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Infection and the Kidney

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 35981

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Prof. Dr. Takashi Oda

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Department of Nephrology and Blood Purification, Kidney Disease Center, Tokyo Medical University Hachioji Medical Center, Tokyo 193-0998, Japan
Interests: rapidly progressive glomerulonephritis; ANCA-associated vasculitis; infection-related glomerulonephritis; post-infectious acute glomerulonephritis; renal interstitial fibrosis; renal transplantation–recurrence of glomerulonephritis; renal transplantation-infection-related complications; role of complements in renal disease; chronic kidney disease; kidney diseases caused by viral infection; kidney diseases caused by bacterial infection
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Special Issue Information

Dear Colleagues,

Infection is known to induce kidney parenchymal injury directly or indirectly through various mechanisms in various renal diseases. For example, severe bacterial infection can cause sepsis that may involve the kidneys in the form of acute kidney injury (AKI), which is a life-threatening condition. It has also been recently revealed that severe infection with COVID-19 can frequently lead to the development of AKI. Direct infection with a virus (such as BK virus) in the parenchyma of the kidneys leads to tubulo-interstitial nephritis, which is a common, kidney-threatening condition in transplanted kidneys. On the other hand, certain infections (bacterial or viral, focal or systemic) can indirectly relate to the development of various renal diseases, such as infection-related glomerulonephritis (IRGN), IgA-dominant IRGN, IgA nephropathy, IgA vasculitis, ANCA-associated glomerulonephritis, and thrombotic microangiopathy (TMA), through various mechanisms, such as nephritogenic bacterial protein with related plasmin activity, bacterial toxin with super-antigenic property, formation of autoantibodies (ANCA, ANA, anti-DNA antibody, antibodies to complement components, etc.), bacterial neuraminidase exposing hidden antigens to naturally existing autoantibodies, and so on.

A detailed understanding of the mechanisms of the relationship between infection and the kidneys is important because it may also lead to the elucidation of the pathogenic mechanism of idiopathic renal diseases. This Special Issue, “Infection and the Kidneys”, welcomes original research and review articles in the field, with a focus on but not limited to kidney injury directly or indirectly related with infection, such as sepsis-associated AKI, AKI in COVID-19, IRGN, IgA-IRGN, IgA nephropathy, IgA vasculitis, infection-induced ANCA-associated glomerulonephritis, infection-associated TMA, and direct viral infection on transplanted kidney.

Prof. Dr. Takashi Oda
Guest Editor

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Keywords

sepsis-associated acute kidney injury (AKI)

COVID-19-associated AKI

infection-related glomerulonephritis (IRGN)

IgA-dominant IRGN

IgA nephropathy

IgA vasculitis

autoantibody

ANCA-associated vasculitis

thrombotic microangiopathy

viral infection on transplanted kidneys

Published Papers (10 papers)

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Editorial

Jump to: Research, Review

3 pages, 457 KiB

Open AccessEditorial

Editorial for the IJMS Special Issue on “Infection and the Kidney”

by Takashi Oda

Int. J. Mol. Sci. 2023, 24(9), 8431; https://doi.org/10.3390/ijms24098431 - 08 May 2023

Viewed by 875

Abstract

The coronavirus disease (COVID-19) pandemic has highlighted the close relationship between infection and kidney injury [...] Full article

(This article belongs to the Special Issue Infection and the Kidney)

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Research

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13 pages, 3087 KiB

Open AccessArticle

Relationship between IgA Nephropathy and Porphyromonas gingivalis; Red Complex of Periodontopathic Bacterial Species

by Yasuyuki Nagasawa, Ryota Nomura, Taro Misaki, Seigo Ito, Shuhei Naka, Kaoruko Wato, Mieko Okunaka, Maiko Watabe, Katsuya Fushimi, Kenzo Tsuzuki, Michiyo Matsumoto-Nakano and Kazuhiko Nakano

Int. J. Mol. Sci. 2021, 22(23), 13022; https://doi.org/10.3390/ijms222313022 - 01 Dec 2021

