Tubular Involvement Research Articles

#2123 Ageing, renal function and frailty: analysis of the FRASNET study

Abstract Background and Aims Frailty is a common geriatric syndrome of significant public health importance. The kidney is one of the organs that progressively loses function with aging leading a decrease of glomerular filtration rate (GFR). In elderly the definition of eGFR threshold for the diagnosis of CKD is debated. FRASNET study aims of identify the role of kidney function (glomerular and tubular involvement) in determining frailty among not community-dwelling elderly adults, also depending on the genetics of each single subject. Method The FRASNET study was a cross-sectional multicentre observational cohort study involving healthy. The exclusion criteria were: i) severe cognitive impairment, ii) severe health problems. They have been characterised for BP, GFR, sodium intake (Kawasaki formula), cognitive status, quality of life, anamnestic factors, health and socio-economic status. Frailty was determined according to modified Fried index by the presence of three conditions among reduced grip strength, reduced gait speed, low physical activity, self-reported exhaustion. We considered the number of drugs as an index of comorbidity. Genotyping of 20 targeted single nucleotide polymorphisms (SNPs) selected on renal and hypertension was performed. ANOVA and conditional inference tree analysis have been carried out. Results 1183 individuals were included in the study sample. Median age was 72 [IQ 69-77]. 328 (27.7%) subjects were robust, 445 (37.6%) pre-frail, 410 (34.7%) frail. Frailty increases with age, especially after 75 years (from 28.9% to 75.7%). The overall mean GFR was 71.8 ± 16.5 ml/min/1.73 m2. Estimated 24 h urinary sodium excretion was 194.5 mEq/24 h with median fractional excretion of sodium (FeNa) 0.75%. In 31.9% of sample FeNa was greater than 1%. Only 3% of subjects reported CKD. Moreover, 21.1% presented eGFR ≤ 60 and the prevalence of CKD increases according to age from 12.3% to 70.3%. CKD prevalence increases in linear manner across frailty classes from 20% in robust to 47.6% in frail. Conditional inference tree analysis confirmed the role of age, comorbidity and GFR in determining frailty. In oldest subjects (>75 years old), the eGFR level most strongly associated with frailty was below 53 (ml/min/1.73 m2) (Fig. 1). No differences in sodium excretion were observed according to frailty classes. Moreover, we observed an increase of FeNa according to age and frailty classes form 0.71% (median (IQR 0.567)) to 0.79% (median (IQR 0.690)). In frail group exaggerated FeNa (>1%) is more frequent than in robust and pre-frail subjects (Chi-squared p = 0.021). Even after the introduction of these variables in inferential trees the new proposed cut-off for GFR (53) is a main determinant of frailty in oldest (Fig. 2). The eGFR parameter resulted associated with two genetic variants in RAAS system, rs5051 in the angiotensinogen gene (AGT) and rs2131127 in the angiotensin II receptor type 1 (AGTR1). The rs4293393 in uromodulin gene (UMOD) was confirmed associated with eGFR value. Conclusion The present study is part of the complex debate on the relationship among renal function, aging and frailty. We can therefore conclude that glomerular filtration (eGFR below 50 and not the presence of CKD) must be considered among the factors that influence frailty. Our study also showed a deterioration of tubular function in frail subject that can be expression of structural changes due to nephroangiosclerosis.

The biology of ferroptosis in kidney disease.

Ferroptosis is a regulated cell death modality triggered by iron-dependent lipid peroxidation. Ferroptosis plays a causal role in the pathophysiology of various diseases, making it a promising therapeutic target. Unlike all other cell death modalities dependent on distinct signaling cues, ferroptosis occurs when cellular antioxidative defense mechanisms fail to suppress the oxidative destruction of cellular membranes, eventually leading to cell membrane rupture. Physiologically, only two such surveillance systems are known to efficiently prevent the lipid peroxidation chain reaction by reducing (phospho)lipid hydroperoxides to their corresponding alcohols or by reducing radicals in phospholipid bilayers, thus maintaining the integrity of lipid membranes. Mechanistically, these two systems are linked to the reducing capacity of glutathione peroxidase 4 (GPX4) by consuming glutathione (GSH) on one hand and ferroptosis suppressor protein 1 (FSP1, formerly AIFM2) on the other. Notably, the importance of ferroptosis suppression in physiological contexts has been linked to a particular vulnerability of renal tissue. In fact, early work has shown that mice genetically lacking Gpx4 rapidly succumb to acute renal failure with pathohistological features of acute tubular necrosis. Promising research attempting to implicate ferroptosis in various renal disease entities, particularly those with proximal tubular involvement, has generated a wealth of knowledge with widespread potential for clinical translation. Here, we provide a brief overview of the involvement of ferroptosis in nephrology. Our goal is to introduce this expanding field for clinically versed nephrologists in the hope of spurring future efforts to prevent ferroptosis in the pathophysiological processes of the kidney.

