bluuebunny/crossref_metadata_2025 huggingface dataset:
ʿAttīḏ-Compounds in Middle Aramaic: Discursive Functions and Tense-Aspect-Modal Characteristics
Authors: Tsolin Dmytro
Published: May 2022

Despite the frequent use of ʿattīḏ-compounds in Middle Aramaic,1 their syntactic and discourse functions as well as the tense-aspect-modal (TAM) characteristics are represented in modern works on Aramaic grammar in a rather fragmentary fashion. On the whole, ʿattīḏ-compounds are considered as competing with yiqṭul-imperfect periphrastic verbal forms that function predominantly in prophetic discourse with the meaning of distant future. However, the range of the discourse functions of ʿattīḏ-compounds goes beyond the scope of prophecy and their TAM-characteristics need to be reconsidered. In this article, compounds with an ʿattīḏ-auxiliary are viewed as possessing the modal meaning of intention originally, and it is this distinctive seme that determines other specificities of their functions. This paper presents the results of cross-dialectical analysis of ʿattīḏ-compounds in Jewish Aramaic dialects, Samaritan Aramaic, Classical Syriac and Christian Palestinian Aramaic, and includes biblical texts translated from Hebrew as well as the original writings in these Middle Aramaic languages.
Loiasis from where you don’t expect it: an illustrative case of misled diagnosis
Authors: Nicolini Ambra Laura , Tamarozzi Francesca , Pomari Elena , Mistretta Manuela , Camera Marco , Sepulcri Chiara , Bassetti Matteo , Gobbi Federico G
Published: May 2022

In the absence of pathognomonic signs, the diagnosis of filarial infections relies on geographical exposure and morphology of microfilariae, which requires expertise. We present a case of loiasis in a patient not reporting exposure in areas of known Loa loa endemicity, whose diagnosis was achieved by molecular analysis of microfilariae.
Chemerin Levels in Acute Coronary Syndrome: Systematic Review and Meta-Analysis
Authors: Ismaiel Abdulrahman , Ashfaq Mohammad Zeeshan , Leucuta Daniel-Corneliu , Ismaiel Mohamed , Ensar Ismaiel Dilara , Popa Stefan-Lucian , Dumitrascu Dan L
Published: May 2022

Objective

We evaluated the relevant published studies exploring the association between chemerin concentrations and acute coronary syndromes (ACSs).

Methods

A systematic search was performed in October 2021 using PubMed, Scopus, Embase, and Cochrane Library. We included full articles and assessed their quality using the Newcastle-Ottawa score.

Results

We found 6 studies in the systematic review and 5 of these were included in our meta-analysis. Mean difference (MD) of 41.69 ng/mL (95% CI, 10.07–73.30), 132.14 ng/mL (95% CI, −102.12–366.40), and 62.10 ng/mL (95% CI, 10.31–113.89) in chemerin levels was seen in ACS patients vs control subjects, ACS patients vs stable angina pectoris patients (SAP), and type 2 diabetes mellitus (T2DM) ACS patients vs nondiabetic ACS patients, respectively.

Conclusion

Chemerin levels were significantly elevated in patients with ACS compared to controls, as well as in T2DM–ACS patients compared to nondiabetic ACS patients. However, no significant MD in chemerin levels was observed between SAP and ACS patients.
Noise-Induced Hearing Loss Treatment: Systematic Review and Meta-analysis
Authors: Ahmed Mostafa M , Allard Rhonda J , Esquivel Carlos R
Published: May 2022

Objective

To determine the efficacy of steroid and hyperbaric oxygen therapy (HBOT) in the setting of acute noise-induced hearing loss.

Methods

Systematic review and meta-analysis of noise-induced hearing loss treatment studies that reported on patients who (1) reported individual frequencies up to 8,000 Hz with mean and SDs; (2) were treated only with steroids ± HBOT; and (3) sustained acute acoustic trauma. The Newcastle-Ottawa Scale was used to assess risk of bias across cohorts. Data sources were Embase, Web of Science, Cochrane Databases (via Ovid EBM Reviews), and PubMed.

Results

Four studies were of retrospective cohorts and one of a prospective cohort. Only one study examined blast acoustic trauma, and the remaining four examined gunfire acoustic trauma. This meta-analysis used a random-effects model for pure tone average (PTA) (0.5, 1, and 2 kHz) and “high-frequency” PTA (HPTA) (4, 6, and 8 kHz) for the five studies included. Steroid therapy demonstrated a 6.55-dB (95% CI, 0.08-13.17 dB) PTA (n = 55) improvement and a 9.02-dB (95% CI, 1.45-16.59 dB) HPTA (n = 71) improvement. Steroid with HBOT demonstrated a 7.00-dB (95% CI, 0.84-13.17 dB) PTA (n = 133) improvement and a 12.41-dB (95% CI, 3.97-20.86 dB) HPTA (n = 150) improvement. According to our statistical analysis of the pooled studies’ heterogeneity, there was moderate inconsistency in the cross-study results of both treatment groups.

Conclusion

Steroids with or without HBOT appear to improve both low and high hearing thresholds following acoustic trauma. Future studies will require inclusion of control groups, precise definition of acoustic trauma intensity and duration, and genetic polymorphisms.
DoD-VA Trauma Infection Research Collaboration
Authors: McDonald Jay , Liang Stephen Y , Li Ping , Stewart Laveta , Tribble David R
Published: May 2022

Background

In the aftermath of wars, there is a surge in the number of wounded service members who leave active duty and become eligible for healthcare through the Department of Veterans Affairs (VA). Collaborations between the Department of Defense (DoD) and VA are crucial to capture comprehensive data and further understand the long-term impact of battlefield trauma. We provide a summary of the development, methodology, and status of an effective collaboration between the Infectious Disease Clinical Research Program and the St. Louis VA Health Care System with the multicenter, observational Trauma Infectious Disease Outcomes Study (TIDOS), which examines the short- and long-term outcomes of deployment-related trauma.

