Recent Advances in the Pathogenesis and Treatment of Kidney Diseases
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Chronic kidney disease (CKD) is a global health burden with associated high economic costs to the health system. Main factors are the increasing number of patients with diabetes and hypertension and the aging of the population. CKD has been associated with increased risks of cardiovascular morbidity, premature mortality, and/or decreased quality of life. In this new volume, renowned Japanese scientists present their recent research results. Papers cover various aspects of kidney diseases such as cystic kidney diseases, treatment of lupus nephritis, renal anemia and iron metabolism, cell sheet engineering, frailty and outcomes of dialysis patients, and the socioeconomics of rituximab in nephrotic syndrome. Due to the wide range of topics presented, this book will be of interest to readers from various clinical and research settings connected with the care of CKD patients.

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Date de parution 07 mai 2018
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EAN13 9783318063509
Langue English
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Recent Advances in the Pathogenesis and Treatment of Kidney Diseases
Contributions to Nephrology
Vol. 195
Series Editor
Claudio Ronco Vicenza
 
Recent Advances in the Pathogenesis and Treatment of Kidney Diseases
Volume Editor
Kosaku Nitta Tokyo
22 figures, 12 in color, and 17 tables, 2018
Contributions to Nephrology (Founded 1975 by Geoffrey M. Berlyne)
_______________________ Kosaku Nitta Kidney Center (Jin Center Dai 4 Nai-ka) Tokyo Women’s Medical University 8-1 Kawada-cho, Shinjuku-ku Tokyo 162-8666 (Japan)
Library of Congress Cataloging-in-Publication Data
Names: Nitta, Kosaku, editor.
Title: Recent advances in the pathogenesis and treatment of kidney diseases / volume editor, Kosaku Nitta.
Other titles: Contributions to nephrology; v. 195. 0302-5144
Description: Basel ; New York : Karger, 2018. | Series: Contributions to nephrology, ISSN 0302-5144; vol. 195 | Includes bibliographical references and indexes.
Identifiers: LCCN 2018009917| ISBN 9783318063493 (hard cover : alk. paper) | ISBN 9783318063509 (electronic version)
Subjects: | MESH: Kidney Diseases--pathology | Kidney Diseases--therapy
Classification: LCC RC903 | NLM WJ 300 | DDC 616.6/106--dc23 LC record available at
https://lccn.loc.gov/2018009917
 
Bibliographic Indices. This publication is listed in bibliographic services, including Current Contents ® and Index Medicus.
Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
© Copyright 2018 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)
www.karger.com
Printed on acid-free and non-aging paper (ISO 9706)
ISSN 0302–5144
e-ISSN 1662–2782
ISBN 978–3–318–06349–3
e-ISBN 978–3–318–06350–9
 
Contents
Preface
Nitta, K. (Tokyo)
The Role of Caveolae on Albumin Passage through Glomerular Endothelial and Epithelial Cells: The New Etiology of Urinary Albumin Excretion
Moriyama, T.; Karasawa, K.; Nitta, K. (Tokyo)
Rituximab as a Therapeutic Option for Steroid-Sensitive Minimal Change Nephrotic Syndrome in Adults
Iwabuchi, Y.; Moriyama, T.; Itabashi, M.; Takei, T.; Nitta, K. (Tokyo)
Large Renal Corpuscle: Clinical Significance of Evaluation of the Largest Renal Corpuscle in Kidney Biopsy Specimens
Kataoka, H.; Mochizuki, T.; Nitta, K. (Tokyo)
New Insights into Cystic Kidney Diseases
Mochizuki, T.; Makabe, S.; Aoyama, Y.; Kataoka, H.; Nitta, K. (Tokyo)
Recent Advances in Treatment Strategies for Lupus Nephritis
Karasawa, K.; Uchida, K.; Takabe, T.; Moriyama, T.; Nitta, K. (Tokyo)
Association between Increases in Normalized Protein Catabolic Rate and Increases in Creatinine Generation Rate in Dialysis Patients
Hanafusa, N.; Kamei, D.; Tsukada, M.; Miwa, N. (Tokyo); Komatsu, M.; Shiohira, S.; Okazaki, M.; Watanabe, R.; Kawaguchi, H. (Fukushima); Tsuchiya, K.; Nitta, K. (Tokyo)
Renal Anemia and Iron Metabolism
Ogawa, C. (Kawasaki); Tsuchiya, K. (Kawasaki/Tokyo); Maeda, K. (Kawasaki); Nitta, K. (Tokyo)
Cell Sheet Engineering and Kidney Diseases
Oka, M.; Miyabe, Y.; Sugiura, N.; Nitta, K. (Tokyo)
Clinical Impact of Left Ventricular Diastolic Dysfunction in Chronic Kidney Disease
Ogawa, T.; Nitta, K. (Tokyo)
Treatment of Posttransplantation Anemia
Unagami, K.; Okumi, M.; Tamura, T.; Ishida, H.; Tanabe, K.; Nitta, K. (Tokyo)
Role of Frailty on Outcomes of Dialysis Patients
Nitta, K.; Hanafusa, N.; Tsuchiya, K. (Tokyo)
Socioeconomics of Administering Rituximab for Nephrotic Syndrome
Takura, T.; Takei, T.; Nitta, K. (Tokyo)
Use of Beta-Blockers on Maintenance Dialysis Patients and Ischemic Cerebral and Cardiovascular Deaths: An Examination Using Propensity Score
Omae, K.; Ogawa, T.; Yoshikawa, M.; Sakura, H.; Nitta, K. (Tokyo)
Direct Effects of Immunomodulatory Agents on Podocytes in Immune-Mediated Glomerular Diseases
Manabe, S. (Tsukuba/Tokyo); Nitta, K. (Tokyo); Nagata, M. (Tsukuba)
Author Index
Subject Index
Preface
Chronic kidney disease (CKD) is a global health burden with a high economic cost to the health system that results from the increasing number of patients with diabetes and hypertension, and from the aging of the population. CKD has been associated with increased risks of cardiovascular morbidity, premature mortality, and/or decreased quality of life (QOL). The current volume entitled Recent Advances in the Pathogenesis and Treatment of Kidney Diseases incorporates many papers reviewed by faculty members of the Department of Medicine, Kidney Center, Tokyo Women’s Medical University, Tokyo, Japan.
