bluuebunny/crossref_metadata_2025_split huggingface dataset:
P0040BASELINE CHARACTERISTICS AND ASSOCIATIONS WITH RENAL FUNCTION IN A GREEK COHORT OF POLYCYSTIC KIDNEY DISEASE
Authors: Kostopoulou Myrto , Louka Michaela , Kanellopoulou Konstantina , Gkika Vasiliki , Fokas Stavros , Koutsogianni Anastasia , Lymperopoulos Konstantinos , Tsirpanlis George 
Published: June 2020

Abstract

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

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

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

Conclusion
In this study, patients with ADPKD were diagnosed at a young age and hypertension developed early on the course of the disease. Both these factors together with higher values of BMI and TKV were independently associated with low eGFR.
P0048THE EFFECT OF GENOTYPING ON THE NUMBER OF PHARMACOTHERAPEUTIC GENE-DRUG INTERVENTIONS IN CKD3-5 PATIENTS
Authors: Kerskes Marieke , Van den Eijnde Carien , Deiman Birgit , Aarnoudse Albert-Jan , Grouls Rene , Deenen Maarten 
Published: June 2020

Abstract

Background and Aims
Most patients with CKD (Chronic Kidney Disease) 3-5 are polypharmacy patients (i.e. use of ≥5 drugs). As renal function is important for the clearance of many drugs, dose adjustment is often necessary and some drugs are even contra-indicated in patients with CKD. Many of these drugs are metabolized by cytochrome P450 (CYP-enzymes) in the liver. Several genetic mutations in these CYP enzymes are known to result in an altered metabolism capacity of drugs. Knowledge of the patients CYP450 genotype may thereby be of added value in reducing the incidence of supratherapeutic concentrations of drugs and reducing side effects, especially in this patient population with already reduced renal function. The aim of this study was to determine the added value of pharmacogenetic testing to the routine medication evaluation in polypharmacy patients with CKD3-5 disease, defined as the total number of pharmacotherapeutic interventions based on a relevant gene-drug interaction as assessed by the nephrologist and hospital pharmacist.

Method
This was a prospective single-centre study in adult polypharmacy patients with CKD3-5 disease not on dialysis who visited the outpatient clinic of the Catharina Hospital Eindhoven, the Netherlands. In each patient enrolled in the study we determined a pharmacogenetic profile consisting of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5 and VKORC1. A gene-drug interaction was considered as relevant based on the DPWG (Dutch Pharmacogenetics Working Group) guideline. Of all these according to the DPWG guideline relevant gene-drug interactions the treating nephrologist and hospital pharmacist assessed the clinical relevance and necessity of a pharmacotherapeutic intervention in the individual patient. Primary endpoint of the study was the total number of applied pharmacotherapeutic interventions based on a relevant gene-drug interaction.

Results
A total of 61 patients were enrolled. Median eGFR in the study population was 18 ml/min. Patients used a median (range) number of 12 (5-20) drugs. Genotyping resulted in a total of 172 altered phenotypes based on a pharmogenetic mutation. We observed a total of 66 gene-drug interactions, of which 56 were considered relevant and resulted in 26 applied pharmacotherapeutic interventions in 20 (32.8%) patients. These interventions consisted of 10 dose adjustments (38.5%), 7 drug stops (26.9%) and 9 drug changes (34.6%).

Conclusion
Pharmacogenetic testing leads to additional pharmacotherapeutic interventions based on relevant gene-drug interactions. This study shows that pharmacogenetic testing in CKD3-5 patients can be of added value to the routine medication evaluation, and may further optimize pharmacotherapy in this population.
P0054ACQUIRED DIFFERENTIAL EXPRESSION IN ACUTE KIDNEY INJURY OF GENES RESPONSIBLE FOR HEREDITARY NEPHROPATHIES
Authors: Carriazo Sol , Sanchez-Nino Maria Dolores , Perez Gomez Maria Vanessa , Castañeda-Infante Laura , Stock da Cunha Teresa , Gonzalez-Martin Guillermo , Avello Alejandro , Gomá Elena , Fernandez-Prado Raul , González-Parra Emilio , Ortiz Alberto 
Published: June 2020

Abstract

Background and Aims
Gene sequencing is becoming an important diagnostic tool in a great number of medical specialties. Despite its interpretation is still a challenge, allows the identification of genes related to hereditary diseases and bild a base for the study of acquired nephropathies. We hypothesize that those genes responsible for hereditary nehpropathies could contribute to the pathogenesis of acquired nephropathies.