Methods

As part of TIDOS, wounded service members who transitioned to participating military hospitals in the United States (2009–2014) were given the opportunity to enroll in a prospective follow-up cohort study to continue to capture infection-related data after their hospital discharge. Enrollees in the TIDOS cohort who left military service and received health care through the VA also had the option of consenting to have relevant VA medical records abstracted and included with the study data. Infections considered to be complications resulting from the initial trauma were examined.

Results

Among 1,336 TIDOS enrollees, 1,221 (91%) registered and received health care through the VA with 633 (47%) consenting to follow-up using VA records and comprising the TIDOS-VA cohort. Of the first 337 TIDOS-VA cohort enrollees, 38% were diagnosed with a new trauma-related infection following hospital discharge (median: 88 days; interquartile range: 18–351 days). Approximately 71% of the infections were identified through DoD sources (medical records and follow-up) and 29% were identified through VA electronic medical records, demonstrating the utility of DoD-VA collaborations. The TIDOS DoD-VA collaboration has also been utilized to assess intermediate and long-term consequences of specific injury patterns. Among 89 TIDOS-VA cohort enrollees with genitourinary trauma, 36% reported sexual dysfunction, 21% developed at least one urinary tract infection, 14% had urinary retention/incontinence, and 8% had urethral stricture. The rate of urinary tract infections was 0.05/patient-year during DoD follow-up time and 0.07/patient-year during VA follow-up time.

Conclusions

Wider capture of infection-related outcome data through the DoD-VA collaboration provided a clearer picture of the long-term infection burden resulting from deployment-related trauma. Planned analyses include assessment of osteomyelitis among combat casualties with amputations and/or open fractures, evaluation of mental health and social factors related to injury patterns, and examination of health care utilization and cost in relation to infectious disease burdens.
Earliest Photic Zone Niches Probed by Ancestral Microbial Rhodopsins
Authors: Sephus Cathryn D. , Fer Evrim , Garcia Amanda K. , Adam Zachary R. , Schwieterman Edward W. , Kacar Betul
Published: May 2022

For billions of years, life has continuously adapted to dynamic physical conditions near the Earth’s surface. Fossils and other preserved biosignatures in the paleontological record are the most direct evidence for reconstructing the broad historical contours of this adaptive interplay. However, biosignatures dating to Earth’s earliest history are exceedingly rare. Here, we combine phylogenetic inference of primordial rhodopsin proteins with modeled spectral features of the Precambrian Earth environment to reconstruct the paleobiological history of this essential family of photoactive transmembrane proteins. Our results suggest that ancestral microbial rhodopsins likely acted as light-driven proton pumps and were spectrally tuned toward the absorption of green light, which would have enabled their hosts to occupy depths in a water column or biofilm where UV wavelengths were attenuated. Subsequent diversification of rhodopsin functions and peak absorption frequencies was enabled by the expansion of surface ecological niches induced by the accumulation of atmospheric oxygen. Inferred ancestors retain distinct associations between extant functions and peak absorption frequencies. Our findings suggest that novel information encoded by biomolecules can be used as “paleosensors” for conditions of ancient, inhabited niches of host organisms not represented elsewhere in the paleontological record. The coupling of functional diversification and spectral tuning of this taxonomically diverse protein family underscores the utility of rhodopsins as universal testbeds for inferring remotely detectable biosignatures on inhabited planetary bodies.
MO013: Relationship between Disease Awareness and Severity of Kidney Disease in Autosomal Dominant Polycystic Kidney Disease Patients
Authors: Dogan Ege , Eren Necmi , Gül Özcan Şeyda , Altunoren Orcun , Gungor Ozkan , Dheir Hamad , Tanrisev Mehmet , Kocyigit Hafsa , ülmecit Yıldız Abd , Kocyigit Ismail , Seyahi Nurhan , Tatar Erhan
Published: May 2022

BACKGROUND AND AIMS

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease with diffuse cysts in both kidneys and is responsible for 5–10% of end-stage renal disease Levy and Feingold (Estimating prevalence in single-gene kidney diseases progressing to renal failure. Kidney Int. 2000;58(3):925). Recently, tolvaptan, which can improve kidney survival, was approved for the management of the disease (Drug Approval Package: Jynarque (tolvaptan) Otsuka Pharmaceutical Development & Commercialization, Inc. application Number: 204 441, Approval Date: 04/23/2018). We examined the relationship between renal and extrarenal findings, disease severity and the level of consciousness of patients with ADPKD patients.

METHOD

About 516 patients who applied to nephrology clinics of seven different centers in Turkey were asked to answer the questionnaire about ADPKD that consisted of 38 questions. Disease severity was determined according to e-GFR, and disease awareness was assessed on a four-point scale by adapting the Disease Perception Scale to ADPKD. Awareness of patients was evaluated comparatively with chronic kidney disease stage, age, region and symptoms.

RESULTS

One out of five patients does not know that this disease is inherited. Mean awareness scores of the patients decreased significantly with increasing age. The average awareness score of the Central Anatolia region was significantly higher compared to other regions. Awareness scores were significantly higher in patients with flank pain and urinary tract stones.

