Severity Of Glomerular Lesions Research Articles

Heterozygous mutations in factor H aggravate pathological damage in a stable IgA deposition model induced by Lactobacillus casei cell wall extract.

Activation of complement through the alternative pathway (AP) has a key role in the pathogenesis of IgA nephropathy (IgAN). We previously showed, by intraperitoneal injection of Lactobacillus casei cell wall extract (LCWE), C57BL/6 mice develop mild kidney damage in association with glomerular IgA deposition. To further address complement activity in causing glomerular histological alterations as suggested in the pathogenesis of IgAN, here we used mice with factor H mutation (FHW/R) to render AP overactivation in conjunction with LCWE injection to stimulate intestinal production of IgA. Dose response to LCWE were examined between two groups of FHW/R mice. Wild type (FHW/W) mice stimulated with LCWE were used as model control. The FHW/R mice primed with high dose LCWE showed elevated IgA and IgA-IgG complex levels in serum. In addition to 100% positive rate of IgA and C3, they display elevated biomarkers of kidney dysfunction, coincided with severe pathological lesions, resembling those of IgAN. As compared to wild type controls stimulated by the same high dose LCWE, these FHW/R mice exhibited stronger complement activation in the kidney and in circulation. The new mouse model shares many disease features with IgAN. The severity of glomerular lesions and the decline of kidney functions are further aggravated through complement overactivation. The model may be a useful tool for preclinical evaluation of treatment response to complement-inhibitors.

The relationship between diabetic retinopathy and diabetic nephropathy in type 2 diabetes.

Diabetic retinopathy (DR) and diabetic nephropathy (DN), are major microvascular complications of diabetes. DR is an important predictor of DN, but the relationship between the severity of DR and the pathological severity of diabetic glomerulopathy remains unclear. To investigate the relationship between severity of diabetic retinopathy (DR) and histological changes and clinical indicators of diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM). Patients with T2DM (n=272) who underwent a renal biopsy were eligible. Severity of DR was classified as non-diabetic retinopathy, non-proliferative retinopathy, and proliferative retinopathy (PDR). Relationship between DN and DR and the diagnostic efficacy of DR for DN were explored. DN had a higher prevalence of DR (86.4%) and DR was more severe. The sensitivity and specificity of DR in DN were 86.4% and 78.8%, while PDR was 26.4% and 98.5%, respectively. In DN patients, the severity of glomerular lesions (p=0.001) and prevalence of KW nodules (p<0.001) significantly increased with increasing severity of DR. The presence of KW nodules, lower hemoglobin levels, and younger age were independent risk factors associated with more severe DR in patients with DN. DR was a good predictor of DN. In DN patients, the severity of DR was associated with glomerular injury, and presence of KW nodules, lower hemoglobin levels and younger age were independent risk factors associated with more severe DR. ClinicalTrails.gov, NCT03865914.

Asparagine endopeptidase protects podocytes in adriamycin-induced nephropathy by regulating actin dynamics through cleaving transgelin

Focal segmental glomerulosclerosis (FSGS) is the most common glomerular disorder causing end-stage renal diseases worldwide. Central to the pathogenesis of FSGS is podocyte dysfunction, which is induced by diverse insults. However, the mechanism governing podocyte injury and repair remains largely unexplored. Asparagine endopeptidase (AEP), a lysosomal protease, regulates substrates by residue-specific cleavage or degradation. We identified the increased AEP expression in the primary proteinuria model which was induced by adriamycin (ADR) to mimic human FSGS. Invivo, global AEP knockout mice manifested increased injury-susceptibility of podocytes in ADR-induced nephropathy (ADRN). Podocyte-specific AEP knockout mice exhibited much more severe glomerular lesions and podocyte injury after ADR injection. In contrast, podocyte-specific augmentation of AEP in mice protected against ADRN. Invitro, knockdown and overexpression of AEP in human podocytes revealed the cytoprotection of AEP as a cytoskeleton regulator. Furthermore, transgelin, an actin-binding protein regulating actin dynamics, was cleaved by AEP, and, as a result, removed its actin-binding regulatory domain. The truncated transgelin regulated podocyte actin dynamics and repressed podocyte hypermotility, compared to the native full-length transgelin. Together, our data reveal a link between lysosomal protease AEP and podocyte cytoskeletal homeostasis, which suggests a potential therapeutic role for AEP in proteinuria disease.