Cited by 14 | Viewed by 2771

Abstract

IgA nephropathy (IgAN) has been considered to have a relationship with infection in the tonsil, because IgAN patients often manifest macro hematuria just after tonsillitis. In terms of oral-area infection, the red complex of periodontal bacteria (Porphyromonas gingivalis (P. gingivalis), Treponema denticol (T. denticola) and Tannerella forsythia (T. forsythia)) is important, but the relationship between these bacteria and IgAN remains unknown. In this study, the prevalence of the red complex of periodontal bacteria in tonsil was compared between IgAN and tonsillitis patients. The pathogenicity of IgAN induced by P. gingivalis was confirmed by the mice model treated with this bacterium. The prevalence of P. gingivalis and T. forsythia in IgAN patients was significantly higher than that in tonsillitis patients (p < 0.001 and p < 0.05, respectively). A total of 92% of tonsillitis patients were free from red complex bacteria, while only 48% of IgAN patients had any of these bacteria. Nasal administration of P. gingivalis in mice caused mesangial proliferation (p < 0.05 at days 28a nd 42; p < 0.01 at days 14 and 56) and IgA deposition (p < 0.001 at day 42 and 56 after administration). Scanning-electron-microscopic observation revealed that a high-density Electron-Dense Deposit was widely distributed in the mesangial region in the mice kidneys treated with P. gingivalis. These findings suggest that P. gingivalis is involved in the pathogenesis of IgAN. Full article

(This article belongs to the Special Issue Infection and the Kidney)

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Review

Jump to: Editorial, Research

25 pages, 1118 KiB

Open AccessReview

Virus-Associated Nephropathies: A Narrative Review

by Christophe Masset, Paul Le Turnier, Céline Bressollette-Bodin, Karine Renaudin, François Raffi and Jacques Dantal

Int. J. Mol. Sci. 2022, 23(19), 12014; https://doi.org/10.3390/ijms231912014 - 10 Oct 2022

Cited by 9 | Viewed by 4539

Abstract

While most viral infections cause mild symptoms and a spontaneous favorable resolution, some can lead to severe or protracted manifestations, specifically in immunocompromised hosts. Kidney injuries related to viral infections may have multiple causes related to the infection severity, drug toxicity or direct or indirect viral-associated nephropathy. We review here the described virus-associated nephropathies in order to guide diagnosis strategies and treatments in cases of acute kidney injury (AKI) occurring concomitantly with a viral infection. The occurrence of virus-associated nephropathy depends on multiple factors: the local epidemiology of the virus, its ability to infect renal cells and the patient’s underlying immune response, which varies with the state of immunosuppression. Clear comprehension of pathophysiological mechanisms associated with a summary of described direct and indirect injuries should help physicians to diagnose and treat viral associated nephropathies. Full article

(This article belongs to the Special Issue Infection and the Kidney)

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22 pages, 593 KiB

Open AccessReview

Coronavirus Disease 2019-Associated Thrombotic Microangiopathy: Literature Review

by Marija Malgaj Vrečko, Andreja Aleš Rigler and Željka Večerić-Haler

Int. J. Mol. Sci. 2022, 23(19), 11307; https://doi.org/10.3390/ijms231911307 - 25 Sep 2022

Cited by 7 | Viewed by 2127

Abstract

Coronavirus disease 2019 (COVID-19) can lead to clinically significant multisystem disorders that also affect the kidney. According to recent data, renal injury in the form of thrombotic microangiopathy (TMA) in native kidneys ranks third in frequency. Our review of global literature revealed 46 cases of TMA in association with COVID-19. Among identified cases, 18 patients presented as thrombotic thrombocytopenic purpura (TTP) and 28 cases presented as atypical hemolytic uremic syndrome (aHUS). Altogether, seven patients with aHUS had previously proven pathogenic or likely pathogenic genetic complement abnormalities. TMA occurred at the time of viremia or even after viral clearance. Infection with COVID-19 resulted in almost no or only mild respiratory symptoms in the majority of patients, while digestive symptoms occurred in almost one-third of patients. Regarding the clinical presentation of COVID-19-associated TMA, the cases showed no major deviations from the known presentation. Patients with TTP were treated with plasma exchange (88.9%) or fresh frozen plasma (11.1%), corticosteroids (88.9%), rituximab (38.9%), and caplacizumab (11.1%). Furthermore, 53.6% of patients with aHUS underwent plasma exchange with or without steroid as initial therapy, and 57.1% of patients received a C5 complement inhibitor. Mortality in the studied cohort was 16.7% for patients with TTP and 10.7% for patients with aHUS. The exact role of COVID-19 in the setting of COVID-19-associated TMA remains unclear. COVID-19 likely represents a second hit of aHUS or TTP that manifests in genetically predisposed individuals. Early identification of the TMA subtype and appropriate prompt and specific treatment could lead to good outcomes comparable to survival and recovery statistics for TMA of all causes. Full article

