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11 pages, 637 KiB

Open AccessArticle

Impact of Early Proteinuria Reduction in Glomerular Disease and Decline of Kidney Function: A Retrospective Cohort

by Filipe Marques, Joana Reis, Iolanda Godinho, Marta Pereira, Paulo Fernandes, Sofia Jorge, José António Lopes and Joana Gameiro

J. Clin. Med. 2022, 11(19), 5968; https://doi.org/10.3390/jcm11195968 - 10 Oct 2022

Cited by 2 | Viewed by 1349

Abstract

Background: In glomerular disease, the degree of proteinuria is closely related to the progression of chronic kidney disease, and its reduction is associated with a slower decline in the glomerular filtration rate (eGFR) and consequent improvement in the renal prognosis. The aim of [...] Read more.

Background: In glomerular disease, the degree of proteinuria is closely related to the progression of chronic kidney disease, and its reduction is associated with a slower decline in the glomerular filtration rate (eGFR) and consequent improvement in the renal prognosis. The aim of this study was to evaluate the impact of proteinuria reduction on the decline of the eGFR in patients with glomerular disease, during the first year after the diagnosis. Methods: This was a retrospective analysis of patients with primary glomerular disease, followed at the Nephrology Department of Centro Hospitalar Universitário Lisboa Norte, during 2019. We analyzed demographic, clinical and laboratorial characteristics (creatinine, GFR, urine analysis and quantification of proteinuria determined by the proteinuria/creatinuria ratio, in the first morning urine or a 24 h urine sample). The outcome assessed was the decline in renal function, defined as a reduction in the GFR ≥ 25%, during the follow-up period. Results: We analyzed 197 patients with glomerular disease, with a mean age of 41.7 ± 19.7 years and follow-up time of 6.5 ± 5.3 years. At the time of the diagnosis, the eGFR was 81.5 ± 49.8 mL/min/1.73 m² and proteinuria was 3.5 g/24 h (IQR 5.8). At one-year follow-up, median proteinuria was 0.9 g/24 h (IQR 2.4). At the end of the follow-up, mean eGFR was 72.1 ± 43.3 mL/min/1.73 m². Proteinuria (p = 0.435) and the eGFR (p = 0.880) at the time of diagnosis did not correlate with long-term decline in the eGFR. Proteinuria < 1 g/24 h (HR 0.45 (95% CI 0.25–0.83) p = 0.011) after the first year was protective against long-term decline in the eGFR. It maintained this association with the long-term eGFR decline, independently of the duration of the follow-up (HR 0.30 (95% CI 0.17–0.52) p < 0.001). Conclusions: Proteinuria reduction to lower than 1 g/24 h, during the first year after diagnosis, was a protective factor for the long-term decline of kidney function, having a more important role than proteinuria or the GFR at the time of the diagnosis. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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12 pages, 1242 KiB

Open AccessArticle

New Insights into Renal Failure in a Cohort of 317 Patients with Autosomal Dominant Forms of Alport Syndrome: Report of Two Novel Heterozygous Mutations in COL4A3

by José María García-Aznar, Luis De la Higuera, Lara Besada Cerecedo, Nerea Paz Gandiaga, Ana Isabel Vega, Gema Fernández-Fresnedo and Domingo González-Lamuño

J. Clin. Med. 2022, 11(16), 4883; https://doi.org/10.3390/jcm11164883 - 19 Aug 2022

Cited by 1 | Viewed by 1501

Abstract

Alport syndrome (AS) is a clinically and genetically heterogeneous disorder with a wide phenotypic spectrum, onset, and progression. X-linked AS (XLAS) and autosomal recessive AS (ARAS) are severe conditions, whereas the severity of autosomal dominant AS (ADAS) may vary from benign familial hematuria [...] Read more.

