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Maslyennikov Y, Bărar AA, Rusu CC, Potra AR, Tirinescu D, Ticala M, Urs A, Pralea IE, Iuga CA, Moldovan DT, Kacso IM. The Spectrum of Minimal Change Disease/Focal Segmental Glomerulosclerosis: From Pathogenesis to Proteomic Biomarker Research. Int J Mol Sci 2025; 26:2450. [PMID: 40141093 PMCID: PMC11941885 DOI: 10.3390/ijms26062450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2025] [Revised: 03/04/2025] [Accepted: 03/06/2025] [Indexed: 03/28/2025] Open
Abstract
Podocyte injury plays a central role in both focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD). Pathogenic mechanisms are diverse and incompletely understood, partially overlap between FSGS and MCD, and are not reflected by kidney biopsy. In order to optimize the current variable response to treatment, personalized management should rely on pathogenesis. One promising approach involves identifying biomarkers associated with specific pathogenic pathways. With the advancement of technology, proteomic studies could be a valuable tool to improve knowledge in this area and define valid biomarkers, as they have in other areas of glomerular disease. This work attempts to cover and discuss the main mechanisms of podocyte injury, followed by a review of the recent literature on proteomic biomarker studies in podocytopathies. Most of these studies have been conducted on biofluids, while tissue proteomic studies applied to podocytopathies remain limited. While we recognize the importance of non-invasive biofluid biomarkers, we propose a sequential approach for their development: tissue proteomics could first identify proteins with increased expression that may reflect underlying disease mechanisms; subsequently, the validation of these proteins in urine or plasma could pave the way to a diagnostic and prognostic biomarker-based approach.
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Affiliation(s)
- Yuriy Maslyennikov
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Andrada Alina Bărar
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Crina Claudia Rusu
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Alina Ramona Potra
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Dacian Tirinescu
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Maria Ticala
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Alexandra Urs
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Ioana Ecaterina Pralea
- Department of Personalized Medicine and Rare Diseases, MedFuture—Research Centre for Biomedical Research, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (I.E.P.); (C.A.I.)
| | - Cristina Adela Iuga
- Department of Personalized Medicine and Rare Diseases, MedFuture—Research Centre for Biomedical Research, “Iuliu Haţieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania; (I.E.P.); (C.A.I.)
- Department of Drug Analysis, Faculty of Pharmacy, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania
| | - Diana Tania Moldovan
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
| | - Ina Maria Kacso
- Department of Nephrology, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (Y.M.); (A.A.B.); (C.C.R.); (A.R.P.); (D.T.); (M.T.); (A.U.); (I.M.K.)
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Zununi Vahed S, Hosseiniyan Khatibi SM, Ardalan M. Canonical effects of cytokines on glomerulonephritis: A new outlook in nephrology. Med Res Rev 2025; 45:144-163. [PMID: 39164945 DOI: 10.1002/med.22074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 08/28/2022] [Accepted: 08/04/2024] [Indexed: 08/22/2024]
Abstract
Glomerulonephritis (GN) is an important cause of renal inflammation resulting from kidney-targeted adaptive and innate immune responses and consequent glomerular damage. Given the lack of autoantibodies, immune complexes, or the infiltrating immune cells in some forms of GN, for example, focal segmental glomerulosclerosis and minimal change disease, along with paraneoplastic syndrome and a special form of renal involvement in some viral infections, the likeliest causative scenario would be secreted factors, mainly cytokine(s). Since cytokines can modulate the inflammatory mechanisms, severity, and clinical outcomes of GN, it is rational to consider the umbrella term of cytokine GN as a new outlook to reclassify a group of previously known GN. We focus here, particularly, on cytokines that have the central "canonical effect" in the development of GN.
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Noda R, Ichikawa D, Shibagaki Y. Machine learning-based diagnostic prediction of minimal change disease: model development study. Sci Rep 2024; 14:23460. [PMID: 39379539 PMCID: PMC11461711 DOI: 10.1038/s41598-024-73898-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Accepted: 09/23/2024] [Indexed: 10/10/2024] Open
Abstract
Minimal change disease (MCD) is a common cause of nephrotic syndrome. Due to its rapid progression, early detection is essential; however, definitive diagnosis requires invasive kidney biopsy. This study aims to develop non-invasive predictive models for diagnosing MCD by machine learning. We retrospectively collected data on demographic characteristics, blood tests, and urine tests from patients with nephrotic syndrome who underwent kidney biopsy. We applied four machine learning algorithms-TabPFN, LightGBM, Random Forest, and Artificial Neural Network-and logistic regression. We compared their performance using stratified 5-repeated 5-fold cross-validation for the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC). Variable importance was evaluated using the SHapley Additive exPlanations (SHAP) method. A total of 248 patients were included, with 82 cases (33%) were diagnosed with MCD. TabPFN demonstrated the best performance with an AUROC of 0.915 (95% CI 0.896-0.932) and an AUPRC of 0.840 (95% CI 0.807-0.872). The SHAP methods identified C3, total cholesterol, and urine red blood cells as key predictors for TabPFN, consistent with previous reports. Machine learning models could be valuable non-invasive diagnostic tools for MCD.
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Affiliation(s)
- Ryunosuke Noda
- Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan.
| | - Daisuke Ichikawa
- Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan
| | - Yugo Shibagaki
- Division of Nephrology and Hypertension, Department of Internal Medicine, St. Marianna University School of Medicine, Miyamae-ku, Kawasaki, Kanagawa, 216-8511, Japan
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Meliambro K, He JC, Campbell KN. Podocyte-targeted therapies - progress and future directions. Nat Rev Nephrol 2024; 20:643-658. [PMID: 38724717 DOI: 10.1038/s41581-024-00843-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/19/2024] [Indexed: 09/14/2024]
Abstract
Podocytes are the key target cells for injury across the spectrum of primary and secondary proteinuric kidney disorders, which account for up to 90% of cases of kidney failure worldwide. Seminal experimental and clinical studies have established a causative link between podocyte depletion and the magnitude of proteinuria in progressive glomerular disease. However, no substantial advances have been made in glomerular disease therapies, and the standard of care for podocytopathies relies on repurposed immunosuppressive drugs. The past two decades have seen a remarkable expansion in understanding of the mechanistic basis of podocyte injury, with prospects increasing for precision-based treatment approaches. Dozens of disease-causing genes with roles in the pathogenesis of clinical podocytopathies have been identified, as well as a number of putative glomerular permeability factors. These achievements, together with the identification of novel targets of podocyte injury, the development of potential approaches to harness the endogenous podocyte regenerative potential of progenitor cell populations, ongoing clinical trials of podocyte-specific pharmacological agents and the development of podocyte-directed drug delivery systems, contribute to an optimistic outlook for the future of glomerular disease therapy.
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Affiliation(s)
- Kristin Meliambro
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - John C He
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kirk N Campbell
- Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Kurasawa S, Kato S, Ozeki T, Akiyama S, Ishimoto T, Mizuno M, Tsuboi N, Kato N, Kosugi T, Maruyama S. Rationale and design of the Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study. Clin Exp Nephrol 2024; 28:431-439. [PMID: 38267800 DOI: 10.1007/s10157-023-02449-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 12/11/2023] [Indexed: 01/26/2024]
Abstract
INTRODUCTION Disease subtyping and monitoring are essential for the management of nephrotic syndrome (NS). Although various biomarkers for NS have been reported, their clinical efficacy has not been comprehensively validated in adult Japanese patients. METHODS The Japanese Biomarkers in Nephrotic Syndrome (J-MARINE) study is a nationwide, multicenter, and prospective cohort study in Japan, enrolling adult (≥18 years) patients with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), C3 glomerulopathy (C3G), and lupus nephritis (LN). Baseline clinical information and plasma and urine samples will be collected at the time of immunosuppressive therapy initiation or biopsy. Follow-up data and plasma and urine samples will be collected longitudinally based on the designated protocols. Candidate biomarkers will be measured: CD80, cytotoxic T-lymphocyte antigen 4, and soluble urokinase plasminogen activator receptor for MCD and FSGS; anti-phospholipase A2 receptor and thrombospondin type-1 domain-containing protein 7A antibodies for MN; fragment Ba, C3a, factor I, and properdin for MPGN/C3G; and CD11b, CD16b, and CD163 for LN. Outcomes include complete and partial remission, relapse of proteinuria, a 30% reduction in estimated glomerular filtration rate (eGFR), eGFR decline, and initiation of renal replacement therapy. The diagnostic accuracy and predictive ability for clinical outcomes will be assessed for each biomarker. RESULTS From April 2019 to April 2023, 365 patients were enrolled: 145, 21, 138, 10, and 51 cases of MCD, FSGS, MN, MPGN/C3G, and LN, respectively. CONCLUSION This study will provide valuable insights into biomarkers for NS and serve as a biorepository for future studies.
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MESH Headings
- Humans
- Biomarkers/blood
- Biomarkers/urine
- Nephrotic Syndrome/urine
- Nephrotic Syndrome/blood
- Nephrotic Syndrome/diagnosis
- Prospective Studies
- Japan
- Glomerulosclerosis, Focal Segmental/urine
- Glomerulosclerosis, Focal Segmental/blood
- Glomerulosclerosis, Focal Segmental/diagnosis
- Receptors, Urokinase Plasminogen Activator/blood
- Glomerulonephritis, Membranous/urine
- Glomerulonephritis, Membranous/blood
- Glomerulonephritis, Membranous/diagnosis
- Adult
- Nephrosis, Lipoid/urine
- Nephrosis, Lipoid/blood
- Nephrosis, Lipoid/diagnosis
- Research Design
- Receptors, Phospholipase A2/immunology
- Thrombospondins/blood
- Glomerulonephritis, Membranoproliferative/blood
- Glomerulonephritis, Membranoproliferative/urine
- Glomerulonephritis, Membranoproliferative/diagnosis
- Male
- Female
- Lupus Nephritis/blood
- Lupus Nephritis/urine
- Lupus Nephritis/diagnosis
- East Asian People
- B7-1 Antigen
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Affiliation(s)
- Shimon Kurasawa
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Sawako Kato
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takaya Ozeki
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Shin'ichi Akiyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Takuji Ishimoto
- Department of Nephrology and Rheumatology, Aichi Medical University, Nagakute, Japan
| | - Masashi Mizuno
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
- Department of Renal Replacement Therapy, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Naotake Tsuboi
- Department of Nephrology, Fujita Health University School of Medicine, Toyoake, Japan
| | - Noritoshi Kato
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Tomoki Kosugi
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
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Kovalik ME, Dacanay MA, Crowley SD, Hall G. Swollen Feet: Considering the Paradoxical Roles of Interleukins in Nephrotic Syndrome. Biomedicines 2024; 12:738. [PMID: 38672094 PMCID: PMC11048099 DOI: 10.3390/biomedicines12040738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/11/2024] [Accepted: 03/15/2024] [Indexed: 04/28/2024] Open
Abstract
Interleukins are a family of 40 bioactive peptides that act through cell surface receptors to induce a variety of intracellular responses. While interleukins are most commonly associated with destructive, pro-inflammatory signaling in cells, some also play a role in promoting cellular resilience and survival. This review will highlight recent evidence of the cytoprotective actions of the interleukin 1 receptor (IL-1R)- and common gamma chain receptor (IL-Rγc)-signaling cytokines in nephrotic syndrome (NS). NS results from the injury or loss of glomerular visceral epithelial cells (i.e., podocytes). Although the causes of podocyte dysfunction vary, it is clear that pro-inflammatory cytokines play a significant role in regulating the propagation, duration and severity of disease. Pro-inflammatory cytokines signaling through IL-1R and IL-Rγc have been shown to exert anti-apoptotic effects in podocytes through the phosphoinositol-3-kinase (PI-3K)/AKT pathway, highlighting the potential utility of IL-1R- and IL-Rγc-signaling interleukins for the treatment of podocytopathy in NS. The paradoxical role of interleukins as drivers and mitigators of podocyte injury is complex and ill-defined. Emerging evidence of the cytoprotective role of some interleukins in NS highlights the urgent need for a nuanced understanding of their pro-survival benefits and reveals their potential as podocyte-sparing therapeutics for NS.
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Affiliation(s)
- Maria E. Kovalik
- Division of Nephrology, Duke University, Durham, NC 27701, USA; (M.E.K.)
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
| | - Monique A. Dacanay
- Division of Nephrology, Duke University, Durham, NC 27701, USA; (M.E.K.)
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
| | - Steven D. Crowley
- Division of Nephrology, Duke University, Durham, NC 27701, USA; (M.E.K.)
| | - Gentzon Hall
- Division of Nephrology, Duke University, Durham, NC 27701, USA; (M.E.K.)