(This article belongs to the Special Issue Infection and the Kidney)

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27 pages, 8214 KiB

Open AccessReview

Nephritis-Associated Plasmin Receptor (NAPlr): An Essential Inducer of C3-Dominant Glomerular Injury and a Potential Key Diagnostic Biomarker of Infection-Related Glomerulonephritis (IRGN)

by Nobuyuki Yoshizawa, Muneharu Yamada, Masayuki Fujino and Takashi Oda

Int. J. Mol. Sci. 2022, 23(17), 9974; https://doi.org/10.3390/ijms23179974 - 01 Sep 2022

Cited by 10 | Viewed by 4882

Abstract

Nephritis-associated plasmin receptor (NAPlr) was originally isolated from the cytoplasmic fraction of group A Streptococci, and was found to be the same molecule as streptococcal glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and plasmin receptor (Plr) on the basis of nucleotide and amino acid sequence homology. Its main functions include GAPDH activity, plasmin-binding capacity, and direct activation of the complement alternative pathway (A-P). Plasmin trapped by deposited NAPlr triggers the degradation of extracellular matrix proteins, such as glomerular basement membranes and mesangial matrix, and the accumulation of macrophages and neutrophils, leading to the induction of plasmin-related endocapillary glomerular inflammation. Deposited NAPlr at glomerular endocapillary site directly activates the complement A-P, and the endocapillary release of complement-related anaphylatoxins, C3a and C5a, amplify the in situ endocapillary glomerular inflammation. Subsequently, circulating and in situ-formed immune complexes participate in the glomerular injury resulting in NAPlr-mediated glomerulonephritis. The disease framework of infection-related glomerulonephritis (IRGN) has been further expanded. GAPDH of various bacteria other than Streptococci have been found to react with anti-NAPlr antibodies and to possess plasmin-binding activities, allowing glomerular NAPlr and plasmin activity to be utilized as key biomarkers of IRGN. Full article

(This article belongs to the Special Issue Infection and the Kidney)

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17 pages, 23982 KiB

Open AccessReview

Staphylococcus aureus Infection-Related Glomerulonephritis with Dominant IgA Deposition

by Mamiko Takayasu, Kouichi Hirayama, Homare Shimohata, Masaki Kobayashi and Akio Koyama

Int. J. Mol. Sci. 2022, 23(13), 7482; https://doi.org/10.3390/ijms23137482 - 05 Jul 2022

Cited by 8 | Viewed by 3746

Abstract

Since 1995, when we reported the case of a patient with glomerulonephritis with IgA deposition that occurred after a methicillin-resistant Staphylococcus aureus (MRSA) infection, many reports of MRSA infection-associated glomerulonephritis have accumulated. This disease is being systematized as Staphylococcus infection-associated glomerulonephritis (SAGN) in light of the apparent cause of infection, and as immunoglobulin A-dominant deposition infection-related glomerulonephritis (IgA-IRGN) in light of its histopathology. This glomerulonephritis usually presents as rapidly progressive glomerulonephritis or acute kidney injury with various degrees of proteinuria and microscopic hematuria along with an ongoing infection. Its renal pathology has shown several types of mesangial and/or endocapillary proliferative glomerulonephritis with various degrees of crescent formation and tubulointerstitial nephritis. IgA, IgG, and C₃ staining in the mesangium and along the glomerular capillary walls have been observed on immunofluorescence examinations. A marked activation of T cells, an increase in specific variable regions of the T-cell receptor β-chain-positive cells, hypercytokinemia, and increased polyclonal immune complexes have also been observed in this glomerulonephritis. In the development of this disease, staphylococcal enterotoxin may be involved as a superantigen, but further investigations are needed to clarify the mechanisms underlying this disease. Here, we review 336 cases of IgA-IRGN and 218 cases of SAGN. Full article