The first paper in this volume of the book series Contributions to Nephrology discusses the role of caveolae in albumin passage through glomerular endothelial and epithelial cells, as shown by Moriyama et al. The authors suggest that albumin enters into glomerular endothelial and epithelial cells through caveolae; subsequent transcytosis of albumin is not actin- or microtubule-dependent in glomerular endothelial cells, but is actin-dependent in glomerular epithelial cells.
Iwabuchi et al. describe that rituximab has a beneficial effect, with the sustained remission or reduction of proteinuria in patients with steroid-dependent minimal change nephrotic syndrome. Rituximab is a chimeric murine/human monoclonal immunoglobulin G1 antibody that targets CD20, a B-cell differentiation marker. B-cell recovery begins at approximately 6 months following the completion of treatment.
Kataoka et al. show that the renal corpuscle size (glomerular size) is an easily measurable parameter and potentially acts as a predictor of long-term renal function. Large renal corpuscles could be used to guide therapy. In this review, after identifying the pitfalls regarding the assessment of mean values in medical research, we propose that the measurement of the maximum glomerular profile in renal biopsies would provide valuable insights into the diagnosis, prognosis, and management of kidney diseases.
According to Mochizuki et al., hereditary cystic kidney diseases are considered as “ciliopathies” caused by abnormalities of the “primary cilia” situated on the tubules. As a result of dysplasia and dysfunction of cilia, formation of cysts occurs at various stages of life. Although occurring at a low incidence, hereditary cystic kidney diseases that develop from the fetal stage to childhood are diverse and are often associated with systemic disorders.
Karasawa et al. demonstrate the concept of therapeutic approach for lupus nephritis (LN). In LN induction therapy until recently, cyclophosphamide in combination with prednisone (PSL) has been the standard method of treatment of proliferative forms of LN. Recently, the combination of mycophenolate mofetil has become a standard treatment option. Furthermore, multi-target therapy with tacrolimus added to PSL and mycophenolate mofetil, with reference to regimen after organ transplantation, has also been reported.
Hanafusa et al. report that older dialysis population is growing, and malnutrition and wasting syndrome is a great concern in this population. However, whether management in the forms of an increase in protein intake has a beneficial effect on muscle mass has not been demonstrated. In this volume, Hanafusa et al. evaluated an association between changes in normalized protein catabolic rate and percent creatinine generation rate (%CGR) in patients receiving hemodialysis (HD). The results showed that increase in normalized protein catabolic rate was associated with increase in %CGR. The association was stronger in patients with baseline %CGR levels below 100%.
Ogawa et al. describe that there was no consideration in terms of iron metabolism or the long-term safety of intravenous iron supplementation. This study presents information regarding iron metabolism in patients on HD, factors that influence iron metabolism in such patients, and the problems with existing treatment guidelines in Japan, apart from discussing the optimal iron levels and optimal Hb production indices.
Oka et al. introduce the therapeutic efficacy of cell sheet transplantation in the treatment of kidney disease. The 2-dimensional cell sheet can produce proteins such as erythropoietin, and is thus suitable for transplantation into the living body. It would be desirable to develop cell sheet therapy for the suppression of kidney damage in future, taking advantage of the beneficial characteristics of cell sheets.
Ogawa et al. show the pathogenesis and treatment of left ventricular diastolic dysfunction (LVDD) in CKD patients. The pathogenesis of LVDD includes abnormal ventricular filling in diastole and a higher LV filling pressure because of LV hypertrophy in addition to myocardial interstitial fibrosis. Therefore, LVDD tends to cause pulmonary congestion. The main strategy for treating LVDD is to minimize the large volume shift to control blood pressure and prevent myocardial interstitial fibrosis.
Unagami et al. describe post-transplantation anemia (PTA), which could be related to a variety of factors, including the renal function status, graft rejection episodes, and infectious causes. Early PTA is associated with a risk of death and cardiovascular disorders; however during this phase, priority is given to appropriate maintenance of immunosuppression rather than to the treatment of anemia. Maintenance-phase PTA exerts a strong influence on the survival, prognosis of the transplanted kidney, QOL, etc. Proper management of PTA could be expected to be associated with an improvement prognosis of the transplanted kidney and improved patient survival in kidney transplant recipients.
Nitta et al. show the role of frailty on outcomes of dialysis patients. Frailty has recently come to be considered one of the risk factors for mortality in the older dialysis population. Interventions to improve frailty have the potential to contribute to better QOL and lower mortality among dialysis patients. In addition, greater attention should be focused on the possibility that early rehabilitation of dialysis patients might improve poor outcomes.
Takura et al. describe the cost effectiveness of rituximab for treating nephrotic syndrome. The research team compared the number of relapses and total medical costs in the 24-month period before and the same period after patients took rituximab. We found that relapse decreased, and the total medical costs shrunk. The study also identified a correlation between lower urinary protein levels and a reduction in total medical costs. Rituximab therefore proved to be clinically beneficial and was also cost-effective.