Clinical and pathological characteristics of DKD patients with early-onset type 2 diabetes

AimsIn diabetic kidney disease (DKD) patients, early-onset T2DM effects on renal disease severity and outcomes remain uncertain. Herein, we aim to investigate the clinicopathological characteristics and renal outcomes in DKD patients with early-onset T2DM. Methods489 patients with T2DM and DKD were retrospectively recruited and classified as having early (age at onset of T2DM < 40 years) and late (age at onset of T2DM ≥ 40 years) T2DM onset, analyzing the clinical and histopathological data. The predictive value of early-onset T2DM to renal outcomes in DKD patients was analyzed by Cox's regression. ResultsAmong 489 DKD patients, 142 and 347 were classified as early and late T2DM onset, respectively. Early-onset T2DM patients exhibited worse glycaemic control (7.36 % ± 1.80 % vs. 6.86 % ± 1.57 %, P = 0.007) and more severe proteinuria (3.69 [1.55 to 7.03] vs. 1.81 [0.50 to 4.33] g/24 h, P < 0.001). Those with early-onset T2DM presented more severe glomerular lesions. In univariable Cox regression, early-onset T2DM showed a significant correlation with renal composite endpoint (HR [95%CI]: 0.56 [0.43 to 0.73], P < 0.001). However, after adjusting for potential confounders, early-onset T2DM was not independently correlated with renal composite endpoint (HR [95%CI]: 0.74 [0.46 to 1.21], P = 0.232). ConclusionsIn DKD patients with early-onset T2DM, renal clinicopathological manifestations were severe. Age at onset in T2DM was significantly correlated with eGFR slope (r = 0.211, P < 0.001).

Clinical value of the renal pathologic scoring system in complement-mediated thrombotic microangiopathy

Objectives This study was initiated to establish a renal thrombotic microangiopathy (TMA) scoring system based on clinical needs and investigate its predictive value for patients’ long-term outcomes. Methods Kidney biopsy-proven Complement-mediated TMA (C-TMA) patients from January 2000 to December 2017 in Peking University First Hospital were retrospectively studied. Both acute and chronic TMA-related lesions, including 15 pathologic indices, were semiquantitatively scored. The interobserver and intraobserver reproducibility and correlation between the pathologic indices and clinical parameters were analyzed. Furthermore, the patients were divided into 2 groups by dialysis use at baseline, and the association of these pathologic indices with their prognostic outcomes was assessed between the two groups. Results Ninety-two patients with renal biopsy-proven C-TMA were enrolled. All fifteen included pathology indices showed good or moderate interobserver and intraobserver reproducibility and correlated well with several clinical parameters. Several clinicopathological indices were worse in the dialysis group than in the nondialysis group, such as serum creatinine, hemoglobin, platelet count, and estimated glomerular filtration rate. Moreover, morphologic features in the dialysis group presented with more severe vascular lesions. Interstitial fibrosis and chronic tubulointerstitial lesions were related to a trend of high risk of continuous dialysis in the dialysis group. Based on univariate and multivariable Cox regression analysis, more severe glomerular lesions, including glomerular mesangiolysis, glomerular basement membrane double contours and glomerular mesangial proliferation, were identified as risk factors predicting worse prognosis. Conclusions Our renal C-TMA semiquantitative scoring system is reliable with good reproducibility and prognostic value in clinical practice, which needs further validation.

Single-cell RNA sequencing reveals the effects of hederasaponin C in the treatment of diabetic nephropathy

There is great demand for the development of novel efficient therapeutic strategies or preventative measures to alleviate the life-threatening complications of type 2 diabetes. Hederasaponin C (PB5), a natural product, has been reported to exhibit significant therapeutic effects in various diseases; however, the possible effects and mechanism underlying PB5 in reducing diabetic renal complications have not been comprehensively reported. Here, we investigated the response of murine diabetic models to PB5 treatment using single-cell RNA-sequencing (scRNA-seq) and proteomics. Our findings revealed the dynamic transcriptional changes of renal cells in response to diabetic nephropathy. PB5 alleviated inflammatory injury by partially reducing pathophysiologic processes. In addition, we observed severe glomerular lesions and functional deficiencies, including GBM thickening and podocyte dysfunction, during the progression of diabetes, which were likewise attenuated by PB5. These results provide insight into how PB5 treatment improves diabetic symptoms and possibly serves as a novel protective measure and therapeutic strategy in the treatment of type 2 diabetes.