(This article belongs to the Special Issue Infection and the Kidney)

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23 pages, 2220 KiB

Open AccessReview

Kidney Injury in COVID-19: Epidemiology, Molecular Mechanisms and Potential Therapeutic Targets

by J. Pedro Teixeira, Sharon Barone, Kamyar Zahedi and Manoocher Soleimani

Int. J. Mol. Sci. 2022, 23(4), 2242; https://doi.org/10.3390/ijms23042242 - 17 Feb 2022

Cited by 17 | Viewed by 3971

Abstract

As of December 2021, SARS-CoV-2 had caused over 250 million infections and 5 million deaths worldwide. Furthermore, despite the development of highly effective vaccines, novel variants of SARS-CoV-2 continue to sustain the pandemic, and the search for effective therapies for COVID-19 remains as urgent as ever. Though the primary manifestation of COVID-19 is pneumonia, the disease can affect multiple organs, including the kidneys, with acute kidney injury (AKI) being among the most common extrapulmonary manifestations of severe COVID-19. In this article, we start by reflecting on the epidemiology of kidney disease in COVID-19, which overwhelmingly demonstrates that AKI is common in COVID-19 and is strongly associated with poor outcomes. We also present emerging data showing that COVID-19 may result in long-term renal impairment and delve into the ongoing debate about whether AKI in COVID-19 is mediated by direct viral injury. Next, we focus on the molecular pathogenesis of SARS-CoV-2 infection by both reviewing previously published data and presenting some novel data on the mechanisms of cellular viral entry. Finally, we relate these molecular mechanisms to a series of therapies currently under investigation and propose additional novel therapeutic targets for COVID-19. Full article

(This article belongs to the Special Issue Infection and the Kidney)

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21 pages, 10396 KiB

Open AccessReview

Role of Palatine Tonsil and Epipharyngeal Lymphoid Tissue in the Development of Glomerular Active Lesions (Glomerular vasculitis) in Immunoglobulin A Nephropathy

by Osamu Hotta, Norio Ieiri, Masaaki Nagai, Ayaki Tanaka and Yasuaki Harabuchi

Int. J. Mol. Sci. 2022, 23(2), 727; https://doi.org/10.3390/ijms23020727 - 10 Jan 2022

Cited by 13 | Viewed by 4625

Abstract

Hematuria is an essential symptom of immunoglobulin A nephropathy (IgAN). Although the etiology of hematuria in IgAN has not been fully elucidated, it is thought that the rupture of the glomerular basement membranes caused by intra-capillary leukocyte influx, so-called glomerular vasculitis, is the pathological condition responsible for severe hematuria. Glomerular vasculitis are active lesions that exist in the glomeruli of acute phase IgAN and it is important because it is suspected to make the transition to segmental glomerular sclerosis (SGS) as a repair scar lesion in the chronic phase, and the progression of SGS would eventually lead to glomerular obsolescence. Worsening of hematuria concomitant with acute pharyngitis is common in patients with IgAN; therefore, elucidating the relationship between the immune system of Waldeyer’s ring, including the palatine tonsil and epipharyngeal lymphoid tissue, and the glomerular vasculitis may lead to understanding the nature of IgAN. The epipharynx is an immunologically activated site even under normal conditions, and enhanced activation of innate immunity is likely to occur in response to airborne infection. Hyperactivation of innate immunity via upregulation of Toll-like receptors in the interfollicular area of the palatine tonsil and epipharyngeal lymphoid tissue, followed by enhanced fractalkine/CX3CR1 interactions, appears to play an important role in the development of glomerular vasculitis in IgAN. As latent but significant epipharyngitis is present in most patients with IgAN, it is plausible that acute upper respiratory infection may contribute as a trigger for the innate epipharyngeal immune system, which is already upregulated in a chronically inflamed environment. Given that epipharyngitis and its effects on IgAN are not fully understood, we propose that the so-called “epipharynx–kidney axis” may provide an important focus for future research. Full article