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
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Catanese L, Rupprecht H, Huber TB, Lindenmeyer MT, Hengel FE, Amann K, Wendt R, Siwy J, Mischak H, Beige J. Non-Invasive Biomarkers for Diagnosis, Risk Prediction, and Therapy Guidance of Glomerular Kidney Diseases: A Comprehensive Review. Int J Mol Sci 2024; 25:3519. [PMID: 38542491 PMCID: PMC10970781 DOI: 10.3390/ijms25063519] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 03/13/2024] [Accepted: 03/18/2024] [Indexed: 04/09/2025] Open
Abstract
Effective management of glomerular kidney disease, one of the main categories of chronic kidney disease (CKD), requires accurate diagnosis, prognosis of progression, assessment of therapeutic efficacy, and, ideally, prediction of drug response. Multiple biomarkers and algorithms for the assessment of specific aspects of glomerular diseases have been reported in the literature. Though, the vast majority of these have not been implemented in clinical practice or are not available on a global scale due to limited access, missing medical infrastructure, or economical as well as political reasons. The aim of this review is to compile all currently available information on the diagnostic, prognostic, and predictive biomarkers currently available for the management of glomerular diseases, and provide guidance on the application of these biomarkers. As a result of the compiled evidence for the different biomarkers available, we present a decision tree for a non-invasive, biomarker-guided diagnostic path. The data currently available demonstrate that for the large majority of patients with glomerular diseases, valid biomarkers are available. However, despite the obvious disadvantages of kidney biopsy, being invasive and not applicable for monitoring, especially in the context of rare CKD etiologies, kidney biopsy still cannot be replaced by non-invasive strategies.
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Affiliation(s)
- Lorenzo Catanese
- Department of Nephrology, Angiology and Rheumatology, Klinikum Bayreuth GmbH, 95445 Bayreuth, Germany; (L.C.); (H.R.)
- Kuratorium for Dialysis and Transplantation (KfH) Bayreuth, 95445 Bayreuth, Germany
- Department of Nephrology, Medizincampus Oberfranken, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Harald Rupprecht
- Department of Nephrology, Angiology and Rheumatology, Klinikum Bayreuth GmbH, 95445 Bayreuth, Germany; (L.C.); (H.R.)
- Kuratorium for Dialysis and Transplantation (KfH) Bayreuth, 95445 Bayreuth, Germany
- Department of Nephrology, Medizincampus Oberfranken, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Tobias B. Huber
- III Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; (T.B.H.); (M.T.L.); (F.E.H.)
| | - Maja T. Lindenmeyer
- III Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; (T.B.H.); (M.T.L.); (F.E.H.)
| | - Felicitas E. Hengel
- III Department of Medicine, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; (T.B.H.); (M.T.L.); (F.E.H.)
| | - Kerstin Amann
- Department of Nephropathology, Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, 91054 Erlangen, Germany;
| | - Ralph Wendt
- Division of Nephrology, St. Georg Hospital, 04129 Leipzig, Germany;
| | - Justyna Siwy
- Mosaiques Diagnostics GmbH, 30659 Hannover, Germany; (J.S.); (H.M.)
| | - Harald Mischak
- Mosaiques Diagnostics GmbH, 30659 Hannover, Germany; (J.S.); (H.M.)
| | - Joachim Beige
- Division of Nephrology, St. Georg Hospital, 04129 Leipzig, Germany;
- Department of Internal Medicine II, Martin-Luther-University Halle-Wittenberg, 06108 Halle, Germany
- Kuratorium for Dialysis and Transplantation (KfH) Leipzig, 04129 Leipzig, Germany
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Aprilia A, Handono K, Sujuti H, Sabarudin A, Winaris N. sCD163, sCD28, sCD80, and sCTLA-4 as soluble marker candidates for detecting immunosenescence. Immun Ageing 2024; 21:9. [PMID: 38243300 PMCID: PMC10799430 DOI: 10.1186/s12979-023-00405-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2023] [Accepted: 12/11/2023] [Indexed: 01/21/2024]
Abstract
BACKGROUND Inflammaging, the characteristics of immunosenescence, characterized by continuous chronic inflammation that could not be resolved. It is not only affect older people but can also occur in young individuals, especially those suffering from chronic inflammatory conditions such as autoimmune disease, malignancy, or chronic infection. This condition led to altered immune function and as consequent immune function is reduced. Detection of immunosenescence has been done by examining the immune risk profile (IRP), which uses flow cytometry. These tests are not always available in health facilities, especially in developing countries and require fresh whole blood samples. Therefore, it is necessary to find biomarkers that can be tested using stored serum to make it easier to refer to the examination. Here we proposed an insight for soluble biomarkers which represented immune cells activities and exhaustion, namely sCD163, sCD28, sCD80, and sCTLA-4. Those markers were reported to be elevated in chronic diseases that caused early aging and easily detected from serum samples using ELISA method, unlike IRP. Therefore, we conclude these soluble markers are beneficial to predict pathological condition of immunosenescence. AIM To identify soluble biomarkers that could replace IRP for detecting immunosenescence. CONCLUSION Soluble costimulatory molecule suchsCD163, sCD28, sCD80, and sCTLA-4 are potential biomarkers for detecting immunosenescence.
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Affiliation(s)
- Andrea Aprilia
- Doctoral Program in Medical Science, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
| | - Kusworini Handono
- Clinical Pathology Department, Faculty of Medicine, Universitas Brawijaya, Veteran Street, Malang, East Java, 65145, Indonesia.
| | - Hidayat Sujuti
- Opthamology Department, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
| | - Akhmad Sabarudin
- Chemistry Department, Faculty of Mathematics and Science, Universitas Brawijaya, Malang, Indonesia
| | - Nuning Winaris
- Department of Parasitology, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
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Chugh SS, Clement LC. "Idiopathic" minimal change nephrotic syndrome: a podocyte mystery nears the end. Am J Physiol Renal Physiol 2023; 325:F685-F694. [PMID: 37795536 PMCID: PMC10878723 DOI: 10.1152/ajprenal.00219.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 09/11/2023] [Accepted: 10/02/2023] [Indexed: 10/06/2023] Open
Abstract
The discovery of zinc fingers and homeoboxes (ZHX) transcriptional factors and the upregulation of hyposialylated angiopoietin-like 4 (ANGPTL4) in podocytes have been crucial in explaining the cardinal manifestations of human minimal change nephrotic syndrome (MCNS). Recently, uncovered genomic defects upstream of ZHX2 induce a ZHX2 hypomorph state that makes podocytes inherently susceptible to mild cytokine storms resulting from a common cold. In ZHX2 hypomorph podocytes, ZHX proteins are redistributed away from normal transmembrane partners like aminopeptidase A (APA) toward alternative binding partners like IL-4Rα. During disease relapse, high plasma soluble IL-4Rα (sIL-4Rα) associated with chronic atopy complements the cytokine milieu of a common cold to displace ZHX1 from podocyte transmembrane IL-4Rα toward the podocyte nucleus. Nuclear ZHX1 induces severe upregulation of ANGPTL4, resulting in incomplete sialylation of part of the ANGPTL4 protein, secretion of hyposialylated ANGPTL4, and hyposialylation-related injury in the glomerulus. This pattern of injury induces many of the classic manifestations of human minimal change disease (MCD), including massive and selective proteinuria, podocyte foot process effacement, and loss of glomerular basement membrane charge. Administration of glucocorticoids reduces ANGPTL4 upregulation, which reduces hyposialylation injury to improve the clinical phenotype. Improving sialylation of podocyte-secreted ANGPTL4 also reduces proteinuria and improves experimental MCD. Neutralizing circulating TNF-α, IL-6, or sIL-4Rα after the induction of the cytokine storm in Zhx2 hypomorph mice reduces albuminuria, suggesting potential new therapeutic targets for clinical trials to prevent MCD relapse. These studies collectively lay to rest prior suggestions of a role of single cytokines or soluble proteins in triggering MCD relapse.
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Affiliation(s)
- Sumant S Chugh
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States
| | - Lionel C Clement
- Glomerular Disease Therapeutics Laboratory, Department of Internal Medicine, Rush University Medical Center, Chicago, Illinois, United States
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Gong X, Huang J, Zhang Y, Wang F, Wang X, Meng L, Cheng X, Liu G, Cui Z, Zhao M. Patients with primary focal segmental glomerulosclerosis with detectable urinary CD80 are more similar to patients with minimal change disease in clinicopathological features. Ren Fail 2023; 45:2279642. [PMID: 37942512 PMCID: PMC10653691 DOI: 10.1080/0886022x.2023.2279642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 10/31/2023] [Indexed: 11/10/2023] Open
Abstract
BACKGROUND Focal segmental glomerulosclerosis (FSGS) is an important cause of refractory nephrotic syndrome (NS) in children and adults. Urinary CD80 is elevated in some patients with primary FSGS, however, its clinical value is not fully clarified. This study aims to evaluate the clinical and pathological significance of urinary CD80 in patients with primary FSGS. METHODS Sixty-one adult patients with biopsy-proven primary FSGS, with standard treatment and long-term follow up, were enrolled retrospectively. Urinary CD80, on the day of kidney biopsy, was measured using commercial ELISA kits and adjusted by urinary creatinine excretion. Their associations with clinical and pathological parameters were investigated. RESULTS Urinary CD80 was detectable in 30/61 (49.2%) patients, who presented with a higher level of proteinuria (10.7 vs. 5.8 g/24h; p = 0.01), a lower level of serum albumin (19.3 ± 3.9 vs. 24.2 ± 8.2 g/L; p = 0.005), a higher prevalence of hematuria (70.0 vs. 38.7%; p = 0.01), and showed a lower percentage of segmental glomerulosclerosis lesion [4.8 (3.7-14.0) vs. 9.1 (5.6-21.1) %; p = 0.06]. The cumulative relapse rate was remarkably high in these patients (log-rank, p = 0.001). Multivariate analysis identified that the elevated urinary CD80 was an independent risk factor for steroid-dependent NS (OR 8.81, 95% CI 1.41-54.89; p = 0.02) and relapse (HR, 2.87; 95% CI 1.29-6.38; p = 0.01). CONCLUSIONS The elevated urinary CD80 is associated with mild pathological change and steroid-dependent cases of primary FSGS adults, which indicates these patients are more similar to minimal change disease (MCD) in clinicopathological features.
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Affiliation(s)
- Xiaojie Gong
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing, China
| | - Jing Huang
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing, China
| | - Yimiao Zhang
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing, China
| | - Fang Wang
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing, China
| | - Xin Wang
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing, China
| | - Liqiang Meng
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing, China
| | - Xuyang Cheng
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing, China
| | - Gang Liu
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing, China
| | - Zhao Cui
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing, China
| | - Minghui Zhao
- Renal Division, Peking University First Hospital; Institute of Nephrology, Peking University; Key Laboratory of Renal Disease, Ministry of Health of China; Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China; Beijing, China
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11
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Kanazawa N, Iyoda M, Suzuki T, Tachibana S, Nagashima R, Honda H. Exploring the significance of interleukin-33/ST2 axis in minimal change disease. Sci Rep 2023; 13:18776. [PMID: 37907612 PMCID: PMC10618262 DOI: 10.1038/s41598-023-45678-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 10/23/2023] [Indexed: 11/02/2023] Open
Abstract
Minimal change disease (MCD), a common cause of idiopathic nephrotic syndrome, has been postulated to exhibit an association with allergic conditions. Recent studies revealed the crucial role of interleukin (IL)-33 in type 2 innate immunity. We hypothesized that development of MCD involves an IL-33-related immune response. We examined 49 patients with biopsy-proven MCD, 6 healthy volunteers, and 29 patients in remission. In addition to clinical features, serum and urinary levels of IL-33 and soluble suppression of tumorigenicity 2 protein (sST2), a secreted form of the receptor of IL-33, were analyzed. Although IL-33 was barely detectable in either MCD or control samples, sST2 levels at diagnosis were elevated in MCD patients. Serum sST2 levels of MCD patients were correlated with serum total protein level (r = - 0.36, p = 0.010) and serum creatinine level (r = 0.34, p = 0.016). Furthermore, the elevated sST2 levels were observed to decrease following remission. Immunofluorescence revealed IL-33 expression in the podocytes among MCD patients, with a significant increase compared with controls. In vitro, mouse podocyte cells incubated with serum from a MCD patient at disease onset showed increased IL-33 secretion. These results suggest an IL-33-related immune response plays a role in MCD.
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Affiliation(s)
- Nobuhiro Kanazawa
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Masayuki Iyoda
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan.
- Department of Microbiology and Immunology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan.
| | - Taihei Suzuki
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Shohei Tachibana
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Ryuichi Nagashima
- Department of Microbiology and Immunology, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8555, Japan
| | - Hirokazu Honda
- Division of Nephrology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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12
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Vincenti F, Angeletti A, Ghiggeri GM. State of the art in childhood nephrotic syndrome: concrete discoveries and unmet needs. Front Immunol 2023; 14:1167741. [PMID: 37503337 PMCID: PMC10368981 DOI: 10.3389/fimmu.2023.1167741] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 06/21/2023] [Indexed: 07/29/2023] Open
Abstract
Nephrotic syndrome (NS) is a clinical entity characterized by proteinuria, hypoalbuminemia, and peripheral edema. NS affects about 2-7 per 100,000 children aged below 18 years old yearly and is classified, based on the response to drugs, into steroid sensitive (SSNS), steroid dependent, (SDNS), multidrug dependent (MDNS), and multidrug resistant (MRNS). Forms of NS that are more difficult to treat are associated with a worse outcome with respect to renal function. In particular, MRNS commonly progresses to end stage renal failure requiring renal transplantation, with recurrence of the original disease in half of the cases. Histological presentations of NS may vary from minimal glomerular lesions (MCD) to focal segmental glomerulosclerosis (FSGS) and, of relevance, the histological patterns do not correlate with the response to treatments. Moreover, around half of MRNS cases are secondary to causative pathogenic variants in genes involved in maintaining the glomerular structure. The pathogenesis of NS is still poorly understood and therapeutic approaches are mostly based on clinical experience. Understanding of pathogenetic mechanisms of NS is one of the 'unmet needs' in nephrology and represents a significant challenge for the scientific community. The scope of the present review includes exploring relevant findings, identifying unmet needs, and reviewing therapeutic developments that characterize NS in the last decades. The main aim is to provide a basis for new perspectives and mechanistic studies in NS.
