Complement Components C3 and C4 Indicate Vasculitis Manifestations to Distinct Renal Compartments in ANCA-Associated Glomerulonephritis

Background: Acute kidney injury (AKI) is a common and severe complication of antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) causing progressive chronic kidney disease (CKD), end-stage renal disease (ESRD) or death. Pathogenic ANCAs, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), trigger a deleterious immune response resulting in pauci-immune necrotizing and crescentic glomerulonephritis (GN), a common manifestation of glomerular injury in AAV. However, there is growing evidence that activation of the complement pathway contributes to the pathogenesis and progression of AAV. We here aimed to compare glomerular and tubulointerstitial lesions in ANCA GN and extrarenal manifestation of AAV in association with levels of circulating complement components C3c and C4. Methods: Plasma levels of C3c and C4 in a total number of 53 kidney biopsies with ANCA GN were retrospectively included between 2015 and 2020. Glomerular and tubulointerstitial lesions were evaluated according to established scoring systems for ANCA GN and analogous to the Banff classification. Results: We here show that circulating levels of C3c and C4 in ANCA GN were comparable to the majority of other renal pathologies. Furthermore, hypocomplementemia was only detectable in a minor subset of ANCA GN and not correlated with renal or extrarenal AAV manifestations. However, low levels of circulating C3c correlated with AKI severity in ANCA GN independent of systemic disease activity or extrarenal AAV manifestation. By systematic scoring of glomerular and tubulointerstitial lesions, we provide evidence that low levels of circulating C3c and C4 correlated with vasculitis manifestations to distinct renal compartments in ANCA GN. Conclusions: We here expand our current knowledge about distinct complement components in association with vasculitis manifestations to different renal compartments in ANCA GN. While low levels of C4 correlated with glomerulitis, our observation that low levels of circulating complement component C3c is associated with interstitial vasculitis manifestation reflected by intimal arteritis implicates that C3c contributes to tubulointerstitial injury in ANCA GN.

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MO083SYSTEMATIC HISTOLOGICAL SCORING OF TUBULOINTERSTITIAL LESIONS CORRELATE WITH CLINICAL PARAMETERS IN ANCA-ASSOCIATED GLOMERULONEPHRITIS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab078.0019 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Björn Tampe ◽

Samy Hakroush

Keyword(s):

High Risk ◽

Immunosuppressive Therapy ◽

Kidney Function ◽

Current Knowledge ◽

Renal Involvement ◽

Remission Induction ◽

Tubulointerstitial Injury ◽

Short Term ◽

Tubulointerstitial Lesions ◽

Renal Biopsies

Abstract Background and Aims Renal involvement is a common and severe complication of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We have previously reported that severe deterioration of kidney function is associated with necrotizing and crescentic ANCA glomerulonephritis (GN), classified into Berden’s crescentic class or ANCA renal risk score (ARRS) high risk. However, tubulointerstitial inflammation associated with either histopathological subgrouping or ARRS remains elusive. Furthermore, clinical and laboratory markers of AAV disease severity or deterioration of kidney function in association with inflammatory findings in the kidney have not been described yet. Since aggressive immunosuppressive therapy is recommended for remission induction especially in severe cases of AAV, we here aimed to expand our current knowledge with regard to histopathological classification of tubulointerstitial injury and inflammatory findings analogous to the Banff classification. Method A total number of 50 renal biopsies with confirmed renal involvement of AAV were retrospectively included between 2015 till 2020 in a single-center observational study. Renal biopsies were evaluated for either focal, crescentic, mixed or sclerotic class (according to Berden et al.) and ARRS low, intermediate or high risk (according to Brix et al.). Inflammatory and fibrotic tubulointerstital alterations were evaluated analogous to Banff scoring system for allograft pathology. Results We here show that distinct inflammatory lesions are associated with glomerular findings classified into either histopathological subgrouping or ARRS. Furthermore, interstitial inflammation and tubulitis correlate with disease severity and decline of kidney function in AAV. Finally, we provide data that tubulointerstitial injury and inflammatory findings correlate with short-term outcome in response to aggressive immunosuppression and remission induction therapy. Conclusion In summary, we here provide evidence that a systematic scoring of inflammatory and degenerative tubulointerstitial lesions correlate with severe renal impairment and short-term response to remission induction therapy. Since aggressive immunosuppressive therapy is recommended for remission induction especially in severe cases of AAV, systematic histopathological scoring of tubuloinsterstital lesions could further improve our current knowledge of ANCA GN progression.