Alport syndrome (AS) is a clinically and genetically heterogeneous disorder with a wide phenotypic spectrum, onset, and progression. X-linked AS (XLAS) and autosomal recessive AS (ARAS) are severe conditions, whereas the severity of autosomal dominant AS (ADAS) may vary from benign familial hematuria to progressive renal disease with extra-renal manifestations. In this study, we collated information from the literature and analyzed a cohort of 317 patients with ADAS carrying heterozygous disease-causing mutations in COL4A3/4 including four patients from two unrelated families who carried two novel variants in COL4A3. Regarding the age of onset of the disease, 80% of patients presented urinalysis alterations (microhematuria, hematuria, and/or proteinuria) before the age of 40 years. The cumulative probability of suffering adverse renal events was mainly observed between 30 and 70 years, without statistical differences between COL4A3 and COL4A4. We observed statistically significant differences between the sexes in the age of developing ESKD in cases affected by mutations in COL4A3/4 (p value = 0.0097), suggesting that males begin experiencing earlier deterioration of renal function than women. This study supports the importance of follow-up in young patients who harbor pathogenic mutations in COL4A3/4. We update the knowledge of ADAS, highlighting differences in the progression of the disease between males and females. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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11 pages, 1433 KiB

Open AccessArticle

Minimal Change Disease Is Associated with Mitochondrial Injury and STING Pathway Activation

by Byung Chul Yu, Ahrim Moon, Kyung Ho Lee, Young Seung Oh, Moo Yong Park, Soo Jeong Choi and Jin Kuk Kim

J. Clin. Med. 2022, 11(3), 577; https://doi.org/10.3390/jcm11030577 - 24 Jan 2022

Cited by 3 | Viewed by 2374

Abstract

We hypothesized that minimal change disease (MCD) pathogenesis may be associated with mitochondrial injury, and that the degree of mitochondrial injury at the time of diagnosis may serve as a valuable prognostic marker. We compared urinary mitochondrial DNA (mtDNA) at the time of [...] Read more.

We hypothesized that minimal change disease (MCD) pathogenesis may be associated with mitochondrial injury, and that the degree of mitochondrial injury at the time of diagnosis may serve as a valuable prognostic marker. We compared urinary mitochondrial DNA (mtDNA) at the time of diagnosis in patients with MCD and age- and sex-matched healthy controls (MHC) (n = 10 each). We analyzed the site and signal intensity of immunohistochemical (IHC) staining of stimulator of interferon genes (STING) using kidney tissues at the time of diagnosis in patients with MCD. Patients with MCD were divided into high (n = 6) and low-intensity (n = 14) subgroups according to the signal intensity. Urinary mtDNA levels were elevated in the MCD groups more than in the MHC group (p < 0.001). Time-averaged proteinuria and frequency of relapses during the follow-up period were higher in the high-intensity than in the low-intensity subgroup (1.18 ± 0.54 vs. 0.57 ± 0.45 g/day, p = 0.022; and 0.72 ± 0.60 vs. 0.09 ± 0.22 episodes/year, p = 0.022, respectively). Mitochondrial injury may be associated with MCD pathogenesis, and the signal intensity of STING IHC staining at the time of diagnosis could be used as a valuable prognostic marker in MCD. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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16 pages, 1215 KiB

Open AccessArticle

Management of Anticoagulant-Related Nephropathy: A Single Center Experience

by Tanja Belčič Mikič, Nika Kojc, Maja Frelih, Andreja Aleš-Rigler and Željka Večerić-Haler

J. Clin. Med. 2021, 10(4), 796; https://doi.org/10.3390/jcm10040796 - 16 Feb 2021

Cited by 7 | Viewed by 3079

Abstract

Background: Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive. Methods: Here, [...] Read more.

Background: Anticoagulant-related nephropathy (ARN) is a form of acute kidney injury that mainly occurs in patients with previously unrecognized glomerular disease in addition to excessive anticoagulation. Since a renal biopsy is not performed in most cases, the diagnosis is often presumptive. Methods: Here, we present the characteristics of a national Slovenian patient cohort with histologically verified ARN, from the first case in 2014 to December 2020, and a review of the current literature (Pubmed database). Results: In Slovenia, ARN has been detected in 13 patients, seven of whom were treated with coumarins, and others with direct oral anticoagulants. In seven patients, ARN appeared after excessive anticoagulation. As many as 11 patients had underlying IgA nephropathy. Similar to the global data presented here, the pathohistological impairment associated with pre-existing glomerulopathy was mild and disproportionate to the degree of functional renal impairment. The majority of our patients with ARN experienced severe deterioration of renal function associated with histological signs of accompanying acute tubular injury, interstitial edema, and occlusive red blood cell casts. These patients were treated with corticosteroids, which (in addition to supportive treatment and discontinuation of the anticoagulant drug) led to a further improvement in renal function. Conclusions: Anticoagulant therapy combined with a pre-existing glomerular injury may lead to ARN. In addition to discontinuation of the anticoagulant and supportive care, corticosteroids, which are currently listed in only a few cases in the world literature, may have a positive influence on the course of treatment. However, the benefits of steroid treatment must be weighed against the risk of complications, especially life-threatening infections. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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11 pages, 1796 KiB