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Affiliation(s)
- Flavio Vincenti
- Division of Nephrology, Department of Medicine and Department of Surgery, University of California San Francisco, San Francisco, CA, United States
| | - Andrea Angeletti
- Nephrology Dialysis and Transplantation, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy
| | - Gian Marco Ghiggeri
- Nephrology Dialysis and Transplantation, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy
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13
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Kleczko EK, Nguyen DT, Marsh KH, Bauer CD, Li AS, Monaghan MLT, Berger MD, Furgeson SB, Gitomer BY, Chonchol MB, Clambey ET, Zimmerman KA, Nemenoff RA, Hopp K. Immune checkpoint activity regulates polycystic kidney disease progression. JCI Insight 2023; 8:e161318. [PMID: 37345660 PMCID: PMC10371237 DOI: 10.1172/jci.insight.161318] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2022] [Accepted: 05/12/2023] [Indexed: 06/23/2023] Open
Abstract
Innate and adaptive immune cells modulate the severity of autosomal dominant polycystic kidney disease (ADPKD), a common kidney disease with inadequate treatment options. ADPKD has parallels with cancer, in which immune checkpoint inhibitors have been shown to reactivate CD8+ T cells and slow tumor growth. We have previously shown that in PKD, CD8+ T cell loss worsens disease. This study used orthologous early-onset and adult-onset ADPKD models (Pkd1 p.R3277C) to evaluate the role of immune checkpoints in PKD. Flow cytometry of kidney cells showed increased levels of programmed cell death protein 1 (PD-1)/cytotoxic T lymphocyte associated protein 4 (CTLA-4) on T cells and programmed cell death ligand 1 (PD-L1)/CD80 on macrophages and epithelial cells in Pkd1RC/RC mice versus WT, paralleling disease severity. PD-L1/CD80 was also upregulated in ADPKD human cells and patient kidney tissue versus controls. Genetic PD-L1 loss or treatment with an anti-PD-1 antibody did not impact PKD severity in early-onset or adult-onset ADPKD models. However, treatment with anti-PD-1 plus anti-CTLA-4, blocking 2 immune checkpoints, improved PKD outcomes in adult-onset ADPKD mice; neither monotherapy altered PKD severity. Combination therapy resulted in increased kidney CD8+ T cell numbers/activation and decreased kidney regulatory T cell numbers correlative with PKD severity. Together, our data suggest that immune checkpoint activation is an important feature of and potential novel therapeutic target in ADPKD.
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Affiliation(s)
- Emily K. Kleczko
- Department of Medicine, Division of Renal Diseases and Hypertension
| | - Dustin T. Nguyen
- Department of Medicine, Division of Renal Diseases and Hypertension
| | - Kenneth H. Marsh
- Department of Medicine, Division of Renal Diseases and Hypertension
| | - Colin D. Bauer
- Department of Medicine, Division of Renal Diseases and Hypertension
| | - Amy S. Li
- Department of Medicine, Division of Renal Diseases and Hypertension
| | | | | | - Seth B. Furgeson
- Department of Medicine, Division of Renal Diseases and Hypertension
| | | | - Michel B. Chonchol
- Department of Medicine, Division of Renal Diseases and Hypertension
- Consortium for Fibrosis Research and Translation, and
| | - Eric T. Clambey
- Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Kurt A. Zimmerman
- Department of Internal Medicine, Division of Nephrology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
| | - Raphael A. Nemenoff
- Department of Medicine, Division of Renal Diseases and Hypertension
- Consortium for Fibrosis Research and Translation, and
| | - Katharina Hopp
- Department of Medicine, Division of Renal Diseases and Hypertension
- Consortium for Fibrosis Research and Translation, and
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14
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Catanese L, Siwy J, Mischak H, Wendt R, Beige J, Rupprecht H. Recent Advances in Urinary Peptide and Proteomic Biomarkers in Chronic Kidney Disease: A Systematic Review. Int J Mol Sci 2023; 24:ijms24119156. [PMID: 37298105 DOI: 10.3390/ijms24119156] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 05/19/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
Biomarker development, improvement, and clinical implementation in the context of kidney disease have been a central focus of biomedical research for decades. To this point, only serum creatinine and urinary albumin excretion are well-accepted biomarkers in kidney disease. With their known blind spot in the early stages of kidney impairment and their diagnostic limitations, there is a need for better and more specific biomarkers. With the rise in large-scale analyses of the thousands of peptides in serum or urine samples using mass spectrometry techniques, hopes for biomarker development are high. Advances in proteomic research have led to the discovery of an increasing amount of potential proteomic biomarkers and the identification of candidate biomarkers for clinical implementation in the context of kidney disease management. In this review that strictly follows the PRISMA guidelines, we focus on urinary peptide and especially peptidomic biomarkers emerging from recent research and underline the role of those with the highest potential for clinical implementation. The Web of Science database (all databases) was searched on 17 October 2022, using the search terms "marker *" OR biomarker * AND "renal disease" OR "kidney disease" AND "proteome *" OR "peptid *" AND "urin *". English, full-text, original articles on humans published within the last 5 years were included, which had been cited at least five times per year. Studies based on animal models, renal transplant studies, metabolite studies, studies on miRNA, and studies on exosomal vesicles were excluded, focusing on urinary peptide biomarkers. The described search led to the identification of 3668 articles and the application of inclusion and exclusion criteria, as well as abstract and consecutive full-text analyses of three independent authors to reach a final number of 62 studies for this manuscript. The 62 manuscripts encompassed eight established single peptide biomarkers and several proteomic classifiers, including CKD273 and IgAN237. This review provides a summary of the recent evidence on single peptide urinary biomarkers in CKD, while emphasizing the increasing role of proteomic biomarker research with new research on established and new proteomic biomarkers. Lessons learned from the last 5 years in this review might encourage future studies, hopefully resulting in the routine clinical applicability of new biomarkers.
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Affiliation(s)
- Lorenzo Catanese
- Department of Nephrology, Angiology and Rheumatology, Klinikum Bayreuth GmbH, 95447 Bayreuth, Germany
- Kuratorium for Dialysis and Transplantation (KfH), 95445 Bayreuth, Germany
- Medizincampus Oberfranken, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Justyna Siwy
- Mosaiques Diagnostics GmbH, 30659 Hannover, Germany
| | | | - Ralph Wendt
- Department of Nephrology, St. Georg Hospital Leipzig, 04129 Leipzig, Germany
| | - Joachim Beige
- Department of Nephrology, St. Georg Hospital Leipzig, 04129 Leipzig, Germany
- Department of Internal Medicine II, Martin-Luther-University Halle/Wittenberg, 06108 Halle/Saale, Germany
- Kuratorium for Dialysis and Transplantation (KfH), 04129 Leipzig, Germany
| | - Harald Rupprecht
- Department of Nephrology, Angiology and Rheumatology, Klinikum Bayreuth GmbH, 95447 Bayreuth, Germany
- Kuratorium for Dialysis and Transplantation (KfH), 95445 Bayreuth, Germany
- Medizincampus Oberfranken, Friedrich-Alexander-University Erlangen-Nürnberg, 91054 Erlangen, Germany
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15
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Ge L, Liu J, Lin B, Qin X. Progress in understanding primary glomerular disease: insights from urinary proteomics and in-depth analyses of potential biomarkers based on bioinformatics. Crit Rev Clin Lab Sci 2023:1-20. [PMID: 36815270 DOI: 10.1080/10408363.2023.2178378] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
Abstract
Chronic kidney disease (CKD) has become a global public health challenge. While primary glomerular disease (PGD) is one of the leading causes of CKD, the specific pathogenesis of PGD is still unclear. Accurate diagnosis relies largely on invasive renal biopsy, which carries risks of bleeding, pain, infection and kidney vein thrombosis. Problems with the biopsy procedure include lack of glomeruli in the tissue obtained, and the sampling site not being reflective of the overall lesion in the kidney. Repeated renal biopsies to monitor disease progression cannot be performed because of the significant risks of bleeding and kidney vein thrombosis. On the other hand, urine collection, a noninvasive method, can be performed repeatedly, and urinary proteins can reflect pathological changes in the urinary system. Advancements in proteomics technologies, especially mass spectrometry, have facilitated the identification of candidate biomarkers in different pathological types of PGD. Such biomarkers not only provide insights into the pathogenesis of PGD but also are important for diagnosis, monitoring treatment, and prognosis. In this review, we summarize the findings from studies that have used urinary proteomics, among other omics screens, to identify potential biomarkers for different types of PGD. Moreover, we performed an in-depth bioinformatic analysis to gain a deeper understanding of the biological processes and protein-protein interaction networks in which these candidate biomarkers may participate. This review, including a description of an integrated analysis method, is intended to provide insights into the pathogenesis, noninvasive diagnosis, and personalized treatment efforts of PGD and other associated diseases.
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Affiliation(s)
- Lili Ge
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Jianhua Liu
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Baoxu Lin
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
| | - Xiaosong Qin
- Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, China.,Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, China
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16
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Zen RDC, Dominguez WV, Braga I, dos Reis LM, Jorge LB, Yu L, Woronik V, Dias CB. Urinary CD80 and Serum suPAR as Biomarkers of Glomerular Disease among Adults in Brazil. Diagnostics (Basel) 2023; 13:diagnostics13020203. [PMID: 36673014 PMCID: PMC9857681 DOI: 10.3390/diagnostics13020203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 12/29/2022] [Accepted: 01/03/2023] [Indexed: 01/06/2023] Open
Abstract
INTRODUCTION Urinary CD80 has been shown to have good specificity for minimal change disease (MCD) in children. However, the investigation of circulating factors such as soluble urokinase plasminogen activator receptor (suPAR) as biomarkers of focal segmental glomerulosclerosis (FSGS) is quite controversial. The objective of this study was to determine whether urinary CD80 and serum suPAR can be used for the diagnosis of MCD and FSGS, respectively, in the adult population of Brazil. We also attempted to determine whether those biomarkers assess the response to immunosuppressive treatment. METHODS This was a prospective study in which urine and blood samples were collected for analysis of CD80 and suPAR, respectively, only in the moment of renal biopsy, from patients undergoing to diagnostic renal biopsy. At and six months after biopsy, we analyzed serum creatinine, serum albumin, and proteinuria in order to evaluate the use of the CD80 and suPAR collected in diagnosis as markers of response to immunosuppressive treatment. In healthy controls were collected urinary CD80 and proteinuria, serum suPAR, and creatinine. RESULTS The results of 70 renal biopsies were grouped, by diagnosis, as follows: FSGS (n = 18); membranous nephropathy (n = 14); MCD (n = 5); and other glomerulopathies (n = 33). There was no significant difference among the groups in terms of the urinary CD80 levels, and serum suPAR was not significantly higher in the FSGS group, as would have been expected. Urinary CD80 correlated positively with nephrotic syndrome, regardless of the type of glomerular disease. Neither biomarker correlated with proteinuria at six months after biopsy. CONCLUSION In adults, urinary CD80 can serve as a marker of nephrotic syndrome but is not specific for MCD, whereas serum suPAR does not appear to be useful as a diagnostic or treatment response marker.
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Affiliation(s)
- Renata de Cássia Zen
- Nephrology Department, Hospital das Clínicas, Faculty of Medicine, University of São Paulo, São Paulo 01246-903, SP, Brazil
- Correspondence: ; Tel.: +55-11-981273865; Fax: +55-11-26617261
| | - Wagner Vasques Dominguez
- Laboratory of Renal Pathophysiology, Hospital das Clínicas, Faculty of Medicine, University of São Paulo, São Paulo 01246-903, SP, Brazil
| | - Ivone Braga
- Laboratory of Renal Pathophysiology, Hospital das Clínicas, Faculty of Medicine, University of São Paulo, São Paulo 01246-903, SP, Brazil
| | - Luciene Machado dos Reis
- Laboratory of Renal Pathophysiology, Hospital das Clínicas, Faculty of Medicine, University of São Paulo, São Paulo 01246-903, SP, Brazil
| | - Lectícia Barbosa Jorge
- Nephrology Department, Hospital das Clínicas, Faculty of Medicine, University of São Paulo, São Paulo 01246-903, SP, Brazil
| | - Luis Yu
- Nephrology Department, Hospital das Clínicas, Faculty of Medicine, University of São Paulo, São Paulo 01246-903, SP, Brazil
| | - Viktoria Woronik
- Laboratory of Renal Pathophysiology, Hospital das Clínicas, Faculty of Medicine, University of São Paulo, São Paulo 01246-903, SP, Brazil
| | - Cristiane Bitencourt Dias
- Laboratory of Renal Pathophysiology, Hospital das Clínicas, Faculty of Medicine, University of São Paulo, São Paulo 01246-903, SP, Brazil
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17
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Glomerular B7-1 staining: toward precision medicine for treatment of recurrent focal segmental glomerulosclerosis. Pediatr Nephrol 2023; 38:13-15. [PMID: 35725967 DOI: 10.1007/s00467-022-05650-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 05/29/2022] [Accepted: 05/31/2022] [Indexed: 01/10/2023]
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Abstract
Idiopathic nephrotic syndrome often responds to immunosuppressive treatment. Nevertheless, this syndrome-and the drugs used to treat it-remain important causes of patient morbidity. Idiopathic nephrotic syndrome is usually caused by minimal change disease or FSGS, diseases that primarily affect the podocytes. In spite of decades of research, the underlying causes of both diseases remain incompletely understood. There is, however, a large body of observational and experimental data linking the immune system with both minimal change disease and FSGS, including associations with systemic infections and hematologic malignancies. Perhaps most compellingly, many different immunomodulatory drugs are effective for treating idiopathic nephrotic syndrome, including biologic agents that have well-defined immune targets. In fact, the unexpected efficacy of targeted therapeutic agents has provided important new insights into the pathogenesis of these diseases. Given the large number of drugs that are available to deplete or block specific cells and molecules within the immune system, a better understanding of the immunologic causes of idiopathic nephrotic syndrome may lead to better diagnostic and therapeutic approaches.