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Different effects of global osteopontin and macrophage osteopontin in glomerular injury

AJP Renal Physiology ◽

10.1152/ajprenal.00458.2017 ◽

2018 ◽

Vol 315 (4) ◽

pp. F759-F768 ◽

Cited By ~ 5

Author(s):

Jessica Trostel ◽

Luan D. Truong ◽

Carlos Roncal-Jimenez ◽

Makoto Miyazaki ◽

Shinobu Miyazaki-Anzai ◽

...

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Reactive Oxygen ◽

Kidney Injury ◽

Oxygen Species ◽

Glomerular Injury ◽

Tubulointerstitial Injury ◽

Crescent Formation ◽

Elevated Expression ◽

Toxin Receptor

Osteopontin (OPN) is a pro-and anti-inflammatory molecule that simultaneously attenuates oxidative stress. Both inflammation and oxidative stress play a role in the pathogenesis of glomerulonephritis and in the progression of kidney injury. Importantly, OPN is highly induced in nephritic kidneys. To characterize further the role of OPN in kidney injury we used OPN−/− mice in antiglomerular basement membrane reactive serum-induced immune (NTS) nephritis, an inflammatory and progressive model of kidney disease. Normal wild-type (WT) and OPN−/− mice did not show histological differences. However, nephritic kidneys from OPN−/− mice showed severe damage compared with WT mice. Glomerular proliferation, necrotizing lesions, crescent formation, and tubulointerstitial injury were significantly higher in OPN−/− mice. Macrophage infiltration was increased in the glomeruli and interstitium in OPN−/− mice, with higher expression of IL-6, CCL2, and chemokine CXCL1. In addition, collagen (Col) I, Col III, and Col IV deposition were increased in kidneys from OPN−/− mice. Elevated expression of the reactive oxygen species-generating enzyme Nox4 and blunted expression of Nrf2, a molecule that inhibits reactive oxygen species and inflammatory pathways, was observed in nephritic kidneys from OPN−/− mice. Notably, CD11b diphteria toxin receptor mice with NTS nephritis selectively depleted of macrophages and reconstituted with OPN−/− macrophages showed less kidney injury compared with mice receiving WT macrophages. These findings suggest that in global OPN−/− mice there is increased inflammation and redox imbalance that mediate kidney damage. However, absence of macrophage OPN is protective, indicating that macrophage OPN plays a role in the induction and progression of kidney injury in NTS nephritis.

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POS0247 INTERSTITIAL ANCA-ASSOCIATED VASCULITIS ASSOCIATES WITH SEVERE KIDNEY INJURY INDEPENDENT OF GLOMERULONEPHRITIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.4296 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 345.2-345

Author(s):

S. Hakroush ◽

B. Tampe

Keyword(s):