Method
In a murine model of acute kidney disease induced by folic acid, we analyzed the kidney transcriptomic after 24 hours of damage. In this database we evaluated if 625 genes described as responsible for hereditary nephropathies were expressed significantly. Later, we evaluated the correlation between diferentially expressed genes and glomerular filtration, using transcriptomic databases of human nephropathies (Nephroseq), so that, we could identify those relevant in acquired human nephropathies and in experimental settings. A functional enrichment analysis was done using the software Gorilla, and some of the genes were validated in our laboratory using RT-PCR.

Results
In acute kidney disease, the renal expression of 3906/25051 (15.59%) genes increased and the expression of 3537 (14.11%) decreased significantly (p&lt;0.05). The percentage of genes expressed diferentially was higher when analysing the 625 genes responsible of familiar nephropathies. We identified 615 of those in the murine model and 105/615 (17.07%) increased it expression, and 155 (25.20%), decreased it (p&lt;0.05 when compared with the database with 25051 genes). 241 of those 260 diferentially expressed genes (92.69%) where associated significantly with glomerular filtration rate in human nephropathies. The most enriched GO process were “complement activation", "protein activation cascade", "activation of immune response" and "RNA processing”. We have validated the expression of 7 of the genes in acute kidney injury (SLC34A1, SLC34A3, Klotho, MAGED2, NLRP3, FN1, COL4A1), which supports the relevance of the transcriptomic results.

Conclusion
Genes involved in familiar nephropathies are overexpressed between genes diferentially expressed in acquired nephropathies, suggesting that they could play a role in the pathogenesis of the last, throught the regulation of the RNA processing, protein activation or immune response and complement regulation. The analysis of the functioning of genes responsible for familiar nephropathies in acquired nephropaties could identify new therapeutic targets in kidney damage.
P0065DOUBLE MUTATION INHERITANCE IN PATIENTS WITH FOCAL SEGMENTAL GLOMERULOSCLEROSIS AND ALPORT SUNDROME
Authors: Xie Jingyuan 
Published: June 2020

Abstract

Background and Aims
Focal segmental glomerulosclerosis (FSGS) and Alport syndrome (AS) are the leading causes of ESRD globally. FSGS and AS are clinically heterogeneous nephropathies and mainly genetic causes are the mutations in genes expressed in podocytes and glomerular basement membrane (GBM) respectively. A simple Mendelian model fail to explain the genetic control of both nephropathies completely because of the heterogeneous nature and presence of incomplete penetrance. Therefore, here we investigated the possible digenic control of FSGS and AS.

Method
To detect the double mutational (mono- or di-genic) cause of FSGS and AS, we conducted whole exome sequencing (WES) and panel sequencing in 67 kidney patients during the period of four years (2015 to June 2019). Inclusion criteria was the proband's clinical symptoms confirming the FSGS or AS based on clinical symptoms and renal biopsy. Clinical and genetic analyses were implemented to correlate the phenotypes with genotypes.

Results
Genetic analysis discovered that 35 out of 67 (52.23%) had genetic cause of selected nephropathies and 24 out of 35 (68.57%) had mutations in COL4A (3,4 & 5) genes and 11 (31.42%) in other genes. Interestingly, we found 7 out of 35 patients (20%) with double mutations (mono- or di-genic) in COL4A3/COL4A4 genes. After the mentioned period, during routine genetic screening, we also found another patient having double mutations in COL4A3 gene. Subsequently, Sanger sequencing confirmed that the identified mutations were co-segregating with the disease(s) in an incomplete penetrance fashion within the family. Lastly, we found 16 mutations in 8 patients having either monogenic or digeneic double mutations in COL4A3 and/or COL4A4 genes. In sum, we found 12 (75%) mutations in COL4A3 and 4 in COL4A4 (25%), and5 probands (62.5%) had compound heterozygous mutations in COL4A3, 1 proband (12.5%) had in COL4A4 and 2 probands (25%) had digenic (COL4A3/COL4A4) mutations. Last of all, among all the mutations, 10 were novel and 6 have been described previously.

