acetazolamide. Her bicarbonate improved to 31 after 12 hours. She had a significant improvement in her respiratory status with no further episodes of apnoea. Her bicarbonate infusion was restarted due to elevated MTX levels. She was discharged home with no further complications.

Conclusion
Iatrogenic Metabolic alkalosis leading to respiratory compromise represents a rare but important complication of urinary alkalinsation protocols for High-dose Methotrexate therapy.
P0009EVALUATION OF THE POTENTIAL FOR DRUG INTERACTIONS WITH VEVERIMER
Authors: Shao Jun , Parsell Dawn , Guttendorf Robert , Wu Yick Sen , Tsao Li , Tabakman Scott , Stasiv Yuri , Lee Angela , Biyani Kalpesh , Klaerner Gerrit 
Published: June 2020

Abstract

Background and Aims
Veverimer is an investigational drug being developed as an orally administered hydrochloric acid binder for the treatment of metabolic acidosis associated with chronic kidney disease (CKD). In clinical studies, treatment with veverimer safely and effectively increased serum bicarbonate and improved objective and subjective measures of physical functioning1-3. Veverimer, a free-amine polymer, is not systemically absorbed; therefore, its potential for drug-drug interactions (DDIs) is limited to those that occur in the gastrointestinal (GI) tract (i.e., direct binding or indirect effects resulting from transient increases in gastric pH). We assessed the potential for DDIs with veverimer both in vitro and in vivo in healthy subjects.

Methods
In vitro binding to veverimer was evaluated with 16 drugs of varying molecular weight and charge. In a separate study, the effect of veverimer on gastric pH was measured continuously in vivo in healthy subjects using a microelectrode pH probe placed in the gastric compartment. Human DDI studies were conducted with 4 orally administered drugs, including those that demonstrated the most in vitro binding to veverimer and those with pH-dependent solubility (furosemide, aspirin, warfarin, dabigatran).

Results
Veverimer did not bind to any of the positively charged, neutral or zwitterionic drugs tested in vitro. It bound to 3 small (MW &lt;332 Da), negatively charged drugs (aspirin, ethacrynic acid, furosemide); these interactions were reduced or eliminated in the presence of physiologically relevant concentrations of chloride. Neither furosemide nor aspirin showed clinically meaningful changes in pharmacokinetic parameters when coadministered with veverimer in human DDI studies (Figure 1).
Veverimer increased gastric pH by ∼3.0 and 1.5 pH units in fasted and fed subjects, respectively. The increase in gastric pH was short-lived, with a peak within 1 hour after dosing and a return to baseline after ∼1.5 hours and ∼3 hours under fasting and fed conditions, respectively. The effect of veverimer on gastric pH was similar in the presence and absence of omeprazole. No clinically meaningful changes in systemic exposure, as indicated by Cmax and AUC, were observed when 3 drugs with pH-dependent solubility were coadministered with veverimer in human DDI studies (Figure 1).

Conclusions
In human DDI studies, we observed: a) no effect of veverimer on the bioavailability of drugs with physicochemical characteristics most susceptible to direct binding to the polymer; b) small, short-lived effects of veverimer on gastric pH; and c) no effect of veverimer on the bioavailability of drugs with pH-sensitive solubility. Therefore, it is concluded that there is a negligible risk of veverimer involvement in clinically significant DDIs.
P0020THE NEPHRO-PROTECTIVE ROUTE OF CGMP DOES NOT COMPENSATE NPRHOGENIC DIABETES INSIPIDUS, BOTH CONDITIONS MEDIATED BY RENAL INTEGRIN LINKED KINASE (ILK)
Authors: Griera-Merino Mercedes , García-Ayuso Diego , Gutiérrez-Calabrés Elena , Bohorquez Magro Lourdes , Campillo de Blas Sofía , Barrionuevo-González Marta , Calleros Laura , Rodríguez-Puyol Diego , Rodríguez-Puyol Manuel , De Frutos García Sergio 
Published: June 2020

Abstract

Background and Aims
Renal ILK transgenic deletion on mice (cKD-ILK) address basal polyuria compatible with nephrogenic diabetes insipidus (NDI), due to disrupted tubular water channel aquaporin 2 (AQP2) AQP2 expression and vesicular trafficking to the apical membrane [Cano-Peñalver JL et al. FASEB J. 2014; Mamuya FA et al. Am J Physiol Renal Physiol. 2016]. An early symptom of chronic renal diseases (CKD) is NDI. ILK depletion also have a nephron-protective effect in renal damage in mice due to the increase in cGMP [Cano-Peñalver JL et al. Mol Med. 2016; de Frutos S et al. Biochim Biophys Acta Mol Basis Dis. 2019], the latter an alternative anti-NDI mediator. Here we demonstrate that ILK-mediated regulation of AQP2, under basal or CKD contexts, does not depend on cGMP.