CONCLUSION

To the best of our knowledge, this is the first study about ADPKD awareness. Although ADPKD is the most common hereditary kidney disease, the rate of patients’ knowledge on this subject is low. Awareness levels may vary according to age, regional differences or symptoms. Increased awareness might lead to better treatment and improved survival in those patients.
MO014: Development and Validation of the Thirst Distress Scale for Patients with Autosomal Dominant Polycystic Kidney Disease
Authors: Gül Özcan Şeyda , Bek Sibel , Eren Necmi , Atli Zeynep , Yıldız Abdülmecit , Kocyigit Ismail , Cavdar Caner , Seyahi Nurhan , Ecder Tevfik , Waldreus Nana
Published: May 2022

BACKGROUND AND AIMS

Abundant water intake is advised for patients with autosomal dominant polycystic kidney disease (ADPKD) Meijer and Casteleijn (Riding the waves: evidence for a beneficial effect of increased water intake in autosomal dominant polycystic kidney disease patients? Nephrol Dialysis Transpl. 2014;29(9):1615–1617). Thirst, which can be defined as a sensation of dryness in the mouth and throat associated with a desire for liquids, is the main driver for fluid consumption Fitzsimons (Thirst. Physiol Rev 1972;52(2):468–561). However, daily routines may limit water intake. There is no established tool to quantify the drivers of water intake in ADPKD patients. In this study, it was aimed to develop and validate a thirst distress scale (TDS) to quantify the factors of water intake in ADPKD patients.

METHOD

The TDS-heart failure questionnaire was first (i) translated to Turkish using the approach recommended by the guidelines of the World Health Organization and finally (ii) modified to adapt to patients with ADPKD with totally 12 questions assessing (a) what may affect water intake, (b) what limit water intake and (c) what disturbing effects thirst may have on quality of life. The guidelines of the World Health Organization were used to translate the questionnaire to Turkish. An electronic survey with SurveyMonkey platform was used to collect data on thirst with TDS-PKD and thirst intensity (visual analog scale, VAS). Internal consistency of the TDS-PKD was evaluated with Cronbach’s alpha. Exploratory factor analysis was conducted to reveal the validity and the factor structure of the questions in the questionnaire.

RESULTS

The questionnaire was filled in by 154 ADPKD patients, of which 116 were on tolvaptan therapy. The time taken to answer the questions was about 4 min. The TDS-PKD questionnaire showed good internal consistency with a Cronbach's alpha value of 0.867. According to the exploratory factor analysis, a three-factor structure was obtained, meaning that there are three constructs about thirst in the TDS-PKD. Three factors explained 62.57% of the total variance. Factor one consisted of questions 1–7, factor two 8–10 and factor three 11–12. All three factors were significantly associated with thirst intensity (r = 0.505, r = 0.244 and r = 197, respectively). The average score of TDS-PDK was 40.2 ± 10.5, and the average VAS score was 8.5 ± 0.7.

CONCLUSION

The TDS-PKD questionnaire is a valid and reliable tool for evaluating the thirst distress in ADPKD patients.
MO025: Long-term follow-up of patients with autosomal dominant polycystic kidney disease treated with tolvaptan
Authors: Martins Muñoz Judith , De Lorenzo Alberto , Espinel Laura , Tarragon Blanca , Teresa Naya and Alfonso Cubas Maria
Published: May 2022

BACKGROUND AND AIMS

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease characterized by the formation of cysts that destroy normal renal parenchyma. Tolvaptan (vasopressin antagonist) is the only drug approved today to slow disease progression. To assess the efficacy and tolerability of long-term treatment in patients with ADPKD.

METHOD

Retrospective observational study of ADPKD patients on tolvaptan treatment after its approval in Spain in 2017.

RESULTS

Of the 182 patients with ADPKD in follow-up in our practice, 18% (n = 33) initiated treatment because they met criteria for rapid progression. A total of 60.6% (n = 20) males with age 47.64 ± 8.64 years, a baseline GFR of 65.24 ± 20.14 mL/min and a height-adjusted total kidney volume (TKV) of 1137.45 ± 667.58 mL. A total of 72.7% reached the maximum dose (120 mg) with a mean maximum dose of 108.18 ± 22.42 mg and a mean time to reach it of 5.8 ± 9.3 weeks. A total of 90.9% (n = 33) presented side effects: 81.8% (n = 27) aquaretic and 12.1% (n = 4) hepatotoxicity. Other side effects observed were as follows: hypernatremia 9.1% (n = 3), hyperuricemia in 24% (n = 8). No other side effects were described. A total of 39.4% (n = 13) of the patients temporarily abandoned treatment after a mean time of 3.01 ± 2.17 months. The reasons for discontinuation were as follows: aquaretic effects 35.7% (n = 5), hepatotoxicity 35.7% (n = 5), 3.03% desire for pregnancy (n = 1), 3.03% cerebral hemorrhage (n = 1) and 3.03 (n = 1) worsening of renal function. Some 30.76% (n = 4) of the patients restarted treatment at 5.5 ± 6.76 months. The reason for previous withdrawal was hepatotoxicity (n = 2) and aquaretic effects (n = 2). Therefore, the definitive abandonment of treatment was 27.2%. The mean follow-up time of the patients was 39.85 ± 10.04 months.

