4336 Renal Tubular Complement C9 Deposition is Associated with Renal Tubular Damage and Fibrosis in Lupus Nephritis

OBJECTIVES/GOALS: Tubulointerstitial damage in lupus nephritis (LN) is a strong predictor of progression to chronic kidney disease and end stage renal disease (ESRD). While complement activation mediates glomerular injury, the role of complement in renal tubular damage has not been evaluated. We investigated the association between complement activation and tubulointerstitial fibrosis. METHODS/STUDY POPULATION: Patients with LN were selected randomly between July 2014 - July 2016. Chromogenic immunohistochemistry was performed on formalin-fixed, paraffin-embedded, 4-µm human renal biopsy sections using unconjugated, murine anti-human Complement C9 (Hycult Biotech, clone X197) as a marker of the terminal complement activation. Positive control is C3 glomerulopathy and negative control is normal kidney. Tubular basement membrane C9 staining intensity were analyzed on semiquantitative scale 0 to 3 by a renal pathologist. Interstitial fibrosis/tubular atrophy were categorized into low (0–10%), medium (11–20%), or high (≥21%). Clinical parameters were assessed at time of biopsy and 6 months post biopsy. Bivariate associations were assessed between presence of tubular C9 (C9+) and other covariates. RESULTS/ANTICIPATED RESULTS: Renal biopsies from 30 LN studied, 23 (77%) of which had proliferative LN. There were 24 (80%) women, mean (SD) age 33 (12) years. Positive tubular C9 staining was observed in 7/30 (23%) biopsies. At time of renal biopsy, C9+ patients had significantly higher urine protein, compared to C9- patients: median (IQR) 6.2g (3.3-13.1) vs. 2.4g (1.3-4.6), p<0.01. The differences persisted at 6 months after induction therapy: 1.08g (1.0-8.3) in C9+ vs. 0.68g (0.2-2.1) in C9- patients, p = 0.06. There was no significant difference in creatinine at renal biopsy between the two groups. Tubular C9 deposition was associated with interstitial fibrosis: 49% had severe interstitial fibrosis vs. none in the C9- group, p = <0.01. Higher proportion of C9+ patients had moderate NIH Chronicity index: 42.9% vs 8.7% in the C9- group, p = 0.07. DISCUSSION/SIGNIFICANCE OF IMPACT: Tubular C9 deposition is significantly associated with proteinuria, interstitial fibrosis and increased chronicity which predict progression to ESRD and high mortality. This finding suggests that complement activation in the tubules may be linked to proteinuria and contribute to mechanism in tubulointerstitial damage in LN.

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Silencing of SOCS‐1 and SOCS‐3 suppresses renal interstitial fibrosis by alleviating renal tubular damage in a rat model of hydronephrosis

Journal of Cellular Biochemistry ◽

10.1002/jcb.26382 ◽

2017 ◽

Vol 119 (2) ◽

pp. 2200-2211 ◽

Cited By ~ 5

Author(s):

Gui‐Hong Zheng ◽

Yong‐Jian Wang ◽

Xin Wen ◽

Xin‐Rui Han ◽

Min Shen ◽

...

Keyword(s):

Rat Model ◽

Interstitial Fibrosis ◽

Tubular Damage ◽

Renal Interstitial Fibrosis ◽

Renal Tubular Damage ◽

Renal Tubular

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Aggravated renal tubular damage and interstitial fibrosis in mice lacking guanylyl cyclase-A (GC-A), a receptor for atrial and B-type natriuretic peptides

Clinical and Experimental Nephrology ◽

10.1007/s10157-014-0982-1 ◽

2014 ◽

Vol 19 (2) ◽

pp. 197-207 ◽

Cited By ~ 4

Author(s):

Fumiki Yoshihara ◽

Takeshi Tokudome ◽

Ichiro Kishimoto ◽

Kentaro Otani ◽

Atsunori Kuwabara ◽

...

Keyword(s):

Guanylyl Cyclase ◽

Natriuretic Peptides ◽

Interstitial Fibrosis ◽

Tubular Damage ◽

Renal Tubular Damage ◽

Renal Tubular

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Fractional excretion of magnesium as an early indicator of renal tubular damage in normotensive diabetic nephropathy

Turkish Journal of Biochemistry ◽

10.1515/tjb-2019-0232 ◽

2020 ◽

Vol 45 (5) ◽

pp. 543-551

Author(s):

Fatih Ozcelik ◽

Serif Kactas ◽

Halime Hanim Pence ◽

Saadet Kurcenli ◽

Erdim Sertoglu ◽

...