Open AccessArticle

Patients with Proliferative Lupus Nephritis Have Autoantibodies That React to Moesin and Demonstrate Increased Glomerular Moesin Expression

by Dawn J. Caster, Erik A. Korte, Michael L. Merchant, Jon B. Klein, Michelle T. Barati, Ami Joglekar, Daniel W. Wilkey, Susan Coventry, Jessica Hata, Brad H. Rovin, John B. Harley, Bahram Namjou-Khales, Kenneth R. McLeish and David W. Powell

J. Clin. Med. 2021, 10(4), 793; https://doi.org/10.3390/jcm10040793 - 16 Feb 2021

Cited by 2 | Viewed by 2126

Abstract

Kidney involvement in systemic lupus erythematosus (SLE)—termed lupus nephritis (LN)—is a severe manifestation of SLE that can lead to end-stage kidney disease (ESKD). LN is characterized by immune complex deposition and inflammation in the glomerulus. We tested the hypothesis that autoantibodies targeting podocyte [...] Read more.

Kidney involvement in systemic lupus erythematosus (SLE)—termed lupus nephritis (LN)—is a severe manifestation of SLE that can lead to end-stage kidney disease (ESKD). LN is characterized by immune complex deposition and inflammation in the glomerulus. We tested the hypothesis that autoantibodies targeting podocyte and glomerular cell proteins contribute to the development of immune complex formation in LN. We used Western blotting with SLE sera from patients with and without LN to identify target antigens in human glomerular and cultured human-derived podocyte membrane proteins. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), we identified the proteins in the gel regions corresponding to reactive bands observed with sera from LN patients. We identified 102 proteins that were present in both the podocyte and glomerular samples. We identified 10 high-probability candidates, including moesin, using bioinformatic analysis. Confirmation of moesin as a target antigen was conducted using immunohistochemical analysis (IHC) of kidney biopsy tissue and enzyme-linked immunosorbent assay (ELISA) to detect circulating antibodies. By IHC, biopsies from patients with proliferative lupus nephritis (PLN, class III/IV) demonstrated significantly increased glomerular expression of moesin (p < 0.01). By ELISA, patients with proliferative LN demonstrated significantly increased antibodies against moesin (p < 0.01). This suggests that moesin is a target glomerular antigen in lupus nephritis. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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21 pages, 3333 KiB

Open AccessArticle

Sulfatase 2 Is Associated with Steroid Resistance in Childhood Nephrotic Syndrome

by Shipra Agrawal, Richard F. Ransom, Saras Saraswathi, Esperanza Garcia-Gonzalo, Amy Webb, Juan L. Fernandez-Martinez, Milan Popovic, Adam J. Guess, Andrzej Kloczkowski, Rainer Benndorf, Wolfgang Sadee, William E. Smoyer and on behalf of the Pediatric Nephrology Research Consortium (PNRC)

J. Clin. Med. 2021, 10(3), 523; https://doi.org/10.3390/jcm10030523 - 02 Feb 2021

Cited by 2 | Viewed by 2436

Abstract

Glucocorticoid (GC) resistance complicates the treatment of ~10–20% of children with nephrotic syndrome (NS), yet the molecular basis for resistance remains unclear. We used RNAseq analysis and in silico algorithm-based approaches on peripheral blood leukocytes from 12 children both at initial NS presentation [...] Read more.