Omae et al. demonstrate the results of the study by showing the relationship between the use of beta-blocker and ischemic cerebral and cardiovascular deaths in HD patients. A total of 108 matched pairs were extracted from a whole cohort. Through the use of beta-blockers, a significant increase in ischemic cerebral and cardiovascular deaths was observed. Beta-blocker administration to dialysis patients may worsen the cardiovascular prognosis, so sufficient examination will be needed in the future.
Manabe et al. show the direct effects of immunomodulatory agents on podocytes in immune-mediated glomerular diseases. In immune-mediated glomerular diseases, a variety of immunomodulatory agents are used to maintain podocytes by systemic immunosuppression. However, in contrast to the indirect therapeutic strategy mediated by immunosuppression, recent data suggest that immunomodulatory agents directly act on podocytes in an agent-dependent manner. In this review, they discuss the molecular targets and mechanisms by which immunomodulatory agents alleviate podocyte injury and examine their clinical significance.
We hope that you will enjoy the diverse range of papers published in this volume of Contributions to Nephrology and that you will plan a future clinical research to find new diagnostic markers and to establish useful therapeutic approach for various kidney diseases.
Kosaku Nitta , Tokyo
 
Nitta K (ed): Recent Advances in the Pathogenesis and Treatment of Kidney Diseases. Contrib Nephrol. Basel, Karger, 2018, vol 195, pp 1–11 (DOI: 10.1159/000486929)
______________________
The Role of Caveolae on Albumin Passage through Glomerular Endothelial and Epithelial Cells: The New Etiology of Urinary Albumin Excretion
Takahito Moriyama · Kazunori Karasawa · Kosaku Nitta
Department of Medicine, Kidney Center, Tokyo Women’s Medical University, Tokyo, Japan
______________________
Abstract
Background : In the traditional theory of albuminuria, small amounts of albumin pass through the fenestrae in glomerular endothelial cells, then through the slit membrane in the gaps between foot processes of glomerular epithelial cells. In the novel theory, large amounts of albumin pass through glomerular capillaries and are taken up by megalin and cubilin receptors on tubular epithelial cells. These etiologies of urinary albumin excretion are still controversial, and the details of albumin passage through the three layers of glomerular capillaries (glomerular endothelial cells, basement membrane, and epithelial cells) have never been entirely elucidated. Summary : Recent advances in basic research have shown that caveolae, which are cell invaginations located on the surface of both glomerular endothelial and epithelial cells, play pivotal roles in the endocytosis, transcytosis, and exocytosis of albumin. Albumin enters into glomerular endothelial and epithelial cells through caveolae; subsequent transcytosis of albumin is not actin- or microtubuledependent in glomerular endothelial cells, but is actin-dependent in glomerular epithelial cells. Exocytosis of albumin in glomerular endothelial cells occurs via early endosomes through a process that bypasses other endosome-associated organelles. In contrast, exocytosis of albumin in glomerular epithelial cells occurs via early endosomes through a process that results in lysosomal degradation of some albumin particles. Key Messages : This caveolae-dependent pathway may provide a new pathophysiology for albumin passage through glomerular endothelial and epithelial cells, leading to a new etiology for urinary albumin excretion that connects both traditional and novel theories of albuminuria.
© 2018 S. Karger AG, Basel
The Roles of Caveolae
Caveolae are 50–80 nm, flask-shaped, membrane invaginations that were originally identified as very small pit-like depressions on the cell membrane of microvilli in 1955 [ 1 ]. Caveolae are primarily located on vascular endothelial cells, smooth muscle cells, cardiomyocytes, and adipocytes; they are enriched with cholesterol, sphingolipids, and glycolipids, and are structured by scaffolding proteins known as caveolin. There are three caveolin proteins encoded by independent genes, which are identified as caveolin-1 (Cav-1), caveolin-2, and caveolin-3. Cav-1 and caveolin-2 are co-expressed on a variety of cells, while caveolin-3 is solely expressed by muscle cells [ 2 , 3 ]. Cav-1 is expressed as 2 isoforms: Cav-1α contains 178 amino acids and Cav-1β contains 147 amino acids, lacking the N-terminal 31 amino acids of Cav-1α. These isoforms arise from 2 different mRNA transcripts of the same gene. Both isoforms of Cav-1 are membrane proteins with a 33-amino-acid hydrophobic domain that constitutes a hairpin loop; the N-termini and C-termini extend into the cytoplasm. Cav-1 proteins assemble as disk-shaped oligomers around the scaffolding domain and are anchored by a portion of the palmitoylated C-terminal within the cell membrane [ 2 , 3 ]. The roles of caveolae are diverse and comprise adjustment of endothelial nitric oxide synthesis and calcium signaling; regulation of intracellular signal transduction, including receptors, such as G-protein coupled receptors, epidermal growth factor receptors, insulin receptors, platelet-derived growth factor receptors (PDGF-R), vascular endothelial growth factor receptors, activin receptor-like kinase, transforming growth factor-β, ras-mitogen activated protein kinase, Src family tyrosine kinases, various forms of protein kinase A, and various forms of protein kinase C ( Table 1 ) [ 4 , 5 ]; and to internalize and transport cholesterol, proteins, insulin, and toxins that play pivotal roles in a variety of diseases (e.g., viral infections, inflammation, cancer, cardiovascular disease, atherosclerosis, myopathies, and diabetes [ 6 – 9 ]). In the kidney, caveolae are expressed by glomerular endothelial cells ( Fig. 1a ), epithelial cells ( Fig. 1a ), mesangial cells, and tubular epithelial cells. However, the specific roles of caveolae in the kidney cells are not yet known.