Keyword(s):

Fractional Excretion ◽

Study Patient ◽

Control Group ◽

Tubular Damage ◽

Renal Tubular Damage ◽

Renal Tubular ◽

Excretion Rates ◽

Urine And Serum ◽

Diagnostic And Prognostic Value

AbstractObjectivesThe aim of the present study is to evaluate the diagnostic powers of fractional magnesium, sodium and potassium as markers of renal tubular damage in normotensive type 2 diabetes mellitus (T2DM) patients with respect to microalbuminuria and estimated glomerular filtration rate (eGFR).Materials and methodsForty healthy volunteers and 91 normotensive T2DM patients were included in the study. Patient group was divided into two according to albuminuria level; 49 were normoalbuminuric and 42 were microalbuminuric. In addition to albumin in urine, urine and serum Na, K, Mg and creatinine values were measured to calculate fractional electrolyte excretion rates.ResultsIn normoalbuminuric and microalbuminuric groups, fractional excretion of magnesium (FEMg) values were found to be significantly higher than the control group (p < 0.05). There was a moderate correlation between FEMg and albümin to cratinin ratio (ACR) (Spearman r = 0.3215, p < 0.05). In the ROC analysis for eGFR and FEMg based on microalbuminuria, the areas under the curve were 0.625 and 0.732, respectively (diagnostic sensitivity 59.52% and 66.67%; specificity 70.79% and 77.53%, p < 0.05).ConclusionFor renal tubular damage predicted by microalbuminuria, FEMg could be accepted as a candidate biochemical marker with diagnostic and prognostic value.

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Tactical approaxhes to diagnosis and treatment of hepatorenal syndrome in patients with blastomatous obstructive jaundice

Problems of Uninterrupted Medical Training and Science ◽

10.31071/promedosvity2021.02.028 ◽

2021 ◽

Vol 42 (2) ◽

pp. 28-31

Author(s):

S. V. Kosulin ◽

◽

Ju. O. Vinnik ◽

Ju. V. Ivanova ◽

◽

...

Keyword(s):

Obstructive Jaundice ◽

Hepatorenal Syndrome ◽

Resistance Index ◽

Doppler Imaging ◽

Coagulation System ◽

Tubular Damage ◽

Renal Tubular Damage ◽

Renal Tubular ◽

Neutrophil Gelatinase

The article discusses problems of early diagnosis and, accordingly, treatment of hepatorenal syndrome (HRS) in case of obstructive jaundice of blastomatous origin. The results of a comprehensive examination of 37 patients with blastomatous obstructive jaundice (OJ) with clinical and laboratory signs of HRS were analyzed. Patients were evaluated for clinical and biochemical parameters of blood and urine, blood electrolytes, indicators of the blood coagulation system according to unified methods. The main work is devoted to the determination of the biomarker of renal tubular damage, neutrophil-gelatinase-associated lipocaine (s-NGAL) as a marker and indicator of HRS severity, careful and detailed analysis, monitoring of levels (s-NGAL) and other bioactive substances as an indicator of treatment efficacy. Introduction of active ultrasound as a replacement for contrast computer tomography to reduce the load on precompromised kidneys. It has been proven that the level of renal tubular damage, neutrophil-gelatinase-associated lipocaine s-NGAL is an early marker of renal damage whose function is to reduce the severity of damage to the proximal tubules of the kidneys, normalize damaged tissue by participating in apoptosis, increase survival of damaged restoration of damaged epithelium, stimulation of differentiation and structural reorganization of renal epithelial cells. The fact that s-NGAL was not significantly reduced in the stage of recovery of diuresis, confirms the presence of patients with blastomatous MF severe and persistent toxic tubulointerstitial disorders. Based on this determination of the biomarker (s-NGAL) in the serum of patients with blastomatous mechanical jaundice and performing in them at primary ultrasound color Doppler mapping and pulsed wave Doppler imaging of the kidneys with the calculation of the resistance index may serve as early signs of damage.

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Chronic Renal Tubular Damage Caused by Cyclosporin A

Nephrotoxicity ◽

10.1007/978-1-4757-2040-2_46 ◽

1989 ◽

pp. 309-314

Author(s):

P. H. Whiting ◽

N. J. Saunders ◽

K. J. Thomson ◽

J. G. Simpson

Keyword(s):

Cyclosporin A ◽

Tubular Damage ◽

Renal Tubular Damage ◽

Renal Tubular

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Soluble receptor for advanced glycation end products protects from ischemia- and reperfusion-induced acute kidney injury

Biology Open ◽

10.1242/bio.058852 ◽

2021 ◽

Author(s):

Taro Miyagawa ◽

Yasunori Iwata ◽

Megumi Oshima ◽

Hisayuki Ogura ◽

Koichi Sato ◽

...