Renal Histologic Findings in Necropsies of Type 2 Diabetes Mellitus Patients

Background Very few studies have analyzed early histologic lesions of diabetic nephropathy (DN) in patients without signs of clinical involvement (microalbuminuria). In this study, we analyzed renal histologic lesions in necropsies of diabetic patients with or without previous signs of DN. Methods Histological material was analyzed from 21 autopsies of type 2 diabetes mellitus (T2DM) patients (9 with albuminuria and 12 without albuminuria) and 4 controls. Histologic lesions were evaluated according to the Tervaert classification. Results Kidneys of diabetic patients presented significantly higher scores in most histologic indices analyzed (glomerular basal membrane thickening, mild and severe mesangial expansion, nodular sclerosis, interstitial fibrosis, and tubular atrophy) than in nondiabetic controls (p < 0.01 in all cases). In contrast, no significant differences were detected between histologic scores when comparing the 21 diabetic patients with and without albuminuria. A significant percentage of cases without albuminuria showed moderate to severe histologic lesions, particularly severe mesangial expansion and severe glomerular vascular lesions. No significant differences were found in age, blood pressure, diabetes vintage, BMI, HbA1c, cholesterol, triglycerides, or treatments between the two (albuminuric vs. nonalbuminuric) T2DM patient groups. Conclusions Our data suggest that histologic lesions of DN are present in the early stages of the disease, even without albuminuria presence. More precise and earlier metabolic control is recommended in T2DM, and monitoring of risk factors can play a role in DN development.

What is the prognosis of ANCA-associated glomerulonephritis with immune deposition?

Objectives This study aimed to analyze histological and clinical characteristics of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) showing renal involvement to investigate the associations between immune complexes (IC) and clinicopathological indicators, and explore the renal outcomes of AAV. Methods We retrospectively evaluated the histopathological features and clinical characteristics of 80 renal biopsies of patients with AAV with renal involvement. Renal morphology was classified into two (with and without the presence of IC and complement deposition). Endpoints included end-stage kidney disease (ESKD) and death. Results Compared with patients without IC, patients with immune deposition had lower complement C3 (0.80 ± 0.27 vs. 0.93 ± 0.20, p = 0.024), more severe hematuria [133 (46–299) vs. 33 (15–115), p = 0.001] but had milder chronic pathology, including chronic tubular atrophy (p = 0.03), chronic interstitial fibrosis (p = 0.049). Patients in the immune deposition group showed a tendency to have more severe crescent formation and less glomerulosclerosis, but the difference was not statistically significant. Endpoints such as death and ESKD were not significantly different between the two groups. Conclusions Immune deposition may indicate lower complement C3, more severe hematuria and glomerular lesions, milder tubular atrophy, and interstitial fibrosis, but it cannot predict the renal outcome.

Aspartate aminotransferase to alanine aminotransferase ratio and the risk of diabetic nephropathy progression in patients with type 2 diabetes mellitus: A biopsy-based study

PurposeTo study the relationship between baseline serum aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR) in both clinicopathological features and renal outcome among type 2 diabetes mellitus (T2DM) patients with biopsy-confirmed diabetic nephropathy (DN). MethodsAs a retrospective cohort study, we included 253 patients with T2DM and biopsy-confirmed DN. For receiver operating characteristic (ROC) curve showed that the optimal cut-off for AAR to predict end stage renal disease (ESRD) was 1.22. So, patients were divided into two groups according to their AAR at the time of renal biopsy: high AAR Group (those with AAR > 1.22); low AAR Group (those with AAR ≤1.22). Association between AAR and clinicopathological features as well as renal outcome were analyzed. ResultsPatients with higher AAR presented elder, more hypertensive, more insulin use, higher serum cholesterol, more proteinuria and lower estimated glomerular filtration rate (eGFR). Compared with low AAR group, patients with high AAR had more severe glomerular pathological lesions and interstitial fibrosis and tubular atrophy. For prognostic analysis, high AAR Group was associated with a higher risk of progression to ESRD in univariate analysis. No matter treated with continuous or categorical variate, higher AAR remained an independent predictor for ESRD after adjusted for various confounding factors: gender, age, the duration of diabetes, serum glucose level, hypertension, serum lipid level, smoking, insulin use, eGFR and proteinuria. ConclusionHigh AAR was associated with more severe renal pathologic lesions and worse renal function in patients with T2DM and DN, which might be a novel noninvasive predictor for ESRD. Clinical relevanceTo our knowledge, there was no biopsy-based cohort study. In our study, high AAR was associated with more severe renal pathologic lesions and worse renal function in patients with T2DM and DN, which might be a novel noninvasive predictor of ESRD for patients with DN.