Method
cKD-ILK and controls (WT) were treated orally with a NO donor, as precursor of cGMP formation (IDN, 300mg / Kg / day) for 24 hours. Urine volume was determined as a measure of tubular functionality. Fresh kidneys from non-treated mice were cultured ex vivo with precursors of cGMP (NO donor SNP, 1 µM or cGMP analogue 8Br-cGMP, 0.2 mM) for 30 minutes. AQP2 in the apical membrane of the tubules was quantified by immunohistochemistry. More cKD-ILK and WT were subjected for 6 weeks to a diet supplemented with 0.2% adenine (A) as CKD inducer or baseline standard diet. Urine volume and total ranal AQP2 levels were determined.

Results
Compared to WT, cGMP axis activation in vivo did not compensate the basal NDI present in cKD-ILK and the activation ex vivo did not improve the apical presence of AQP2 in cKD-ILK. Both WT and cKD-ILK subjected to CKD showed exacerbated polyuria and decreased levels of renal AQP2, but no differences were observed between groups.

Conclusion
ILK regulates AQP2, both in a basal and pathological context (CKD) independent of cGMP which otherwise is nephron-protective. Our results probably explain the co-existence of cGMP increase together with AQP2 decrease observed in the cKD-ILK kidneys.
P0022INNATE IMMUNE RESPONSES ELICITED BY TOLL-LIKE RECEPTORS ARE POSSIBLY INVOLVED IN THE PATHOGENESIS OF NEPHROTIC SYNDROME
Authors: Tanaka Eriko , Hada Ichiro , Mikami Naoaki , Yan Kunimasa 
Published: June 2020

Abstract

Background and Aims
Pathogenesis of idiopathic nephrotic syndrome (INS) is yet to be fully elucidated. Immunological disorders are reported to be involved in the etiology of INS. Due to the efficacy of immunosuppressant agents such as calcineurin inhibitor and rituximab in treating nephrotic syndrome, aberrant activation of the acquired immune system through T and B cells are considered to be the underlying pathogenic mechanisms of INS. Nevertheless, there is a possibility that the innate immune system plays a key role in INS pathogenesis. This study aims to investigate the involvement of innate immunity in INS pathogenesis by examining the expressions of toll-like receptors (TLRs).

Method
Kidney tissue samples from two INS patients were collected at two points of time: the first biopsy was performed during nephrosis and the second during remission. Total RNA was extracted from the kidney tissue samples, and RNA-sequencing was performed to investigate RNA expression profiles. The differences between RNA expression profiles of TLRs and molecules related to TLR pathways in the tissue samples collected during nephrosis and remission were analyzed.

Results
There was a significant decrease in RNA expression of TLR9 and TLR10 during remission compared to nephrosis: fold change in each patient was -2.12 and -2.12 for TLR9, and -2.51 and -2.09 for TLR10. RNA expression of TLR8 also decreased: fold change in each patient was -1.19 and -1.75. There were no significant changes in the RNA expression profiles of TLR1, 2, 3, 4, 5, 6, and 7. In addition, there were no differences in the RNA expression profiles of MYD88, IRAK family, and TRAF family molecules that are associated with TLR pathways. However, RNA expressions of IL6, IL1B, IL12B, and TNF, as well as the cytokines controlled by TLR8 and TLR9 pathways, which were activated during nephrosis, disappeared or decreased during remission.