Glucocorticoid (GC) resistance complicates the treatment of ~10–20% of children with nephrotic syndrome (NS), yet the molecular basis for resistance remains unclear. We used RNAseq analysis and in silico algorithm-based approaches on peripheral blood leukocytes from 12 children both at initial NS presentation and after ~7 weeks of GC therapy to identify a 12-gene panel able to differentiate steroid resistant NS (SRNS) from steroid-sensitive NS (SSNS). Among this panel, subsequent validation and analyses of one biologically relevant candidate, sulfatase 2 (SULF2), in up to a total of 66 children, revealed that both SULF2 leukocyte expression and plasma arylsulfatase activity Post/Pre therapy ratios were greater in SSNS vs. SRNS. However, neither plasma SULF2 endosulfatase activity (measured by VEGF binding activity) nor plasma VEGF levels, distinguished SSNS from SRNS, despite VEGF’s reported role as a downstream mediator of SULF2’s effects in glomeruli. Experimental studies of NS-related injury in both rat glomeruli and cultured podocytes also revealed decreased SULF2 expression, which were partially reversible by GC treatment of podocytes. These findings together suggest that SULF2 levels and activity are associated with GC resistance in NS, and that SULF2 may play a protective role in NS via the modulation of downstream mediators distinct from VEGF. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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11 pages, 1610 KiB

Open AccessArticle

Lyso-Gb3 Increases αvβ3 Integrin Gene Expression in Cultured Human Podocytes in Fabry Nephropathy

by Hernán Trimarchi, Alberto Ortiz and Maria Dolores Sánchez-Niño

J. Clin. Med. 2020, 9(11), 3659; https://doi.org/10.3390/jcm9113659 - 13 Nov 2020

Cited by 7 | Viewed by 1966

Abstract

Background: Podocyturia in Fabry nephropathy leads to glomerulosclerosis and kidney disease progression. Integrins are involved in podocyte attachment to the glomerular basement membrane. We hypothesized that in Fabry nephropathy, lyso-Gb3 could modulate αvβ3 expression in podocytes. Together with UPAR, the αvβ3 integrin is [...] Read more.

Background: Podocyturia in Fabry nephropathy leads to glomerulosclerosis and kidney disease progression. Integrins are involved in podocyte attachment to the glomerular basement membrane. We hypothesized that in Fabry nephropathy, lyso-Gb3 could modulate αvβ3 expression in podocytes. Together with UPAR, the αvβ3 integrin is a key mechanism involved in podocyte detachment and podocyturia. Methods: In cultured human podocytes stimulated with lyso-Gb3, the mRNA expression of the ITGAV and ITGB3 genes encoding integrins αv and β3, respectively, was analyzed by RT-qPCR. Results: In cultured human podocytes, lyso-Gb3 at concentrations encountered in the serum of Fabry patients increased ITGAV and ITGB3 mRNA levels within 3 to 6 h. This pattern of gene expression is similar to that previously observed for PLAUR (UPAR) gene expression but is in contrast to the delayed (24 h) upregulation of other markers of podocyte stress and mediators of injury, such as CD80, TGFβ1, CD74, Notch1, and HES. Conclusions: Human podocyte stress in response to glycolipid overload in Fabry nephropathy, exemplified by lyso-Gb3, is characterized by an early increase in the expression of components of the αvβ3/UPAR system, which contrasts with the delayed rise in the expression of other mediators of podocyte injury. This suggests that the αvβ3/UPAR system may be a therapeutic target in Fabry nephropathy. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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13 pages, 1535 KiB

Open AccessArticle

Renal Survival in Children with Glomerulonephritis with Crescents: A Pediatric Nephrology Research Consortium Cohort Study

by Joseph G. Maliakkal, M. John Hicks, Mini Michael, David T. Selewski, Katherine Twombley, Michelle N. Rheault, Meredith Seamon, Jason M. Misurac, Cheryl L. Tran, Loretta Reyes, Joseph T. Flynn, Ali M. Onder, Alexandru R. Constantinescu, Vaishali Singh, Cynthia Pan, Abiodun Omoloja, Qiang Wu, William E. Smoyer, Guillermo Hidalgo and Scott E. Wenderfer

J. Clin. Med. 2020, 9(8), 2385; https://doi.org/10.3390/jcm9082385 - 26 Jul 2020

Cited by 11 | Viewed by 4234

Abstract

There is no evidence-based definition for diagnosing crescentic glomerulonephritis. The prognostic implications of crescentic lesions on kidney biopsy have not been quantified. Our objective was to determine risk factors for end-stage kidney disease (ESKD) in patients with glomerulonephritis and crescents on kidney biopsy. [...] Read more.