(This article belongs to the Special Issue Infection and the Kidney)

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20 pages, 22587 KiB

Open AccessReview

Title IgA Nephropathy and Oral Bacterial Species Related to Dental Caries and Periodontitis

by Yasuyuki Nagasawa, Taro Misaki, Seigo Ito, Shuhei Naka, Kaoruko Wato, Ryota Nomura, Michiyo Matsumoto-Nakano and Kazuhiko Nakano

Int. J. Mol. Sci. 2022, 23(2), 725; https://doi.org/10.3390/ijms23020725 - 10 Jan 2022

Cited by 13 | Viewed by 4340

Abstract

A relationship between IgA nephropathy (IgAN) and bacterial infection has been suspected. As IgAN is a chronic disease, bacteria that could cause chronic infection in oral areas might be pathogenetic bacteria candidates. Oral bacterial species related to dental caries and periodontitis should be candidates because these bacteria are well known to be pathogenic in chronic dental disease. Recently, several reports have indicated that collagen-binding protein (cnm)-(+) Streptococcs mutans is relate to the incidence of IgAN and the progression of IgAN. Among periodontal bacteria, Treponema denticola, Porphyromonas gingivalis and Campylobacte rectus were found to be related to the incidence of IgAN. These bacteria can cause IgAN-like histological findings in animal models. While the connection between oral bacterial infection, such as infection with S. mutans and periodontal bacteria, and the incidence of IgAN remains unclear, these bacterial infections might cause aberrantly glycosylated IgA1 in nasopharynx-associated lymphoid tissue, which has been reported to cause IgA deposition in mesangial areas in glomeruli, probably through the alteration of microRNAs related to the expression of glycosylation enzymes. The roles of other factors related to the incidence and progression of IgA, such as genes and cigarette smoking, can also be explained from the perspective of the relationship between these factors and oral bacteria. This review summarizes the relationship between IgAN and oral bacteria, such as cnm-(+) S. mutans and periodontal bacteria. Full article

(This article belongs to the Special Issue Infection and the Kidney)

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11 pages, 615 KiB

Open AccessReview

Infections, Reactions of Natural Killer T Cells and Natural Killer Cells, and Kidney Injury

by Takahiro Uchida, Shuhji Seki and Takashi Oda

Int. J. Mol. Sci. 2022, 23(1), 479; https://doi.org/10.3390/ijms23010479 - 01 Jan 2022

Cited by 7 | Viewed by 2531

Abstract

Natural killer T (NKT) cells and NK cells are representative innate immune cells that perform antitumor and antimicrobial functions. The involvement of these cells in various renal diseases, including acute kidney injury (AKI), has recently become evident. Murine NKT cells are activated and cause AKI in response to various stimuli, such as their specific ligand, cytokines, and bacterial components. Both renal vascular endothelial cell injury (via the perforin-mediated pathway) and tubular epithelial cell injury (via the tumor necrosis factor-alpha/Fas ligand pathway) are independently involved in the pathogenesis of AKI. NK cells complement the functions of NKT cells, thereby contributing to the development of infection-associated AKI. Human CD56⁺ T cells, which are a functional counterpart of murine NKT cells, as well as a subpopulation of CD56⁺ NK cells, strongly damage intrinsic renal cells in vitro upon their activation, possibly through mechanisms similar to those in mice. These cells are also thought to be involved in the acute exacerbation of pre-existing glomerulonephritis triggered by infection in humans, and their roles in sepsis-associated AKI are currently under investigation. In this review, we will provide an overview of the recent advances in the understanding of the association among infections, NKT and NK cells, and kidney injury, which is much more profound than previously considered. The important role of liver macrophages in the activation of NKT cells will also be introduced. Full article

(This article belongs to the Special Issue Infection and the Kidney)

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