CONCLUSION

Long-term use of tolvaptan in patients with ADPKD can be considered safe both from the point of view of renal function and side effects. The aquaretic effects are the most frequent. The aquaretic effects and hepatotoxicity are the main reasons for treatment discontinuation. All cases of hepatotoxicity reverted to normal, thus not being considered a serious effect in our experience.
MO026: IgA-nephropathy in Alport syndrome patients: one center data
Authors: Aksenova Marina , Stolyarevich Ekaterina , Povilaitite Patrisia
Published: May 2022

BACKGROUND AND AIMS

The association between Alport syndrome (AS) and IgA-nephropathy (IgAN) recently shown suggests that the abnormal glomerular basement membrane (GBM) resulting from the pathogenic COL4A3/A4/A5 variants may predispose to immune-mediated injury. The aim of study was to identify the frequency of IgAN in children with AS.

METHOD

We analyzed the morphological (light, immunofluorescence, electron microscopy), clinical [sensorineural deafness (SND)], laboratory [eGFR, proteinuria (Pr)] data of 102 children (12 ± 4 years at biopsy) with AS observed in nephrology department since 1993. AS was confirmed by next-generation sequencing (NGS) based genetic tests in 65 points (q = 0.64). The IgAN was diagnosed by the presence of glomerular proliferative lesions with predominant IgA immunofluorescence and electron dense deposits in the mesangial area.

RESULTS

IgAN was revealed in 3 points (q = 0.03) with AS (Table 1) and presented by acute development of steroid-resistant nephrotic syndrome (SRNS) (one case) and nephrotic proteinuria in top of gross hematuria (2 points). Immunosuppressive treatment led to complete SRNS remission and was ineffective in one child.

CONCLUSION

IgAN was revealed in 3% of our points with AS and probably led to serious disease flare-ups in these points. Immunosuppression treatment was effective in children with IgA-related SRNS.
MO033: Parathyroid hormone determination as an early predictor of progression in autosomal dominant polycystic kidney disease
Authors: Viera Ramírez Elizabeth , Castillo Rodriguez Esmeralda , Martin Irene , Fernandez Lucas Milagros
Published: May 2022

BACKGROUND AND AIMS

Total kidney volume (TKV) in patients with autosomal dominant polycystic kidney disease (ADPKD) is a known progression factor in these patients. Low levels of klotho and high levels of FGF23 in the blood of patients with ADPKD have been correlated with higher TKV even in early stages of the disease, even with glomerular filtration rate (eGFR) >90 mL/min/1.73 m2. Therefore, alterations in the levels of parathyroid hormone (PTH), vitamin D, tubular reabsorption of phosphates or urinary calcium could be correlated with the TKV and serve as an early serum biomarker of progression of kidney disease.

METHOD

Observational, cross-sectional, single-center study in a population of 87 patients under follow-up at our center during 2019–2020 for ADPKD. The TKV, obtained by the ellipsoid formula measured by magnetic resonance imaging (MRI) and the values of PTH, vitamin D, tubular phosphate reabsorption and urinary calcium were retrospectively collected. Subsequently, a statistical analysis of correlation between the different variables was performed.

RESULTS

Spearman's Rho correlation analysis obtained a positive correlation of moderate–strong intensity between the TKR of the sample and PTH levels (r = 0.638, P <0 0.0001) and a negative correlation of moderate intensity with tubular phosphate reabsorption (r = −0.479, P < 0.005). No statistically significant correlation was obtained between the TKV and the levels of urinary calcium or serum vitamin D. TKV was higher among patients with an eGFR >90 mL/min/1.73 m2 (CKD-EPI) with an elevated PTH (> 65 pg/mL), with a median of 530 mL (interquartile range 403–1184 mL), compared with the TKV of those patients with an eGFR >90 mL/min/1.73 m2 with normal PTH, whose median was 405 mL (interquartile range 258–576 mL). Despite this trend, the Mann–Whitney U test did not show a statistically significant difference between medians in the subgroup of patients with eGFR >90 mL/min/1.73 m2. However, the comparison of medians in the subgroup of patients with eGFR <90 mL/min/1.73 m2 was statistically significant with a P < 0.019, with higher TKR in those patients with high PTH.

CONCLUSION

The increase in PTH in patients with ADPKD has a strong positive correlation with TKV. Even with normal eGFR, elevated PTH is associated with a higher TKV, which could be an early serum biomarker of kidney disease progression in this group of patients.
MO036: Detection of copy number variations by single-nucleotide-polymorphism array in patients with end-stage renal disease of unknown etiology
Authors: Granhøj Jeff , Venborg Pedersen Katja , Birn Henrik , Lildballe Dorte L , Jørgensen Mads , Aagaard Graakjær Jesper , Rasmussen Maria
Published: May 2022

BACKGROUND AND AIMS

Establishing the genetic basis of renal disease is pivotal to improve diagnostic and treatment strategies. Pathogenic copy number variations (CNVs) caused by chromosomal imbalances contribute significantly to the pediatric renal disease burden, especially in children with congenital anomalies of the kidney and urinary tract (CAKUT). The role of CNVs in chronic kidney disease of unknown etiology (uCKD) is scarcely investigated, although this group comprises about 20% of adults with end-stage renal disease (ESRD). We screened for causal CNVs in a preliminary sample of patients with ESRD from unknown etiology.

METHOD

We recruited 94 patients registered with ESRD ≤age 50 from uCKD or hypertension from the Danish Nephrology Registry. Medical records and previous kidney biopsies were initially reviewed, and patients were excluded if a specific cause of kidney disease other than hypertension was identified (n = 35). We performed genome-wide single-nucleotide-polymorphism (SNP) array in 59 patients to identify copy number gains and losses. All CNVs were systematically evaluated as possible causes of kidney disease and broadly classified into three main categories: ‘Normal’, ‘Pathogenic’ or ‘Variant of uncertain significance.’