The Roles of Caveolae in the Kidney
A variety of roles for caveolae in the kidney have been reported in previous studies. In rat kidneys exhibiting anti-Thy-1 nephritis, Cav-1 was highly expressed by glomeruli; Cav-1 on glomerular mesangial cells was suspected to play a role in the pathogenesis of mesangial proliferative glomerular disease through PDGF signaling [ 10 ]. In contrast, overexpression of Cav-1 in mesangial cells suppressed basic fibroblast growth factor-induced and PDGF-induced activation of p42/44 mitogen activated protein kinase, Raf-1 and extracellular signal-regulated protein kinase, thereby suppressing mesangial cell proliferation [ 11 ]. Exposure to TGFβ and high glucose increased fibronectin expression and RhoA activation through Cav-1 phosphorylation, whereas suppression of Cav-1 prevented an increase in fibronectin expression [ 12 , 13 ]. However, the detailed roles of Cav-1 in mesangial cells are still intensely debated. In the parietal epithelial cells of Bowman’s capsule in normal kidney, Cav-1 is strongly expressed; however, in pediatric patients with focal segmental glomerulosclerosis and lupus nephritis, Cav-1 expression decreased as a response to cellular reconstruction [ 14 ]. In a study of acute kidney injury, Cav-1 was expressed in injured proximal tubules that exhibited loss of basement membrane, as well as in apoptotic cells [ 15 ], and its expression was correlated with the induction and maintenance phases of acute kidney injury [ 16 ]. In cases of obstructive nephritis, Cav-1 expression by both proximal tubule epithelial cells and collecting duct epithelial cells resulted in the enhancement of angiotensin II, decrease in endothelial nitric oxide synthesis, and increase in the severity of tubulointerstitial injury [ 17 ]. Further, BK virus, which induces viral nephritis after renal transplantation, was observed to enter into tubular proximal epithelial cells through caveolae, facilitating its ultimate replication in host cells [ 18 ]. As discussed here, the detailed roles of caveolae in tubular epithelial cells continue to be unclear.
Table 1 . Caveolae-associated signaling molecules and transduction proteins
Receptors
G protein coupled receptors (adrenergic, muscarinic, opioid, angiotensin II, adenosine, bradykinin, endothelin, serotonin, etc.)
Transforming growth factor-β receptors
Tyrosine kinase (insulin, EGF-R, PDGF-R, VEGF-R)
Interacting proteins
eNOS
Src
Ras-MAP kinase
Protein kinase A
Protein kinase Cα
MEK/ERK
Phospholipase D1
Membrane proteins
CD36, SR-BI (lipoprotein receptor)
Gp60 (albumin receptor)
PV-1
P-glycoprotein
MMP-1
MMP-2
uPAR
Ion channels
Transient receptor potential cation
L-type Ca 2+
K ATP
Ca 2+ pumps

Fig. 1 . Caveolae and caveolin-1 expression. a In electron micrographs depicting AL-amyloidosis, caveolae in glomerular endothelial cells are present in the cytoplasm and on both cell surfaces, facing the capillary lumen and glomerular basement membrane (black arrows); fenestrae are also present (arrow heads). Caveolae are present in the cytoplasm of glomerular epithelial cells (white arrows), and foot processes are fused. b In an immunofluorescence study of membranoproliferative glomerulonephritis, Caveolin-1 was highly expressed on the capillaries in the glomeruli. It was also detected on the arterioles.
Albumin Transportation through Caveolae
Glomerular Endothelial Cells
In our previous reports, we showed that Cav-1 is expressed very weakly in the glomeruli in 0-hour renal biopsy specimens of renal transplant donors as healthy control subjects; however, upon renal biopsy we found that Cav-1 expression significantly increased in glomeruli in patients suffering from glomerular diseases, such as IgA nephropathy, crescentic glomerulonephritis, minimal change disease, focal segmental glomerular disease, membranous nephritis, membranoproliferative glomerulonephritis, and diabetic nephropathy ( Fig. 1b ). Interestingly, in cases of glomerulonephritis that were treated with immunosuppressive agents and showed decreases in urinary protein excretion, the expression of Cav-1 decreased to a similar extent as it did in healthy controls. In this cohort of patients and healthy subjects, Cav-1 expression was positively correlated with urinary albumin excretion levels; further, Cav-1 co-localized with the pathologische anatomie leiden-endothelium (typically known as PAL-E) endothelial marker on histologic analysis. These results suggest that caveolae may play a pivotal role in the etiology of albuminuria, allowing albumin to pass through glomerular endothelial cells by a caveolae-dependent pathway [ 19 ]. To test this hypothesis, we utilized an in vitro study that employed human renal glomerular endothelial cells and found that Alexa Fluor 488-labeled albumin particles were highly co-localized with Cav-1, but not with clathrin, which was present in other invaginations on the cell surface. The caveolae-disrupting agents, methyl-beta-cyclodextrin (MBCD) and nystatin significantly decreased albumin internalization into glomerular endothelial cells, demonstrated by western blotting and immunofluorescence analyses. Upon siRNA knockdown of Cav-1 expression in glomerular endothelial cells, their uptake of albumin also significantly decreased. These results indicate that albumin enters glomerular endothelial cells through caveolae [ 20 ]. After the endocytosis of albumin through caveolae, albumin particles co-localized with early endosomes, but not with actin, microtubules, lysosomes, proteasomes, endoplasmic reticulum (ER), and Golgi apparatus (GA). We also showed that albumin particles were excreted to the other side of cells in a study using transwell plates. These results suggested that, after the endocytosis of albumin through caveolae, albumin was transported to early endosomes without moving along cytoskeletal components such as actin and microtubules, and that albumin particles were sorted at early endosomes for transport directly to the other side of the cells without undergoing either degradation in lysosomes and proteasomes, or modification in the ER or GA. In vivo analysis using the puromycin aminonucleoside (PAN) mouse model demonstrated that the amount of albuminuria significantly decreased following treatment with MBCD, as indicated by a decrease in Cav-1 expression in the capillaries [ 21 ]. Taken together, these analyses indicate that albumin is endocytosed, transcytosed, and exocytosed through glomerular endothelial cells via a caveolae-dependent pathway, and suggest that this caveolae-dependent pathway might provide an alternative etiology of albuminuria in addition to the classical fenestrae pathway.