Kidney Function ◽

Current Knowledge ◽

Interstitial Fibrosis ◽

Kidney Injury ◽

Small Vessel ◽

Small Vessel Vasculitis ◽

Tubular Atrophy ◽

Anca Associated Vasculitis ◽

Tubulointerstitial Lesions ◽

Peritubular Capillaritis

Background:Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis affecting multiple organ systems, including the kidney. Small vessels in the kidney include small-sized arteries (interlobular artery, afferent and efferent arteriole), capillaries (glomerular and peritubular capillary) and venules.Objectives:Although crescentic ANCA glomerulonephritis (GN) is a common histological finding reflecting glomerular small vessel vasculitis, it is reasonable that manifestation of AAV could also contribute to interstitial small vessel vasculitis. Therefore, we here aimed to expand our current knowledge focusing on interstitial vasculitis in ANCA GN by systematic histological scoring of vascular lesions analogous to Banff.Methods:A total number of 49 kidney biopsies with confirmed renal involvement of AAV at the University Medical Center Göttingen were retrospectively included between 2015 till 2020. A renal pathologist (SH) evaluated all biopsies and was blinded to clinical data collection and analysis. A detailed methological section is provided in the Supplementary material and methods section.Results:Since previous studies established that crescentic ANCA GN associates with severe kidney injury and acute deterioration of kidney function in AAV, we first systematically scored interstitial vasculitis in association with requirement of renal replacement therapy (RRT). Among all active and chronic tubulointerstitial lesions analogous to the Banff scoring system, the only association between severe kidney injury requiring RRT was observed for interstitial vasculitis in AAV reflected by peritubular capillaritis (ptc, p=0.0002) and arteritis (v, p=0.0069), affecting 5/49 (10.2%) and 11/49 (22.4%) of renal biopsies, respectively. Since it is known that severe deterioration of kidney function also correlates with crescentic ANCA GN, we next directly compared glomerular and tubulointerstitial lesions. The fraction of normal glomeruli was inversely associated with interstitial fibrosis (ci), total (ti) and inflammation in IFTA (i-IFTA), whereas glomerular crescents were associated with interstitial inflammation (i), tubulitis (t) and total inflammation (ti). In contrast, global glomerular sclerosis associated with less interstitial inflammation (i) but correlated with interstitial fibrosis (ci) and tubular atrophy (ct), confirming established mechansim that chronic glomerular injury leads to tubular atrophy and interstitial fibrosis. Interestingly, no association between interstitial vasculitis (ptc and v correlating with severe kidney injury) and any glomerular lesion in ANCA GN (also correlating with severe kidney injury) was observed, thereby confirming that interstitial vasculitis contributes to severe kidney injury independent of ANCA GN. By contrast, short-term renal recovery from RRT was equal in both groups, suggesting a distinct association with acute decline of kidney function at disease onset.Conclusion:Taken together, by using the Banff scoring system we here expand our current knowledge of renal interstitial lesions in AAV revealing peritubular capillaritis and arteritis as important histological alterations associated with severe kidney injury in a considerable subset of AAV. Furthermore, our findings that interstitial vasculitis did not correlate with crescentic ANCA GN implicate that the characteristics of each vasculitis manifestation are independent and could further improve our understanding of mechanisms contributing to renal injury. These observations suggest that interstitial vasculitis in AAV may also affect long-term prognosis requiring further investigation.Disclosure of Interests:None declared

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Protective Role of Nrf2 in Renal Disease

Antioxidants ◽

10.3390/antiox10010039 ◽

2020 ◽

Vol 10 (1) ◽

pp. 39

Author(s):

Melania Guerrero-Hue ◽

Sandra Rayego-Mateos ◽

Cristina Vázquez-Carballo ◽

Alejandra Palomino-Antolín ◽

Cristina García-Caballero ◽

...

Keyword(s):

Oxidative Stress ◽

Current Knowledge ◽

Unmet Need ◽

Kidney Injury ◽

Protective Role ◽

Renal Diseases ◽

Related Factor ◽

Ckd Progression ◽

Protective Mechanisms ◽

Novel Therapeutic Strategies

Chronic kidney disease (CKD) is one of the fastest-growing causes of death and is predicted to become by 2040 the fifth global cause of death. CKD is characterized by increased oxidative stress and chronic inflammation. However, therapies to slow or prevent CKD progression remain an unmet need. Nrf2 (nuclear factor erythroid 2-related factor 2) is a transcription factor that plays a key role in protection against oxidative stress and regulation of the inflammatory response. Consequently, the use of compounds targeting Nrf2 has generated growing interest for nephrologists. Pre-clinical and clinical studies have demonstrated that Nrf2-inducing strategies prevent CKD progression and protect from acute kidney injury (AKI). In this article, we review current knowledge on the protective mechanisms mediated by Nrf2 against kidney injury, novel therapeutic strategies to induce Nrf2 activation, and the status of ongoing clinical trials targeting Nrf2 in renal diseases.

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Proteinuria Indicates Decreased Normal Glomeruli in ANCA-Associated Glomerulonephritis Independent of Systemic Disease Activity

Journal of Clinical Medicine ◽

10.3390/jcm10071538 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1538

Author(s):

Désirée Tampe ◽

Peter Korsten ◽

Philipp Ströbel ◽

Samy Hakroush ◽

Björn Tampe

Keyword(s):