MO071: Hemolysis is Associated with Altered Heparan Sulfate of Endothelial Glycocalyx And with Local Complement Activation in Thrombotic Microangiopathies

Abstract BACKGROUND AND AIMS The complement system plays a key role in the pathophysiology of renal thrombotic microangiopathies (TMA), as illustrated by atypical hemolytic uremic syndrome (HUS) characterized by a high rate of mutations in complement proteins. However, complement abnormalities are not fully sufficient to drive to TMA lesions. Among other suspected pathophysiological actors, we hypothesize that the alteration of heparan sulfate (HS) of endothelial glycocalyx—a cell membrane glycoaminoglycans and glycoproteins matrix able of regulating complement by binding factor H—may play a significant role. METHOD We recorded clinical and histological features in native kidney biopsies from a monocentric retrospective cohort of 72 TMA-patients. Glomerular HS integrity and local complement activation markers (C3 and C5b9 staining) were analyzed by immunofluorescence (IF) and immunohistochemistry. Using an in vitro endothelial cells model (human umbilical vein endothelial cells, HUVECs), we studied the impact of heme exposure (30’, 37°C)—a major product of hemolysis—on endothelial HS integrity by IF and flow cytometry (FCM). Heme-induced HS disruption was studied by slot blot of HS core-protein Syndecan (SDC) 1 and 4 in cells supernatant. Artificial enzymatic degradation of HS was achieved after exposure of HUVECs to a combination of heparinases I, II and III (30', 37°C), and we studied its effect on the ability of the HS-free cell membrane to locally activate complement by analyzing C3b deposition by IF and FCM, and the release of complement anaphylatoxins C3a and soluble attack complex membrane s-C5b9 in the cell supernatants by ELISA. The HS remodeling process induced by heme exposure (16 h, 37°C) were indirectly analyzed via a transcriptional profiling of the expression of the key enzymes involved in HS synthesis by RT–qPCR. RESULTS Glomerular HS staining decreased in 57 TMA-patients (79%), moderately (2+) or strongly (0–1+) in 20 (28%) and 37 (51%) cases, respectively. Reduced HS density was significantly associated with hemolysis at the time of biopsy (P = 0.008) and local complement activation (C3d and/or C5b-9 deposits, P &amp;lt; 0.001). Hemolysis at the time of biopsy was associated with more severe glomerular TMA lesions (P = 0.025), the presence of vascular thrombi (P = 0.007) and local complement activation (C3d and/or C5b-9 deposits, P = 0.006). On endothelial cells (HUVECs), we confirmed that HS expression was decreased after heme exposure in IF and FCM (P &amp;lt; 0.01). Coherently, HS core-proteins SDC-1 and 4 were significantly increased in HUVECs supernatant (P &amp;lt; 0.05), suggesting a negative heme-driven impact on HS integrity. Artificial HS degradation increased C3b membrane deposition on HUVECs on average ∼ 3 fold by FCM and ∼ 10 by IF, and we observed an increased release of complement C3a and s-C5b9 in cells supernatant (P &amp;lt; 0.05). Finally, we showed that prolonged exposure to heme induced a decreased of genic expression of C5-Epimerase and an increase in 6-OST1 and 3-OST1 expression (P &amp;lt; 0.05), the very three crucial genes of HS remodeling specifically and sequentially involved in the generation of anti-thrombin pattern, the well-known key regulator of the HS/heparin-driven inhibition of coagulation. CONCLUSION This study highlights the impact of hemolysis on the integrity of endothelial glycocalyx HS, both in kidney biopsy of TMA-patients and in an in vitro endothelial cell model, and suggests that acute alteration of HS is a mechanism of heme-induced complement activation. The endothelial glycocalyx appears then to be an important key in the understanding of TMA and could lead to the development of therapeutics targeting its preservation and/or reconstitution, in order to better control the disease.

Addition of glomerular lesion severity improves the value of anemia status for the prediction of renal outcomes in Chinese patients with type 2 diabetes

We aimed to determine the utility of biopsy data and anemia for the prediction of renal outcomes in Chinese patients with type 2 diabetes. In total, 441 Chinese patients with type 2 diabetes and biopsy-confirmed diabetic nephropathy (DN) were enrolled in a retrospective study. Their renal pathology was assessed using the Renal Pathology Society system. Cox proportional hazards models were used to estimate hazard ratios (HRs) for end-stage renal disease (ESRD), and immunofluorescence staining was used to assess the expression of hypoxia-inducible factor (HIF)-α in patients’ kidneys. We found that glomerular pathology classification was an independent pathological predictor of low hemoglobin concentration, according to linear and logistic regression analyses. Each 1 g/dL decrease in baseline hemoglobin concentration was associated with a 42% higher risk of an adverse renal outcome, after adjustment for clinical and pathologic covariates. In patients with severe glomerular lesions, the risk of progression to ESRD was significantly higher if mild or moderate/severe anemia was present, but in patients with mild glomerular lesions, the risk was only significantly higher in those with moderate or severe anemia than in the absence of anemia. Harrell’s C Concordance was improved, but the Akaike information criterion was worsened by adding the glomerular pathology classification to the use of anemia status and clinical data. Immunofluorescence staining revealed that renal HIF-1α and HIF-2α expression was significantly higher in classes II–IV than class I. Thus, the addition of glomerular pathology classification increases the value of anemia status for the prediction of the progression to ESRD.