Non-albumin proteinuria marks tubular involvement and is associated with arterial stiffness in subjects affected by severe obesity

IntroductionObesity is a well-established risk factor for kidney disease, and tubular damage can play a pivotal role in the development of obesity-related kidney damage. This study aimed to investigate the pathophysiological pathways involved in the development of non-albumin proteinuria (NAP), a marker of tubular involvement, in a cohort of subjects with severe obesity and preserved kidney function. MethodsA total of 106 subjects with BMI ≥ 35 kg/m2 in waiting list for bariatric surgery underwent blood chemistry analysis including metabolic and lipid profile, vascular tests for cardiovascular risk stratification and a comprehensive assessment of kidney function, including renal resistive index (RRI) and NAP measurement. ResultsNineteen patients with ACR ≥ 30 mg/g regardless of NAP values (ALB+), nineteen with NAP≥ 150 mg/g and albuminuria < 30 mg/g (iNAP) and sixty-eight without proteinuria (No-P) were found. Both ALB+ and iNAP groups exhibited a higher prevalence of hypertension and anti-hypertensive treatment compared to No-P, while the prevalence of diabetes was similar between groups. Concerning lipid profile, no differences in total, HDL and LDL cholesterol were found, while ALB+ patients had higher serum triglyceride levels than the other two groups. RRI and carotid-femoral pulse wave velocity (cf-PWV) was significantly higher in ALB+ and iNAP groups compared to No-P. Remarkably, cf-PWV remained still significant after adjustment for age, sex and MBP (p = 0.0004). In overall population, a multiple regression analysis showed that cf-PWV was an independent determinant of NAP in a model including age, sex, glycated hemoglobin, systolic and mean blood pressure (R2 =0.17, p = 0.031). ConclusioniNAP subjects showed increased arterial stiffness comparable to that observed in ALB+ group, suggesting that they may represent a subgroup at higher cardiovascular risk, often unrecognized in clinical practice.

Renal Involvement in Multisystem Inflammatory Syndrome in Children: Not Only Acute Kidney Injury.

Kidney involvement has been poorly investigated in SARS-CoV-2 Multisystem Inflammatory Syndrome in Children (MIS-C). To analyze the spectrum of renal involvement in MIS-C, we performed a single-center retrospective observational study including all MIS-C patients diagnosed at our Pediatric Department between April 2020 and May 2022. Demographic, clinical, pediatric intensive care unit (PICU) admission's need and laboratory data were collected at onset and after 6 months. Among 55 MIS-C patients enrolled in the study, kidney involvement was present in 20 (36.4%): 13 with acute kidney injury (AKI) and 7 with isolated tubular dysfunction (TD). In eight patients, concomitant AKI and TD was present (AKI-TD). AKI patients needed higher levels of intensive care (PICU: 61.5%, p < 0.001; inotropes: 46.2%, p = 0.002; second-line immuno-therapy: 53.8%, p < 0.001) and showed lower levels of HCO3- (p = 0.012), higher inflammatory markers [neutrophils (p = 0.092), PCT (p = 0.04), IL-6 (p = 0.007)] as compared to no-AKI. TD markers showed that isolated TD presented higher levels of HCO3- and lower inflammatory markers than AKI-TD. Our results indicate a combination of both pre-renal and inflammatory damage in the pathogenesis of kidney injury in MIS-C syndrome. We highlight, for the first time, the presence of tubular involvement in MIS-C, providing new insights in the evaluation of kidney involvement and its management in this condition.

Enfermedades renales tubulointersticiales. Nefritis intersticial crónica

Interstitial kidney disease covers a group of disorders which cause interstitial inflammation associated with tubular damage. Traditionally, interstitial nephritis has been classified morphologically and clinically as either acute or chronic. Acute interstitial nephritis (AIN) usually induces rapid deterioration of kidney function, with a marked inflammatory interstitial response that is characterized by the infiltration of mononuclear cells with or without eosinophils, interstitial oedema and tubular involvement. On the other hand, chronic interstitial nephritis (CIN) follows a more indolent course, and it is characterized by interstitial fibrosis, tubular atrophy and, almost always, interstitial infiltrate of mononuclear cells. The tubulointerstitial lesion is clinically important because it is a predictor of present and future kidney function.

