bluuebunny/crossref_metadata_2025 huggingface dataset:
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

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

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<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<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

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

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<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

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

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<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

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 (>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<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

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 < 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 < 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.
P0100CALORIC RESTRICTION ALLEVIATES AGING-RELATED FIBROSIS OF KIDNEY THROUGH MIR-21 DOWNREGULATION IN EXTRACELLULAR VESICLES
Authors: Cai Guang-Yan
Published: June 2020

Background and Aims

The mechanism of renal interstitial fibrosis occurs with kidney aging is unknown. Caloric restriction and caloric restriction mimetics (CRM) alleviate aging-related-fibrosis. The aim of this study is to investigate whether extracellular microvesicles (EVs) derived from senescent cells facilitate fibrosis development in aging kidney and the potential signalling pathway involved in the process.

Method

In this study, animal experiments included 3-mon-old ad libitum(YAL) rats, 24-mon-old ad libitum(OAL) rats and 24-mon-old caloric restriction(OCR) rats, which was given 70% of OAL’s for 8 months. Senescent cells were induced in proximal tubular epithelial cells(PTCs) by high glucose and further treated with resveratrol as CRM. The expression of miR-21, peroxisome proliferator-activated receptor(PPARα), hypoxia-inducible factor(HIF1α) in the kidney of rats and PTCs were examined. Epithelial to mesenchymal transition (EMT) and the related signalling pathway were detected by up- or down-regulation of miR-21, respectively.

Results

Long-term caloric restriction ameliorated senescent changes and aging-related fibrosis in aged ad libitum rat kidney. Caloric restriction blunted the increased expressions of miR-21 and HIF1α, the decreased expression of PPARα in renal tissue of old rats. High glucose induced PTCs senesence phenotype and EMT. miR-21 was detected in extracellular vesicles secreted by senescent PTC cells. CRMs resveratrol prevented EMT through downregulation of miR-21 in extracellular vesicles from the senescent PTC cells. Further, inhibiting miR-21 of donor senescent cells prevented the occurrence of EMT in recipient PTC cells. Finally, miR-21 induced EMT mainly through targeting PPARα protein and enhancing HIF1α expression.

Conclusion

This study demonstrated that miR-21-containing extracellular microvesicles derived from the senescent cells could facilitate tubular phenotype transition of neighbouring PTC cells via PPARα-HIF1α signalling pathway. Long-term caloric restriction and caloric restriction mimetics alleviate aging-related renal fibrosis through downregulation of miR-21 excretion.
P0103ANALYSIS OF GLOMERULAR IGG SUBCLASSES SWITCH IN IDIOPATHIC MEMBRANOUS NEPHROPATHY CLASSIFIED BY GLOMERULAR PHOSPHOLIPASE A2 RECEPTOR ANTIGEN AND SERUM ANTIBODY
Authors: Cui Haoyuan , Li Chao , Li Hang , Wen Yu-bing , Yan Xi-wei , Hu Yu-ting , Li Xuemei , Chen Limeng , Qin Yan , Li Xuewang
Published: June 2020

Background and Aims

IgG subclass switch phenomenon in early pathological stage of idiopathic membranous nephropathy (IMN) was reported recently. However, the profile of serum anti-phospholipase A2 receptor (PLA2R) antibody and glomerular PLA2R antigen was not reported in previous studies. The objective of our study was to testify whether glomerular IgG subclass switch phenomenon was present in PLA2R-related and PLA2R-unrelated IMN, respectively.

Method

This was a retrospective study including 157 Chinese patients with biopsy-proven IMN in a tertiary referral hospital between September 2017 and November 2019. IMN patients were classified into PLA2R-related (n = 132) and PLA2R-unrelated (n = 25) subgroups. We compared the immunofluorescence intensity of glomerular IgG subclass between two groups among different electron microscopic (EM) stages.