Keyword(s):

Acute Kidney Injury ◽

Advanced Glycation End Products ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Tubular Damage ◽

Advanced Glycation ◽

Renal Tubular Damage ◽

Glycation End Products ◽

End Products ◽

Renal Tubular

The full-length receptor for advanced glycation end products (RAGE) is a multiligand pattern recognition receptor. High-mobility group box 1 (HMGB1) is a RAGE ligand of damage-associated molecular patterns that elicits inflammatory reactions. The shedded isoform of RAGE and endogenous secretory RAGE (esRAGE), a splice variant, are soluble isoforms (sRAGE) that act as organ-protective decoys. However, the pathophysiologic roles of RAGE/sRAGE in acute kidney injury (AKI) remain unclear. We found that AKI was more severe, with enhanced renal tubular damage, macrophage infiltration, and fibrosis, in mice lacking both RAGE and sRAGE than in wild-type control mice. Using murine tubular epithelial cells (TECs), we demonstrated that hypoxia upregulated messenger RNA (mRNA) expression of HMGB1 and tumor necrosis factor α (TNF-α), whereas RAGE and esRAGE expressions were paradoxically decreased. Moreover, the addition of recombinant sRAGE canceled hypoxia-induced inflammation and promoted cell viability in cultured TECs. sRAGE administration prevented renal tubular damage in models of ischemia/reperfusion-induced AKI and of anti-glomerular basement membrane (anti-GBM) glomerulonephritis. These results suggest that sRAGE is a novel therapeutic option for AKI.

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Renal Tubular Damage in Infantile Gastro-enteritis

Archives of Disease in Childhood ◽

10.1136/adc.34.174.158 ◽

1959 ◽

Vol 34 (174) ◽

pp. 158-165 ◽

Cited By ~ 3

Author(s):

J. Black

Keyword(s):

Tubular Damage ◽

Renal Tubular Damage ◽

Renal Tubular

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Intrarenal activation of adaptive immune effectors is associated with tubular damage and impaired renal function in lupus nephritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2018-213485 ◽

2018 ◽

Vol 77 (12) ◽

pp. 1782-1789 ◽

Cited By ~ 15

Author(s):

Cristina Pamfil ◽

Zuzanna Makowska ◽

Aurélie De Groof ◽

Gaëlle Tilman ◽

Sepideh Babaei ◽

...

Keyword(s):

Renal Function ◽

Lupus Nephritis ◽

Cell Activation ◽

Immune Cell ◽

Tubular Cell ◽

Tubular Damage ◽

Renal Tubular Cell ◽

Chronic Renal Impairment ◽

Adaptive Immune ◽

Renal Tubular

ObjectivesChronic renal impairment remains a feared complication of lupus nephritis (LN). The present work aimed at identifying mechanisms and markers of disease severity in renal tissue samples from patients with LN.MethodsWe performed high-throughput transcriptomic studies (Illumina HumanHT-12 v4 Expression BeadChip) on archived kidney biopsies from 32 patients with LN and eight controls (pretransplant donors). Histological staging (glomerular and tubular scores) and immunohistochemistry experiments were performed on the same and on a replication set of 37 LN kidney biopsy samples.ResultsA group of LN samples was identified by unsupervised clustering studies based on their gene expression features, that is, the overexpression of transcripts involved in antigen presentation, T and B cell activation. These samples were characterised by a significantly lower estimated glomerular filtration rate (eGFR) at the time of biopsy (T0) compared with the other systemic lupus erythematosus samples. Yet, apparent disease duration at T0, double-stranded DNA antibody titres at T0 and other relevant characteristics (serum C3, proteinuria, histological scores, numbers of previous flares) were not different between groups.Immunohistochemistry studies confirmed the association between interstitial infiltration by adaptive immune effectors and decreased renal function in the same and in a replication group of LN kidney biopsies. This was associated with transcriptomic, histological and immunohistochemical evidence of renal tubular cell involvement.ConclusionInterstitial infiltration of LN kidney biopsies by adaptive immune effectors is associated with impaired renal tubular cell function and decreased eGFR. These results open new perspectives in evaluating and treating patients with LN, focusing on intrarenal mechanisms of immune cell activation.

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