Conclusion
This genetic analysis provides the first evidence for digenic inheritance of FSGS. The nephrologists and clinical geneticists should keep this possibility in mind for the accuracy in diagnosis, disease management and genetic counseling in future. Additionally, we are also adding 10 novel mutations in COL4A3 and COL4A4 genetic pools.
P0067PREDICTORS OF LONG-TERM OUTCOME IN A SPANISH COHORT OF PATIENTS WITH FABRY DISEASE ON ENZYME REPLACEMENT THERAPY
Authors: Goicoechea Marian , Gomez-Preciado Francisco , Benito Silvia , Torras Joan , Torra Roser , Huerta Ana , Restrepo Alejandra , Ugalde Jessica , Astudillo Daniela , Agraz Irene , Lopez-Mendoza Manuel , De Arriba Gabriel , Corchete Elena , Quiroga Borja , Martin-Conde Maria Luisa , Gutierrez Maria Jose , Lopes Vanessa , Ramos Carmela , Mendez Irene , Cao Mercedes , Dominguez Fernando , Ortiz Alberto 
Published: June 2020

Abstract

Background and Aims
Fabry disease may be treated by enzyme replacement therapy (ERT), but the impact of chronic kidney disease (CKD) on the response to therapy remains unclear. The aim of the present study was to analyse the incidence and predictors of clinical events in Fabry disease patients on ERT.

Method
Multicentre retrospective observational analysis of patients diagnosed and treated with ERT for Fabry disease. The primary outcome was the first renal, neurological or cardiological events or death during a follow-up of 60 months (24-120).

Results
In 69 patients (42 males, 27 females, mean age 44.6 ±13.7 years), at the end of follow-up, eGFR and the left ventricular septum thickness remained stable and the urinary albumin: creatinine ratio tended to decrease, but this decrease only approached significance in patients on agalsidase-beta (242 to 128 mg/g (p = 0.05).
At the end of follow-up, 21 (30%) patients had suffered an incident clinical event: 6 renal, 2 neurological and 13 cardiological (including 3 deaths). Events were more frequent in patients with baseline eGFR ≤60 ml/min/1.73 m2 (log Rank 12.423, p=0.001), and this remained significant even after excluding incident renal events (log Rank 4.086, p=0.043), being these differences more relevant in females (log Rank 18.514, p&lt;0.001) than males (logRank: 3.442, p=0.064). Lower baseline eGFR was associated with a 3- to 7-fold increase in the risk of clinical events in different Cox models.

Conclusion
GFR at the initiation of ERT is the main predictor of clinical events, both in males and in females, suggesting that start of ERT prior to the development of CKD is associated with better outcomes. For the first time, we show that initiation of ERT in women before renal function deteriorates has a similar or even larger impact as in Fabry males to prevent clinical events.
P0075EXPERT OPINION ON THE MULTIDISCIPLINARY MANAGEMENT OF CYSTINOSIS IN ADOLESCENT AND ADULT PATIENTS
Authors: Webb Nicholas , Das Anibh M , Hulton Sally , Levtchenko Elena , Servais Aude , Wanner Christoph 
Published: June 2020

Abstract

Background and Aims
Cystinosis is a rare autosomal recessive lysosomal storage disorder caused by mutations in the CTNS gene on chromosome 17p13. It affects between 1:150,000–1:200,000 live births, with a prevalence of approximately 1.6 per million. It is a life-long progressive disease which results in an abnormal lysosomal accumulation of the amino acid cystine in multiple organs and tissues of the body. The most common presentation of cystinosis (95%) is the infantile nephropathic form, with renal symptoms developing in the first few months of life. Over the next 10–20 years, extra-renal manifestations of cystinosis become apparent, which require multidisciplinary care. Here we describe a consensus-based programme with the objective of creating clinical recommendations to support HCPs with the management of adolescents and adults living with the multi-organ effects of cystinosis.

Method
The programme was led by a Steering Committee (SC) of European clinicians with expertise in managing cystinosis. Recommendations were developed using a quasi-Delphi methodology. The SC identified and prioritised a list of key questions. An Extended Faculty (EF) of additional specialists with extensive experience managing cystinosis in patients of all ages, were invited to answer the questions via an online digital platform. The consolidated answers of expert opinion were summarised into recommendations that were supported by evidence-based guidance and additional published data where possible. The EF were invited to agree / disagree with the draft clinical recommendations. Where there was disagreement, the SC members amended the recommendations and the EF re-voted on the revisions. This process continued until consensus was achieved on all final recommendations.