Results

Positive rate of anti-PLA2R antibody was 56.0% (88/157) and glomerular PLA2R deposition was 75.8% (119/157). The intensity of IgG4 deposition in PLA2R-related group was stronger than that in unrelated group (2.1 ± 0.6 vs. 1.6 ± 0.7, P = 0.001). In stage I, IgG4 showed difference in predominant or co-dominant rate (pre/co rate) between two groups (P = 0.015). IgG4 was predominant in early stage (stage I) of both groups (pre/co rate 97% vs 57%). IgG1 was the less predominant subtype in stage I (pre/co rate 39% vs 43%). Pre/co rate of IgG3 declined with EM stage (P = 0.013).

Conclusion

IgG subclass switch were not found in PLA2R-related or unrelated IMN. IgG4 was the predominant IgG subtype in all stages of PLA2R-related IMN. The positive rate of glomerular PLA2R antigen was higher than serum PLA2R antibody.
P0111AN UPDATE ON EPIDEMIOLOGY AND CLINICOPATHOLOGIC CORRELATION OF RENAL BIOPSY FINDINGS - A TERTIARY KIDNEY CENTRE REPORT
Authors: Bagherzadegan Hadia , Ossareh Shahrzad , Mehrazma Mitra
Published: June 2020

Background and Aims

Several studies have reported the results of renal biopsies from different registries and single centres. In most series focal and segmental glomerulosclerosis (FSGS), IgA nephropathy (IgAN), membranous glomerulopathy (MG) and lupus nephritis (LN) have been reported as the most common primary and secondary glomerulonephritis (GN). This study was conducted to update the reports of our hospital, as the main referral kidney centre of the country.

Method

Data from 4713 patients, who had undergone renal biopsy between Sept-1999 to Sept.-2019 were extracted from the GN data registry of our centre. Demographic data, renal syndrome at presentation and laboratory findings were studied. Almost all kidney specimens had been studied with light and immunofluoroscent microscopes and in selected cases with electron microscope. Nephrotic syndrome (NS) was defined as proteinuria >3.5 g/day or >3 g/day, if associated with hyperlipidemia, hypoalbuminemia and edema. Nephritic syndrome was defined as proteinuria >500 mg/day and hematuria, with or without hypertension and/or serum Cr (SCr) ≥1.4 mg/dl. Subnephrotic (SN) proteinuria was defined as proteinuria of 200 -3000 mg/day. Acute kidney injury (AKI) was defined as increase in SCr >1.4 during the past few days to weeks before admission.

Results

The most frequent type of renal pathology was MG (25.2%) followed by FSGS (13.6%), IgAN (12%), LN (8.9%), minimal change disease (MCD) (7%), crescentic GN (6.2%) and paraprotein associated GN (4.3%). The prevalence of different renal pathologies changed significantly over time (p-value:0.000) (figure).The most common clinical presentation was NS (60.2%), followed by SN proteinuria (15.2%), nephritic syndrome (12%) and AKI (7.5%). Age, sex, clinical syndrome at presentation and hypertension were significantly different between major pathological diagnostic groups (p=0.000). Table shows the detailed clinical features of the most important glomerulonephritides in our centre. Figure shows the changes in prevalence of each pathologic diagnosis over 21 years.

Conclusion

In our series the most common types of GN were MG, FSGS and IgAN, which are the most frequent glomerulonephritides in other biopsy series with various orders. Most of our patients presented with NS, followed by SN proteinuria. The relative frequency of MPGN and LN have reduced and FSGS has increased over time.
P0113STANDARDIZED GRADING OF CHRONIC CHANGES IN MINIMAL CHANGE DISEASE: A VALIDATION STUDY IN NATIVE KIDNEY BIOPSY SPECIMENS
Authors: Stefan Gabriel , Stancu Simona , Hoinoiu Madalina , Petre Nicoleta , Zugravu Adrian Dorin , Mircescu Gabriel
Published: June 2020

Background and Aims

Recently, a group of pathologists and nephrologists devised a simple scoring system for chronic changes based on the grading of glomerulosclerosis (GS), tubular atrophy (TA), interstitial fibrosis (IF) and arteriosclerosis (AS). We aimed to validate for the first time this score in patients with minimal change disease.