A Study on Correlation between Contrast-Enhanced Ultrasound Parameters and Pathological Features of Diabetic Nephropathy.

The objective of this study was to evaluate the correlation between contrast-enhanced ultrasound (CEUS) parameters and histopathological features in patients with diabetic nephropathy (DN). Sixty-two patients with DN (44 men, mean age: 52.61 ± 10.63 y) were enrolled. They underwent renal biopsy for DN at the Department of Ultrasound, PLA Hospital, between May 2017 and February 2020. Renal tissue was obtained by ultrasound-guided percutaneous needle biopsy. CEUS was performed, and time-intensity curves (TICs) and renal perfusion parameters were analyzed. Differences in CEUS parameters were analyzed according to the glomerular classification and interstitial fibrosis-tubular atrophy (IFTA) score. Continuous variables were evaluated using the analysis of variance or Mann-Whitney U-test. Discontinuous variables were compared with the χ2-test. Spearman correlation analyses evaluated associations among quantitative ultrasound perfusion parameters and histopathological characteristics. Peak enhancement (PE), wash-in rate (WiR), wash-in perfusion index (WiPI) and wash-out rate (WoR) of the cortex, and their cortex/medulla ratios, decreased with increasing glomerular classification grade (p < 0.05). The fall time (FT) of the cortex, and their cortex/medulla ratios, increased with increasing glomerular classification grade (p < 0.05). There were no significant differences in the CEUS parameters for different IFTA scores. The perfusion volume-relevant parameters (such as PE, WiR and WiPI) had a negative correlation (p < 0.05), while the perfusion time-relevant parameters (such as RT and FT) had a positive correlation (p < 0.05), with the severity of glomerular lesions, glomerulosclerosis rate and number of Kimmelstiel-Wilson lesions. The CEUS parameters of the cortex could reflect pathological characteristics, especially changes in glomerular lesions.

MO648SERUM SOLUBLE UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR IN PATIENTS WITH DIABETIC KIDNEY DISEASE

Abstract Background and Aims Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide, associated with significant cardiovascular morbidity and mortality. Soluble urokinase plasminogen activator receptor (suPAR) is a novel biomarker associated with inflammation, endothelial dysfunction and kidney disease. There is a lack of studies that investigate the role of suPAR in patients with DKD. Our aim was to assess the level of serum suPAR and to evaluate its association with kidney function, proteinuria and histological lesions in patients with DKD. Method We performed a cross-sectional study on 75 patients with DKD evaluated in our department between 2019 and 2020. Inclusion criteria were: age&amp;gt; 18 years, diagnosis of type 1 or type 2 diabetes mellitus, DKD and absence of malignancy, autoimmune disease, infectious disease and liver disease. Demographical, clinical and laboratory parameters were collected at the time of admission. A subset analysis was performed on 28 patients with biopsy- proven diabetic nephropathy (DN) to investigate the association of serum suPAR with histological lesions. Kidney function was evaluated based on serum creatinine and estimated with CKD-EPI formula, proteinuria was reported as 24h proteinuria and albumin/creatinine ratio (ACR) and serum suPAR levels were measured with a solid-phase ELISA kit. The detection range of the kit was 12 -360 pg/ml (7.8- 500). Results Among the 75 patients, mean age was 57.9±12.2 years, male was the dominant gender (65.3%), mean BMI was 30.7±5.5 kg/m2, most patients had hypertension (97.3%) and 22.7% were active smokers. Sixty six out of 75 patients (88%) had type 2 diabetes and the median duration of diabetes was 180 months (120- 240). Median values of estimated glomerular filtration rate (eGFR), 24h proteinuria and ACR were 24.3 ml/min (15- 36), 4.8 g/24h (1.9- 7.1) and 2000 mg/g, respectively. Median serum level of suPAR at the time of evaluation was 2857.2 pg/ml (1916.4- 3700.1). Its level was positively correlated with duration of diabetes (r= 0.278, p= 0.01), eGFR (r= 0.634, p&amp;lt; 0.001), 24h proteinuria (r= 0.490, p&amp;lt; 0.001), ACR (r= 0.524, p&amp;lt; 0.001) and negatively correlated with urine specific gravity (r= -0.284, p= 0.01). In the subset analysis on 28 patients with biopsy-proven DN, median suPAR level was 2474 pg/ml (1782-3745) and was positively correlated with DN class (r= 0.493, p=0.008) and interstitial fibrosis and tubular atrophy (IFTA) score (r= 506, p=0.006), but not with interstitial inflammation, arteriolar hyalinosis or arteriolosclerosis. Conclusion Our study showed a high serum level of suPAR in patients with DKD and its association with duration of diabetes, urinary specific gravity, kidney function and proteinuria. We also found a positive correlation with severity of glomerular lesions and IFTA.