Disease Activity ◽

Systemic Disease ◽

Renal Involvement ◽

Kidney Injury ◽

Antineutrophil Cytoplasmic Antibody ◽

Clinicopathological Characteristics ◽

Renal Outcome ◽

Study Results ◽

Renal Biopsies ◽

Stage Renal Disease

Background: Renal involvement is a common and severe complication of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), potentially resulting in a pauci-immune necrotizing and crescentic ANCA glomerulonephritis (GN) with acute kidney injury (AKI), end-stage renal disease (ESRD) or death. There is recent evidence that the degree of proteinuria at diagnosis is associated with long-term renal outcome in ANCA GN. Therefore, we here aimed to systematically describe the association between proteinuria and clinicopathological characteristics in 53 renal biopsies with ANCA GN and corresponding urinary samples at admission. Methods: A total number of 53 urinary samples at admission and corresponding renal biopsies with confirmed renal involvement of AAV were retrospectively included from 2015 to 2021 in a single-center study. Results: Proteinuria correlated with myeloperoxidase (MPO) subtype, diagnosis of microscopic polyangiitis (MPA) and severe deterioration of kidney function. Proteinuria was most prominent in sclerotic class ANCA GN and ANCA renal risk score (ARRS) high risk attributed to nonselective proteinuria, including both glomerular and tubular proteinuria. Finally, there was no association between proteinuria and systemic disease activity, suggesting that proteinuria reflected specific renal involvement in AAV rather that systemic disease activity. Conclusions: In conclusion, proteinuria correlated with distinct clinicopathological characteristics in ANCA GN, mostly attributed to a reduced fraction of normal glomeruli. Furthermore, proteinuria in ANCA GN reflected specific renal involvement in AAV rather than systemic disease activity. Therefore, urinary findings could further improve our understanding of mechanisms promoting kidney injury and progression of ANCA GN.

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In progressive nephropathies, overload of tubular cells with filtered proteins translates glomerular permeability dysfunction into cellular signals of interstitial inflammation.

Journal of the American Society of Nephrology ◽

10.1681/asn.v971213 ◽

1998 ◽

Vol 9 (7) ◽

pp. 1213-1224 ◽

Cited By ~ 2

Author(s):

M Abbate ◽

C Zoja ◽

D Corna ◽

M Capitanio ◽

T Bertani ◽

...

Keyword(s):

Time Course ◽

Early Stage ◽

Protein Accumulation ◽

Glomerular Injury ◽

Cellular Mechanisms ◽

Proinflammatory Response ◽

Glomerular Permeability ◽

Tubular Cells ◽

Interstitial Inflammation ◽

Tubulointerstitial Lesions

Progression to end-stage renal failure is the final common pathway of many forms of glomerular disease, independent of the type of initial insult. Progressive glomerulopathies have in common persistently high levels of urinary protein excretion and tubulointerstitial lesions at biopsy. Among the cellular mechanisms that may determine progression regardless of etiology, the traffic of excess proteins filtered from glomerulus in renal tubule may have functional importance by initiating interstitial inflammation in the early phase of parenchymal injury. This study analyzes the time course and sites of protein accumulation and interstitial cellular infiltration in two different models of proteinuric nephropathies. In remnant kidneys after 5/6 renal mass ablation, albumin and IgG accumulation by proximal tubular cells was visualized in the early stage, preceding interstitial infiltration of MHC-II-positive cells and macrophages. By double-staining, infiltrates developed at or near tubules containing intracellular IgG or luminal casts. This relationship persisted thereafter despite more irregular distribution of infiltrate. Similar patterns were found in an immune model (passive Heymann nephritis), indicating that the interstitial inflammatory reaction develops at the sites of protein overload, regardless of the type of glomerular injury. Osteopontin was detectable in cells of proximal tubules congested with protein in both models at sites of interstitial infiltration, and by virtue of its chemoattractive action this is likely mediator of a proximal tubule-dependent inflammatory pathway in response to protein load. Protein overload of tubules is a key candidate process translating glomerular protein leakage into cellular signals of interstitial inflammation. Mechanisms underlying the proinflammatory response of tubular cells to protein challenge in diseased kidney should be explored, as well as ways of limiting protein reabsorption/deposition to prevent consequent inflammation and progressive disease.

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Machine Learning for Mortality Prediction in Pediatric Myocarditis

Frontiers in Pediatrics ◽

10.3389/fped.2021.644922 ◽

2021 ◽

Vol 9 ◽

Author(s):

Fu-Sheng Chou ◽

Laxmi V. Ghimire

Keyword(s):