Evaluating Serum RBP4 as an Auxiliary Biomarker for CKDu Diagnosis

Background: A chronic interstitial disease, chronic kidney disease of uncertain etiology (CKDu), has emerged as a notable contributor to the CKD burden in rural Sri Lanka. Most therapeutic and diagnostic approaches to CKD focus on glomerular diseases, and thus are not fully applicable to CKDu. Serum proteins, specifically those with the profile of markers representing different facets of a disease, are beneficial for a comprehensive evaluation of diseases, and hence in CKD. Our aim was to identify the role of serum-retinol-binding protein 4 (RBP4), a marker of the proximal tubule, in the diagnosis of CKDu. Methods: Definite CKDu cases were recruited from the renal clinic in Girandurukotte and Wilgamuwa (endemic regions). Healthy controls were recruited from Mandaramnuwara (nonendemic area). The levels of RBP4 and creatinine in serum were measured. An immunoassay (ELISA) was performed on the serum samples. The stages of CKD/ CKDu were classified according to eGFR. Results: Serum RBP4 was significantly increased in CKDu patients compared to CKD patients and healthy controls. The results show that the ratio of normalized serum RBP4 to serum creatine (S.cr) acts as a better competitive marker for CKDu (AUC 0.762, sensitivity 0.733) than CKD (AUC 0.584, sensitivity 0.733) when compared against healthy controls. Furthermore, the RBP4:S.cr ratio showed higher discriminating power (AUC 0.743) between CKDu and CKD, suggesting that the RBP4: S.cr ratio has potential as a serum marker to differentiate CKDu from CKDu. Conclusion: The RBP4: S.cr ratio was identified as a plausible indicator for differentiating CKDu from CKD with &gt;70% sensitivity and specificity. Therefore, it could be used in the evaluation of the tubular interstitial involvement of CKD.

MO620ANTIFIBROTIC EFFECTS OF SGLT2 INHIBITION IN THE KIDNEY AND PROXIMAL TUBULAR CELLS*

Abstract Background and Aims Diabetic kidney disease (DKD) is a major cause of chronic kidney disease and end stage renal disease, therefore identification of novel therapeutic strategies that reduce the risk of DKD is a research priority. Recent large clinical trials suggest that improved renal outcomes by sodium-glucose cotransporter 2 inhibitors (SGLT2i) are partly beyond their glucose lowering effects. Enhanced glucose reabsorption in diabetes leads to tubular hypoxia triggering fibrotic response. Hyperglycemia is in strong association with increased protein O-GlcNAcylation, a post-translational modification contributing to renal fibrosis. Considering the proximal tubular involvement in DKD pathogenesis and the key role of SGLT2 in glucose metabolism, here we investigated the effects of SGLT2i on tubular hypoxia and O-GlcNAcylation. Method Diabetes (D) was induced by streptozotocin (65 mg/bwkg, ip.) in adult, male Wistar rats. Following the onset of diabetes rats were treated for six weeks with dapagliflozin (D+DAPA, 1 mg/bwkg/day, po.). Metabolic parameters and renal function were evaluated. Novel urinary biomarkers of extracellular matrix remodeling (Pro-C3, uC3M, tumstatin) and profibrotic growth factors (TGF-β, CTGF, PDGF) were determined. Histological evaluation of glomerular damage (PAS), tubulointerstitial fibrosis (Masson’s trichrome, Picrosirius red) and fibronectin accumulation were performed. The effect of hyperglycemia was tested in human proximal tubular epithelial cells (HK-2) kept under normal glucose (5.5 mM), high glucose (35 mM) or high mannitol (osmotic control, 35 mM) conditions for 24 hours. HG cells were treated with 10 µM DAPA. O-GlcNAc, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) were measured. To test the effect of hypoxia cells were treated with 10 µM DAPA and were placed in a hypoxic chamber (1% O2) for 2 hours. Hypoxic injury was investigated using three different methods (qRT-PCR, Western blot, immunofluorescence analysis). HIF-1α, EPO, VEGFA and profibrotic factors were measured. Results DAPA decreased blood glucose levels (D: 37±2.7 vs. D+DAPA: 18±5.6 mmol/L; p&amp;lt;0.05) and improved renal function (creatinine clearance: D: 3.8±0.4 vs. D+DAPA: 8.9±1.0 mL/min; p&amp;lt;0.01). In parallel, novel urinary biomarkers of extracellular matrix remodeling, profibrotic growth factor expressions and extensive fibrotic tissue accumulation were reduced in the kidney. DAPA minimized hyperglycemia-induced total protein O-GlcNAcylation in HK-2 cells. Hypoxia-induced HIF-1α elevation was suspended by DAPA treatment. Moreover, DAPA treatment prevented HIF-1α translocation to the nucleus, thereby confirming abolished HIF-1α activation. EPO, VEGFA and profibrotic factor levels were also increased in hypoxia and DAPA prevented EPO, TGFB and PDGF elevation. Conclusion These data highlight the role of ameliorated O-GlcNAcylation and diminished tubular hypoxia as important benefits of SGLT2i treatment. Our results support the link between glucose toxicity, tubular hypoxia and fibrosis, a vicious trio, which seem to be targeted by SGLT2i. All these mechanisms are important parts in the puzzle of the complex system behind the protective effect of SGLT2i. OTKA-FK124491-K135398, 2017-1.3.1-VKE-2017-00006, 2020-4.1.1.-TKP2020-6183169273, 2020-4.1.1.-TKP2020-6183069269