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Affiliation(s)
- Ruth E. Campbell
- Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, Colorado
| | - Joshua M. Thurman
- Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, Colorado
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19
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Matsuyama Y, Asanuma K, Yoshida K, Hagi T, Iino T, Nakamura T, Sudo A. The role of soluble CD80 in patients with soft tissue tumors. J Orthop Surg Res 2022; 17:404. [PMID: 36064421 PMCID: PMC9446575 DOI: 10.1186/s13018-022-03283-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/01/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Immune checkpoint protein (ICP), which is a central factor group of the immune system, has been reported to have a correlation between the degree of its expression and the prognosis of patients with malignant tumors, and many inhibitors have appeared as therapeutic targets. On the other hand, a soluble form of ICP in circulating blood induced systemic immunosuppression. In this study, we investigated the relationship between the soluble form of CD80 (sCD80) which is a ligand for the inhibitory system CTLA-4, in blood, and clinicopathological parameters in patients with soft tissue tumors. METHODS A total of 119 patients with primary soft tissue tumors were enrolled in this study. The sCD80 levels were measured by enzyme immunoassay. RESULTS There were no significant differences in sCD80 levels between benign (34) and soft tissue sarcoma (STS) patients (85). In STS, the high-sCD80 group had significantly lower metastasis-free survival (MS) and lower overall survival (OS) than the low-sCD80 group at 5 years using the log-rank test (OS: high > 404 pg/mL, low ≤ 404 pg/mL, MS: high > 531 pg/ml, low ≤ 531 pg/ml). On multivariate Cox proportional hazard analysis, the high-sCD80 group had significant differences in 5MS and 5OS compared to the low-sCD80 group. CONCLUSIONS In conclusion, sCD80 may negatively affect systemic immune circumstances, in STS, and may have potential as a therapeutic target.
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Affiliation(s)
- Yumi Matsuyama
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan
| | - Kunihiro Asanuma
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan.
| | - Keisuke Yoshida
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan
| | - Tomohito Hagi
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan
| | - Takahiro Iino
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan
| | - Tomoki Nakamura
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan
| | - Akihiro Sudo
- Department of Orthopaedic Surgery, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu City, Mie, 514-8507, Japan
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Cara-Fuentes G, Andres-Hernando A, Bauer C, Banks M, Garcia GE, Cicerchi C, Kuwabara M, Shimada M, Johnson RJ, Lanaspa MA. Pulmonary surfactants and the respiratory-renal connection in steroid-sensitive nephrotic syndrome of childhood. iScience 2022; 25:104694. [PMID: 35847557 PMCID: PMC9284382 DOI: 10.1016/j.isci.2022.104694] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 05/23/2022] [Accepted: 06/24/2022] [Indexed: 01/21/2023] Open
Abstract
Steroid-sensitive nephrotic syndrome (SSNS) in childhood is usually due to minimal change disease (MCD). Unlike many glomerular conditions, SSNS/MCD is commonly precipitated by respiratory infections. Of interest, pulmonary inflammation releases surfactants in circulation which are soluble agonists of SIRPα, a podocyte receptor that regulates integrin signaling. Here, we characterized this pulmonary-renal connection in MCD and performed studies to determine its importance. Children with SSNS/MCD in relapse but not remission had elevated plasma surfactants and urinary SIRPα. Sera from relapsing subjects triggered podocyte SIRPα signaling via tyrosine phosphatase SHP-2 and nephrin dephosphorylation, a marker of podocyte activation. Further, addition of surfactants to MCD sera from patients in remission replicated these findings. Similarly, nasal instillation of toll-like receptor 3 and 4 agonists in mice resulted in elevated serum surfactants and their binding to glomeruli triggering proteinuria. Together, our data document a critical pulmonary-podocyte signaling pathway involving surfactants and SIRPα signaling in SSNS/MCD.
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Affiliation(s)
| | - Ana Andres-Hernando
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA,Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR, USA
| | - Colin Bauer
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Mindy Banks
- Rocky Mountain Pediatric Kidney Center, Denver, CO, USA
| | - Gabriela E. Garcia
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Christina Cicerchi
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Masanari Kuwabara
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Michiko Shimada
- Department of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
| | - Richard J. Johnson
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Miguel A. Lanaspa
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA,Division of Nephrology and Hypertension, Oregon Health & Science University, Portland, OR, USA,Corresponding author
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21
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Second and Third Generational Advances in Therapies of the Immune-Mediated Kidney Diseases in Children and Adolescents. CHILDREN 2022; 9:children9040536. [PMID: 35455580 PMCID: PMC9030090 DOI: 10.3390/children9040536] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/06/2022] [Accepted: 04/08/2022] [Indexed: 11/17/2022]
Abstract
Therapy of immune-mediated kidney diseases has evolved during recent decades from the non-specific use of corticosteroids and antiproliferative agents (like cyclophosphamide or azathioprine), towards the use of more specific drugs with measurable pharmacokinetics, like calcineurin inhibitors (cyclosporine A and tacrolimus) and mycophenolate mofetil, to the treatment with biologic drugs targeting detailed specific receptors, like rituximab, eculizumab or abatacept. Moreover, the data coming from a molecular science revealed that several drugs, which have been previously used exclusively to modify the upregulated adaptive immune system, may also exert a local effect on the kidney microstructure and ameliorate the functional instability of podocytes, reducing the leak of protein into the urinary space. The innate immune system also became a target of new therapies, as its specific role in different kidney diseases has been de novo defined. Current therapy of several immune kidney diseases may now be personalized, based on the detailed diagnostic procedures, including molecular tests. However, in most cases there is still a space for standard therapies based on variable protocols including usage of steroids with the steroid-sparing agents. They are used as a first-line treatment, while modern biologic agents are selected as further steps in cases of lack of the efficacy or toxicity of the basic therapies. In several clinical settings, the biologic drugs are effective as the add-on therapy.
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22
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Kitsou K, Askiti V, Mitsioni A, Spoulou V. The immunopathogenesis of idiopathic nephrotic syndrome: a narrative review of the literature. Eur J Pediatr 2022; 181:1395-1404. [PMID: 35098401 DOI: 10.1007/s00431-021-04357-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 10/21/2021] [Accepted: 12/19/2021] [Indexed: 12/18/2022]
Abstract
UNLABELLED Idiopathic nephrotic syndrome (INS) is a common glomerular disease in childhood, and the immunological involvement in the pathogenesis of non-genetic INS, although not fully elucidated, is evident. This narrative review aims to offer a concise and in-depth view of the current knowledge on the immunological mechanisms of the development of INS as well as the role of the immunological components of the disease in the responsiveness to treatment. T cell immunity appears to play a major role in the INS immunopathogenesis and has been the first to be linked to the disease. Various T cell immunophenotypes are implicated in INS, including T-helper-1, T-helper-2, T-helper-17, and T regulatory cells, and various cytokines have been proposed as surrogate biomarkers of the disease; however, no distinct T helper or cytokine profile has been conclusively linked to the disease. More recently, the recognition of the role of B cell mediated immunity and the various B cell subsets that are dysregulated in patients with INS have led to new hypotheses on the underlying immunological causes of INS. Finally, the disambiguation of the exact mechanisms of the INS development in the future may be the key to the development of more targeted personalized approaches in managing INS. CONCLUSIONS INS demonstrates particularly interesting immunopathogenetic pathways, in which multiple interactions between T cell and B cell immunity and the podocyte are involved. The disambiguation of these pathways will provide promising novel therapeutic targets in INS. WHAT IS KNOWN • INS is the most common glomerular disease in the paediatric population, and its onset and relapses have been linked to various immunological triggers. • Multiple immunological mechanisms have been implicated in the pathogenesis of INS; however, no single distinct immunological profile has been recognized. WHAT IS NEW • Th17 cells and Treg cells play an important role in the immune dysregulation in INS. • Transitional B cell levels as well as the transitional/memory B cell ratio have been correlated to nephrotic relapses and have been proposed as biomarkers of INS relapses in SSNS patients.
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Affiliation(s)
- Konstantina Kitsou
- Immunobiology and Vaccinology Research Laboratory, First Department of Paediatrics, School of Medicine, "Aghia Sophia" Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece.
| | - Varvara Askiti
- Department of Nephrology, "P. and A. Kyriakou" Children's Hospital, Athens, Greece
| | - Andromachi Mitsioni
- Department of Nephrology, "P. and A. Kyriakou" Children's Hospital, Athens, Greece
| | - Vana Spoulou
- Immunobiology and Vaccinology Research Laboratory, First Department of Paediatrics, School of Medicine, "Aghia Sophia" Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece
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23
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Li ZH, Guo XY, Quan XY, Yang C, Liu ZJ, Su HY, An N, Liu HF. The Role of Parietal Epithelial Cells in the Pathogenesis of Podocytopathy. Front Physiol 2022; 13:832772. [PMID: 35360248 PMCID: PMC8963495 DOI: 10.3389/fphys.2022.832772] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 02/07/2022] [Indexed: 02/05/2023] Open
Abstract
Podocytopathy is the most common feature of glomerular disorder characterized by podocyte injury- or dysfunction-induced excessive proteinuria, which ultimately develops into glomerulosclerosis and results in persistent loss of renal function. Due to the lack of self-renewal ability of podocytes, mild podocyte depletion triggers replacement and repair processes mostly driven by stem cells or resident parietal epithelial cells (PECs). In contrast, when podocyte recovery fails, activated PECs contribute to the establishment of glomerular lesions. Increasing evidence suggests that PECs, more than just bystanders, have a crucial role in various podocytopathies, including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, diabetic nephropathy, IgA nephropathy, and lupus podocytopathy. In this review, we attempt to dissect the diverse role of PECs in the pathogenesis of podocytopathy based on currently available information.
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Abstract
Nephrotic syndrome (NS) encompasses a variety of disease processes leading to heavy proteinuria and edema. Minimal change disease (MCD) remains the most common primary cause of NS, as well as the most responsive to pharmacologic treatment with often minimal to no chronic kidney disease. Other causes of NS include focal segmental glomerulosclerosis, which follows MCD, and secondary causes, including extrarenal or systemic diseases, infections, and drugs. Although initial diagnosis relies on clinical findings as well as urine and blood chemistries, renal biopsy and genetic testing are important diagnostic tools, especially when considering non-MCD NS. Moreover, biomarkers in urine and serum have become important areas for research in this disease. NS progression and prognosis are variable and depend on etiology, with corticosteroids being the mainstay of treatment. Other alternative therapies found to be successful in inducing and maintaining remission include calcineurin inhibitors and rituximab. Disease course can range from recurrent disease relapse with or without acute kidney injury to end-stage renal disease in some cases. Given the complex pathogenesis of NS, which remains incompletely understood, complications are numerous and diverse and include infections, electrolyte abnormalities, acute kidney injury, and thrombosis. Pediatricians must be aware of the presentation, complications, and overall long-term implications of NS and its treatment.
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25
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Purohit S, Piani F, Ordoñez FA, de Lucas-Collantes C, Bauer C, Cara-Fuentes G. Molecular Mechanisms of Proteinuria in Minimal Change Disease. Front Med (Lausanne) 2022; 8:761600. [PMID: 35004732 PMCID: PMC8733331 DOI: 10.3389/fmed.2021.761600] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 10/15/2021] [Indexed: 11/13/2022] Open
Abstract
Minimal change disease (MCD) is the most common type of idiopathic nephrotic syndrome in childhood and represents about 15% cases in adults. It is characterized by massive proteinuria, edema, hypoalbuminemia, and podocyte foot process effacement on electron microscopy. Clinical and experimental studies have shown an association between MCD and immune dysregulation. Given the lack of inflammatory changes or immunocomplex deposits in the kidney tissue, MCD has been traditionally thought to be mediated by an unknown circulating factor(s), probably released by T cells that directly target podocytes leading to podocyte ultrastructural changes and proteinuria. Not surprisingly, research efforts have focused on the role of T cells and podocytes in the disease process. Nevertheless, the pathogenesis of the disease remains a mystery. More recently, B cells have been postulated as an important player in the disease either by activating T cells or by releasing circulating autoantibodies against podocyte targets. There are also few reports of endothelial injury in MCD, but whether glomerular endothelial cells play a role in the disease remains unexplored. Genome-wide association studies are providing insights into the genetic susceptibility to develop the disease and found a link between MCD and certain human haplotype antigen variants. Altogether, these findings emphasize the complex interplay between the immune system, glomerular cells, and the genome, raising the possibility of distinct underlying triggers and/or mechanisms of proteinuria among patients with MCD. The heterogeneity of the disease and the lack of good animal models of MCD remain major obstacles in the understanding of MCD. In this study, we will review the most relevant candidate mediators and mechanisms of proteinuria involved in MCD and the current models of MCD-like injury.