RESULTS

The SNP array results were normal in 57 patients (96.6%). In the remaining two patients (3.4%), we detected pathogenic CNVs with incomplete penetrance in hot spot loci associated with CAKUT: One male patient with ESRD at age 18 was a heterozygous carrier of a 545 kb microdeletion on chromosome 16p11.2 (29.63 Mb to 30.18 Mb). He had left-side renal agenesis and a hypoplastic right kidney at presentation, but no history of developmental delay or dysmorphic features. The microdeletion was considered likely causal, because it included the CAKUT driver gene TBX6 similar to other heterozygous carriers of 16p11.2 microdeletions with isolated renal agenesis or dysplasia. A second patient with ESRD at age 49 had 3.66 Mb duplication on chromosome 1q21.1 (145.43 Mb to 149.09 Mb) in heterozygous form. The patient had no reported CAKUT or other features associated with CNVs in the 1q21.1 loci, and the duplication was therefore deemed unrelated to his renal disease.

CONCLUSION

Disease-causing CNVs are not frequent in this limited sample of patients with ESRD from unknown etiology. CNV analysis by SNP-array may be most effective in patients with uCKD combined with CAKUT features.
MO040: Development of BBP-711, a small molecule inhibitor of glycolate oxidase for primary hyperoxaluria type 1 and recurrent kidney stone formers
Authors: Sinha Uma , Rajasingham Thulashitha , Xavier Fernandez Miguel , Ji Alan , Sukhun Rajaa , Rao Satish , Henry Chris , D'souza Kahlil , Lafountaine Justin
Published: May 2022

BACKGROUND AND AIMS

BBP-711 is an investigational small molecule inhibitor of glycolate oxidase (GO), currently in development for the treatment of primary hyperoxaluria type 1 (PH1) and recurrent nephrolithiasis. Selection of BBP-711 as a drug candidate followed structural activity optimization and a pharmacological testing strategy that included functional activity in enzyme assays, target engagement in cellular assays and efficacy studies in a rodent model (Agxt−/− mice) of primary hyperoxaluria type 1.

METHOD

BBP-711 was developed by iterative synthesis and study of the structure–activity relationship of more than 50 GO inhibitors. Lead molecules including BBP-711 were assessed for functional activity by determining inhibition of the conversion of glycolate to oxalate with purified human, mouse and rat HAOX1 enzymes. The ability of BBP-711 to bind directly to immobilized purified hGO (HAOX1 gene product) was evaluated by surface plasmon resonance. Selectivity of BBP-711 was assessed by determining its inhibition of several physiologically related gene products including that from HAOX2. In vitro efficacy of BBP-711 was tested via inhibition of oxalate production in primary hepatocytes cultured from hyperoxaluric Agxt−/− mice. In vivo efficacy of BBP-711 on urinary oxalate excretion was assessed at various doses given by oral gavage in Agxt −/− mice. Pharmacokinetics of BBP-711 was investigated to assess plasma and liver concentrations associated with efficacy.

RESULTS

BBP-711 is a potent inhibitor of human, rat and mouse GO (IC50 = 15.4 nM, 22.4 nM and 149 nM, respectively). BBP-711 demonstrated stronger direct binding to hGO1 (KD = 6.31 nM) than to rGO2 (KD = 12.8 nM), indicating its preference for GO1 as a target. BBP-711 specificity was demonstrated with <10% activity against off-target enzymes D-amino acid oxidase, dihydroorotate dehydrogenase and lactate dehydrogenase-A at 10 µM. BBP-711 demonstrated concentration-dependent inhibition of oxalate production by Agxt−/− hepatocytes (IC50 = 24.2 nM at 24 hours, IC50 = 42.9 nM at 48 hours). When orally dosed at 7 mg/kg for 5 days in Agxt−/− mice, BBP-711 produced a maximum reduction of urinary oxalate (60%) as well as maximum inhibition of GO activity (>88%). Higher doses did not result in greater reduction in urinary oxalate. Liver exposures (AUC0-24hr) were higher than plasma exposures at all doses tested. GO engagement by BBP-711 was also assessed in an ex vivo assay. Liver extracts from Agxt−/− and wild-type mice dosed with BBP-711 show a dose-dependent reduction in ex vivo GO activity at 1 and 4-hour post-dose.

CONCLUSION

Iterative and rational optimization of small molecule GO inhibitors resulted in BBP-711, a potent and specific inhibitor of GO with drug-like properties.
MO050: The First Report from the National COVID-19 Autopsy Registry in Germany
Authors: von Stillfried Saskia , David Bülow Roman , Röhrig Rainer , Boor Peter
Published: May 2022

BACKGROUND AND AIMS

Autopsies are an invaluable tool in medicine for studying the pathophysiology of diseases, including kidney diseases and causes of death. To facilitate multicenter autopsy-based studies and to provide a single point of contact for data analysis and reporting, the German COVID-19 Autopsy Registry (DeRegCOVID) was launched in April 2020 to uncover effects on pulmonary (micro)vasculature, systemic viral spread including the kidneys or interaction with the immune system.

METHOD

The electronic registry uses a web-based electronic data collection system. Participation is voluntary and biomaterial remains at each site (decentralized biobanking). As of October 2021, the registry included N = 1129 autopsy cases with 69 271 individual data points containing information on 18 674 available biospecimens, including kidneys as part of the standard sampling protocol, collected at 29 German sites.