Clinicopathologic features and prognostic factors in older patients with biopsy-proven diabetic nephropathy.

The older population has increased sharply in China. However, renal clinical and histopathological data in this population are lacking. This study investigated the clinicopathologic features and the related risk factors for long-term renal survival in older patients with diabetic nephropathy (DN). In this retrospective observational study, 74 older patients (≥ 60years old) with type 2 diabetes mellitus and biopsy-proven DN from 2007 to 2019 were included. Clinical data were extracted from electronic records. Renal biopsy specimens were semiquantitatively evaluated using the Renal Pathology Society (RPS) classification system. Cox proportional hazard analysis was used to estimate hazard ratios (HRs) for progression to end-stage renal disease (ESRD). During the median follow-up period of 22months, 24 (32%) older patients progressed to ESRD. Older patients who progressed to ESRD had poorer renal function, lower hemoglobin and albumin concentrations, more severe glomerular lesions, and higher percentages of Kimmelstiel-Wilson lesions than those who did not progress to ESRD. After adjusting for age, sex, baseline renal function, and pathological parameters, multivariate Cox proportional hazard analysis showed that RPS glomerular classification (HR 2.49, 95% confidence interval [CI] 1.03-6.04), estimated glomerular filtration rate (eGFR) (HR 0.76, 95% CI 0.58-0.99), and proteinuria (HR 3.85, 95% CI 1.44-10.27) were independent risk factors for progression to ESRD. Lower eGFR, heavier proteinuria, and more severe RPS glomerular lesions were associated with ESRD in older patients with type 2 diabetes mellitus and DN.

P0167HYPERTENSION IN PATIENTS WITH LUPUS NEPHRITIS

Abstract Background and Aims Hypertension is a common manifestation during systemic lupus erythematosus (SLE). Its mechanism is multifactorial and microthromboses of renal arterioles seem to be the most important mechanism. The objective of our study is to identify the histological and evolutionary characteristics of patients with lupus nephritis (LN) presenting with hypertension. Method A retrospective study of 85 patients followed for LES with lupus nephritis documented by a renal biopsy collected in 17 years and presenting with hypertension. Results Among 174 patients with LN, eighty-five (48.58%) are hypertensive. A sex ratio F / H of 6.08. The mean age of LN diagnosis was 36.4 years old [13 -75 years old]. The average time to onset of hypertension was 25.8 months [0-204 months]. Malignant hypertension was present in 12% of patients. Antiphospholipid Antibody Syndrome (APLS) was found in 35.3% of cases. Renal biopsy showed LN class II in 2 cases, class III in 8 cases, class IV in 43 cases, class V isolated in 8 cases and class VI in 3 cases. Vascular lesions were arteriolosclerosis in 40% of cases and thrombotic microangiopathy (TMA) lesions in 17.6% of cases. The treatment was essentially based on blockers of the renin angiotensin system, either as monotherapy or in combination with calcium channel blockers, beta blockers or central antihypertensives. The evolution was marked by the occurrence of cerebrovascular accidents associated in 7 cases with APLS and coronary artery disease in 2 cases. Renal evolution was marked by total and durable remission in 27.5%, chronic renal disease in 31.7%, and end-stage renal failure in 40.8% of cases. Blood pressure was balanced in 40,5 % of cases and unbalanced in 59,5% of cases. Conclusion In our lupus patients, hypertension was common, associated with severe glomerular and vascular lesions and a rather severe renal prognosis.