Defective lysosomal storage in Fabry disease modifies mitochondrial structure, metabolism and turnover in renal epithelial cells

Fabry disease (FD) is an X-linked lysosomal storage disorder. Deficiency of the lysosomal enzyme alpha-galactosidase (GLA) leads to accumulation of potentially toxic globotriaosylceramide (Gb3) on a multisystem level. Cardiac and cerebrovascular abnormalities as well as progressive renal failure are severe, life-threatening long-term complications. The complete pathophysiology of chronic kidney disease (CKD) in FD and the role of tubular involvement for its progression are unclear. We established human renal tubular epithelial cell lines from the urine of male FD patients and male controls. The renal tubular system is rich in mitochondria and involved in transport processes at high-energy costs. Our studies revealed fragmented mitochondria with disrupted cristae structure in FD patient cells. Oxidative stress levels were elevated and oxidative phosphorylation was upregulated in FD pointing at enhanced energetic needs. Mitochondrial homeostasis and energy metabolism revealed major changes as evidenced by differences in mitochondrial number, energy production and fuel consumption. The changes were accompanied by activation of the autophagy machinery in FD. Sirtuin1, an important sensor of (renal) metabolic stress and modifier of different defense pathways, was highly expressed in FD. Our data show that lysosomal FD impairs mitochondrial function and results in severe disturbance of mitochondrial energy metabolism in renal cells. This insight on a tissue-specific level points to new therapeutic targets which might enhance treatment efficacy.

Transient generalized proximal tubular dysfunction in an infant with a urinary tract infection: the effect of maternal infliximab therapy?

Abstract Objectives Urinary tract infections (UTIs) are common in childhood. Distal tubular dysfunction during a UTI is relatively common, but proximal tubular involvement is a unique feature in humans. Case presentation We present the first case of transient generalized proximal tubular dysfunction (renal Fanconi syndrome) in an infant with an UTI. During pregnancy, his mother was treated for Crohn’s disease with infliximab (last dose at 28 weeks of gestation). He presented at the age of six weeks with a reduced intake, and was found to have amino-aciduria, glucosuria, and urinary loss of potassium, bicarbonate and low-molecular-weight proteins. Within a few weeks after antibiotic treatment for the UTI, no proximal tubular disorder remained and the boy is doing well. Conclusions We hypothesize that the inflammatory response caused by the UTI was more profoundly present due to the maternal infliximab therapy, and thereby included not only the distal but also the proximal tubules.

Assessment of urinary NGAL for differential diagnosis and progression of diabetic kidney disease

ObjectiveChronic kidney disease (CKD) related to diabetes has become more common than glomerulonephritis in recent years. Given the inefficient and difficult identification of diabetic kidney disease (DKD) from non-diabetic kidney disease (NDKD) as well as a result of emerging evidence supporting a role for tubular involvement in DKD, we aimed to investigate the utility of urinary neutrophil gelatinase-associated lipocalin (uNGAL) in the differential diagnosis and predictive value of DKD from NDKD. MethodsData for 100 type 2 diabetic patients with CKD at our center from June 2016 to August 2019 were reviewed. All the patients were categorized into 2 groups by the renal biopsy results: DKD and NDKD. Urinary NGAL levels were normalized by urinary creatinine and calculated as uNGAL/creatinine ratios (uNCR). The independent factors of the occurrence of DKD and the diagnostic implications of uNCR were explored by logistic regression and receiver-operating characteristic (ROC) curve analysis. In addition, we analyzed the relationship between uNCR and proteinuria in patients with DKD by Pearson test and linear regression. Kaplan-Meier survival analysis was performed to assess the prospective association of uNCR with the renal outcome. ResultsSignificantly higher levels of uNCR were observed in patients with DKD when compared to those with NDKD (28.65 ng/mg vs 27.47 ng/mg, p< .001). uNCR was identified as an independent risk factor for the occurrence of DKD in diabetic patients with CKD (odds ratio [OR] = 1.020; 95%CI = [1.001–1.399], p = .042). The optimal cutoff value of uNCR for predicting DKD was 60.685 ng/mg with high specificity (90.5%) but relatively low sensitivity (55.7%). In Pearson test, uNCR was positively correlated with proteinuria, serum creatine, blood urea nitrogen, duration of diabetes, interstitial inflammation score and global sclerosis, whereas it was inversely correlated with eGFR, hemoglobin, serum albumin and 25-hydroxy vitamin D. Furthermore, in a fully adjusted model including eGFR, serum albumin and total cholesterol, the group with uNCR>60.685 ng/mg was associated with 7.595 times higher likelihood of nephrotic-range proteinuria compared to the group with uNCR≤60.685 ng/mg. In the Kaplan-Meier survival analysis, the event-free survival probability in patients with uNCR>60.685 ng/mg was significantly lower than those with uNCR≤60.685 ng/mg (p = .048). ConclusionsuNCR might serve as a potential tool for identifying cases in which there was a high clinical suspicion of DKD and that in whom confirmatory biopsy could be considered, and the best predictive cutoff value of normalized uNCR for DKD diagnosis was 60.685 ng/mg. Type 2 diabetic patients with increased level of uNCR had higher risk to nephrotic-range proteinuria and worse renal outcome.