RESULTS

In the N = 1095 eligible records, the male-to-female ratio was 1–8:1, with peaks at 65–69 and 80–84 years in men and >85 years in women. Analysis of the chain of events leading directly to death showed that in 86% of autopsy cases, COVID-19 was the actual cause of death, whereas in 14% of cases, COVID-19 was a concomitant disease. The most common immediate cause of death was diffuse alveolar injury/acute respiratory distress syndrome, followed by multiorgan failure, including the kidneys. The registry supports several scientific projects, informs the public and provides reports to federal health authorities, which led to a change in the German Infection Protection Act and facilitated autopsies during pandemics.

CONCLUSION

A national autopsy registry can provide multicenter quantitative information on COVID-19 deaths at the national level to support medical research, policy decisions and public discussions. Previous and ongoing studies also showed the potential of autopsies for nephrology research.
MO053: Are Renal Prognostic Markers Different in Patients with Exostosin 1/2 Positive or Negative Membranous Lupus Nephritis? A Single Center Experience in Turkey
Authors: Ebru Eser Zeynep , Turgutalp Kenan , Karabulut Yasemin , Akcali Esra , Cagatay Kose Emre , Ballı Ebru , Bardak Simge , Demir Serap , Kıykım Ahmet
Published: May 2022

BACKGROUND AND AIMS

Recently, prognostic importance of antibodies in primary membranous nephropathy is well defined. However, knowledge about antibodies related to disease activity in membranous lupus nephritis (MLN) is limited. Exostosin1 and exostosin2 (EXT1/2) are novel antibodies detected in MLN, and further studies are needed for the prognostic significance of them as a marker.

The aim of this study is to determine whether renal prognostic markers differ between EXT1/2 positive and negative MLN patients.

METHOD

This is a single-center, retrospective and observational study. Class 5 MLN patients aged 18 or older were included in the study. Clinical characteristics, results of biochemical analysis and histopathological examination were recorded from 6 to 18 months. The end-point of the study was determined as complete remission, partial remission, need for renal replacement therapy (RRT) and exitus. Group 1: EXT1/2 positive patients. Group 2: EXT1/2 negative patients. Light, immunofluorescent and electron microscopy findings and laboratory parameters were evaluated in EXT1/2 positive and negative patients.

RESULTS

Group 1: n = 11 patients. Group 2: n = 7 patients. The main demographic, biochemical and histopathological characteristics of the groups were shown in Table 1. EXT1/2 negative patients, a higher number of sclerotic glomeruli, interstitial fibrosis and a higher amount of proteinuria were present than positive patients (P < 0.05). EXT1/EXT2 negative patients had significantly lower C3 and C4 levels than positive patients (P < 0.05). EXT1/EXT2 negative patients had a higher RRT or exitus rate within 18 months than positive patients (P < 0.05). In contrast, EXT1/EXT2 positive patients had a higher rate of achieving complete or partial remission within 18 months than negative patients (P < 0.05). The effect of immunosuppressive drug use other than steroids and glomerulosclerosis remission was statistically significant (P = 0.04 and P = 0.011).

CONCLUSION

EXT1/2 negative class 5 LMN patients have more poor renal prognostic indicators than positive patients. RRT or exitus rate is higher in EXT1/EXT2 negative patients than positive patients. However, more randomized controlled studies are needed.
MO057: Serum Irisin and Prediction of Cardiovascular Events in Elderly Patients with CKD Stage 3–5
Authors: Del Mastro Teresa , Arcidiacono Teresa , Bologna Arianna , Edvige Foligno Nadia , Avino Monica , Vezzoli Giuseppe
Published: May 2022

BACKGROUND AND AIMS

Irisin is a circulating myokine released by skeletal muscle after exercise. Its production decreases in chronic kidney disease (CKD) as a potential consequence of sarcopenia and physical inactivity. Irisin produces beneficial effects in glucose and lipid homeostasis: it promotes glucose tolerance and lipid metabolism and improves insulin resistance, stimulates browning of white adipose tissue and upregulates thermogenesis. Irisin may also produce a protective effect on the cardiovascular system as it promoted the proliferation of cardiomyocytes and suppressed myocardial fibrosis and hypertrophy. Low serum irisin was proposed as a predictor of cardiovascular mortality. We studied the relationship of serum irisin with cardiovascular risk in a sample of patients at different stages of CKD not undergoing dialysis and characterized for their artery calcification and mineral metabolism variables.

METHOD

Seventy-nine consecutive patients with stage 3–5 CKD were recruited from the patients of the nephrology outpatient clinic of our institute in Milan from 2010 to 2014. Serum irisin levels were measured at baseline in all recruited patients and in 20 healthy controls. Incident cardiovascular events were recorded during a 3-year follow-up. They included myocardial infarction, angina pectoris, coronary revascularization, congestive heart failure, stroke, TIA and cardiovascular death.

RESULTS

Serum irisin was significantly higher in controls than that in patients with CKD and in patients with CKD stage 3 than that in patients at stage 4 and 5 taken together. Taking controls and patients with CKD together eGFR was positively correlated with serum irisin. Patients with CKD were grouped according to tertiles of serum irisin. Patients in the lowest tertile had lower serum 1,25(OH)2D levels than patients in the middle and the highest tertile. Patients in the highest tertile had lower Kauppila aortic calcification score than patients in the middle and the lowest tertiles. Twenty patients suffered from cardiovascular events during a 3-year follow-up. Cox regression analysis confirmed the association of serum irisin with incident cardiovascular events during the follow-up, as patients in the highest tertile of serum irisin showed a lower cardiovascular risk than patients in the middle or the lowest tertile. Kaplan–Meier survival analysis showed that patients in the highest serum irisin tertile developed less cardiovascular events during the follow-up than patients in the other tertiles taken together (P = 0.049).