Glomerular Epithelial Cells
Albumin particles have been shown to pass through abnormal slit membrane in cases of decreased nephrin expression between the foot processes of glomerular epithelial cells (podocytes). However, in cases of nephrotic syndrome, foot processes are dramatically effaced and the number of slit membranes in the gap is drastically decreased; this provides a useful model to study the intracellular trafficking pathways by which albumin traverses through glomerular epithelial cells.
Tojo et al. [ 22 ] reported that in the induced-nephrotic syndrome rat model (using intraperitoneal injection of PAN), a high density of gold-labeled albumin particles were detected in the endosomes of glomerular epithelial cells, and larger FITC-labeled albumin particles were also detected in the bodies of glomerular epithelial cells [ 22 ]. Tojo et al. [ 22 ] also reported that the Fc receptor (FcRn) functions as a receptor for albumin transportation; in PAN-treated rats, they showed an increase in FcRn-bound albumin in glomerular epithelial cells and a decrease in urinary protein excretion and albumin uptake in podocytes by treatment with anti-FcRn antibody [ 23 ]. Recently, in an in vitro study using human urine-derived podocyte-like epithelial cells, FITC-labeled albumin was co-localized with FcRn and endosomes [ 24 ], supporting the hypothesis that albumin uses intracellular trafficking pathways to traffic through glomerular epithelial cells. Moreover, Dobrinskikh et al. [ 24 ] reported that FITC-labeled albumin particles co-localized with Cav-1 but not with clathrin; in the same study, nystatin (an inhibitor of caveolae-dependent endocytosis) interfered with the internalization of albumin into glomerular epithelial cells, but pitstop2 (an inhibitor of clathrin-mediated endocytosis) did not [ 24 ]. The cholesterol-lowering agents, statins, also interfered with the endocytosis of albumin into glomerular epithelial cells during in vitro and in vivo assays [ 25 ]. Additionally, caveolae are enriched in cholesterol and sphingolipids, and statins have been reported to interfere with caveolae-dependent BK virus internalization into renal proximal tubular epithelial cells [ 26 ], further supporting the hypothesis of the endocytosis of albumin through caveolae. Taken together, these results suggest that FcRn-bound albumin particles enter glomerular epithelial cells through caveolae and are transported to early endosomes. In another study, it was demonstrated that, after the endocytosis of albumin through caveolae, albumin particles were transported to early endosomes that move along actin; further, several albumin particles were degraded in lysosomes [ 27 ]. Albumin exposure also induced cell apoptosis through combined activation of caspase 3/7 and nuclear factor kappa B and release of interleukin-1β, tumor necrosis factor, and interleukin-6 [ 28 ]. In a recent report, Schießl et al. [ 29 ] used an intravital multiphoton microscope to show transcellular transport of albumin – through caveolae – across the glomerular epithelial cells, and noted that this transcytosis increased upon stimulation with angiotensin II [ 30 ]. These data imply that there may be a transcellular pathway for albumin transport across glomerular epithelial cells.
New Intracellular Trafficking Pathway of Albumin through Glomerular Endothelial and Epithelial Cells
The glomerular capillary wall is composed of glomerular epithelial cells, glomerular basement membrane (GBM), and glomerular endothelial cells. Glomerular endothelial cells comprise the innermost layer and connect to capillary lumen; glomerular epithelial cells comprise the outermost layer and connect to Bowman’s space; and GBM is located between the glomerular endothelial and epithelial cells. These three components serve as the glomerular filtration barrier to form a crude urine filtrate from blood. Traditionally, in glomerular endothelial cells, albumin particles pass through fenestrae that are 100 nm in size and lack a diaphragm, while in glomerular epithelial cells, albumin passes through a slit diaphragm located in the gap between podocyte foot processes ( Fig. 2a ). However, in several kinds of primary and secondary glomerulonephritis, glomerular endothelial cells become swollen, causing the fenestrae to narrow and the foot processes of glomerular epithelial cells to fuse; this fusion results in the loss of the gap between foot process ( Fig. 2b ). In this situation, the caveolae pathway is repurposed to serve as an alternative albumin pathway across glomerular endothelial and epithelial cells. In glomerular endothelial cells, albumin particles enter through caveolae using an unknown receptor, move freely and not in conjunction with cytoskeletal structures (e.g., actin and microtubules), and arrive at early endosomes. In early endosomes, these albumin particles are able to bypass typical endosome-associated organelles (e.g., GA and ER) without undergoing modifications, such as glycosylation, proteolytic processing, sulfation or phosphorylation; the albumin particles also bypass the lysosome and proteasome without undergoing degradation and are transported directly to the other side of the cells for ultimate excretion ( Fig. 3 ).