Method

We included 79 adult patients (age 50.3 (46.3, 54.3) years, 57% male, eGFR 54.7 (44.2, 63.5) mL/min) with biopsy proven MCD between 2010-2015 who were followed up until January 1, 2017. The extent of GS, TA and AS was scored from 0 to 3, 0 to 3 and 0 to 1, respectively. The scores were then added (total renal chronicity score) to grade the overall severity of the chronic lesions into minimal (0–1 total score), mild (2–4 total score), moderate (5–7 total score) and severe (>8 total score). The outcomes were: patient survival; kidney survival defined as doubling of serum creatinine or ESRD; partial (proteinuria 0.3 to 3.5g/24h) or complete remission (proteinuria <0.3g/24h) - whichever came first. Variables related to renal outcome were further evaluated in a multivariate Cox proportional hazard (CPH) model.

Results

Minimal chronic lesions were found in 77%, mild in 18% and moderate in 5% of the studied patients. Fifty percent had a null score of chronicity; they were younger (44 (29-53) versus 62 (44-66) years, p<0.001), had higher eGFR (65.0 (42.1-83.2) versus 43.4 (25.8-63.9) mL/min, p<0.01) but similar proteinuria (4.8 (1.9-8.2) versus 4.5 (1.1-6.7) g/g, p=0.3). Patients with a score higher than one had higher mortality (18% versus 0%, p<0.001) and started RRT more often (15% versus 0%, p=0.01). There were no differences regarding the presentation as acute kidney injury, and in reaching complete or partial remission. Moreover, there were no clinical or pathology features that predicted remission. 17% of the patients reached the composite endpoint of kidney survival; mean kidney survival time was 5.7 (5.2, 6.3) years. In the CPH analysis the only independent predictors of decreased renal survival were elevated chronicity score (HR 1.56 (95%CI 1.14-2.14), p<0.01), lower serum albumin (HR 0.27 (95%CI 0.08-0.88), p=0.03) and the presence of hypertension (HR 0.18 (95%CI 0.03-0.93), p=0.04).

Conclusion

To the best of our knowledge, this is the first study to validate the standardized grading of chronic changes as an independent predictor of renal survival in patients with minimal change disease.
P0115EFFECT OF CARDIOPULMONARY BYPASS ON THE DEVELOPMENT OF ACUTE KIDNEY INJURY AFTER OPEN-HEARD SURGERY
Authors: Molchan Nikolai , Akmalova Regina , Sokolov Dmitriy , Galkina Olga , Polushin Yuri , Levykina Elena
Published: June 2020

Background and Aims

Assessment of factors associated with cardiopulmonary bypass (CPB) in acute renal dysfunction in patients in the early postoperative period after cardiac surgery.

Method

Monocentric observational study in patients (n = 97) who underwent elective open-heart cardiac surgery (coronary artery bypass grafting -50.44%, aortic valve prosthetics - 31.04%, mitral valve prosthetics - 12.61%) using cardiopulmonary bypass. Inclusion criteria: the study included patients not younger than 18 years old, undergoing cardiac surgery with CPB lasting up to 95 minutes (coronary bypass surgery, valve replacement), without signs of end-stage chronic kidney disease (CKD).

Using nonparametric correlation analysis, we evaluated the effect on the development of acute kidney injury (AKI) of the following extracorporeal circulation factors: duration of CPB, aortic cross-clamp, mean arterial pressure (MAP), cardiac index (CI), perfusion flow rate (PFR), transport, consumption and oxygen extraction variables. The diagnosis of AKI was made on the basis of the KDIGO classification, the studied parameters were recorded initially (before the operation), 15 minutes after the start of general anesthesia, 30 minutes after the start of cardiopulmonary bypass and 15 minutes after the end of general anesthesia.