P1025HISTOLOGICAL AND CLINICAL FINDINGS IN ADULT AUTOPSIES OF TYPE 2 DIABETES MELLITUS PATIENTS WITH OR WITHOUT DIABETIC KIDNEY DISEASE

Abstract Background and Aims Few studies have analyzed early lesions of diabetic nephropathy (DN) in those patients who do not have clinical signs of this involvement, since the indication of renal biopsy is usually performed in patients with significant renal manifestations.The aim of the study was to analyze renal histological lesions from autopsies of diabetic patients with or without clinical expression of DN. Thus, we analyze their correlation according to the presence or absence of proteinuria (albumin/creatinine to ratio &amp;gt; 300). Autopsies from non-diabetic patients was used as a control group. Method Kidneys from autopsies of 21 patients with type 2 diabetes mellitus (T2DM) and 4 non-diabetic controls were analyzed by two pathologists. The histological lesions score of DN was performed according to the classification of Tervaert et al. (JASN. 2010; 21: 556–63), and a description of histological findings, clinical and analytical data were made. Results The mean glomeruli per sample was: 170 ±88. Patient demographics of autopsies: mean age 76 ± 11 years, mean duration of diabetes 6.08 ± 3.2 years (20%&amp;gt; 10 years). Last known eGFR: 51 ± 28, HbA1c: 7.3 ± 1.9%. Albuminuria and cardiovascular disease were present in 42% and 60% of patients with T2DM. Histological and clinical data are shown in Table and Graphics. Conclusion A high percentage of diabetics without early clinical lesions of DN (albuminuria) already express moderate to severe histological changes, especially severe mesangial expansion and severe glomerular vascular lesions. The control group showed minimal histological lesions except for mild expansion of the mesangium and inflammation associated with IFTA. Our data suggest renal involvement in T2DM is present in earlier stages (patients without albuminuria). Therefore, early metabolic control is important, as well as other risk factors that may influence in the development of DN. Large sample size studies are pending to confirm these data.

Diabetic Retinopathy, Classified Using the Lesion-Aware Deep Learning System, Predicts Diabetic End-Stage Renal Disease in Chinese Patients

Objective: To characterize the relationship between diabetic retinopathy (DR) and diabetic nephropathy (DN) in Chinese patients and to determine whether the severity of DR predicts end-stage renal disease (ESRD). Methods: Bilateral fundic photographs of 91 Chinese type 2 diabetic patients with biopsy-confirmed DN, not in ESRD stage, were obtained at the time of renal biopsy in this longitudinal study. The baseline severity of DR was determined using the Lesion-aware Deep Learning System (RetinalNET) in an open framework for deep learning and was graded using the Early Treatment Diabetic Retinopathy Study severity scale. Cox proportional hazard models were used to estimate the hazard ratio (HR) for the effect of the severity of diabetic retinopathy on ESRD. Results: During a median follow-up of 15 months, 25 patients progressed to ESRD. The severity of retinopathy at the time of biopsy was a prognostic factor for progression to ESRD (HR 2.18, 95% confidence interval 1.05 to 4.53, P = .04). At baseline, more severe retinopathy was associated with poor renal function, and more severe glomerular lesions. However, 30% of patients with mild retinopathy and severe glomerular lesions had higher low-density lipo-protein-cholesterol and more severe proteinuria than those with mild glomerular lesions. Additionally, 3% of patients with severe retinopathy and mild glomerular changes were more likely to have had diabetes a long time than those with severe glomerular lesions. Conclusion: Although the severity of DR predicted diabetic ESRD in patients with type 2 diabetes mellitus and DN, the severities of DR and DN were not always consistent, especially in patients with mild retinopathy or microalbuminuria. Abbreviations: CI = confidence interval; DM = diabetic mellitus; DN = diabetic nephropathy; DR = diabetic retinopathy; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; HbA1c = hemoglobin A1c; HR = hazard ratio; NPDR = nonproliferative diabetic retinopathy; PDR = proliferative diabetic retinopathy; SBP = systolic blood pressure; T2DM = type 2 diabetes mellitus; VEGF = vascular endothelial growth factor.

SUN-177 HYPERTENSION AND RENAL DISEASE IN SYSTEMIC LUPUS ERYTHEMATOSUS

Hypertension is a common manifestation during systemic lupus erythematosus (SLE). Its mechanism is multifactorial and microthromboses of renal arterioles seem to be the most important mechanism. The objective of our study is to identify the histological and evolutionary characteristics of patients with lupus nephritis (LN) presenting with hypertension. A retrospective study of 85 patients followed for LES with lupus nephritis documented by a renal biopsy collected between 1998 and 2015 and presenting with hypertension. Among 174 patients with LN, eighty-five (48.58%) are hypertensive. A sex ratio F / H of 6.08. The mean age of LN diagnosis was 36.4 years old [13 -75 years old]. The average time to onset of hypertension was 25.8 months [0-204 months]. Malignant hypertension was present in 12% of patients. Antiphospholipid Antibody Syndrome (APLS) was found in 35.3% of cases. Renal biopsy showed LN class II in 2 cases, class III in 8 cases, class IV in 43 cases, class V isolated in 8 cases and class VI in 3 cases. Vascular lesions were arteriolosclerosis in 40% of cases and thrombotic microangiopathy (TMA) lesions in 17.6% of cases. The treatment was essentially based on blockers of the renin angiotensin system, either as monotherapy or in combination with calcium channel blockers, beta blockers or central antihypertensives. The evolution was marked by the occurrence of cerebrovascular accidents associated in 7 cases with APLS and coronary artery disease in 2 cases. Renal evolution was marked by total and durable remission in 27.5%, chronic renal disease in 31.7%, and end-stage renal failure in 40.8% of cases. Blood pressure was balanced in 40,5 % of cases and unbalanced in 59,5% of cases. In our lupus patients, hypertension was common, associated with severe glomerular and vascular lesions and a rather severe renal prognosis.