P0064RENAL PHENOTYPES IN A GROUP OF PATIENTS WITH MITOCHONDRIAL DISEASES

Abstract Background and Aims Mitochondrial diseases (MDs) are one of the most common inherited metabolic disorders caused by mutations of either mitochondrial or nuclear genes involved in the oxidative phosphorylation pathway. Tissues with high energy demand (i.e. brain and skeletal muscle) are preferentially affected, and MDs are not rarely referred to as mitochondrial encephalomyopathies. However, one of the hallmarks of MDs is multisystemic involvement, with large clinical variability and severity due to different mitochondrial DNA heteroplasmy levels. Given the possibility of multisystemic phenotype of MDs, renal involvement has been suggested, based on renal cells vulnerability to poor energy supply. A specific mitochondrial kidney disease is thought to underlie renal manifestations, therefore theoretically every district of the nephron might be affected by MDs. Regarding tubular involvement, we suggested a possible association between nephrolithiasis and MDs, based on data of 3 related stone formers with reduced urinary citrate excretion and MELAS syndrome. The aim of this study is to provide a clinical description of the renal phenotypes of patients with MDs. Method In 2019, 6 patients with MDs routinely followed by the Neurology outpatient clinic of our Institution were randomly asked to perform renal screening. Genetic tests, blood and 24-hour urine analyses were assessed in the whole population. The main comorbidities were recorded. Glomerular filtration rate (GFR) was estimated using creatinine clearance. Results Half of the patients were female, the average age at renal evaluation was 48±15 years; diabetes, hypertension and neurosensorial hypoacusia occurred in 4, 1 and 2 subjects, respectively. Five patients had m.3243A&amp;gt;G mutation, responsible for more than 85% of maternal inherited diabetes and deafness (MIDD) and syndrome of mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS). The remaining patient carried the m.8363G&amp;gt;A variant, reported to be associated with a multisystem MDs known as Leigh syndrome (subacute necrotizing encephalomyelopathy). Median serum creatinine was 0.6 mg/dL (IQR: 0.5-1.1) with median GFR of 92 mL/min/1.73 m2 (IQR: 40-117). Three patients exhibited signs of kidney disease: one had both reduced GFR and proteinuria (eGFR 37 mL/min/1.73 m2 and 750 mg/day respectively), one had renal impairment (58 mL/min/1.7 3m2) and severe hypocitraturia (22 mg/day), one showed increased urinary calcium excretion (348 mg/day). In one patient, evaluation of the type of proteinuria has not been performed yet. Serum lactate was 3.1±1.9 mmol/L, urinary pH 5.8±0.3 and median urinary citrate excretion 593 mg/24h (IQR: 310-923). No relevant results were found on serum and/or urinary levels of sodium, potassium, magnesium, phosphorus, urate, chloride, oxalate, parathyroid hormone and 25-OH vitamin D. Conclusion These results confirmed the presence of renal disease and its heterogeneity in patients with MDs. A complete renal screening is necessary in these subjects in order to early recognize renal involvement and carefully select candidates for further diagnostic work-up including renal biopsy. A consensus on the optimal renal screening for these patients has yet to be established.