After passage through GBM, albumin particles enter glomerular epithelial cells through FcRn present in caveolae, then move along cytoskeletal components (e.g., actin) and arrive at early endosomes. In early endosomes, some albumin particles are sorted for degradation by lysosomes or may induce cell apoptosis through cytokine activation; however, other albumin particles are transported to Bowman’s space. In the experimental diabetic nephritis mouse model, MBCD treatment decreased albuminuria, without effects on blood glucose, body weight, or kidney weight. Moreover, MBCD treatment did not affect glomerular deterioration, demonstrated by the measurement of glomerular and mesangial surface area [ 31 ]. Combined with our reports that MBCD treatment decreases Cav-1 expression on glomerular capillaries and decreases albuminuria in the PAN-induced nephrotic syndrome mouse model, these data indicate that the caveolae pathway in both glomerular endothelial and epithelial cells may provide an additional etiology for albuminuria along with the classical fenestral pathway in glomerular endothelial cells and the slit membrane pathway in glomerular epithelial cells.


Fig. 2. Passage of albumin particles through glomerular capillary. a In the normal kidney, few albumin particles pass through fenestra in the glomerular endothelial cells, through glomerular basement membrane, then through the slit membrane in the gap between foot processes of glomerular epithelial cells. b In glomerulonephritis, fenestrae in the glomerular endothelial cells are narrowed and gaps between foot processes in glomerular epithelial cells are fused. In this situation, albumin may pass through glomerular endothelial and epithelial cells by caveolae-dependent pathways.


Fig. 3 . Albumin endocytosis, transcytosis, and exocytosis through glomerular endothelial cells. After albumin particles (yellow) are captured in caveolae, caveolae are pinched off from cell membrane. Albumin particles in the caveolae-coated pit move independently from the cytoskeleton and arrive at early endosomes. Albumin particles are then sorted to the other side of cell membrane for exocytosis and avoid degradation by any of the following: proteasome, lysosome, Golgi apparatus, or endoplasmic reticulum.
Conclusions
In this report, we reviewed the new pathway by which albumin travels through caveolae in both glomerular endothelial and epithelial cells. This caveolae-dependent pathway appears to match several aspects of pathophysiology in glomerulonephritis, including the narrowing of fenestra in glomerular endothelial cells and the fusion of foot processes in podocytes. We suspect that this new theory may become part of the general etiology of albuminuria along with the fenestral pathway and the slit membrane pathway.
Acknowledgements
We thank Ryan Chastain-Gross, PhD, from Edanz Group ( www.edanzediting.com/ac ) for editing a draft of this manuscript.
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13 Peng F, Zhang B, Wu D, Ingram AJ, Gao B, Krepinsky JC: TGF beta-induced RhoA activation and fibronectin production in mesangial cells require caveolae. Am J Physiol Renal Physiol 2008;295:F153–F164.
14 Ostalska-Nowicka D, Nowicki M, Zachwieja J, Kasper M, Witt M: The significance of caveolin-1 expression in parietal epithelial cells of Bowman’s capsule. Histopathology 2007;51:611–621.
15 Mahmoudi M, Willgoss D, Cuttle L, Yang T, Pat B, Winterford C, Endre Z, Johnson DW, Gobé GC: In vivo and in vitro models demonstrate a role for caveolin-1 in the pathogenesis of ischaemic acute renal failure. J Pathol 2003;200:396–405.
16 Zager RA, Johnson A, Hanson S, dela Rosa V: Altered cholesterol localization and caveolin expression during the evolution of acute renal failure. Kidney Int 2002;61:1674–1683.
17 Vallés PG, Manucha W, Carrizo L, Vega Perugorria J, Seltzer A, Ruete C: Renal caveolin-1 expression in children with unilateral ureteropelvic junction obstruction. Pediatr Nephrol 2007;22:237–248.
18 Moriyama T, Marquez JP, Wakatsuki T, Sorokin A: Caveolae endocytosis is critical for BK virus infection of human renal proximal tubular epithelial cells. J Virol 2007;81:8552–8562.
19 Moriyama T, Tsuruta Y, Shimizu A, Itabashi M, Takei T, Horita S, Uchida K, Nitta K: The significance of caveolae in the glomeruli in glomerular disease. J Clin Pathol 2011;64:504–509.
20 Moriyama T, Takei T, Itabashi M, Uchida K, Tsuchiya K, Nitta K: Caveolae may enable albumin to enter human renal glomerular endothelial cells. J Cell Biochem 2015;116:1060–1069.
21 Moriyama T, Sasaki K, Karasawa K, Uchida K, Nitta K: Intracellular transcytosis of albumin in glomerular endothelial cells after endocytosis through caveolae. J Cell Physiol 2017;232:3565–3573.
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23 Kinugasa S, Tojo A, Sakai T, Tsumura H, Takahashi M, Hirata Y, Fujita T: Selective albuminuria via podocyte albumin transport in puromycin nephrotic rats is attenuated by an inhibitor of NADPH oxidase. Kidney Int 2011;80:1328–1338.
24 Dobrinskikh E, Okamura K, Kopp JB, Doctor RB, Blaine J: Human podocytes perform polarized, caveolae-dependent albumin endocytosis. Am J Physiol Renal Physiol 2014;306:F941–F951.
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26 Moriyama T, Sorokin A: Repression of BK virus infection of human renal proximal tubular epithelial cells by pravastatin. Transplantation 2008;85:1311–1317.
27 Carson JM, Okamura K, Wakashin H, McFann K, Dobrinskikh E, Kopp JB, Blaine J: Podocytes degrade endocytosed albumin primarily in lysosomes. PLoS One 2014;9:e99771.