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Affiliation(s)
- Shrey Purohit
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Department of Pediatrics, Section of Pediatric Nephrology, Children's Hospital Colorado, Aurora, CO, United States
| | - Federica Piani
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Department of Medicine and Surgery Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Flor A Ordoñez
- Division of Pediatric Nephrology, Hospital Universitario Central de Asturias, Oviedo, Spain
| | | | - Colin Bauer
- Department of Pediatrics, Section of Pediatric Nephrology, Children's Hospital Colorado, Aurora, CO, United States
| | - Gabriel Cara-Fuentes
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.,Department of Pediatrics, Section of Pediatric Nephrology, Children's Hospital Colorado, Aurora, CO, United States
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26
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Tamura H. Trends in pediatric nephrotic syndrome. World J Nephrol 2021; 10:88-100. [PMID: 34631479 PMCID: PMC8477269 DOI: 10.5527/wjn.v10.i5.88] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2021] [Revised: 05/15/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Nephrotic syndrome (NS) is relatively common in children, with most of its histological types being minimal changed disease. Its etiology has long been attributed to lymphocyte (especially T-cell) dysfunction, while T-cell-mediated vascular hyperpermeability increases protein permeability in glomerular capillaries, leading to proteinuria and hypoproteinemia. Based on this etiology, steroids and immunosuppressive drugs that are effective against this disease have also been considered to correct T-cell dysfunction. However, in recent years, this has been questioned. The primary cause of NS has been considered damage to glomerular epithelial cells and podocyte-related proteins. Therefore, we first describe the changes in expression of molecules involved in NS etiology, and then describe the mechanism by which abnormal expression of these molecules induces proteinuria. Finally, we consider the mechanism by which infection causes the recurrence of NS.
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Affiliation(s)
- Hiroshi Tamura
- Department of Pediatrics, Kumamoto University, Kumamoto 8608556, Japan
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27
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Cara-Fuentes G, Smoyer WE. Biomarkers in pediatric glomerulonephritis and nephrotic syndrome. Pediatr Nephrol 2021; 36:2659-2673. [PMID: 33389089 DOI: 10.1007/s00467-020-04867-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 10/16/2020] [Accepted: 11/18/2020] [Indexed: 12/21/2022]
Abstract
Glomerular diseases are often chronic or recurring and thus associated with a tremendous physical, psychological, and economic burden. Their etiologies are often unknown, and their pathogeneses are frequently poorly understood. The diagnoses and management of these diseases are therefore based on clinical features, traditional laboratory markers, and, often, kidney pathology. However, the clinical presentation can be highly variable, the kidney pathology may not establish a definitive diagnosis, and the therapeutic responses and resulting clinical outcomes are often unpredictable. To try to address these challenges, significant research efforts have been made over the last decade to identify potential biomarkers that can help clinicians optimize the diagnosis and prognosis at clinical presentation, as well as help predict long-term outcomes. Unfortunately, these efforts have to date only identified a single biomarker for glomerular disease that has been fully validated and developed for widespread clinical use (anti-PLA2R antibodies to diagnose membranous nephropathy). In this manuscript, we review the definitions and development of biomarkers, as well as the current knowledge on both historical and novel candidate biomarkers of glomerular disease, with an emphasis on those associated with idiopathic nephrotic syndrome.
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Affiliation(s)
- Gabriel Cara-Fuentes
- Department of Pediatrics, Division of Pediatric Nephrology, University of Colorado, 12700 E 19th Ave, R2 building, Room 7420D, Aurora, CO, 80045, USA.
| | - William E Smoyer
- Center for Clinical and Translational Research, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA.,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA
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28
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CD80 Insights as Therapeutic Target in the Current and Future Treatment Options of Frequent-Relapse Minimal Change Disease. BIOMED RESEARCH INTERNATIONAL 2021; 2021:6671552. [PMID: 33506028 PMCID: PMC7806396 DOI: 10.1155/2021/6671552] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 12/26/2020] [Indexed: 12/14/2022]
Abstract
Minimal change disease (MCD) is the most common cause of idiopathic nephrotic syndrome in children, and it is well known for its multifactorial causes which are the manifestation of the disease. Proteinuria is an early consequence of podocyte injury and a typical sign of kidney disease. Steroid-sensitive patients react well with glucocorticoids, but there is a high chance of multiple relapses. CD80, also known as B7-1, is generally expressed on antigen-presenting cells (APCs) in steroid-sensitive MCD patients. Various glomerular disease models associated with proteinuria demonstrated that the detection of CD80 with the increase of urinary CD80 was strongly associated closely with frequent-relapse MCD patients. The role of CD80 in MCD became controversial because one contradicts finding. This review covers the treatment alternatives for MCD with the insight of CD80 as a potential therapeutic target. The promising effectiveness of CD20 (rituximab) antibody and CD80 inhibitor (abatacept) encourages further investigation of CD80 as a therapeutic target in frequent-relapse MCD patients. Therapeutic-based antibody towards CD80 (galiximab) had never been investigated in MCD or any kidney-related disease; hence, the role of CD80 is still undetermined. A new therapeutic approach towards MCD is essential to provide broader effective treatment options besides the general immunosuppressive agents with gruesome adverse effects.
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29
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Chiba Y, Nagasawa T, Kin S, Takahashi K, Yoshida M, Oe Y, Okamoto K, Sato H, Miyazaki M. Spontaneous remission of minimal change nephrotic syndrome in an elderly man. CEN Case Rep 2021; 10:301-307. [PMID: 33398783 DOI: 10.1007/s13730-020-00554-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2020] [Accepted: 10/31/2020] [Indexed: 11/29/2022] Open
Abstract
Minimal change nephrotic syndrome (MCNS) cases achieving spontaneous remission without external factors are rarely reported. We report a case of MCNS that achieved spontaneous remission without external factors that triggered its onset. An 82-year-old male patient was admitted to the hospital for close examination of nephrotic syndrome. Renal biopsy was performed and MCNS was diagnosed. Owing to the patient's age and history of foot and microvascular arteriovenous thrombosis, we did not start immunosuppressive drugs, including steroids, and opted for conservative management. After conservative treatment, proteinuria gradually decreased, and the patient achieved complete remission. Given that the patient had a history of urinary protein and thrombosis, recurrence of MCNS was considered again this time. In addition, the involvement of external factors that trigger the onset of MCNS was not found. In conclusion, in elderly-onset MCNS, clinicians generally hesitate to initiate treatment with an immunosuppressive drug, containing steroids, because of its many complications. Thus, our data provide valuable insight into MCNS.
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Affiliation(s)
- Yuki Chiba
- Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
| | - Tasuku Nagasawa
- Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Saori Kin
- Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Kei Takahashi
- Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Mai Yoshida
- Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yuji Oe
- Department of Community Medical Support Tohoku Medical Megabank Organization, Tohoku University School of Medicine, Sendai, Miyagi, Japan
| | - Koji Okamoto
- Department of Community Medical Support Tohoku Medical Megabank Organization, Tohoku University School of Medicine, Sendai, Miyagi, Japan
| | - Hiroshi Sato
- Japanese Railways Sendai Hospital, Sendai, Miyagi, Japan
| | - Mariko Miyazaki
- Division of Nephrology, Endocrinology and Vascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
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30
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MicroRNAs as Biomarkers for Nephrotic Syndrome. Int J Mol Sci 2020; 22:ijms22010088. [PMID: 33374848 PMCID: PMC7795691 DOI: 10.3390/ijms22010088] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 12/19/2020] [Accepted: 12/22/2020] [Indexed: 12/15/2022] Open
Abstract
Nephrotic syndrome represents the clinical situation characterized by presence of massive proteinuria and low serum protein caused by a variety of diseases, including minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephropathy. Differentiating between diagnoses requires invasive renal biopsies in general. Even with the biopsy, we encounter difficulties to differentiate MCNS and FSGS in some cases. There is no other better option currently available for the diagnosis other than renal biopsy. MicroRNAs (miRNAs) are no-coding RNAs of approximately 20 nucleotides in length, which regulate target genes in the post-transcriptional processes and have essential roles in many diseases. MiRNAs in serum and urine have been shown as non-invasive biomarkers in multiple diseases, including renal diseases. In this article, we summarize the current knowledge of miRNAs as the promising biomarkers for nephrotic syndrome.
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31
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Mishra OP. Urinary CD 80 in Nephrotic Syndrome: A Biomarker to Distinguish Minimal Change Disease From Other Glomerular Diseases. Kidney Int Rep 2020; 5:1851-1852. [PMID: 33165400 PMCID: PMC7610000 DOI: 10.1016/j.ekir.2020.09.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Affiliation(s)
- Om P. Mishra
- Division of Pediatric Nephrology, Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India
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32
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Cara-Fuentes G, Venkatareddy M, Verma R, Segarra A, Cleuren AC, Martínez-Ramos A, Johnson RJ, Garg P. Glomerular endothelial cells and podocytes can express CD80 in patients with minimal change disease during relapse. Pediatr Nephrol 2020; 35:1887-1896. [PMID: 32399663 PMCID: PMC8528162 DOI: 10.1007/s00467-020-04541-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 03/05/2020] [Accepted: 03/18/2020] [Indexed: 12/19/2022]
Abstract
BACKGROUND Urinary CD80 has emerged as potential biomarker in idiopathic nephrotic syndrome (INS). However, its cellular source remains controversial. The aim of the study was to assess whether CD80 is truly expressed by glomerular cells in INS patients during relapse and in the LPS mouse model of podocyte injury. METHODS The presence of CD80 in glomeruli was evaluated by combining immunostaining, immunogold labeling, and in situ hybridization techniques. RESULTS CD80 was present along the surface of glomerular endothelial cells (GEC) and rarely in podocytes in six of nine minimal change disease (MCD) patients in relapse, two of eleven patients with focal segmental glomerulosclerosis in relapse, and absent in controls. In mice, CD80 was upregulated at mRNA and protein level in GEC and podocytes, in a similar pattern to that seen in MCD patients. CONCLUSIONS Glomerular endothelial cells and podocytes can express CD80 in patients with MCD during relapse. A better understanding of the role of CD80 in glomerular cells may provide further insights into the mechanisms of proteinuria in INS.
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Affiliation(s)
- Gabriel Cara-Fuentes
- Division of Pediatric Nephrology, Department of Pediatrics, University of Michigan, MSRB-2, Room 1574, 1500 E Medical Center Dr, Ann Arbor, MI, 48109, USA.
| | - Madhusudan Venkatareddy
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, USA
| | - Rakesh Verma
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, USA
| | - Alfons Segarra
- Division of Nephrology, Hospital Vall d’Hebron, Barcelona, Spain
| | | | | | - Richard J Johnson
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, USA
| | - Puneet Garg
- Division of Nephrology, Department of Internal Medicine, University of Michigan, Ann Arbor, USA
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33
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Niitsuma S, Kudo H, Kikuchi A, Hayashi T, Kumakura S, Kobayashi S, Okuyama Y, Kumagai N, Niihori T, Aoki Y, So T, Funayama R, Nakayama K, Shirota M, Kondo S, Kagami S, Tsukaguchi H, Iijima K, Kure S, Ishii N. Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome. Int Immunol 2020; 32:283-292. [PMID: 31954058 DOI: 10.1093/intimm/dxz081] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 12/19/2019] [Indexed: 12/11/2022] Open
Abstract
Nephrotic syndrome (NS) is a renal disease characterized by severe proteinuria and hypoproteinemia. Although several single-gene mutations have been associated with steroid-resistant NS, causative genes for steroid-sensitive NS (SSNS) have not been clarified. While seeking to identify causative genes associated with SSNS by whole-exome sequencing, we found compound heterozygous variants/mutations (c.524T>C; p.I175T and c.662G>A; p.R221H) of the interleukin-1 receptor accessory protein (IL1RAP) gene in two siblings with SSNS. The siblings' parents are healthy, and each parent carries a different heterozygous IL1RAP variant/mutation. Since IL1RAP is a critical subunit of the functional interleukin-1 receptor (IL-1R), we investigated the effect of these variants on IL-1R subunit function. When stimulated with IL-1β, peripheral blood mononuclear cells from the siblings with SSNS produced markedly lower levels of cytokines compared with cells from healthy family members. Moreover, IL-1R with a variant IL1RAP subunit, reconstituted on a hematopoietic cell line, had impaired binding ability and low reactivity to IL-1β. Thus, the amino acid substitutions in IL1RAP found in these NS patients are dysfunctional variants/mutations. Furthermore, in the kidney of Il1rap-/- mice, the number of myeloid-derived suppressor cells, which require IL-1β for their differentiation, was markedly reduced although these mice did not show significantly increased proteinuria in acute nephrotic injury with lipopolysaccharide treatment. Together, these results identify two IL1RAP variants/mutations in humans for the first time and suggest that IL1RAP might be a causative gene for familial NS.