Results

The frequency of AKI in 24 hours after surgery was 56.3% (58 cases): including stage 1 in 37 (35.9%), stage 2 in 17 (16.5%), stage 3 - in 4 (3.9%) patients. In the 48th hour of the postoperative period signs of AKI regressed, and were presented in only 26 people (25.2%), including the stage 1 in 18 (17.5%), the stage 2 - in 5 (4.8%), stage 3 - in 3 (2.9%). Among the risk factors for AKI in cardiac surgery with CPB, the main effect of of the anemia was revealed, especially a decrease in hemoglobin levels of less than 90 g / l and hematocrit of less than 25%.

Conclusion

Hemodilution below the "threshold" values of hemoglobin and hematocrit during the CPB provoke acute kidney injury in patients undergoing open-heart surgery.
P0116DISCOVERY OF A NOVEL ANTIMICROBIAL COMPOUND AGAINST PSEUDOMONAS AERUGINOSA FROM URINE OF KTX PATIENTS
Authors: Knafl Daniela , Mitulovic Goran , Pichler Peter , Reiter Thomas , Wagner Ludwig , Winnicki Wolfgang
Published: June 2020

Background and Aims

The urinary microbiome harbors a great repertoire of bacteria, which possess an immense potential for the biosynthesis of different biochemical products such as polyketide synthases. Traditionally such compounds have been utilized as pharmaceutical drugs, for example as antibiotics or cytostatic substances or agrochemical agents. While examining the urinary microbiome of KTX-patients during AKI and concomitant antibiotic treatment a remarkable decrease of Candidatus solibacter usitatus in one patient attracted our attention. Surprised about detecting a putative close relative of a bacterium, which originally has been found in Australian soil in our patient’s urine, we examined the genome and protein coding regions of Candidatus solibacter usitatus. Thereby we identified a biosynthetic pathway, which allowed us to clone and produce an up-to-now unknown polyketide type 1 synthase, which we named Dananase.

Method

The dananase gene was synthesized, cloned into the pEX-A258 for replication and inserted into the p-TOPO-entry-D gateway vector following PCR amplification. The resultant insert was shifted into the pEXP1- DEST gateway vector. E. coli transformants were selected for dananase expression. BAP1-E. coli was transformed with the dananase-pEXP1- DEST expression plasmid and grown in liquid culture under induction with IPTG. The supernatant was filtered and utilized for antimicrobial activity testing against Pseudomonas aeruginosa. Metabolome analysis of BAP1- pEXP1-DEST-dananase following induction with IPDG was performed and compared to LB-media alone and supernatants of dummy plasmid transformed BAP1-E. coli. In addition, the molecular structure of dananase product was determined using trans-AT polyketide synthase predictor web application genome mining tool.

Results

The 1646 amino acid long polyketide synthase type 1 named dananase was cloned into pEXP1 expression vector and expressed in BAP1. The supernatant contained specific antimicrobial activity against clinical isolates of Pseudomonas aeruginosa. This highly active compound could be further purified by HPLC but not yet identified in its structure. In silico prediction analysis suggested a polyketide as follows CC(C(O)*)C=CC(CC(NC([K])C(CC(O)=O)=O)=O)=O. Mass spectrometric analysis revealed several Dananase-specific peaks representing most likely its product in the supernatant.

Conclusion

The dananase gene of Candidatus solibacter usitatus consists of 4941bp and encodes a polymodular polyketide synthase type-1, its product successfully inhibits growth of Pseudomonas aeruginosa in vitro.
P0118ANEMIA AS A RISK FACTOR FOR CONTRAST-INDUCED NEPHROPATHY
Authors: Chaabouni Emna , Jbali Hela , Mariem Najjar , Khadija Mzoughi , Karim Zouaghi
Published: June 2020

Background and Aims

Contrast-induced nephropathy is a potentially serious complication following coronary angiography and percutaneous coronary intervention .