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Takahito Moriyama Department of Medicine, Kidney Center Tokyo Women’s Medical University 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666 (Japan) E-Mail takamori@kc.twmu.ac.jp
 
Nitta K (ed): Recent Advances in the Pathogenesis and Treatment of Kidney Diseases. Contrib Nephrol. Basel, Karger, 2018, vol 195, pp 12–19 (DOI: 10.1159/000486930)
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Rituximab as a Therapeutic Option for Steroid-Sensitive Minimal Change Nephrotic Syndrome in Adults
Yuko Iwabuchi · Takahito Moriyama · Mitsuyo Itabashi · Takashi Takei · Kosaku Nitta
Department of Medicine, Kidney Center, Tokyo Women’s Medical University, Tokyo, Japan
______________________
Abstract
Minimal change nephrotic syndrome (MCNS) usually responds to steroids but frequently relapses, requiring additional treatment with immunosuppressive agents. Rituximab is a chimeric murine/human monoclonal immunoglobulin G1 antibody that targets CD20, a B-cell differentiation marker. B-cell recovery begins at approximately 6 months following the completion of treatment. Rituximab has a beneficial effect, with the sustained remission or reduction of proteinuria in patients with steroid-dependent MCNS. Relapses are thought to be associated with an increase in CD19 cells. The mean serum half-life of rituximab was reported to be 10–15 days in patients with steroid-dependent MCNS. Only infusion reactions, such as rash and chills, occurred after single-dose rituximab infusion and can be managed by pre-medication or infusion rate adjustments. Even though severe adverse effects of rituximab are not expected, we must be aware of potentially life-threatening adverse effects. Controlled randomized trials that include adult patients with steroid-dependent MCNS are required to prove the efficacy and safety of rituximab and to evaluate the cost-effectiveness of rituximab treatment. In this review, we highlight recent studies and discuss the effects of these studies on the management of patients with MCNS in adults.
© 2018 S. Karger AG, Basel
Minimal change nephrotic syndrome (MCNS) accounts for 12.6% of all cases of primary adult nephrotic syndrome in Japan [ 1 ]. MCNS usually responds to glucocorticoids (steroids), and the long-term prognosis is generally good. However, up to 50% of MCNS patients frequently relapse, requiring additional treatment with immunosuppressive agents. Frequent relapses may need prolonged treatment with 2 or more immunosuppressive drugs, with the result that these patients develop steroid-dependent nephrotic syndrome as adults [ 2 ]. Most cases of MCNS are idiopathic and not directly associated with an underlying disease in adults.
The pathophysiology of MCNS remains poorly understood. Shalhoub proposed that the cause of MCNS is a T cell-secreted circulating factor that damages the glomerular basement membrane [ 3 ]. Although this circulating factor has not been identified, a recent study highlights a role of immune dysregulation in MCNS. T-regulatory cells, which attenuate immune response by suppression of T-effector cells, are dysfunctional in humans with MCNS [ 4 ]. In contrast to the well-established involvement of T-cells in MCNS, the role of B cells is uncertain. Recently, it was shown that nuclear factor-related kappa B is upregulated during the relapse of MCNS, mainly in CD4+ T cells and B cells, and this induces the activation of AP1 signaling [ 5 ]. B-cell biology, however, has attained more attention lately, since treatment with rituximab, a monoclonal antibody directed against CD20 bearing cells, has shown good therapeutic responses in the treatment of MCNS.
Mechanism of Rituximab Action
CD20 is a hydrophobic transmembrane protein, with a molecular weight of approximately 35 kD, located on pre-B and mature B cells, and is not found on other cell types or free in the circulation [ 6 ]. CD20 regulates an early step in the activation process for cell cycle initiation and differentiation and possibly functions as a calcium ion channel. Rituximab is a chimeric murine/human monoclonal immunoglobulin G1 antibody that targets CD20, which is a B-cell differentiation marker.
As shown in Figure 1 , 3 different mechanisms have been proposed for the elimination of B cells by rituximab, including complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and stimulation of the apoptotic pathway. Complement-dependent cytotoxicity is most likely the dominant mechanism in vivo. Rituximab improved abnormalities in B-cell homeostasis, with a decreased proportion of autoreactive memory B cells and reconstitution of the B-cell lineage. Therefore, the rituximab-induced depletion of memory B cells may also prevent the activation of autoreactive T cells through interactions with B cells, resulting in the down-regulation of CD40L on CD4-positive T cells and implying that rituximab may improve the disease course by resetting the immune response ( Fig. 2 ).


Fig. 1 . Schematic illustration of the mechanism of rituximab action.


Fig. 2 . Rituximab reduces memory B cells and induces the reconstitution of the B-cell lineage, leading to clinical efficacy in inflammatory autoimmune diseases.
Pharmacokinetics of Rituximab Infusion
Rituximab is composed of 2 heavy chains of 451 amino acids and 2 light chains of 213 amino acids, with a molecular weight of 145 kD. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 n M . The mean serum half-life of rituximab was reported to be 10–15 days in patients with steroid-dependent nephrotic syndrome [ 7 ]. In a single-dose study in subjects with renal failure, the substantial half-life was found to range from 10 to 14 days [ 8 ]. In a small, single-dose, dose-escalation study, 50 mg/m 2 resulted in the same degree and duration of peripheral B-cell suppression and the same effect on the antibody response as 375 mg/m 2 [ 9 ].
In human disease states for which rituximab is administered, circulating B cells are rapidly eliminated. Some preliminary data suggest that a single dose of rituximab can deplete tissue CD20-positive cells in transplant recipients [ 10 ]. B-cell recovery begins at approximately 6 months following the completion of treatment [ 11 ]. The median B-cell levels return to normal by 12 months after the completion of treatment. Even once the total B-cell count returns to normal, a change in phenotype appears to occur, with the B cells present being relatively deficient in the expression of CD27, a surface marker of memory B cells [ 12 ]. This finding suggests that the B cells that do repopulate are primarily naïve, at least as late as 2 years after a single dose.