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Affiliation(s)
- Sou Niitsuma
- Department of Microbiology and Immunology, Endocrinology and Vascular Medicine, Sendai, Japan.,Department of Pediatrics, Endocrinology and Vascular Medicine, Sendai, Japan
| | - Hiroki Kudo
- Department of Pediatrics, Endocrinology and Vascular Medicine, Sendai, Japan
| | - Atsuo Kikuchi
- Department of Pediatrics, Endocrinology and Vascular Medicine, Sendai, Japan
| | - Takaya Hayashi
- Department of Microbiology and Immunology, Endocrinology and Vascular Medicine, Sendai, Japan
| | - Satoshi Kumakura
- Department of Microbiology and Immunology, Endocrinology and Vascular Medicine, Sendai, Japan.,Department of Nephrology, Endocrinology and Vascular Medicine, Sendai, Japan
| | - Shuhei Kobayashi
- Department of Microbiology and Immunology, Endocrinology and Vascular Medicine, Sendai, Japan
| | - Yuko Okuyama
- Department of Microbiology and Immunology, Endocrinology and Vascular Medicine, Sendai, Japan
| | - Naonori Kumagai
- Department of Pediatrics, Endocrinology and Vascular Medicine, Sendai, Japan
| | - Tetsuya Niihori
- Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoko Aoki
- Department of Medical Genetics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takanori So
- Department of Microbiology and Immunology, Endocrinology and Vascular Medicine, Sendai, Japan.,Laboratory of Molecular Cell Biology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Ryo Funayama
- Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keiko Nakayama
- Division of Cell Proliferation, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Matsuyuki Shirota
- Division of Interdisciplinary Medical Science, United Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shuji Kondo
- Department of Pediatrics, Tokushima University Graduate School, Tokushima, Japan.,Department of Pediatrics, NHO Shikoku Medical Center for Children and Adults, Zentsuji, Japan
| | - Shoji Kagami
- Department of Pediatrics, Tokushima University Graduate School, Tokushima, Japan
| | - Hiroyasu Tsukaguchi
- Second Department of Internal Medicine, Kansai Medical University, Hirakata, Japan
| | - Kazumoto Iijima
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Shigeo Kure
- Department of Pediatrics, Endocrinology and Vascular Medicine, Sendai, Japan
| | - Naoto Ishii
- Department of Microbiology and Immunology, Endocrinology and Vascular Medicine, Sendai, Japan
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Chen P, Chen Y, Jiang M, Mo Y, Ying H, Tang X, Zhang J. Usefulness of the cytokines expression of Th1/Th2/Th17 and urinary CD80 excretion in adult-onset minimal change disease. PeerJ 2020; 8:e9854. [PMID: 33194357 PMCID: PMC7485503 DOI: 10.7717/peerj.9854] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/11/2020] [Indexed: 12/16/2022] Open
Abstract
Background Minimal change disease (MCD) is a common form of nephrotic syndrome in adults. However, the molecular mechanism underlying the pathogenesis of MCD remains incompletely understood. In this study, we aimed to investigate the role of the cytokines expression of Th1/Th2/Th17 and urinary CD80 excretion in adult-onset MCD patients. Methods The lymphocyte subsets, 34 cytokine levels of Th1/Th2/Th17, serum and urine concentrations of CD80, and expression of CD80 in glomeruli were analyzed in 28 cases (15 males and 13 females; average age: 34.1 years, age range: 18–56 years), including 10 patients with MCD in relapse, nine patients with MCD in remission and nine healthy controls. Results There was no significant difference of CD3+CD4+ cells proportion among patients with MCD in relapse, MCD in remission and healthy controls (P = 0.802). The cytokine levels of GM-CSF and tumor necrosis factor (TNF)-related activation-induced cytokine (TRANCE) in patients with MCD in relapse increased 1.5 times higher than those in remission. An evident increase in the excretion of urinary CD80 was found in patients with relapsed MCD compared with those in remission (598.4 ± 115.8 vs 81.78 ± 7.04 ng/g creatinine, P < 0.001) and healthy controls (598.4 ± 115.8 vs 67.44 ± 8.94 ng/g creatinine, P < 0.001). CD80 expression was observed in podocyte of MCD patient in relapse by immunofluorescence technique. Conclusions The cytokines GM-CSF and TRANCE are increased and the urinary CD80 levels are elevated in adult-onset MCD patients in relapse, indicating a disorder of Th1/Th2/Th17 balance and that the elevated excretion of CD80 may underlie the pathogenesis and development of adult-onset MCD.
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Affiliation(s)
- Ping Chen
- Department of Nephrology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China.,Department of Nephrology, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Yan Chen
- Department of Physical Examination, Ningbo First hospital, Ningbo, Zhejiang, China
| | - Maoqing Jiang
- Department of Nuclear Medicine, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Yijun Mo
- Department of Laboratory Medicine, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Huanhuan Ying
- Department of Laboratory Medicine, Ningbo First Hospital, Ningbo, Zhejiang, China
| | - Xun Tang
- Department of Nephrology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China
| | - Jun Zhang
- Department of Nephrology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong, China
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Gonzalez Guerrico AM, Lieske J, Klee G, Kumar S, Lopez-Baez V, Wright AM, Bobart S, Shevell D, Maldonado M, Troost JP, Hogan MC, Nephrotic Syndrome Study Network Consortium (NEPTUNE). Urinary CD80 Discriminates Among Glomerular Disease Types and Reflects Disease Activity. Kidney Int Rep 2020; 5:2021-2031. [PMID: 33163723 PMCID: PMC7609973 DOI: 10.1016/j.ekir.2020.08.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2020] [Revised: 07/17/2020] [Accepted: 08/04/2020] [Indexed: 02/07/2023] Open
Abstract
Introduction Heterogeneity of nephrotic diseases and a lack of validated biomarkers limits interventions and reduces the ability to examine outcomes. Urinary CD80 is a potential biomarker for minimal change disease (MCD) steroid-sensitive nephrotic syndrome (NS). We investigated and validated a CD80 enzyme-linked immunosorbent assay (ELISA) in urine in a large cohort with a variety of nephrotic diseases. Methods A commercial CD80 ELISA was enhanced and analytically validated for urine. Patients were from Mayo Clinic (307) and Nephrotic Syndrome Study Network Consortium (NEPTUNE; 104) as follows: minimal change disease (MCD, 56), focal segmental glomerulosclerosis (FSGS, 92), lupus nephritis (LN, 25), IgA nephropathy (IgAN, 20), membranous nephropathy (MN, 49), autosomal dominant polycystic kidney disease (ADPKD, 10), diabetic nephropathy (DN; 106), pyuria (19), and controls (34). Analysis was by Kruskal−Wallis test, generalized estimating equation (GEE) models, and receiver operating characteristic (AUC) curve. Results Urinary CD80/creatinine values were highest in MCD compared to other glomerular diseases and were increased in DN with proteinuria >2 compared to controls (control = 36 ng/g; MCD = 139 ng/g, P < 0.01; LN = 90 ng/g, P < 0.12; FSGS = 66 ng/g, P = 0.18; DN = 63, P = 0.03; MN = 69 ng/g, P = 0.33; ng/g, P = 0.07; IgA = 19 ng/g, P = 0.09; ADPKD = 42, P = 0.36; and pyuria 31, P = 0.20; GEE, median, P vs. control). In proteinuric patients, CD80 concentration appears to be independent of proteinuria levels, suggesting that it is unrelated to nonspecific passage across the glomeruli. CD80/creatinine values were higher in paired relapse versus remission cases of MCD and FSGS (P < 0.0001, GEE). Conclusion Using a validated ELISA, urinary CD80 levels discriminate MCD from other forms of NS (FSGS, DN, IgA, MN) and primary from secondary FSGS.
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Affiliation(s)
| | - John Lieske
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - George Klee
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Sanjay Kumar
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Victor Lopez-Baez
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Adam M. Wright
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Shane Bobart
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
| | - Diane Shevell
- Bristol-Myers Squibb, Lawrenceville, New Jersey, USA
| | | | - Jonathan P. Troost
- Michigan Institute for Clinical and Health Research, University of Michigan, Ann Arbor, Michigan, USA
| | - Marie C. Hogan
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota, USA
- Correspondence: Marie C. Hogan, Division of Nephrology and Hypertension, Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55902, USA.
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CTLA4-Ig Abatacept Ameliorates Proteinuria by Regulating Circulating Treg/IL-17 in Adriamycin-Induced Nephropathy Rats. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2347827. [PMID: 32420329 PMCID: PMC7201454 DOI: 10.1155/2020/2347827] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/24/2019] [Revised: 02/09/2020] [Accepted: 03/20/2020] [Indexed: 12/30/2022]
Abstract
Objective This study is aimed at investigating the efficacy of CTLA4-Ig abatacept in normalizing proteinuria and its possible mechanism in adriamycin-induced nephropathy (AIN) rats. Methods A total of 32 healthy male Sprague-Dawley rats were randomly divided into a normal group, an AIN group, an abatacept group, and a prednisone group. Adriamycin (6.5 mg/kg) was injected once via the tail vein of rats to induce nephrotic syndrome. After adriamycin treatment, the abatacept group rats were given abatacept (0.5 mg/kg) once by intraperitoneal injection on day 14. In addition, the prednisone group rats were given prednisone (12.5 mg/kg) daily consecutively by gavage from day 14 to day 21. Blood, urine, and kidney tissue specimens were collected when sacrificed on day 21. The 24-hour urinary protein, serum albumin, cholesterol, creatinine, and urea nitrogen were then detected. An enzyme-linked immunosorbent assay was used to determine the level of urine CD80 and serum IL-17. Flow cytometry was used to investigate the prevalence of circulating Treg. Hematoxylin-eosin staining and electron microscopy were used for a renal histological study. Immunofluorescence staining was performed to confirm the CD80 expression of renal tissue. Results The 24-hour urinary protein of the abatacept group was significantly lower than that of the prednisone group and the AIN group. The level of urine CD80 of the abatacept group was significantly lower than that of the AIN group. Compared with the AIN group and the prednisone group, the circulating Treg prevalence of the abatacept group was significantly higher, while the level of serum IL-17 was lower. A negative kidney staining of CD80 expression was demonstrated in each group in this study. The 24-hour urinary protein had a negative correlation with the circulating Treg prevalence and Treg/IL-17 and a positive correlation with the urine CD80 and serum IL-17. Urinary CD80 had a positive correlation with serum IL-17 and no correlation with the circulating Treg prevalence. Conclusions CTLA4-Ig abatacept can reduce proteinuria of adriamycin-induced nephropathy rats, possibly at least partially as a result of regulating circulating Treg/IL-17. CTLA4-Ig abatacept could be a promising regimen for idiopathic nephrotic syndrome.
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Candelier JJ, Lorenzo HK. Idiopathic nephrotic syndrome and serum permeability factors: a molecular jigsaw puzzle. Cell Tissue Res 2019; 379:231-243. [PMID: 31848752 DOI: 10.1007/s00441-019-03147-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Accepted: 11/19/2019] [Indexed: 12/14/2022]
Abstract
Nephrotic syndrome is traditionally defined using the triad of edema, hypoalbuminemia, and proteinuria, but this syndrome is very heterogeneous and difficult to clarify. Its idiopathic form (INS) is probably the most harmful and essentially comprises two entities: minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). We will consider some hypotheses regarding the mechanisms underlying INS: (i) the presence of several glomerular permeability factors in the sera of patients that alter the morphology and function of podocytes leading to proteinuria, (ii) the putative role of immune cells. Thanks to recent data, our understanding of these disorders is evolving towards a more multifactorial origin. In this context, circulating factors may be associated according to sequential kinetic mechanisms or micro-environmental changes that need to be determined. In addition, the resulting proteinuria may trigger more proteinuria enhancing the glomerular destabilization.
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Affiliation(s)
- Jean-Jacques Candelier
- INSERM U1197, Hôpital Paul Brousse, 14 Avenue Paul Vaillant Couturier, 94800, Villejuif, France.,Université Paris-Saclay, Campus Universitaire d'Orsay, 91405, Orsay, France
| | - Hans-Kristian Lorenzo
- INSERM U1197, Hôpital Paul Brousse, 14 Avenue Paul Vaillant Couturier, 94800, Villejuif, France. .,Université Paris-Saclay, Campus Universitaire d'Orsay, 91405, Orsay, France. .,Service de Néphrologie, Hôpital Bicêtre, Faculté de Médecine Paris-Saclay, 94270, Le Kremlin-Bicêtre, France.