Conclusion
The involvement of the innate immune system in the pathogenesis of nephrotic syndrome has been suggested in some reports. Based on the fact that the onset or recurrence of nephrosis is triggered by non-specific viral infection, it is highly possible that innate immunity is involved in the pathogenesis of nephrotic syndrome. TLRs play a key role in innate immunity as they elicit the innate immune system after detecting pathogens, induce inflammatory cytokine production, and trigger signaling pathways that activate lymphocytes via maturation of dendritic cells. Specifically, TLR8, 9, and 10 mediate pathways of the first immune response to viral infections. Our study reveals that TLRs play a pivotal role in innate immunity associated with renal tissue during the onset of nephrosis.
P0023RNA-BINDING PROTEIN HUR REGULATES HYPOXIA-INDUCED PARKIN/BNIP3L EXPRESSIONS AND MITOPHAGY IN RENAL TUBULAR CELLS
Authors: Li Chi-Yuan , Li Xin 
Published: June 2020

Abstract

Background and Aims
Mitochondrial dysfunction contributes to the pathophysiology of acute kidney injury (AKI). Mitophagy selectively degrades damaged mitochondria and thereby regulates cellular function and homeostasis. RNA-binding proteins (RBPs) regulate RNA processing at multiple levels and thereby control cellular function. In this study, we report that RBP, human antigen R (HuR) regulates mitophagy in renal tubular cells (HK-2) under hypoxia condition.

Method
Human kidney proximal tubular 2 (HK-2) were cultured in Rosewell Park Memorial Institute (RPMI) 1640 medium (Gibco, Invitrogen, GmbH, Germany) supplemented with 10% fetal bovine serum (FBS) (Gibco, Invitrogen, GmbH, Germany), 1% penicillin/streptomycin (Gibco, Invitrogen, GmbH, Germany) at 37°C and 5% CO2. The cells were exposed to normoxia (37°C; 5% CO2) or hypoxia (serum and glucose deprived RPMI medium, 37°C, 1% O2) conditions. Mitophagy marker expressions (Parkin, p-Parkin, PINK1, BNIP3L, BNIP3, LC3) were determined by western blot analysis. ROS and mitochondrial membrane potential were determined using DCF-DA and JC-1 dye. Parkin and LC3 localization to mitochondria were performed by confocal laser scanning microscopy. HuR bound Parkin/BNIP3L mRNA expressions were determined by RNA-immunoprecipitation analysis.

Results
In this study, up-regulated mitophagy markers such as Parkin, PINK1, BNIP3 and BNIP3L protein expressions and mitophagosome formation were found in HK-2 cells under hypoxia condition. Stable HuR knockdown studies revealed that, HuR regulates mitophagy by mitophagosome (LC3 co-localization with mitochondria) and mitolysosome (mitochondria co-localization with lysosome) formation under hypoxia. Further, we show that HuR significantly regulated hypoxia-induced mitophagy by regulating Parkin/BNIP3L protein expressions and their mitochondrial localization. Bioinformatics studies showed that, HuR specifically binds to the AU-rich region in 3’UTR and CDS of Parkin and BNIP3L mRNA sequence. HuR was significantly bound to Parkin and BNIP3L mRNA and thereby regulated their mRNA stability under hypoxic conditions.

Conclusion
Altogether our data highlight on the functional importance of HuR in regulating mitophagy under hypoxic conditions in renal tubular cells through Parkin/BNIP3L expressions.
P0026METFORMIIN IMPROVES DYSFUNCTION OF MESENCHYMAL STEM CELLS ASSOCIATED WITH CHRONIC KIDNEY DISEASE VIA SENESCENCE INHIBITION
Authors: Noh Hyunjin , Yu Mi Ra , Choi Kyoungin , Hwang Dohui 
Published: June 2020

Abstract

Background and Aims
Mesenchymal stem cells (MSC) are promising source of cell-based regenerative therapy; however, adequate cell functionality is a critical factor for the success of autotransplantation.

Method
We investigated the effects of metformin on chronic kidney disease (CKD)-associated cellular senescence using MSC isolated from sham operated and subtotal nephrectomized mice and further explored the protective role of metformin-treated CKD MSC in renal progression.

Results
When compared to normal MSC, MSC isolated from CKD mice displayed reduced proliferation and early senescence as determined by enlarged cell morphology, increased oxidative stress, accumulation of DNA damage response marker p53 binding protein 1 (53BP1), phospho p53, p16INK4a, and β-gal expression, and decreased cyclin-dependent kinase 4 (CDK4) and cyclin D. CKD MSC exhibited activation of NFκB resulting in expression of senescence-associated secretory phenotype (SASP) factors compared to normal MSC. All of these changes were significantly prevented by metformin treatment. In vivo, metformin-treated CKD MSC attenuated inflammation and fibrosis in UUO kidney as compared to CKD MSC. Co-culture of LPS or TGF-β1-treated HK2 cells with metformin-treated CKD MSC markedly decreased LPS or TGF-β-induced tubular expression of proinflammatory markers and fibrogenesis when compared to CKD MSC suggesting paracrine action of CKD MSC enhanced by metformin treatment.