The association between severity of anemia and Contrast-induced nephropathy following coronary angiography is not well-established. In this prospective study, we aimed at assessing the association of anemia of various severity with the risk of Contrast-induced nephropathy in patients who underwent coronary angiography

Method

We prospectively enrolled 158 patients who underwent coronary angiography with or without percutaneous coronary intervention from December 2017 to February 2018 at a cardiology department .

CIN was defined as an increase in serum creatinine level >25% or 0.5 mg/dL after 48 hours and anemia was defined as a value of Hb level ≤ 13 g/dl in male patients or ≤ 12 g/dl in female patients.

Patients were stratified into three subgroups—mild (11.1 to 13.0 g/dL) in male patients and (11.1 to 12.0 g/dL) in female patients, moderate (9.1 to 11.0 g/dL) and severe anemia (7.0 to 9.0 g/dL).

we used a multivariable logistic-regression model.

Results

158 patients (females = 36.1%, mean age 60.0 ± 11 years) who underwent coronary angiography, 15 (9,5%) developed Contrast-induced nephropathy .

Presence of anemia was associated with increased risk of developing Contrast-induced nephropathy (OR = 3.04, 95% confidence interval [CI] = 1.03 to 8.96, p= 0,043).

Risk of Contrast-induced nephropathy was increasingly higher with increasing severity of the anemia; mild (OR = 1.67, 95% CI = 1.38 to 2.17, p=0,036), moderate (OR = 3.3, 95% CI = 0.61 to 10.6, p=0,028) .There was no patient with severe anemia.

Conclusion

In conclusion, severity of anemia is a strong predictor of CIN following coronary angiography.
P0123THE IMPORTANCE OF PPAR-ALPHA IN AKI TO CKD TRANSITION IN NEPHROPATHY INDUCED BY FOLIC ACID
Authors: Estrela Gabriel , Arruda Adriano , Freitas-Lima Leandro , Barrera-Chimal Jonatan , Araujo Ronaldo
Published: June 2020

Background and Aims

PPAR-alpha is a nuclear receptor which plays major role in the regulation of lipid metabolism, activation of PPAR-alpha has been shown to have beneficial effects in renal diseases. Acute kidney injury (AKI), even if followed by renal recovery, is a risk factor for the future development of chronic kidney disease (CKD) and end-stage renal disease (ESRD). Our main objective was to determine the importance of PPAR-alpha in AKI to CKD transition in folic acid induced nephropathy.

Method

Male C57/Bl6 and PPARKO (C57Bl6 background) mice were divided in 4 groups, Control, Folic Acid, Gemfibrozil + Folic Acid and PPARKO + Folic Acid. Animals has been treated with single dose of Folic Acid (250mg/kg i.p) and Gemfibrozil (150mg/kg gavage) euthanized after 48 hours for AKI assessment and 28 days for CKD. Renal parameters, histology, real time PCR were performed to investigate renal injury, inflammation and fibrosis.

Results

After 48 hours of folic acid inducing AKI, PPARKO mice showed decreased urea levels (Folic Acid: 178,9±25,2 PPARKO: 92,4±15,5), less tubular injury (Folic Acid: 0,61±0,05 PPARKO: 0,21±0,03), lower mRNA expression of NGAL (Folic Acid; 32,2±7,67 PPARKO 3,74±1,71), KIM-1 (Folic Acid: 671,8±170,2 PPARKO: 43,4±29,7) and TNF-alpha (Folic Acid: 2,81±0,58 PPARKO: 0,67±0,14), while PPAR-alpha activation with gemfibrozil showed to have no effects in AKI. After 28 days of folic acid inducing CKD. PPARKO showed same levels of injury than folic acid alone treated mice, however PPAR-alpha activation with gemfibrozil decreased urea levels (Folic Acid: 79,2±3,2 Gemfibrozil: 46,1±3,8), showed less tubulointerstitial fibrosis (Folic Acid: 0,60±0,05 Gemfibrozil: 0,18±0,02) and lower urine protein/creatinine ratio (Folic Acid: 5,48±0,58 Gemfibrozil: 2,53±0,12),