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Eroglu FK, Orhan D, İnözü M, Duzova A, Gulhan B, Ozaltin F, Topaloglu R. CD80 expression and infiltrating regulatory T cells in idiopathic nephrotic syndrome of childhood. Pediatr Int 2019; 61:1250-1256. [PMID: 31513327 DOI: 10.1111/ped.14005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 07/05/2019] [Accepted: 09/06/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND CD80 (also known as B7-1) is a co-stimulatory molecule that is expressed in biopsies and also excreted in urine in patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS). CD80 is inhibited by the cytotoxic T-lymphocyte-associated-antigen 4 (CTLA4), which is mainly expressed on regulatory T cells (Tregs). Ineffective circulating Treg response is involved in the pathogenesis of nephrotic syndrome. In this study, we evaluated CD80 expression and infiltrating Tregs in children with MCD and FSGS. METHODS Evaluation of CD80 expression and semi-quantitative evaluation of Tregs (FOXP3-positive CD4 T cells) were carried out in 31 kidney biopsies (12 MCD, 19 FSGS) with immunofluorescence and immunohistochemistry staining. RESULTS All MCD sections were stained negative; whereas six out of 19 FSGS sections (all from steroid-resistant (SR) patients), including one from a Wilms' tumor 1 (WT1) mutation-positive FSGS patient, stained positive for anti-CD80 goat antibody, and negative for anti-CD80 rabbit antibody. FSGS biopsy specimens had significantly higher FOXP3-positive cells/mm2 compared with MCD and control samples (P < 0.001). Biopsy samples from SR-FSGS patients (n = 12) with positive CD80 staining (n = 6) had significantly less Tregs (FOXP3-positive CD4 T cells) compared with CD80 (-) biopsies (n = 6; P = 0.004). CONCLUSION CD80 expression was not detected in the majority of the archival biopsy sections and the results were not consistent across the different antibodies. In the SR-FSGS sections, however, CD80-positive biopsies had decreased FOXP3-positive CD4 T cells, suggesting that a decreased anti-inflammatory milieu may be the cause of increased CD80 expression.
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Affiliation(s)
- Fehime Kara Eroglu
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Diclehan Orhan
- Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Mihriban İnözü
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Ali Duzova
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Bora Gulhan
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Fatih Ozaltin
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Rezan Topaloglu
- Division of Pediatric Nephrology, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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Abstract
Minimal change disease (MCD) or minimal change glomerulonephritis and focal segmental glomerulosclerosis (FSGS) are the two major causes of nephrotic syndrome in children and young adults. Both disease entities resemble each other and can sometimes only be discriminated on the basis of their clinical courses. MCD and FSGS display two classical examples that share a common pathophysiology in which the glomerular podocyte and the cytoskeleton of its foot processes play important roles. Therefore, the term "podocytopathy" was introduced for both diseases. In this article, we compare their differences and similarities, and summarized new data on pathophysiology and treatment. In adults, only a renal biopsy including electron microscopy allows for the discrimination of MCD and FSGS and other differential diagnoses. The identification of a primary or secondary form of the disease is based on the clinical course. Data from studies on the treatment are sparse; hence, treatment is still based on high-dose steroids followed by additional immunosuppressive agents. In secondary forms, treatment of the underlying disease is elementary.
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Grywalska E, Smarz-Widelska I, Mertowski S, Gosik K, Mielnik M, Podgajna M, Abramiuk M, Drop B, Roliński J, Załuska W. CTLA-4 Expression Inversely Correlates with Kidney Function and Serum Immunoglobulin Concentration in Patients with Primary Glomerulonephritides. Arch Immunol Ther Exp (Warsz) 2019; 67:335-349. [PMID: 31177287 PMCID: PMC6732130 DOI: 10.1007/s00005-019-00548-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Accepted: 05/21/2019] [Indexed: 12/01/2022]
Abstract
Major causes of chronic kidney disease are primary proliferative and nonproliferative glomerulonephritides (PGN and NPGN). However, the pathogenesis of PGN and NPGN is still not fully understood. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a T-cell membrane receptor that plays a key role in T-cell inhibition. Despite its role in autoimmunological diseases, little is known about the involvement of CTLA-4 in the pathogenesis of PGN and NPGN. The objective of this study was to determine the role of CTLA-4 in the pathogenesis of PGN and NPGN by evaluating the frequencies of T and B lymphocytes expressing CTLA-4 and the serum concentration of the sCTLA-4 isoform in patients with PGN and NPGN in relation to clinical parameters. The study included peripheral blood (PB) samples from 40 PGN and NPGN patients and 20 healthy age- and sex-matched volunteers (control group). The viable PB lymphocytes were labeled with fluorochrome-conjugated monoclonal anti-CTLA-4 antibodies and analyzed using flow cytometry. The serum concentration of sCTLA-4 was measured using ELISA. The frequencies and absolute counts of CD4+/CTLA-4+ T lymphocytes, CD8+/CTLA-4+ T lymphocytes and CD19+/CTLA-4+ B lymphocytes and the serum sCTLA-4 concentration were lower in PGN and NPGN patients that in the control group. Reduced sCTLA-4 expression was associated with a lower concentration of serum immunoglobulins. Our results indicate that deregulation of CTLA-4 expression may result in continuous activation of T cells and contribute to the pathogenesis of PGN and NPGN.
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Affiliation(s)
- Ewelina Grywalska
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland.
| | - Iwona Smarz-Widelska
- Department of Nephrology, Cardinal Stefan Wyszynski Provincial Hospital in Lublin, Lublin, Poland
| | - Sebastian Mertowski
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland
| | - Krzysztof Gosik
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland
| | - Michał Mielnik
- Department of Hematooncology and Bone Marrow Transplantation, Medical University of Lublin, Lublin, Poland
| | - Martyna Podgajna
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland
| | - Monika Abramiuk
- The First Department of Gynecologic Oncology and Gynecology, Medical University of Lublin, Lublin, Poland
| | - Bartłomiej Drop
- Department of Informatics and Medical Statistics, Medical University of Lublin, Lublin, Poland
| | - Jacek Roliński
- Department of Clinical Immunology and Immunotherapy, Medical University of Lublin, Chodzki 4a, 20-093, Lublin, Poland
| | - Wojciech Załuska
- Department of Nephrology, Medical University of Lublin, Lublin, Poland
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Lorenzo HK, Candelier JJ. [Idiopathic nephrotic syndrome: une Arlésienne?]. Med Sci (Paris) 2019; 35:659-666. [PMID: 31532378 DOI: 10.1051/medsci/2019128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
The renal filtration is ensured by the kidney glomeruli selective for filtering the blood. The main actor of the glomerular filter is the podocyte whose interlaced pedicels bear protein complexes (nephrin, podocin, etc.) creating a molecular sieve (slit diaphragm) to achieve the filtration. Alterations of these podocytes lead to massive proteinuria, which characterizes the nephrotic syndrome. The idiopathic form is one of the most malignant and essentially comprises two entities: minimal change disease and focal segmental glomerulosclerosis. Many observations indicated that (1) immune cells are involved and that (2) there are several permeability factors in the blood that affect the morphology and function of podocytes (slit diaphragm with fractional foot processes fusion/effacement). Evidence for a permeability factor was chiefly derived from remission of proteinuria observed after implantation of a kidney with FSGS in healthy recipients or with other kidney diseases. Today, we are moving towards a multifactorial conception of the nephrotic syndrome where all these barely known factors could be associated according to a sequential kinetic mechanism that needs to be determined.
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Affiliation(s)
- Hans-Kristian Lorenzo
- Inserm U1197, Interactions cellules souches-niches-physiologie, tumeurs et réparations tissulaires, Hôpital Paul Brousse, Bâtiment Lavoisier, 14, avenue Paul-Vaillant Couturier, 94800 Villejuif, France. - Université Paris-Saclay, Campus universitaire d'Orsay, 91 405 Orsay, France. - Service de néphrologie, CHU Bicêtre, 94270 Le Kremlin Bicêtre, France
| | - Jean-Jacques Candelier
- Inserm U1197, Interactions cellules souches-niches-physiologie, tumeurs et réparations tissulaires, Hôpital Paul Brousse, Bâtiment Lavoisier, 14, avenue Paul-Vaillant Couturier, 94800 Villejuif, France. - Université Paris-Saclay, Campus universitaire d'Orsay, 91 405 Orsay, France
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Netti GS, Sangregorio F, Spadaccino F, Staffieri F, Crovace A, Infante B, Maiorano A, Godeas G, Castellano G, Di Palma AM, Prattichizzo C, Cotoia A, Mirabella L, Gesualdo L, Cinnella G, Stallone G, Ranieri E, Grandaliano G. LPS removal reduces CD80-mediated albuminuria in critically ill patients with Gram-negative sepsis. Am J Physiol Renal Physiol 2019; 316:F723-F731. [PMID: 30672713 DOI: 10.1152/ajprenal.00491.2018] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
LPS-induced sepsis is a leading cause of acute kidney injury (AKI) in critically ill patients. LPS may induce CD80 expression in podocytes with subsequent onset of proteinuria, a risk factor for progressive chronic kidney disease (CKD) frequently observed after AKI. This study aimed to investigate the therapeutic efficacy of LPS removal in decreasing albuminuria through the reduction of podocyte CD80 expression. Between January 2015 and December 2017, 70 consecutive patients with Gram-negative sepsis-induced AKI were randomized to either have coupled plasma filtration and adsorption (CPFA) added to the standard care ( n = 35) or not ( n = 35). To elucidate the possible relationship between LPS-induced renal damage, proteinuria, and CD80 expression in Gram sepsis, a swine model of LPS-induced AKI was set up. Three hours after LPS infusion, animals were treated or not with CPFA for 6 h. Treatment with CPFA significantly reduced serum cytokines, C-reactive protein, procalcitonin, and endotoxin levels in patients with Gram-negative sepsis-induced AKI. CPFA significantly lowered also proteinuria and CD80 urinary excretion. In the swine model of LPS-induced AKI, CD80 glomerular expression, which was undetectable in control pigs, was markedly increased at the podocyte level in LPS-exposed animals. CPFA significantly reduced LPS-induced proteinuria and podocyte CD80 expression in septic pigs. Our data indicate that LPS induces albuminuria via podocyte expression of CD80 and suggest a possible role of timely LPS removal in preventing the maladaptive repair of the podocytes and the consequent increased risk of CKD in sepsis-induced AKI.
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Affiliation(s)
- Giuseppe Stefano Netti
- Clinical Pathology Unit and Center for Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia , Foggia , Italy
| | - Fabio Sangregorio
- Nephrology Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia , Foggia , Italy
| | - Federica Spadaccino
- Clinical Pathology Unit and Center for Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia , Foggia , Italy
| | - Francesco Staffieri
- Veterinary Surgery Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro , Bari , Italy
| | - Antonio Crovace
- Veterinary Surgery Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro , Bari , Italy
| | - Barbara Infante
- Nephrology Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia , Foggia , Italy
| | - Annamaria Maiorano
- Nephrology Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia , Foggia , Italy
| | - Giulia Godeas
- Nephrology Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia , Foggia , Italy
| | - Giuseppe Castellano
- Nephrology Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro , Bari , Italy
| | - Anna Maria Di Palma
- Nephrology Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro , Bari , Italy
| | - Clelia Prattichizzo
- Clinical Pathology Unit and Center for Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia , Foggia , Italy
| | - Antonella Cotoia
- Anesthesia and Intensive Care Unit, Department of Medical and Surgical Sciences, University of Foggia , Foggia , Italy
| | - Lucia Mirabella
- Anesthesia and Intensive Care Unit, Department of Medical and Surgical Sciences, University of Foggia , Foggia , Italy
| | - Loreto Gesualdo
- Nephrology Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro , Bari , Italy
| | - Gilda Cinnella
- Anesthesia and Intensive Care Unit, Department of Medical and Surgical Sciences, University of Foggia , Foggia , Italy
| | - Giovanni Stallone
- Nephrology Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia , Foggia , Italy
| | - Elena Ranieri
- Clinical Pathology Unit and Center for Molecular Medicine, Department of Medical and Surgical Sciences, University of Foggia , Foggia , Italy
| | - Giuseppe Grandaliano
- Nephrology Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia , Foggia , Italy
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Stone H, Magella B, Bennett MR. The Search for Biomarkers to Aid in Diagnosis, Differentiation, and Prognosis of Childhood Idiopathic Nephrotic Syndrome. Front Pediatr 2019; 7:404. [PMID: 31681707 PMCID: PMC6805718 DOI: 10.3389/fped.2019.00404] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Accepted: 09/18/2019] [Indexed: 12/13/2022] Open
Abstract
Identification of genes associated with childhood-onset nephrotic syndrome has significantly advanced our understanding of the pathogenesis of this complex disease over the past two decades, however the precise etiology in many cases remains unclear. At this time, we still rely on invasive kidney biopsy to determine the underlying cause of nephrotic syndrome in adults. In children, response to steroid therapy has been shown to be the best indicator of prognosis, and therefore all children are treated initially with corticosteroids. Because this strategy exposes a large number of children to the toxicities of steroids without providing any benefit, many researchers have sought to find a marker that could predict a patient's response to steroids at the time of diagnosis. Additionally, the identification of such a marker could provide prognostic information about a patient's response to medications, progression to end stage renal disease, and risk of disease recurrence following transplantation. Major advances have been made in understanding how genetic biomarkers can be used to predict a patient's response to therapies and disease course, especially after transplantation. Research attempting to identify urine- and serum-based biomarkers which could be used for the diagnosis, differentiation, and prognosis of nephrotic syndrome has become an area of emphasis. In this review, we explore the most exciting biomarkers and their potential clinical applications.