A Novel Potential of SGLT2 Inhibition: Antifibrotic Effect in Diabetes

Background and aimsIdentification of novel therapeutic strategies that reduce the risk of diabetic kidney disease (DKD) is a research priority. Clinical data suggest that improved renal outcomes by sodium‐glucose cotransporter 2 inhibitors (SGLT2i) are partly beyond their glucose lowering effects; however, mechanisms are still elusive. Enhanced glucose reabsorption in diabetes leads to tubular hypoxia playing part in fibrogenesis. Hyperglycemia is in strong association with increased protein O‐GlcNAcylation, a post‐translational modification contributing to renal fibrosis. Considering the proximal tubular involvement in DKD pathogenesis and the key role of SGLT2 in glucose metabolism, here we investigated the effects of SGLT2i on tubular hypoxia and O‐GlcNAcylation.MethodsDiabetes (D) was induced by streptozotocin (65 mg/bwkg, ip.) in adult, male Wistar rats. Following the onset of diabetes rats were treated for six weeks with dapagliflozin (D+DAPA, 1 mg/bwkg/day, po.). Metabolic parameters and renal function were evaluated. Novel urinary biomarkers of extracellular matrix remodeling (Pro‐C3, uC3M, tumstatin) and profibrotic growth factors (TGF‐β, CTGF, PDGF) were determined. Histological evaluation of glomerular damage (PAS) and tubulointerstitial fibrosis (Masson’s trichrome, Picrosirius red, fibronectin) were performed. The effect of hyperglycemia was tested in human proximal tubular epithelial cells (HK‐2) kept under normal glucose (5.5 mM), high glucose (35 mM) or high mannitol (osmotic control, 35 mM) conditions for 24 hours. HG cells were treated with 10 μM DAPA. O‐GlcNAc, O‐GlcNAc transferase (OGT) and O‐GlcNAcase (OGA) were measured. To test the effect of hypoxia cells were treated with 10 μM DAPA and were placed in a hypoxic chamber (1% O2) for 2 hours. HIF‐1α, EPO, VEGFA and profibrotic factors were measured. Immunocytochemistry (ICC) staining for HIF‐1α was performed.ResultsDAPA decreased blood glucose levels (D: 37±2.7 vs. D+DAPA: 18±5.6 mmol/L; p&lt;0.05) and improved renal function (creatinine clearance: D: 3.8±0.4 vs. D+DAPA: 8.9±1.0 mL/min; p&lt;0.01). Subsequently novel fibrosis biomarkers, profibrotic growth factor expressions and renal fibrotic tissue accumulation were reduced. DAPA minimized hyperglycemia‐induced total protein O‐GlcNAcylation in HK‐2 cells. Hypoxia‐induced HIF‐1α elevation was suspended by DAPA treatment. EPO, VEGFA and profibrotic factor levels were also increased in hypoxia and DAPA prevented EPO and CTGF elevation.ConclusionsThese data highlight the role of ameliorated O‐GlcNAcylation and diminished tubular hypoxia as important benefits of SGLT2i treatment. Our results support the link between glucose toxicity, tubular hypoxia and fibrosis, a vicious trio that could be targeted by SGLT2i. All these mechanisms are important parts in the puzzle of the complex system behind the protective effect of SGLT2i.Support or Funding InformationOTKA‐FK124491, VKE‐2017‐00006, FIKP, UNKP‐19‐3‐III‐SE‐6, EFOP‐VEKOP‐16‐2017‐0009

Prognostic value of the Oxford classification and the Oxford score in IgA nephropathy: A Tunisian study.

Immunoglobulin A nephropathy is the most common primary glomerular disease. The main challenge in this disease is the evaluation of prognostic factors for end-stage renal disease. The aim of our study was to describe the characteristics of immunoglobulin A nephropathy, to evaluate the histological data according to Oxford classification, and to identify factors associated with renal survival. This was a retrospective study, including adults with primary immunoglobulin A nephropathy. The study was conducted over a period of 10 years. Renal biopsies were scored according to Oxford classification. Oxford score, based on the sum of the different histological lesions of Oxford classification, was calculated for each patient. We included 50 patients with a gender ratio (male:female) of 2.8. The average age was 35.6 ± 10.6 years. Fifty-eight percent of the patients had hypertension (HTN). The median proteinuria was 1.9 g/day. The median of the glomerular filtration rate was 47.6 mL/min/1.73 m2. According to Oxford classification, mesangial proliferation, endocapillary proliferation, glomerulosclerosis, interstitial fibrosis, and/or tubular atrophy and crescents were present in 40%, 38%, 88%, 36%, and 22% of the cases, respectively. The median Oxford score was 2. The median follow-up duration was 30 months. Ten patients (20%) reached end-stage renal disease. At univariate analysis, HTN, glomerular filtration rate, proteinuria, tubular involvement, and Oxford score >3 were associated with progression to end-stage renal disease (ESRD). Tubular involvement was an independent risk factor for ESRD. Our study confirms the prognostic value of the Oxford classification in immunoglobulin A nephropathy.