CONCLUSION

The present study suggests that irisin is a marker of cardiovascular risk in patients with CKD. It might contribute to the cardiovascular protection that physical exercise and active lifestyle produce in patients with CKD.
MO058: Do Renal Biopsies Assist Understanding of Loin Pain Hematuria Syndrome?
Authors: Sharma Aditi , Prasad Bhanu , Jafari Maryam , Dokouhaki Pouneh
Published: May 2022

BACKGROUND AND AIMS

Loin pain-hematuria syndrome (LPHS) first described in 1967 is a complex and poorly understood rare disease, with a prevalence of 0.012%. It predominantly affects young women in their late 20s and early 30s2. Patients with LPHS experience extreme flank (loin) pain that can be unilateral or bilateral, along with gross or microscopic hematuria. In most cases, the pain is so severe that the patients are forced to quit their jobs, become opiate dependent, need antidepressants, require long term disability and a proportion contemplate committing suicide. Due to inadequate understanding of the pathophysiology of LPHS, the goal of management has been limited to symptomatic relief and pain management. As there are still gaps in our understanding of glomerular hematuria, we opted to assess the histopathological features of kidney biopsies of 14 LPHS patients to evaluate the correlation of glomerular basement membrane (GBM) alterations with hematuria and pain.

METHOD

In this cross-sectional study, 14 patients with LPHS underwent kidney biopsies. Demographic data (sex, age, ethnicity, weight and height), renal biomarkers (urine blood, urine protein and serum creatinine) and comorbidities were obtained prior to the procedure. The kidney biopsies were investigated under light microscopy, immunofluorescence microscopy and electron microscopy. Descriptive statistics were used to report baseline characteristics and histology findings.

RESULTS

All 14 patients were female, with median age 37 years. About 78.6% of the patients were Caucasian. None of the 14 patients had an abnormal glomerular filtration rate or an elevated albumin creatinine ratio (>3 mg/mmoL). 11/14 patients had macroscopic hematuria with 7/11 reporting gross hematuria with exacerbations of loin pain. 5/14 patients showed evidence of endothelial injury. Of the 14 patients, 1/14 had an insufficient sample, 1/13 had thick glomerular basement membrane, 1/13 had IgA nephropathy and 11/13 had normal GBM (Table 1). Regardless of GBM thickness, most patients had RBC cells ± casts implying glomerular leak. There was no evidence of podocyte injury. The presence of endothelial cell injury by electron microscopy may suggest a role for vascular damage in the pathogenesis of at least a subgroup of LPHS patients.

CONCLUSION

The array of histological changes identified in our study offers some understanding of the hematuria component but cannot explain pain as most patients did not have histological evidence of interstitial edema. In conclusion, our findings indicate that there is an urgent need for advanced understanding of molecular mechanisms underlying the heterogeneity of this disease. In our next phase of the study, we intend to compare gene signatures of LPHS patients with patients with isolated hematuria (without pain) to help enhance our understanding of unique genetic predisposing factors to this disease.
MO070: Noncanonical IKKS and the Type 1 Interferon Pathway Activate Inflammation and Cell Death in Tubular Cells and Contribute to Renal Injury
Authors: Marcela Córdoba David Gina , García-Giménez Jorge , Ortiz Alberto , Mario Ramos Cortassa Adrián
Published: May 2022

BACKGROUND AND AIMS

Deleterious consequences of type 1 interferons (T1-INFs) in the renal tissue have been envisioned in the context of viral and autoimmune diseases and in clinical therapies dealing with their administration.(1–3) Moreover, a participation of the T1-INF pathway has been suggested in the acutely injured kidney. (4) However, the pathogenic processes triggered by the T1-INFs in the kidneys are still not well defined and hence they need to be better defined. Therefore, we aimed to address whether the T1-INF pathway and molecular routes leading to its activation regulate critical pathogenic mechanisms underlying kidney damage.

METHOD

The overall activation of the T1-INF pathway, which involves upstream signaling through TBK1/IKKε/IRF3 and downstream engagement of the INFα/β receptor (IFNAR) (5) was studied in models of cultured murine tubular cells (MCT) and mice challenged with the INFs α and β and the proinflammatory inducers TWEAK and LPS. Pharmacological, immune-modulator and genetic approaches were used to inhibit signaling from TBK1/IKKε/IRF3 or IFNAR in tubular cells as well as in murine models of kidney injury induced by LPS or folic acid.

RESULTS

INFs α and β activated the T1-INF pathway from their interaction with IFNAR thus stimulating intertwined antiviral ISG and inflammatory NF-κB-associated responses in tubular cells and kidney tissue. Both ISGs and NF-κB were also activated by TWEAK and LPS through the TBK1/IKKε/IRF3 signaling pathway, which also mediates cell death programs. Simultaneous pharmacological inhibition of TBK1/IKKε restrained the cytokine production and the ISG response elicited by TWEAK or LPS, and the TWEAK-dependent apoptosis triggered in the presence of proinflammatory cytokines. Moreover, TBK1 silencing also protected from inflammation and prevented the ISG reaction although it promoted cell death. The activity of IKKε accelerated the TBK1-induced NF-κB activation without showing relevant participation in this mechanism by itself, despite it having a contribution to cell death. An improvement of the kidney injury (inflammation and tubular cell death) in murine models of LPS and folic acid nephrotoxicity was observed by restraining the T1-INF pathway through pharmacological inhibition of TBK1/IKKε or IFNAR immune-neutralization. By contrast, fueling the TBK1/IKKε or the IFNAR signaling worsened the renal injury.