Conclusion

PPAR-alpha deletion protects against AKI induced by folic acid but did not showed protection in chronic phase, in the other hand ppar-alpha activation with gemfibrozil did not protect in AKI but show to be effective in CKD.
P0124PREDICTIVE VALUE OF RENAL RISK SCORE AND CHRONICITY SCORE IN PREDICTING RENAL OUTCOME IN ANCA ASSOCIATED GLOMERULONEPHRITIS
Authors: Chen Yong-Xi , An Xiao-Ning , Wei Zhao-Nan
Published: June 2020

Background and Aims

Renal Risk Score (RRS) and Chronicity Score (CS) are both newly proposed tools to predict End stage renal disease (ESRD) which could be applicable in Antineutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis (AGN) patients. Their predictive value has not been fully studied and compared.

Method

Patients with newly biopsy-proven AGN at Department of Nephrology, Ruijin Hospital were retrospectively studied. Patients were evaluated with RRS and CS for clinical factors, pathological lesions and outcome. Their predictive value of renal survival was also compared with 2010 histological classification.

Results

There were 252 AGN patients enrolled in current study, including 212 MPA, 12 GPA, 4 EGPA and 24 renal limited vasculitis (RLV). In current study, the median serum creatinine of patients at diagnosis was 245.5 μmol/L (IQR 128-487.5 μmol/L) and median eGFR was 20.3 ml/min (IQR 9-45.3 ml/min). Fifty (19.8%) patients required dialysis at disease onset. The median RRS score at diagnosis was 6 (IQR 0-9) and CS score was 4 (IQR 3-7).

During up to 217 months of follow-up (mean 63.9 months), 71(28.2%) patients progressed to end stage renal disease (ESRD) and required renal replacement therapy. Significant differences were found regarding dialysis dependency within RRS and CS groups (p<0.001 and p<0.01 respectively).

The C statistic of the predictive models was 0.828 (95% CI, 0.775-0.880) for developing ESRD required renal replacement therapy. The addition of RRS or CS scoring scheme to the model significantly improved discrimination.

Compared with the 2010 histopathological classification, RRS and CS both showed adequate and similar discrimination, but significantly greater discrimination than 2010 histopathological classification.

Conclusion

Among AGN patients, RRS and CS achieved similar discrimination, but the discrimination of RRS was superior.
P0127ROUTINE USE OF COMBINATION CD3/PAS STAIN IN EVALUATING RENAL ALLOGRAFT BIOPSIES FOR REJECTION RESULTS IN MORE ACCURATE BANFF SCORES FOR TUBULITIS
Authors: Ziadie Mandolin , Abrahams Lauren , Freeman-Costin Katherine , Obregon Cecilia , Abrahams Neil
Published: June 2020

Background and Aims

The BANFF Classification of renal allograft rejection consists of scores for cellular rejection which rely primarily on the evaluation of lymphocytic infiltration into tubules (t), non-atrophic interstitial inflammation (i), total inflammation (ti), and endotheliatis (v.) CD3/PAS is a combination stain that highlights T lymphocytes (CD3) and basement membrane (PAS). The original BANFF scoring was developed using a hematoxylin and eosin (H&E) stain only. This study compares scores for (t) using H&E versus CD3/PAS.

Method

50 consecutive renal allograft biopsies were retrieved and on each case H&E and CD3/PAS combination stains (Ventana/Roche tissue Diagnostics Clone 2GV6 for CD3) were performed. One blinded group of matching CD3/PAS and H&E slides were evaluated and reviewed independently by two renal pathologists (Reviewer 1 and 2). Each case was graded in an identical manner following criteria designated for (t) as previously described in the Banff Classification for Renal Allograft Biopsies. Briefly (t)=0 no lymphocytes in 10 tubule cross section (tcx), (t)=1 between 1-4 lymphocytes per tcx, (t)=2 5-10 lymphocytes per tcx and (t)=3 greater than 10 lymphocytes per tcx. Cases were not graded for (v) as there were too few cases with endotheliatis to allow for statistical evaluation. The difference between CD3/PAS versus H&E scores were tested for significance using the Wilcoxon Signed Rank test. All p values were two-tailed and values of <0.05 were considered statistically significant.