Histopathological features of low-dose organophosphate exposure.

Organophosphate (OP) use remains largely available worldwide despite more strict regulatory measures, in agriculture, parks or households, leading to a daily low-dose exposure. The systemic dysfunction appears partly due to acetylcholinesterase inhibition, exhibiting a primary toxic effect on the endocrine system but also on the liver and kidneys, which are responsible for products metabolization and elimination. Prolonged OP exposure can be responsible for histopathological (HP) changes that can either evolve or worsen pre-existing conditions. We conducted an experimental study including six male Wistar rats divided into two groups (four rats in the study group and two in the control group). The subjects in the first group were administered 100 mg/kg Chlorpyrifos half median lethal dose (LD50) at baseline and at 48 hours, under general anesthesia. Organ harvesting was achieved after one week. HP modifications were discovered in all kidney samples, with dystrophic changes and vacuolization of mesangial cells, dilation of renal tubules and epithelial atrophy. Congestion of vascular structures also occurred. The liver samples showed severe alteration in both vessels and hepatocytes. Adrenal gland impairment was confirmed through an increase in vacuole number in all areas, while a decrease in colloid content was noted in the thyroid gland simultaneously with a modified foamy aspect. This study is the first to certify the extent of organ injury induced by OP exposure, describing both glomerular and tubular involvement in the kidneys, liver necrosis and endocrine disturbances.

25-LB: SGLT2 Inhibitors Are Renoprotective via Mitigation of Tubular Hypoxia and Protein O-GlcNAcylation

Tubular hypoxia has a major pathogenic role in diabetic kidney disease (DKD). Hypoxia is in strong association with elevated glucose reabsorption and increased protein O-GlcNAcylation which could contribute to renal fibrosis. We recently showed that SGLT2 inhibitors (SGLT2i) are renoprotective in experimental type 1 diabetes. Considering emerging evidence of proximal tubular involvement in DKD and the major role of SGLT2 in glucose metabolism, here we investigated the direct effects of SGLT2i on hypoxia and O-GlcNAcylation. Diabetes (D) was induced by streptozotocin in adult, male Wistar rats. Rats were treated for six weeks with dapagliflozin (D+DAPA, 1 mg/bwkg/day). Renal function and fibrosis were evaluated. The effect of hyperglycaemia was tested in human proximal tubular epithelial cells (HK-2) kept under normal glucose (5.5 mM), high glucose (35 mM) or high mannitol (osmotic control, 35 mM) conditions. HG cells were treated with 10 µM DAPA. O-GlcNAc, O GlcNAc transferase (OGT) and O GlcNAcase (OGA) were measured. To test the effect of hypoxia cells were treated with 10 µM DAPA and were placed in a hypoxic chamber for 2 hours. HIF1-α, EPO, VEGFA and PAI-1 were measured. Immunocytochemistry (ICC) of HIF1-α was performed. DAPA improved renal function (creatinine clearance: D: 3.8±0.4 vs. D+DAPA: 8.9±1.0 mL/min; p&amp;lt;0.01) and decreased fibrosis. DAPA minimized hyperglycemia-induced total protein O-GlcNAcylation and OGT, while OGA was elevated in HK-2 cells. Hypoxia-induced HIF-1α elevation was suspended by DAPA treatment. Abolishment of HIF-1α upregulation by DAPA was confirmed by ICC staining. EPO, VEGFA and PAI-1 levels were also increased in hypoxia and DAPA prevented EPO and PAI-1 elevation. Here we identified a novel mechanism of SGLT2i by which the direct reduction of tubular hypoxia and inhibition of OGT by DAPA results in decreased O-GlcNAcylation in proximal tubular cells. These processes contribute to improved renal function and alleviated kidney fibrosis. Disclosure D.B. Balogh: None. J. Hodrea: None. L. Lenart: None. A. Hosszu: None. C. Mezei: None. L. Wagner: None. A.J. Szabo: None. A. Fekete: None. Funding Hungarian Academy of Sciences (LP008/2017, OTKA-K112629-FK124491-NN-114607, VKE-2017-00006); Semmelweis University; New National Excellence Program of the Hungarian Ministry of Human Capacities (?NKP-18-3)

Hepatitis B and renal failure: prevalence and associated factors in National University Hospital Center of Cotonou