There is no evidence-based definition for diagnosing crescentic glomerulonephritis. The prognostic implications of crescentic lesions on kidney biopsy have not been quantified. Our objective was to determine risk factors for end-stage kidney disease (ESKD) in patients with glomerulonephritis and crescents on kidney biopsy. A query of the Pediatric Nephrology Research Consortium’s Pediatric Glomerulonephritis with Crescents registry identified 305 patients from 15 centers. A retrospective cohort study was performed with ESKD as the primary outcome. Median age at biopsy was 11 years (range 1–21). The percentage of crescents was 3–100% (median 20%). Etiologies included IgA nephropathy (23%), lupus (21%), IgA vasculitis (19%) and ANCA-associated GN (13%), post-infectious GN (5%), and anti-glomerular basement membrane disease (3%). The prevalence of ESKD was 12% at one year and 16% at last follow-up (median = 3 years, range 1–11). Median time to ESKD was 100 days. Risk factors for ESKD included %crescents, presence of fibrous crescents, estimated GFR, and hypertension at biopsy. For each 1% increase in %crescents, there was a 3% decrease in log odds of 1-year renal survival (p = 0.003) and a 2% decrease in log odds of renal survival at last follow-up (p < 0.001). These findings provide an evidence base for enrollment criteria for crescentic glomerulonephritis in future clinical trials. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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16 pages, 944 KiB

Open AccessArticle

Genetic Study in Korean Pediatric Patients with Steroid-Resistant Nephrotic Syndrome or Focal Segmental Glomerulosclerosis

by Eujin Park, Chung Lee, Nayoung K. D. Kim, Yo Han Ahn, Young Seo Park, Joo Hoon Lee, Seong Heon Kim, Min Hyun Cho, Heeyeon Cho, Kee Hwan Yoo, Jae Il Shin, Hee Gyung Kang, Il-Soo Ha, Woong-Yang Park and Hae Il Cheong

J. Clin. Med. 2020, 9(6), 2013; https://doi.org/10.3390/jcm9062013 - 26 Jun 2020

Cited by 21 | Viewed by 3630 | Correction

Abstract

Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage renal disease (ESRD) in childhood and is mostly associated with focal segmental glomerulosclerosis (FSGS). More than 50 monogenic causes of SRNS or FSGS have been identified. Recently, the mutation detection rate [...] Read more.

Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage renal disease (ESRD) in childhood and is mostly associated with focal segmental glomerulosclerosis (FSGS). More than 50 monogenic causes of SRNS or FSGS have been identified. Recently, the mutation detection rate in pediatric patients with SRNS has been reported to be approximately 30%. In this study, genotype-phenotype correlations in a cohort of 291 Korean pediatric patients with SRNS/FSGS were analyzed. The overall mutation detection rate was 43.6% (127 of 291 patients). WT1 was the most common causative gene (23.6%), followed by COQ6 (8.7%), NPHS1 (8.7%), NUP107 (7.1%), and COQ8B (6.3%). Mutations in COQ6, NUP107, and COQ8B were more frequently detected, and mutations in NPHS2 were less commonly detected in this cohort than in study cohorts from Western countries. The mutation detection rate was higher in patients with congenital onset, those who presented with proteinuria or chronic kidney disease/ESRD, and those who did not receive steroid treatment. Genetic diagnosis in patients with SRNS provides not only definitive diagnosis but also valuable information for decisions on treatment policy and prediction of prognosis. Therefore, further genotype-phenotype correlation studies are required. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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Review

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20 pages, 1524 KiB

Open AccessReview

The Non-Coding RNA Landscape in IgA Nephropathy—Where Are We in 2021?

by Izabella Z. A. Pawluczyk, Haresh Selvaskandan and Jonathan Barratt

J. Clin. Med. 2021, 10(11), 2369; https://doi.org/10.3390/jcm10112369 - 28 May 2021

Cited by 1 | Viewed by 2655

Abstract

IgA nephropathy (IgAN) is the most commonly diagnosed primary glomerulonephritis worldwide. It is a slow progressing disease with approximately 30% of cases reaching end-stage kidney disease within 20 years of diagnosis. It is currently only diagnosed by an invasive biopsy and treatment options [...] Read more.