Conclusion
Our data suggest that metformin inhibits cellular senescence of CKD MSC and improves their renoprotective effects.
P0027METFORMIN INHIBITS TGF-BETA1-INDUCED FIBROTIC RESPONSE IN MOUSE INNER MEDULLARY COLLECTING DUCT CELLS IN ASSOCIATION WITH ACTIVATION OF PPARA SIGNALLING
Authors: Liu Shanying , Li Yan , Liu Dan , Liang Diefei 
Published: June 2020

Abstract

Background and Aims
Metformin has been recognized to inhibit renal fibrosis through protection of proximal tubular epithelial cells from inflammation and fibrotic response. However, the role of other segments of renal tubular epithelial cells in the development of renal fibrosis remains unclear. This study aimed to investigate the profibrotic effects of TGF-beta1 and the anti-fibrotic effects of metformin in mouse inner medullary collecting duct cells using mIMCD-3 cell line.

Method
Cultured mIMCD-3 cells were treated with TGF-beta 1 and metformin either alone or in combination. The morphological change of cells was inspected under an inverted microscope. The mRNA of genes associated with renal fibrosis was evaluated by real-time quantitative PCR. The protein expression of E-cadherin, Vimentin, alpha-SMA were evaluated by Western blot.

Results
The shape of mIMCD-3 cells changed from cobblestone to spindle-like after exposure to TGF-beta 1 at 10ng/mL for 72 hours, which can be inhibited by co-treatment with metformin. TGF-beta 1 remarkably increased the expression of alpha-SMA and PAI-1, while decreased E-cadherin mRNA in mIMCD-3 cells. Metformin inhibited TGF-beta 1-induced reduction of E-cadherin and upregulation of PAI-1. The protein level of E-cadherin was also decreased and alpha-SMA increased by TGF-beta 1. Metformin inhibited TGF-beta 1-induced protein expression of alpha-SMA and vimentin, and downregulation of E-cadherin. It has been reported that impaired renal PPARα signaling promoted renal fibrosis. In this study, we found that metformin upregulated basal level of PPARα mRNA. PPARα target genes including Acadvl and Cpt1a were downregulated by TGF-beta 1 in mIMCD-3 cells, which could be prevented by metformin.

Conclusion
Metformin inhibits the profibrotic effects of TGF-beta 1 probably through suppression of EMT and maintaining PPARα signaling in mouse inner medullary collecting duct cells.
P0033COMPARISON OF ANXIETY, DEPRESSION AND QUALITY OF LIFE IN PATIENTS WITH AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE: A CROSS-SECTIONAL, RANDOMIZED CONTROLLED PILOT STUDY
Authors: Ozler Tuba Elif , Alay Cemal , Cebeci Egemen , Uzun Sami , Karadag Serhat , Ozkan Oktay , Bashan Yagmur , Dag Burcu , Karaali Zeynep , Ozturk Savas 
Published: June 2020

Abstract

Background and Aims
Patients with autosomal dominant polycystic kidney (ADPKD), in addition to uremic signs and symptoms, the need for renal replacement therapy and the risk of transferring the disease to their children put them under physical and mental stress. This may affect the psychosocial status of patients. In this study, we compared diabetic nephropathy (DN) patients who were expected to progress rapidly with early-stage ADPKD patients to reveal anxiety, depression and quality of life.

Method
In our cross-sectional, randomized controlled and single-center study, 55 adult patients with early stage ADPKD with eGFR ≥ 60 ml/min/1.73 m2 and 50 patients with DN as control group were included. Both groups were applied to state trait anxiety inventory (STAI), patient health questionnaire 9 (PHQ-9), quality of life short form 36 and Beck depression inventory in order to evaluate their depression, anxiety and quality of life. Depression, anxiety and quality of life questionnaires’ results, demographic and clinical characteristics, laboratory findings of the two groups were compared.