Results
The expert-agreed clinical recommendations reflect the multi-organ effects of cystinosis. Thus, advice on factors relating to the nervous system, muscle involvement, ophthalmology, cardio-respiratory system, dental care and nutrition, dermatology, endocrine system, and gastrointestinal and hepatological involvement, are given, along with renal considerations. Guidance on fertility and family planning that reflect some of the major advances in recent years, are also provided. Ideas on improving psychological well-being and adherence includes recommendations on the use of validated screening tests, increasing access to occupational therapy, and interacting with patient groups. The programme has also produced an online checklist to support HCPs in their daily clinical practice by providing a focus to guide regular consultations with the patient.

Conclusion
These expert recommendations offer HCPs relevant advice that support them in the management of adolescents and adults living with the multi-organ effects of cystinosis. The recommendations complement existing international and local guidance and aim to improve patient outcomes.
P0076HOMOARGININE ASSOCIATES WITH RENAL AND CARDIAC FUNCTION IN FABRY DISEASE
Authors: Drechsler Christiane , Menitzer Andreas , Maerz Winfried , Gutjahr-Lengsfeld Lena , Oder Daniel , Üçeyler Nurcan , Sommer Claudia , Nordbeck Peter , Wanner Christoph 
Published: June 2020

Abstract

Background and Aims
Patients with Fabry disease frequently develop progressive Fabry nephropathy, hypertrophic cardiomyopathy with arrhythmias and subsequent death, transient ischemic attacks and early cerebral stroke. Homoarginine is an amino acid derivative, mainly produced in the kidney from its precursor lysine. Homoarginine may increase nitric oxide availability, decrease the release of cytokines, modulate the renin-angiotensin-aldosterone system and improve cardiac contractility. We hypothesize that high homoarginine levels associate with less clinical symptoms and better renal function in patients with Fabry disease.

Method
This study investigated the homoarginin status and its association with renal function, left ventricular (LV) mass and adverse clinical symptoms in patients with Fabry disease. Homoarginine was measured by high-performance liquid chromatography in 162 patients who were genetically proven to have Fabry disease. GFR was determined by DTPA clearance. LV mass and cardiomyopathy were assessed by magnetic resonance imaging and echocardiography. In cross-sectional analyses, associations with adverse clinical outcomes were determined by linear and binary logistic regression analyses, respectively, and were adjusted for age, sex, and BMI.

Results
Patients had a mean age of 39±14 years and 41% were male. The mean homoarginine concentration was 2.0±1.0 µmol/l. Patients had a mean BMI of 23.7±4.5 kg/m2 and a mean GFR of 93±37 ml/min. Homoarginine was significantly correlated with GFR and proteinuria. The better the homoarginine status of the patients, the higher was their GFR (r=0.20, p=0.04) and the lower proteinuria (r=-0.21, p=0.03). Furthermore, LV mass was significantly higher with lower homoarginine levels (r=-0.30, p&lt;0.01). Patients of the lowest homoarginine tertile had a 4-fold higher risk of myocardial hypertrophy (OR 4.17, 95% CI 1.44-12.02), especially with septal and posterior hypertrophy, compared to those of the upper tertiles. Similarly, patients of the lowest homoarginine tertile had a higher rate of angina pectoris (OR 4.2, 95% CI 1.3-13.3) and chronic pain (OR 4.1, 95% CI 1.7-10.1), compared to patients of the upper tertiles. At lower homoarginine status, the median levels of proteinuria increased, as well as the prevalence rates of heart failure and the need for analgesic therapy.

Conclusion
In conclusion, low homoarginine status was strongly associated with cardiomyopathy, renal function and adverse clinical symptoms in patients with Fabry disease. Whether homoarginine supplementation improves complications of Fabry disease, requires a randomized controlled trial.
P0081IMPACT OF RENAL FAILURE ON OVERALL SURVIVAL OF PATIENTS WITH FABRY DISEASE
Authors: Karovaikina Ekaterina , Moiseev Sergey , Bulanov Nikolay , Moiseev Alexey , Kuchieva Agunda , Fomin Viktor 
Published: June 2020

Abstract

Background and Aims
End-stage renal disease (ESRD) is associated with significant morbidity and mortality among patients with Fabry disease (FD). The aim of our study was to evaluate impact of renal failure on overall survival of patients with FD.