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Affiliation(s)
- Hillarey Stone
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Bliss Magella
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
| | - Michael R Bennett
- Division of Nephrology and Hypertension, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States
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Cytotoxic T- Lymphocyte Antigen-4 (CTLA4) Gene Expression and Urinary CTLA4 Levels in Idiopathic Nephrotic Syndrome. Indian J Pediatr 2019; 86:26-31. [PMID: 29968132 DOI: 10.1007/s12098-018-2734-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2018] [Accepted: 06/08/2018] [Indexed: 11/27/2022]
Abstract
OBJECTIVES To detect Cytotoxic T- Lymphocyte Antigen-4 (CTLA4) single nucleotide polymorphisms (SNPs) at +49A/G (rs231775) and -318C/T (rs5742909) positions in children with idiopathic nephrotic syndrome (INS) and also assay urinary soluble CTLA4 (sCTLA4) levels in children with minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and steroid sensitive nephrotic syndrome (SSNS) in remission. METHODS The study included 59 patients of INS (MCD-23, FSGS-15 and SSNS in remission-21) and 35 healthy controls. The CTLA4 SNPs profiling was done in peripheral blood mononuclear cells and urinary sCTLA4 level was assayed by ELISA kit. RESULTS Although frequency of homozygous +49 GG (rs4553808) genotype (26.3% vs. 11.4%; p = 0.231) and G allele (52.6% vs. 40%; p = 0.216) were found to be higher in INS as compared to controls, the differences were statistically non-significant. Genotypes GG, AG, AA and alleles A and G frequencies were comparable among MCD, FSGS and controls. SNP at -318 C/T (rs5742909) did not show homozygous TT genotype both in INS as well as controls. Median urinary sCTLA4/creatinine level was significantly higher in MCD as compared to FSGS (p = 0.027), SSNS in remission (p = 0.001) and controls (p = 0.003). CONCLUSIONS The positive associations of +49 GG genotype and G allele in patients with nephrotic syndrome were not observed. The frequencies did not differ significantly among MCD, FSGS and controls. Urinary sCTLA4 level was significantly increased in MCD; suggesting its possible role in the pathogenesis of disease.
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Mehta A. Association of Cytotoxic T-Lymphocyte Antigen-4 (CTLA4) Gene and CD80 Expression in Children with Idiopathic Nephrotic Syndrome. Indian J Pediatr 2019; 86:3. [PMID: 30328084 DOI: 10.1007/s12098-018-2803-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 09/24/2018] [Indexed: 12/01/2022]
Affiliation(s)
- Amarjeet Mehta
- Division of Pediatric Nephrology, Department of Pediatrics, SMS Medical College, Jaipur, Rajasthan, India.
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Minamikawa S, Nozu K, Maeta S, Yamamura T, Nakanishi K, Fujimura J, Horinouchi T, Nagano C, Sakakibara N, Nagase H, Shima H, Noda K, Ninchoji T, Kaito H, Iijima K. The utility of urinary CD80 as a diagnostic marker in patients with renal diseases. Sci Rep 2018; 8:17322. [PMID: 30470792 PMCID: PMC6251900 DOI: 10.1038/s41598-018-35798-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 11/06/2018] [Indexed: 01/23/2023] Open
Abstract
CD80, which regulates T cell activation, may provide a differential diagnostic marker between minimal change disease (MCD) and other renal diseases, including focal segmental glomerular sclerosis (FSGS). However, recent reports show contrasting results. Therefore, we evaluated the utility of urinary CD80 as a diagnostic biomarker. We collected 65 urine samples from 55 patients with MCD (n = 31), FSGS (n = 4), inherited nephrotic syndrome (n = 4), Alport syndrome (n = 5) and other glomerular diseases (n = 11), and control samples (n = 30). We measured urinary CD80 levels by ELISA. Urinary CD80 (ng/gCr) (median, interquartile range) levels were significantly higher in patients with MCD in relapse (91.5, 31.1-356.0), FSGS (376.2, 62.7-1916.0), and inherited nephrotic syndrome (220.1, 62.9-865.3), than in patients with MCD in remission (29.5, 21.7-52.8) (p < 0.05). Elevation of urinary CD80 was observed, even in patients with inherited nephrotic syndrome unrelated to T cell activation. Additionally, urinary CD80 was positively correlated with urinary protein levels. Our results suggest that urinary CD80 is unreliable as a differential diagnostic marker between MCD in relapse and FSGS or inherited kidney diseases. Increased urinary CD80 excretion was present in all patients with active kidney disease.
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Affiliation(s)
- Shogo Minamikawa
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kandai Nozu
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan.
| | - Shingo Maeta
- Sysmex Corporation, Technology Development, Elemental Technology Development 2, Kobe, Japan
| | - Tomohiko Yamamura
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Keita Nakanishi
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Junya Fujimura
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Tomoko Horinouchi
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - China Nagano
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Nana Sakakibara
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroaki Nagase
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hideaki Shima
- Sysmex Corporation, Technology Development, Elemental Technology Development 2, Kobe, Japan
| | - Kenta Noda
- Sysmex Corporation, Technology Development, Elemental Technology Development 2, Kobe, Japan
| | - Takeshi Ninchoji
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hiroshi Kaito
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Kazumoto Iijima
- Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
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Bhatia D, Sinha A, Hari P, Sopory S, Saini S, Puraswani M, Saini H, Mitra DK, Bagga A. Rituximab modulates T- and B-lymphocyte subsets and urinary CD80 excretion in patients with steroid-dependent nephrotic syndrome. Pediatr Res 2018; 84:520-526. [PMID: 29983411 DOI: 10.1038/s41390-018-0088-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Revised: 05/29/2018] [Accepted: 06/05/2018] [Indexed: 12/25/2022]
Abstract
BACKGROUND Rituximab, a monoclonal antibody targeting B lymphocytes, effectively sustains remission in steroid-dependent nephrotic syndrome (SDNS). We studied its effects on lymphocyte subsets and urinary CD80 excretion (uCD80) in patients with SDNS. METHODS Blood and urine samples were collected from 18 SDNS patients before rituximab, and after 1 month and 1 year or at first relapse. T and B lymphocytes and uCD80 were determined by flow cytometry and ELISA, respectively. RESULTS Treatment was associated with reduction in counts of Th17, Th2, and memory T cells, and increased T-regulatory (Treg) cells. The Th17/Treg ratio declined from baseline (median 0.6) to 1 month (0.2, P = 0.006) and increased during relapse (0.3, P = 0.016). Ratios of Th1/Th2 cells at baseline, 1 month after rituximab, and during relapse were 7.7, 14.0 (P = 0.0102), and 8.7, respectively. uCD80 decreased 1 month following rituximab (45.5 vs. 23.0 ng/g creatinine; P = 0.0039). B lymphocytes recovered earlier in relapsers (60.0 vs.183.0 days; P < 0.001). Memory B cells were higher during relapse than remission (29.7 vs.18.0 cells/µL; P = 0.029). CONCLUSION Rituximab-induced sustained remission and B-cell depletion was associated with reduced numbers of Th17 and Th2 lymphocytes, and increased Treg cells; these changes reversed during relapses. Recovery of B cells and memory B cells predicted the occurrence of a relapse.
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Affiliation(s)
- Divya Bhatia
- Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Aditi Sinha
- Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Pankaj Hari
- Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Shailaja Sopory
- Pediatric Biology Center, Translational Health Science & Technology Institute, Faridabad, India
| | - Savita Saini
- Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Mamta Puraswani
- Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Himanshi Saini
- Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
| | - Dipendra K Mitra
- Department of Transplant Immunology & Immunogenetics, All India Institute of Medical Sciences, New Delhi, India
| | - Arvind Bagga
- Division of Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India.
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Zhao B, Han H, Zhen J, Yang X, Shang J, Xu L, Wang R. CD80 and CTLA-4 as diagnostic and prognostic markers in adult-onset minimal change disease: a retrospective study. PeerJ 2018; 6:e5400. [PMID: 30083478 PMCID: PMC6078067 DOI: 10.7717/peerj.5400] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2018] [Accepted: 07/18/2018] [Indexed: 12/11/2022] Open
Abstract
Background Minimal change disease (MCD) is a form of idiopathic nephrotic syndrome. Compared to children, adult-onset MCD patients are reported to have delayed responses to glucocorticoid treatment. Several studies of children have suggested detecting urinary CD80 levels to diagnose MCD. There are no effective diagnostic methods to distinguish steroid-sensitive MCD from steroid-resistant MCD unless treatments are used. Methods In a total of 55 patients with biopsy-proven MCD and 26 patients with biopsy-proven idiopathic membranous nephropathy, CD80 and cytotoxic T-lymphocyte antigen-4 (CTLA-4) levels in serum, urine and renal tissue were analyzed. Results Steroid-sensitive MCD patients in remission had lower urinary CD80 levels and higher CTLA-4 levels than patients in relapse (156.65 ± 24.62 vs 1066.40 ± 176.76 ng/g creatinine; p < 0.0001), (728.73 ± 89.93 vs 151.70 ± 27.01 ng/g creatinine; p < 0.0001). For MCD patients in relapse, mean urinary CD80 level was higher, and CTLA-4 level was lower for those who were steroid-sensitive than those who were steroid-resistant (1066.40 ± 176.76 vs. 203.78 ± 30.65 ng/g creatinine; p < 0.0001), but the mean urinary CTLA-4 level was lower (151.70 ± 27.01 vs. 457.83 ± 99.45 ng/g creatinine; p < 0.0001). CD80 expression in glomeruli was a sensitive marker to diagnose MCD. The absent or minimal expression of CTLA-4 in glomeruli could distinguish steroid-sensitive MCD from steroid-resistant MCD. Conclusions Glucocorticoid treatment may result in complete remission for only MCD patients with strongly positive CD80 expression and negative CTLA-4 expression in glomeruli, or higher urinary CD80 level and lower CTLA-4 level.
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Affiliation(s)
- Bing Zhao
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Hui Han
- Department of Intensive Care Unit, Shandong University Qilu Hospital, Jinan, China
| | - Junhui Zhen
- School of Medicine, Shandong University, Jinan, China
| | - Xiaowei Yang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Jin Shang
- Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Liang Xu
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
| | - Rong Wang
- Department of Nephrology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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Cara-Fuentes G, Lanaspa MA, Garcia GE, Banks M, Garin EH, Johnson RJ. Urinary CD80: a biomarker for a favorable response to corticosteroids in minimal change disease. Pediatr Nephrol 2018; 33:1101-1103. [PMID: 29492674 PMCID: PMC5990433 DOI: 10.1007/s00467-018-3886-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 01/04/2018] [Indexed: 01/16/2023]
Abstract
Minimal Change Disease (MCD) is the most common type of nephrotic syndrome in children. The etiology has remained unknown, although it is commonly thought to be due to an unknown circulating factor that triggers podocyte dysfunction. To date, several changes in podocytes have been reported in MCD, of which one is the expression of CD80, also known as B7.1, which is a costimulatory molecule that is normally expressed on antigen -presenting cells. Some studies suggest that subjects with steroid-sensitive MCD may express CD80 in their podocytes during relapse and that this expression is associated with high urinary levels of CD80. Indeed, subjects with MCD in remission, or subjects with other glomerular diseases, such as focal segmental glomerulosclerosis, have substantially lower levels of urinary CD80 excretion. A recent study has now reported that high levels of urinary CD80 may be a sensitive marker for steroid-sensitivity and that their presence is also associated with long-term preservation of renal function. Thus, urinary CD80 is emerging as a potential biomarker for steroid-responsiveness in children presenting with primary nephrotic syndrome.
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Affiliation(s)
| | - Miguel A Lanaspa
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA.
| | - Gabriela E Garcia
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
| | - Mindy Banks
- Rocky Mountain Pediatric Kidney Center, Suite 330, 2055 High Street, Denver, CO, USA
| | - Eduardo H Garin
- Division of Pediatric Nephrology, Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Richard J Johnson
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO, USA
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Urinary CD80 excretion is a predictor of good outcome in children with primary nephrotic syndrome. Pediatr Nephrol 2018; 33:1183-1187. [PMID: 29569191 DOI: 10.1007/s00467-018-3885-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 01/02/2018] [Accepted: 01/04/2018] [Indexed: 10/17/2022]
Abstract
BACKGROUND The level of urinary cluster of differentiation 80 (uCD80) is elevated in most children with minimal change disease (MCD) as opposed to focal segmental glomerulosclerosis (FSGS) during the acute phase. The objective of this follow-up study was to evaluate whether uCD80 elevation is actually associated with MCD and whether it signals better prognosis. METHODS We evaluated uCD80 levels and a series of putative progression factors in a cohort of 64 patients with nephrotic syndrome (NS) seen between 2011 and 2016. We monitored progression of chronic kidney disease (CKD), assessed as a glomerular filtration rate of < 90 ml/min/1.73 m2 for at least 3 months. Patients were classified according to uCD80 level and to the progression rate as calculated by Kaplan-Meier survival analysis and Cox's regression analysis. RESULTS During a mean follow-up period of 4.8 ± 0.6 (range 3.5-6.0) years, 13 children (20%) evolved to at least CKD stage 2. The 64 patients with NS and normal baseline renal function were divided into two groups based on uCD80 excretion, i.e. below or above a defined cutoff (< or > 328.98 ng/g creatinine). The predicted response to immunosuppression therapy was 34.5 and 100% in the low- and high-uCD80 excretion, respectively (p < 0.001). Progression to CKD was 41.4 vs. 2.9% in NS patients (p < 0.001). Using the Cox model, only uCD80 excretion (p = 0.013, relative risk 6.171) predicted progression to CKD. CONCLUSIONS Urinary CD80 predicts progression and remission in children with NS. The use of uCD80 as a prognostic marker facilitates the identification of high-risk patients at an early stage and may lead to better treatment selection.
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