CONCLUSION

T1-INFs and proinflammatory modulators activate related proinflammatory and antiviral signaling pathways in tubular cells that otherwise may favor kidney injury thus offering alternative targets for nephroprotection.
MO076: GLUT2 as a Key Factor in the Pathogenesis of Diabetic Kidney Disease
Authors: Ahmad Majdoleen , Hinden Liad , Hamad Sharleen , Abramovitch Rinat , Thorens Bernard , Tam Joseph
Published: May 2022

BACKGROUND AND AIMS

Diabetic kidney disease (DKD) affects more than 30% of all diabetic patients. It is strongly associated with increased morbidity, mortality and global healthcare burden. Furthermore, it is considered the primary cause of end-stage kidney disease (ESKD). The renal proximal tubular cells (RPTCs) are highly susceptible to diabetes-induced hyperglycaemia, and glucose handling in these cells plays a central role in the pathophysiology of DKD; yet, the molecular mechanisms underlying hyperglycaemia-induced tubulopathy are poorly understood. Although glucose transporter 2 (GLUT2) is a major glucose transporter in the RPTCs, its exclusive role and the underlying mechanism by which it contributes to the pathogenesis of DKD are poorly known. Here, we reveal its fundamental role in the pathogenesis of DKD.

METHOD

By using the Cre-lox technique, we developed a novel mouse strain with reduced GLUT2 expression specifically in the RPTCs and crossed it with the Akita-diabetic mouse strain to generate diabetic RPTC-GLUT2-/- mice. We evaluated the renal phenotype of the null mice and compared it with their diabetic wild-type (WT) littermate controls by assessing renal patho-morphological changes, measuring blood and urine biochemical alterations, and testing renal function by qPCR, immunohistochemistry and ELISAs. Moreover, we measured glucose uptake by the kidney in the diabetic RPTC-GLUT2-/- mice and their WT controls by utilizing µPET-MRI imaging of tail vein-injected 18[F]-deoxy-D-glucose (FDG).

RESULTS

Whereas no significant changes were found in the weight or the diabetic status of the null mice in comparison with the WT animals, considerable improvements of renal function in the diabetic RPTC-GLUT2-/- mice were measured. These positive changes included significant reductions in urine creatinine, albuminuria, albumin-to-creatinine ratio (ACR) and urinary kidney injury marker 1 (KIM-1) levels. Interestingly, the hyperglycemia-induced patho-morphological changes in the kidney as well as renal injury, fibrosis and inflammation were significantly attenuated in the diabetic RPTC-GLUT2-/- mice. Moreover, the renal uptake of 18[F]-FDG was significantly decreased in the diabetic RPTC-GLUT2-/- mice compared with their WT littermate controls.

CONCLUSION

Fundamental novel observations regarding the contribution of GLUT2 in RPTCs to the development and pathogenesis of DKD have emerged. Our findings suggest that RPTC-GLUT2 not only affects glucose reabsorption but also modulates cellular function, eventually affecting the degree of renal inflammation, tubulointerstitial fibrosis, diabetic kidney injury and renal patho-morphology. Correspondingly, our results indicate that GLUT2-linked molecular mechanisms greatly affect DKD pathophysiology. Therefore, studying these cellular pathways have a major potential for therapeutic intervention of DKD and other kidney diseases.
MO104: Predictors for Early Mortality in Myeloma-Related Kidney Disease
Authors: Cadri Vilma , Saraci Armanda , Pasko Nevi , Imeraj Matilda , Toska Loriana , Straokosha Arjana , Rista Elvana , Cili Alma , Ivanaj Arben , Rroji (Molla) Merita , Barbullushi Myftar
Published: May 2022

BACKGROUND AND AIMS

Renal failure severe enough to require dialysis is an independent predictor of poor survival outcomes in multiple myeloma (MM). Significant early mortality (EM) was also determined in patients with MM infected by COVID-19. To evaluate the EM rate and investigate the risk factors associated with EM in MM patients.

METHOD

Medical records of patients from the hematology unit of UHC ‘Mother Teresa’ with MM between January 2020 and March 2021 were reviewed. Out of 183 patients, 33.3% have in presentation myeloma-related kidney disease (MRKD). The statistical methods consisted of Kaplan–Meier survival curves, the log-rank test, logistic regression analysis and the ROC curve for mortality analysis.

RESULTS

We evaluated 61 patients with MRKD, with 67.2% men; the mean age was 66.2+ (8.7) years. The incidence of MRKD was 41%, and 19.7% of MRKD patients underwent haemodialysis treatment. The 1-year mortality rate was found 29.5% (P < .01), where the EM rate was 13.1%, from which 62.5% needed dialysis. During follow-up, 10% of patients with MRKD had confirmed positive SARS-COV2 tests, associated with a high mortality rate of around 67%. AUC for creatinine value was 0.828, while it had a specificity of 88.37% and a sensitivity of 77.78% at a cut-off value >4 mg/dL (Figure 1). Multivariate logistic regression found creatinine >4 mg/dL,  haemodialysis  and COVID-19 remained independent predictors of high mortality in MRKD patients after being adjusted for cofounders (Figure 2).

CONCLUSION

High incidence of MRKD indicates under recognition of MM. Mortality from COVID-19 infection in MRKD was relatively high, 22.2%. Renal failure is the second most common cause, after infection, of EM in MM patients. It is potentially reversible, so it is of high-interest early diagnosis and management of MRKD for more prolonged survival. Prophylactic measures in patients with preexisting-kidney failure may further reduce this risk.