Method
We recruited 117 adult (&gt;18 years) patients with FD that was confirmed by enzymatic and genetic studies. ESRD was defined according to the KDIGO guidelines (2012). Kaplan-Meyer analysis and Log Rank test were used to estimate overall survival of patients with FD.

Results
Thirty-seven (36 males and 1 female) of 117 patients had ESRD. Thirty-three of them were treated with chronic hemodialysis, whereas four patients have undergone renal transplantation. Among patients with ESRD eleven (29.7%) patients died at the median age of 43 (37; 46) years. All deceased patients were males. The median time from dialysis initiation to death was 32 (6; 67) months. The causes of death included sudden cardiac death (n=9), stroke (n=1) and peritonitis (n=1). Only 2 deceased patients received enzyme replacement therapy over 3 and 11 months. There were deaths only in the ESRD group (Table). There was a decline in survival function after the age of 30 years in patients with ESRD. In Kaplan-Meyer analysis overall survival was 51.2 years (95% Confidence interval 47.7-54.7) and was lower in patients with ESRD (Log Rank (mantel-Cox) χ2=17.5, df 1, р&lt;0.0001, Figure). Five- and 10-year survival after dialysis initiation was 72.5% and 54.1%, respectively.

Conclusion
ESRD was the major factor associated with low survival of patients with FD in Russia. One out of every 3 dialysis patients died in 5 years after dialysis initiation.
P0090SPIRONOLACTONE ALLEVIATES ISCHEMIC STROKE SEVERITY IN MALE MICE WITH CHRONIC KIDNEY DISEASE
Authors: Lando Mathilde , Grissi Maria , Boudot Cedric , Poirot Sabrina , Boullier Agnès , Lenglet Gaëlle , Avondo Carine , Choukroun Gabriel , Kamel Saïd , Chillon Jean-Marc , Henaut Lucie 
Published: June 2020

Abstract

Background and Aims
Ischemic stroke is highly prevalent in patients with chronic kidney disease (CKD) and has been associated with poor outcomes. In experimental studies, CKD mice display wider and more inflammatory ischemic lesions as well as poorer functional outcomes than mice with normal renal function. In rodents with normal renal function, treatment with a mineralocorticoid receptor antagonist decreases brain ischemic lesion and improves functional outcomes. The goal of this study was to investigate the impact of a treatment with spironolactone, a mineralocorticoid receptor antagonist, on stroke outcomes in CKD mice.

Method
Male C57BL/6J mice were randomly assigned to CKD or SHAM groups. CKD was induced through right kidney cortical electrocautery in 8 week-old mice followed 2 weeks later by left total nephrectomy. Mice received spironolactone (50 µg/kg/day) or placebo (subcutaneous tablets, Innovative Research of America) for 6 weeks until stroke induction by transient middle cerebral artery occlusion (tMCAO). Neurological deficits were monitored daily, 3 days before and 1 day after stroke induction. Mice were euthanized 24 hours after tMCAO. Total infarct volumes and apoptosis were determined by cresyl violet staining and TUNEL respectively. Immunohistochemical detection of neurons was performed using an anti-NeuN antibody. To characterize the pro-inflammatory polarization of microglia/macrophages, M1 signature genes’ expression (CD-32, IL-1β and IL-6) was analyzed by qPCR.

Results
Untreated CKD mice displayed wider ischemic lesions (40.3 ± 4.5 versus 23.8 ± 3.9 mm3; p &lt; 0.05) and poorer neurological score, grip strength and prehensile abilities compared to untreated sham mice. Pro-inflammatory M1 signature genes’ expression (CD-32, IL-1β and IL-6) was significantly increased in the ischemic hemisphere of CKD mice compared to the non-ischemic hemisphere. Treatment with spironolactone decreased ischemic lesion (19.3 ± 5.1 mm3; p &lt; 0.05) and improved neurological score, grip strength and prehensile abilities in CKD mice. Treatment with spironolactone also reduced apoptosis, neuronal loss and microglia/macrophages pro-inflammatory M1 signature genes’ expression in CKD mice. In contrast, treatment with spironolactone had no effect in sham mice.

Conclusion
These data demonstrate that the mineralocorticoid receptor could be a promising therapeutic target to decrease brain inflammation and improve stroke recovery in CKD.