Results
Comparison of patients’ and control groups demographic and clinical characteristics, and laboratory data were shown in Table 1. According to state trait anxiety inventory; moderate and high levels of anxiety were present in 94% patients with ADPKD and in 66% patients with DN (p&lt;0.001). According to Beck depression inventory; depression is detected in 58.2% patients with ADPKD and in 26% patients with DN (p=0.001). When the PHQ-9 results were compared; depression is prevalent in 55.6% patients with ADPKD and in 34.7% patients with DN (p=0.037). Although ADPKD patients were at an early stage, we found anxiety and depression more frequent and severe than DN patients. While physical life quality was similar in both group; mental quality of life was lower in ADPKD patients according to quality of life short form 36 (p= 0.32 and p= 0.03 respectively) (Table 2). Independent variables affecting Beck depression inventory score; being a woman, smoking and being diagnosed with ADPKD; independent variables affecting PHQ9 score; being female and the excess of the number of medical tablets used daily; independent variables affecting personal trait anxiety score; being a woman, smoking, being diagnosed with ADPKDD, and presence of hypertension.

Conclusion
In ADPKD patients, anxiety, depression and decrease in quality of life can be seen more frequently than other uremic patients even in the early period when renal functions are preserved. This group of patients should be evaluated in this respect from the early stages of the disease.
P0034IDENTIFICATION OF FACTORS ASSOCIATED WITH PROGRESSION, PROGNOSIS AND TOLVAPTAN INDICATION IN POLYCYSTIC KIDNEY DISEASE PATIENTS
Authors: Kostopoulou Myrto , Louka Michaela , Fokas Stavros , Tigka Eirini , Drakopoulos Angelos , Gkika Vasiliki , Tsagkatakis Mihail , Tsirpanlis George 
Published: June 2020

Abstract

Background and Aims
The identification of possible risk factors for the progression of Autosomal Dominant Polycystic Kidney Disease (ADPKD) is an emerging field especially after the introduction of the first disease-specific treatment. The present study aims to explore the associations between epidemiological, clinical and imagining data in a large cohort of ADPKD patients.

Method
This study was from a single outpatient clinic following patients with ADPKD. Patients were included in the study if they had a recent Magnetic Resonance Imaging (MRI) for measurement of Total Kidney Volume (TKV), a validated biomarker for disease progression. For all patients, the Mayo Clinic Imagining Category (MCIC) and the respective prediction for End Stage Renal Disease (ESRD) were calculated. Patients eligible for tolvaptan treatment (MCIC 1C, 1D, 1E, age &lt; 55 years old and estimated-glomerular filtration rate (e-GFR) ≥ 25 ml/min) were identified. Characteristics including individual medical history, clinical and laboratory data were examined for possible associations with renal and imagining parameters using linear regression models.

Results
A total of 158 patients were included. Based on measurements of height-adjusted TKV (ht-TKV) and age, 5% of the patients were classified as 1A, 20% as 1B, 34% as 1C, 25% as 1D and 16% as 1E, MCIC. In multivariable analysis, patient’s age (p = 0.01), male sex (p &lt; 0.001), parent’s age at which ESRD was reached (adjusted for patient age) (p &lt; 0.001) and proteinuria (p = 0.04) were associated with ht-TKV. Parent’s age at ESRD differed significantly between the MCICs of the offspring (mean±(SD)), 70.83 (12.90) in 1A, 63.79 (11.39) in 1B, 57.32 (10.42) in 1C, 51.42 (9.18) in 1D and 47.94 (5.73) years old in 1E, (p &lt; 0.001). Similarly, there were significant differences in the presence and the age of hypertension onset (p =0.004 and p = 0.003, respectively). In 104 patients (50 females, 54 males) who were eligible for tolvaptan treatment age at ADPKD diagnosis, age at hypertension onset and parent’s age reaching at ESRD were all significantly lower (p &lt; 0.001 for all) when compared to non-eligible patients. Finally, factors associated with the prediction score of ESRD (e-GFR 10/ml/min) were hypertension, uric acid and the age at ESRD of the affected parent (p = 0.001, 0.02 and 0.01, respectively).

Conclusion
The age at which an affected parent had reached ESRD, as heritability estimator, was significantly associated with a worst phenotype, prognosis and tolvaptan indication. Early diagnosis of the disease, hypertension and its early onset, proteinuria and male sex are also possible risk factors for the progression of ADPKD.