The tetraspanin CD9 controls invasive migration and proliferation of parietal epithelial cells and glomerular disease progression

Introduction Crescentic glomerulonephritis (CGN) and focal segmental glomerulosclerosis (FSGS) are life-threatening diseases leading to irreversible renal failure. Increasing evidence supports the notion that glomerular parietal epithelial cells (PEC) are implicated in the formation of crescents in CGN and in glomerular scarring during FSGS. However, the mechanisms underlying the change in PEC phenotype remain unclear, as do those driving their oriented migration towards the glomerular tuft and their increased capacity to proliferate and form hypercellular and sclerotic lesions. Methodes Aiming to identify factors underlying PEC activation, we revealed increased expression of CD9 using comparative deep RNA sequencing of mouse and human normal and diseased glomeruli, confirmed expression by immunohistochemistry, and investigated roles of this tetraspanin in CGN and FSGS pathogeny. As CD9 de novo expression in glomeruli was observed in PEC in human CGN and FSGS and, given the recognized role of PEC in the progression of extracapillary lesions, we generated mice with a specific Cd9 deletion in PEC (iPec-Cd9lox/lox mice) that were challenged in experimental CGN and FSGS models. Cd9 gene knock-down were performed in a PEC line to evaluate its influence on migration, spreading and proliferation. Results During the CGN model, iPec-Cd9 wt/wt control mice showed a rapid increase in albuminuria, renal failure and severe glomerular crescentic lesions. Conversely, iPec-Cd9lox/lox mice displayed marked renal protection. We challenged iPec-Cd9lox/lox mice with the DOCA-salt and unilateral nephrectomy FSGS model. Glomerular ultrastructure and function was preserved in iPec-Cd9lox/lox DOCA mice, whereas iPec-Cd9 wt/wt DOCA mice exhibited flocculo-capsular synechiae and sclerosis. In vitro, we found that CD9 deficiency impairs the ability of PECs to proliferate and to migrate towards a steep gradient of chemoattractant in microfluidic channels. Conclusion These results indicate that de novo expression of CD9 in PECs participates in crescents in experimental CGN and is also critically involved in the development of glomerular lesions in FSGS.

Serum fibrinogen predicts diabetic ESRD in patients with type 2 diabetes mellitus

AimsAlthough increased serum fibrinogen level was often observed in patients with diabetic nephropathy (DN), its association with DN severity and progression remains unclear. The aim of this study was to investigate the relationship between the serum fibrinogen levels and clinicopathological features and renal prognosis in Chinese patients with type 2 diabetes mellitus (T2DM) and DN. MethodsA total of 174 patients with T2DM and biopsy-proven DN were enrolled. Patients were stratified by the quartiles of serum fibrinogen levels; Q1: <3.30 g/L; Q2: between 3.30 and 4.00 g/L; Q3: between 4.00 and 4.74 g/L; Q4:≥4.74 g/L. The renal outcomes were defined by reaching end stage renal disease (ESRD). The influence of serum fibrinogen levels on renal outcomes was evaluated using Cox regression analysis. ResultsThe factors associated with higher level of fibrinogen (Q3 and Q4) were diabetic retinopathy, low e-GFR, high proteinuria and severe glomerular and tubulointerstitial lesions. Importantly, in adjusted analysis, higher levels of fibrinogen were independently related with a greater risk of reaching ESRD with a hazard ratio (HR) of 1.64 per standard deviation (SD) of the natural log-transformed fibrinogen concentration (95%CI, 1.22–2.20; p = 0.001). In reference to the Q1, the risk of renal failure increased by quartiles of the serum fibrinogen level: the HRs were 7.12 for the Q2 (95%CI, 2.29–22.16; p = 0.001), 5.77 for Q3 (95%CI, 1.99–16.75; p = 0.001), and 8.81 for Q4 (95%CI, 2.79–27.80; p < 0.001). ConclusionsThese findings suggested that the elevated serum levels of fibrinogen were associated with diabetic ESRD in patients with T2DM.