Single-Dose Rituximab Therapy for Steroid-Dependent MCNS
Kidney Disease Improving Global Outcomes guidelines recommended the usage of steroids to induce remission in adults with MCNS [ 13 ]. However, the evidence for this comes from small randomized controlled trials (RCTs) and observational studies in adults. The recommended dosage of steroids is 1 mg/kg/day for 4–16 weeks, tapered slowly over 6 months. For patients with frequent relapses and steroid resistance, Kidney Disease Improving Global Outcomes guidelines suggest alkylating agents (oral cyclophosphamide 2–2.5 mg/kg/day for 8 weeks). If there are contraindications for alkylating agents, calcineurin inhibitors could be used.
In adults, 2 retrospective analyses described patients with steroid-dependent or frequently relapsing MCNS despite immunosuppressive therapy treated with rituximab [ 14 , 15 ]. Both case series found an increase in remission in about 60% of patients. We have shown that the first prospective cohort study compared rituximab treatment in 25 patients with steroid-dependent and frequently relapsing MCNS to historical controls and confirmed reduction of relapses in adults with MCNS [ 16 ]. As shown in Figure 3 , a single dose of rituximab (375 mg/m 2 ; max 500 mg) was administered 4 times every 6 months. For the first 6 months from the first dose of rituximab, the dosage of steroid and immunosuppressants were reduced each month and stopped. Rules for dose reduction of immunosuppressants: steroid reduction by 10 mg every month to discontinuation followed by cyclosporine reduction and discontinuation or Mizoribine reduction and discontinuation. This order can be changed according to the onset of adverse drug effects. A significant reduction in the number of relapses and the total dose and the maintenance dose of steroids administered was observed during the 12-month period after the first rituximab infusion. Complete remission was achieved in all patients undergoing B-cell depletion. A follow-up study to this prospective cohort study showed 8 relapses in 24 months after complete remission compared to 108 episodes in 24 months before rituximab [ 17 ]. However, complete remission was maintained in all 20 patients in the rituximab continuation group during the 12-month observation period after the first 4 rituximab infusions. Thus, rituximab may be considered as a radical therapeutic agent for adult patients with MCNS. No RCTs in adults have been conducted comparing rituximab treatment in either frequently relapsing or steroid-dependent patients or as a first-line therapy of MCNS.


Fig. 3 . Study protocol of rituximab treatment to reduce the dose of immunosuppressants in steroid-dependent minimal change nephrotic syndrome.
Side Effects of Rituximab Treatment
Rituximab infusion was globally well tolerated. The risk of adverse effects attributed to rituximab varies. With rituximab treatment, the most commonly reported adverse effects are infusion reactions, such as rash and chills; these reactions can be managed by pre-medication or infusion rate adjustments [ 2 ]. Each of these reactions is thought to be associated with an underlying disease or to be a result of concomitant immunosuppressive therapy, rather than a direct result of rituximab administration. We have recently assessed the improvement in adverse effects of steroids and the safety of rituximab treatment in adults with steroid-dependent MCNS [ 18 ]. A total of 54 adult patients were treated with 4 single-dose 6-monthly infusions of rituximab and the adverse effects with steroids between the first rituximab infusion (baseline) and the end of the 24-month observation period compared. The steroid dose was significantly lower at 24 months than at the baseline. Eight patients with diabetes mellitus showed improved glycemic control at 24 months as compared to that at the baseline. There were no severe adverse effects of rituximab.
Perspectives
Almost all patients whose steroid and other immunosuppressive therapies are withdrawn after rituximab treatment have relapses after the recovery of peripheral B-cell counts. Therefore, further modification of rituximab treatment, including repeated courses of rituximab and adjunct immunosuppressive therapies, may be necessary for maintaining long-term remission. Kimata et al. [ 19 ] reported a case series which showed that rituximab administration for 4 times at 3-month intervals induced long-term remission without serious adverse events in children with complicated steroid-dependent MCNS [ 19 ]. A case series by Ito et al. [ 20 ] suggested that maintenance therapy with mycophenolate mofetil after rituximab administration was effective for maintaining long-term remission in children with complicated frequently relapsing NS/steroid-dependent NS [ 20 ]. The efficacy, safety, and cost-effectiveness of various rituximab dosing regimens should be compared to determine an appropriate rituximab treatment regimen for complicated frequently relapsing NS/steroid-dependent NS in adults. Large-scale multicenter cohort studies or multicenter RCTs to compare treatment outcomes after different dosing regimens are required to clarify the optimal dosage of rituximab to use. We have recently shown that treatment with rituximab was possibly superior to previous pharmacological treatments from a health economics perspective [ 21 ].
Conclusion
We demonstrated that rituximab treatment was effective and safe in adult patients with steroid-dependent MCNS and dose reduction or discontinuation of the steroid. In addition, rituximab leads to the amelioration of adverse effects of the steroid. Only infusion reactions, such as rash and chills, occurred after single-dose rituximab infusion, and these reactions could be managed by premedication or infusion rate adjustments. Consequently, careful clinical monitoring is mandatory for these patients. The measurement of the peripheral CD19 cell count seems to be a crude monitoring tool, but it is not a reliable means of deciding whether to proceed with rituximab therapy. Controlled randomized trials that include adult patients with steroid-dependent MCNS are required to prove the efficacy and safety of rituximab and to evaluate the cost-effectiveness of rituximab treatment.
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