Machine Learning ◽

Linear Regression ◽

Regression Model ◽

Current Knowledge ◽

External Validation ◽

Model Development ◽

Kidney Injury ◽

High Specificity ◽

Mortality Prediction ◽

Linear Regression Models

Background: Pediatric myocarditis is a rare disease. The etiologies are multiple. Mortality associated with the disease is 5–8%. Prognostic factors were identified with the use of national hospitalization databases. Applying these identified risk factors for mortality prediction has not been reported.Methods: We used the Kids' Inpatient Database for this project. We manually curated fourteen variables as predictors of mortality based on the current knowledge of the disease, and compared performance of mortality prediction between linear regression models and a machine learning (ML) model. For ML, the random forest algorithm was chosen because of the categorical nature of the variables. Based on variable importance scores, a reduced model was also developed for comparison.Results: We identified 4,144 patients from the database for randomization into the primary (for model development) and testing (for external validation) datasets. We found that the conventional logistic regression model had low sensitivity (~50%) despite high specificity (>95%) or overall accuracy. On the other hand, the ML model struck a good balance between sensitivity (89.9%) and specificity (85.8%). The reduced ML model with top five variables (mechanical ventilation, cardiac arrest, ECMO, acute kidney injury, ventricular fibrillation) were sufficient to approximate the prediction performance of the full model.Conclusions: The ML algorithm performs superiorly when compared to the linear regression model for mortality prediction in pediatric myocarditis in this retrospective dataset. Prospective studies are warranted to further validate the applicability of our model in clinical settings.

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NAFLD and Infection, a Nuanced Relationship

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2021/5556354 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Abimbola Adenote ◽

Igor Dumic ◽

Cristian Madrid ◽

Christopher Barusya ◽

Charles W. Nordstrom ◽

...

Keyword(s):

Current Knowledge ◽

Systemic Disease ◽

Type Ii Diabetes Mellitus ◽

Low Grade ◽

Extrahepatic Manifestations ◽

Nonalcoholic Fatty Liver ◽

Multiple Organs ◽

Clostridioides Difficile ◽

Low Grade Inflammation ◽

Ovarian Syndrome

The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased significantly over the last few decades mirroring the increase in obesity and type II diabetes mellitus. NAFLD has become one of the most common indications for liver transplantation. The deleterious effects of NAFLD are not isolated to the liver only, for it has been recognized as a systemic disease affecting multiple organs through protracted low-grade inflammation mediated by the metabolic activity of excessive fat tissue. Extrahepatic manifestations of NAFLD such as cardiovascular disease, polycystic ovarian syndrome, chronic kidney disease, and hypothyroidism have been well described in the literature. In recent years, it has become evident that patients suffering from NAFLD might be at higher risk of developing various infections. The proposed mechanism for this association includes links through hyperglycemia, insulin resistance, alterations in innate immunity, obesity, and vitamin D deficiency. Additionally, a risk independent of these factors mediated by alterations in gut microbiota might contribute to a higher burden of infections in these individuals. In this narrative review, we synthetize current knowledge on several infections including urinary tract infection, pneumonia, Helicobacter pylori, coronavirus disease 2019, and Clostridioides difficile as they relate to NAFLD. Additionally, we explore NAFLD’s association with hidradenitis suppurativa.

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Lupus-like nephritis with positive anti-neutrophil cytoplasmic antibodies and negative antinuclear antibodies

Brazilian Journal of Nephrology ◽

10.1590/2175-8239-jbn-2020-0114 ◽

2020 ◽

Author(s):

Joana Eugénio Santos ◽

Rita Vicente ◽

Beatriz Malvar ◽

Iolanda Santos ◽

Miguel Coimbra ◽

...

Keyword(s):

Lupus Erythematosus ◽

Antinuclear Antibodies ◽

Kidney Biopsy ◽

Kidney Injury ◽

Steroid Treatment ◽

Antineutrophil Cytoplasmic Antibodies ◽

Small Vessel Vasculitis ◽

Laboratory Findings ◽

Clinical Criteria ◽

Immunological Markers

Abstract Antineutrophil cytoplasmic antibodies (ANCAs) are associated with small vessel vasculitis but their prevalence is not rare in other immune diseases. In lupus nephritis (LN), their pathological role and clinical relevance have been the target of controversial views. We present a case of acute kidney injury and nephrotic syndrome in a young woman with diffuse global proliferative and membranous nephritis on her kidney biopsy, showing a full-house immunofluorescence pattern, very allusive of class IV + V LN, but lacking associated clinical criteria and laboratory findings to support the diagnosis of systemic lupus erythematosus (SLE). Furthermore, the patient presented with high titers of ANCA, steadily decreasing alongside the renal function and proteinuria improvements, with mycophenolate mofetil (MMF) and steroid treatment. The authors believe this is a case of lupus-like nephritis, in which ANCAs are immunological markers, although they are not directly involved in the pathogenesis.

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