Introductionles relations entre les reins et l'hépatite B sont complexes. L'objectif de cette étude était de déterminer la prévalence et les facteurs associés à l'atteinte rénale chez des personnes vivant avec le virus de l'hépatite B (PVVHB) à Cotonou.Méthodesil s'agissait d'une étude transversale à visée descriptive et analytique, menée dans le service d'hépato-gastroentérologie du CNHU-HKM de mai à août 2017. Elle avait inclus les patients porteurs d'Ag HBs reçus dans la période. Une insuffisance rénale était retenue si le débit de filtration glomérulaire estimé par la formule du MDRD était en dessous de 90 mL/min/1,73m2.Résultats105 patients porteurs d'Ag HBs étaient inclus. Parmi eux, 65 (61,9%) étaient sous traitement anti-VHB (dont 62 sous ténofovir). Des 105 patients, 41 avaient une insuffisance rénale (39%). Cette insuffisance rénale était associée à 2 cas d'atteinte tubulaire et 4 cas d'atteinte glomérulaire. La fonction rénale s'était dégradée dans le temps chez 22 patients (21%) et s'était améliorée chez 6 patients (5,7%). En analyse univariée, les facteurs associés à la survenue d'une insuffisance rénale étaient l'âge supérieur à 50 ans (p = 0,0125), la présence d'une hypertension artérielle (p = 0,0037), une fonction rénale initialement altérée (p < 0,0003) et les co-médications (p = 0,0007). Le traitement anti-VHB n'était pas associé à la survenue d'une insuffisance rénale (p = 0,2887).Conclusionla prévalence de l'insuffisance rénale chez les PVVHB était élevée (39%). L'âge, l'hypertension artérielle, une insuffisance rénale préexistante et les co-médications étaient identifiés comme des facteurs associés au déclin de la fonction rénale chez les PVVHB.

Hyperinsulinaemic hypoglycaemia, renal Fanconi syndrome and liver disease due to a mutation in the HNF4A gene.

SummaryHNF4A gene mutations have been reported in cases of transient and persistent hyperinsulinaemic hypoglycaemia of infancy (HHI), particularly in families with adulthood diabetes. The case of a patient with HHI, liver impairment and renal tubulopathy due to a mutation in HNF4A is reported.Learning points:Urine specimen study in cases of HHI with diazoxide response is necessary to rule out specific metabolic conditions (l-3-hydroxyacyl-coenzyme A dehydrogenase deficiency) or tubular renal involvement.Hyperinsulinaemic hypoglycaemia due to the heterozygous mutation (p.Arg63Trp, c. 187C > T) in the HNF4A gene is associated with renal tubulopathy and liver involvement.Follow-up of patients diagnosed of HHI is mandatory to detect associated conditions.

Effect of interferon free antiviral therapy on glomerular and tubular kidney involvement in HCV child-A cirrhosis

Effect of interferon free antiviral therapy on glomerular and tubular kidney involvement in HCV child-A cirrhosis

THU-261 - Effect of interferon free antiviral therapy on glomerular and tubular kidney involvement in hepatitis C virus child-A cirrhosis

THU-261 - Effect of interferon free antiviral therapy on glomerular and tubular kidney involvement in hepatitis C virus child-A cirrhosis

SAT-144 - High SVR Rates with SMV + SOF in HCV GT1 and GT4 Patients with Cirrhosis or Advanced Fibrosis: A Real Practice Analysis from a Large Regional Database in Tuscany, Italy

s / Digestive and Liver Disease 48S (2016) e1–e17 e5 eGFR was ≥60mL/min/1.73m2 in 92 patients (93.8%) and between45and59mL/min/1.73m2 in6patients (6.1%).Glomerular involvement was found in 19 patients (19.4%), tubular involvement in 31 (31.6%) and they co-occurred in 10 patients (p=0.034). Subjects with glomerular or tubular involvement, or both, showed significantly lower eGFRvalues (p=0.005). AROC curvewasdrafted and a cut point of 90ml/min predicted renal involvement (RI) (sensitivity 63%, specificity 75%), although it was unable to distinguish tubular vs glomerular involvement (p=0.914). Patients with RI were older, had higher ACR and 1MCR levels and exhibited a more severe KDIGO stage. No association was found between RI and: HCV-RNA levels, liver stiffness and liver function tests. L-FABP andKIM-1 levelswere significantlyhigher inpatientswithRI. Tubular involvement was significantly associated with increased levels of L-FABPandKIM-1,while glomerular involvementwas associated only with high L-FABP level. Conclusion: Tubular and/or glomerular involvement are quite frequent in HCV cirrhotic patients. The occurrence of eGFR<90ml/min/1.73m2 allows to suspect renal involvement and should prompt to monitor renal function more closely. http://dx.doi.org/10.1016/j.dld.2015.12.024