IgA nephropathy (IgAN) is the most commonly diagnosed primary glomerulonephritis worldwide. It is a slow progressing disease with approximately 30% of cases reaching end-stage kidney disease within 20 years of diagnosis. It is currently only diagnosed by an invasive biopsy and treatment options are limited. However, the current surge in interest in RNA interference is opening up new horizons for the use of this new technology in the field of IgAN management. A greater understanding of the fundamentals of RNA interference offers exciting possibilities both for biomarker discovery and, more importantly, for novel therapeutic approaches to target key pathogenic pathways in IgAN. This review aims to summarise the RNA interference literature in the context of microRNAs and their association with the multifaceted aspects of IgA nephropathy. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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20 pages, 5351 KiB

Open AccessReview

The Clone Wars: Diagnosing and Treating Dysproteinemic Kidney Disease in the Modern Era

by Rupali S. Avasare, Nicole K. Andeen, Andrea Havasi and Jonathan J. Hogan

J. Clin. Med. 2021, 10(8), 1633; https://doi.org/10.3390/jcm10081633 - 12 Apr 2021

Cited by 1 | Viewed by 3089

Abstract

Dysproteinemic kidney diseases are disorders that occur as the result of lymphoproliferative (B cell or plasma cell) disorders that cause kidney damage via production of nephrotoxic monoclonal immunoglobulins or their components. These monoclonal immunoglobulins have individual physiochemical characteristics that confer specific nephrotoxic properties. [...] Read more.

Dysproteinemic kidney diseases are disorders that occur as the result of lymphoproliferative (B cell or plasma cell) disorders that cause kidney damage via production of nephrotoxic monoclonal immunoglobulins or their components. These monoclonal immunoglobulins have individual physiochemical characteristics that confer specific nephrotoxic properties. There has been increased recognition and revised characterization of these disorders in the last decade, and in some cases, there have been substantial advances in disease understanding and treatments, which has translated to improved patient outcomes. These disorders still present challenges to nephrologists and patients, since they are rare, and the field of hematology is rapidly changing with the introduction of novel testing and treatment strategies. In this review, we will discuss the clinical presentation, kidney biopsy features, hematologic characteristics and treatment of dysproteinemic kidney diseases. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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22 pages, 1714 KiB

Open AccessReview

ANCA-Associated Vasculitis: An Update

by Salem Almaani, Lynn A. Fussner, Sergey Brodsky, Alexa S. Meara and David Jayne

J. Clin. Med. 2021, 10(7), 1446; https://doi.org/10.3390/jcm10071446 - 01 Apr 2021

Cited by 67 | Viewed by 17835

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) represents a group of small vessel vasculitides characterized by granulomatous and neutrophilic tissue inflammation, often associated with the production of antibodies that target neutrophil antigens. The two major antigens targeted by ANCAs are leukocyte proteinase 3 (PR3) [...] Read more.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) represents a group of small vessel vasculitides characterized by granulomatous and neutrophilic tissue inflammation, often associated with the production of antibodies that target neutrophil antigens. The two major antigens targeted by ANCAs are leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). AAV can be classified into 3 categories based on patterns of clinical involvement: namely, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic GPA (EGPA). Clinically, AAV involves many organ systems including the lungs, kidneys, skin, and nervous system. The prognosis of AAV has improved dramatically due to advances in the understanding of its pathogenesis and treatment modalities. This review will highlight some of the recent updates in our understanding of the pathogenesis, clinical manifestations, and treatment options in patients with AAV focusing on kidney involvement. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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13 pages, 571 KiB

Open AccessReview

Expanding the Role of Complement Therapies: The Case for Lupus Nephritis

by Nicholas L. Li, Daniel J. Birmingham and Brad H. Rovin

J. Clin. Med. 2021, 10(4), 626; https://doi.org/10.3390/jcm10040626 - 07 Feb 2021

Cited by 19 | Viewed by 5068

Abstract

The complement system is an innate immune surveillance network that provides defense against microorganisms and clearance of immune complexes and cellular debris and bridges innate and adaptive immunity. In the context of autoimmune disease, activation and dysregulation of complement can lead to uncontrolled [...] Read more.