Results

Mean age was 44 years with a range of 9 -75 years. Standard deviation (SD) for age was 18 years. Gender distribution was 20% female and 80% male. 28 cases were graded as (t) = 0 in H&E versus 18 in the CD3/PAS group (59% versus 36%). 17 cases were graded as (t)=1 in H&E group versus 19 in the CD3/PAS group (36% versus 38% respectively). 2 cases were graded (t)=>2 in H&E versus 12 cases in CD3/PAS groups (4% versus 24% respectively). In all categories of (t) there was a higher (t) score when using a CD3/PAS with 42% showing a one digit score increase and 8% showing a 2 digit increase. The difference in scoring for (t) between the H&E set versus the CD3/PAS set for both Reviewers 1 and 2 were statistically significant (p<0.0001).

Conclusion

This study showed statistically significant higher tubulitis scores when using a CD3/PAS combination stain to grade allograft biopsies. Since (t) scores directly affect the diagnosis of cellular rejection, we propose routine use of CD3/PAS in addition to H&E when reviewing renal allograft biopsies. Compared with H&E, CD3/PAS makes recognition and quantification of lymphocytes crossing the tubular basement membrane easier to detect and therefore more accurate.
P0128COMPARISON OF ULTRASTRUCTURE FEATURES BETWEEN PATIENTS WITH MERCURY-ASSOCIATED MEMBRANOUS NEPHROPATHY AND IDIOPATHIC MEMBRANOUS NEPHROPATHY
Authors: Qin Aibo , Lin Zishan , Zhou Fude , Zhao Minghui , Wang Suxia , Cui Zhao
Published: June 2020

Background and Aims

Prolonged exposure to mercury can cause membranous nephropathy. The routine clinicopathological features of mercury-associated membranous nephropathy (M-MN) and idiopathic membranous nephropathy (I-MN) are similar. The difference in ultrastructure between them was observed clinically. The current study retrospectively compared the ultrastructure features, clinical and pathological data, treatment and prognosis of patients with M-MN and I-MN.

Method

Thirteen patients with M-MN and 13 patients with I-MN were enrolled. The clinical and pathological data were retrospectively collected. Electron micrographs of glomerular capillaries were taken and the foot process width (FPW) and the number of foot processes per 10 μm glomerular basement membrane (GBM) were measured. The presence and location of electron-dense deposits in mesangium and subendothelial region were recorded.

Results

Patients with M-MN were younger (38.7±8.5 versus 45.8±5.7 years, P=0.020), with a shorter duration of complete remission (9.0±6.1 versus 20.3±9.8 months, P=0.004) and lower relapse rate (0% versus 45.5%, P=0.014) than patients with I-MN. As to ultrastructure, patients with M-MN had lower levels of FPW [974.3nm (range 791.2∼1504.4) versus 2370.6nm (range 2219.4∼2559.1), P=0.001, Figure 1], more foot processes per 10 μm GBM [8.1 (range 5.2∼10.0) versus 3.3 (range 3.1∼3.5), P=0.001], and higher ratio of mesangial electron-dense deposits (41.7% versus 0, P=0.015, Figure 2) than those with I-MN. Multivariate analysis showed that type of disease (M-MN or I-MN) and stage of MN (stageIor stageIIand above) were the two only determinants of FPW. FPW over 1645 nm differentiated M-MN from I-MN with high sensitivity (92.3%) and specificity (83.3%).

Conclusion

The quantitative analysis of foot processes may offer a potential tool to distinguish M-MN from I-MN. Better prognosis in patients with M-MN may be related to minor podocyte damage.