The complement system is an innate immune surveillance network that provides defense against microorganisms and clearance of immune complexes and cellular debris and bridges innate and adaptive immunity. In the context of autoimmune disease, activation and dysregulation of complement can lead to uncontrolled inflammation and organ damage, especially to the kidney. Systemic lupus erythematosus (SLE) is characterized by loss of tolerance, autoantibody production, and immune complex deposition in tissues including the kidney, with inflammatory consequences. Effective clearance of immune complexes and cellular waste by early complement components protects against the development of lupus nephritis, while uncontrolled activation of complement, especially the alternative pathway, promotes kidney damage in SLE. Therefore, complement plays a dual role in the pathogenesis of lupus nephritis. Improved understanding of the contribution of the various complement pathways to the development of kidney disease in SLE has created an opportunity to target the complement system with novel therapies to improve outcomes in lupus nephritis. In this review, we explore the interactions between complement and the kidney in SLE and their implications for the treatment of lupus nephritis. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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18 pages, 9794 KiB

Open AccessReview

Advances in Membranous Nephropathy

by Pierre Ronco, Emmanuelle Plaisier and Hanna Debiec

J. Clin. Med. 2021, 10(4), 607; https://doi.org/10.3390/jcm10040607 - 05 Feb 2021

Cited by 47 | Viewed by 12386

Abstract

Membranous nephropathy (MN) is a rare auto-immune disease where the glomerulus is targeted by circulating auto-antibodies mostly against podocyte antigens, which results in the formation of electron-dense immune complexes, activation of complement and massive proteinuria. MN is the most common cause of nephrotic [...] Read more.

Membranous nephropathy (MN) is a rare auto-immune disease where the glomerulus is targeted by circulating auto-antibodies mostly against podocyte antigens, which results in the formation of electron-dense immune complexes, activation of complement and massive proteinuria. MN is the most common cause of nephrotic syndrome in adults leading to severe thrombotic complications and kidney failure. This review is focused on the recent therapeutic and pathophysiological advances that occurred in the last two years. For a long time, we were lacking a head-to-head comparison between cyclophosphamide considered as the gold standard therapy and other medications, notably rituximab. Substantial progress has been achieved owing to three randomized controlled trials. MENTOR (Membranous Nephropathy Trial of Rituximab) and STARMEN (Sequential Therapy with Tacrolimus and Rituximab in Primary Membranous Nephropathy) conclusively established that calcineurin inhibitor-based regimens are slower to result in an immunologic response than rituximab or cyclophosphamide, achieve fewer complete clinical remissions, and are less likely to maintainremission. Rituximab Versus Steroids and Cyclophosphamide in the Treatment of Idiopathic Membranous Nephropathy (RI-CYCLO) suggested that competition between cyclophosphamide and rituximab remains open. Given the technological leap combining laser microdissection of glomeruli and mass spectrometry of solubilized digested proteins, four “new antigens” were discovered including NELL-1 and Semaphorin 3B in so-called primary MN, and exostosins 1 and 2 and NCAM 1 in lupus MN. NELL-1 is associated with about 8% of primary MN and is characterized by segmental immune deposits and frequent association with cancer (30%). Semaphorin 3B-associated MN usually occurs in children, often below the age of two years, where it is the main antigen, representing about 16% of non-lupus MN in childhood. Exostosins 1/2 and NCAM 1 are associated with 30% and 6% of lupus MN, respectively. Exostosins 1/2 (EXT1/2) staining is associated with a low rate of end-stage kidney disease (ESKD) even in mixed classes III/IV+V. These findings already lead to revisiting the diagnostic and therapeutic algorithms toward more personalized medicine. Full article

(This article belongs to the Special Issue Clinical Advances in the Management of Glomerular Disease)

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