Factors Affecting the Progression of Infection-Related Glomerulonephritis to Chronic Kidney Disease

International Journal of Molecular Sciences

Review Factors Affecting the Progression of Infection-Related Glomerulonephritis to Chronic Kidney Disease

Takashi Oda 1,* and Nobuyuki Yoshizawa 2

1 Kidney Disease Center, Department of Nephrology and Blood Puriﬁcation, Tokyo Medical University Hachioji Medical Center, Hachioji, Tokyo 193-0998, Japan 2 Hemodialysis Unit, Showanomori Hospital, Akishima, Tokyo 196-0024, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-42-665-5611; Fax: +81-42-665-1796

Abstract: Acute glomerulonephritis (AGN) triggered by infection is still one of the major causes of acute kidney injury. During the previous two decades, there has been a major paradigm shift in the epidemiology of AGN. The incidence of poststreptococcal acute glomerulonephritis (PSAGN), which develops after the cure of group A Streptococcus infection in children has decreased, whereas adult AGN cases have been increasing, and those associated with nonstreptococcal infections, particularly infections by Staphylococcus, are now as common as PSAGN. In adult AGN patients, particularly older patients with comorbidities, infections are usually ongoing at the time when glomerulonephritis is diagnosed; thus, the term “infection-related glomerulonephritis (IRGN)” has recently been popularly used instead of “post-infectious AGN”. The prognosis of children with PSAGN is generally considered excellent compared with that of adult IRGN cases. However, long-term epidemiological analysis demonstrated that an episode of PSAGN in childhood is a strong risk factor for chronic kidney disease (CKD), even after the complete remission of PSAGN. Although the precise mechanism of the transition from IRGN to CKD remains unknown, its clariﬁcation is important as it will lead to the prevention of CKD. In this review, we therefore focus on the possible factors that may contribute to the progression of IRGN into CKD. Four factors, namely, persistent infection, genetic background Citation: Oda, T.; Yoshizawa, N. of the host’s complement system, tubulointerstitial changes, and pre-existing histological damage, Factors Affecting the Progression of are discussed. Infection-Related Glomerulonephritis to Chronic Kidney Disease. Int. J. Mol. Keywords: acute kidney injury; poststreptococcal acute glomerulonephritis; infection-related Sci. 2021, 22, 905. https://doi.org/ glomerulonephritis; chronic kidney disease; tubulo-interstitial change; nephritis-associated plasmin 10.3390/ijms22020905 receptor; alpha-smooth muscle actin

Received: 8 December 2020 Accepted: 14 January 2021 Published: 18 January 2021 1. Introduction

Publisher’s Note: MDPI stays neutral Acute kidney injury (AKI) has been increasing in the previous few decades and has with regard to jurisdictional claims in recently been recognized as an important cause of chronic kidney disease (CKD), which published maps and institutional afﬁl- may progress to end stage renal disease (ESRD) [1]. However, the precise mechanism of iations. the transition from AKI to CKD remains obscure and is a matter of great concern. Acute glomerulonephritis (AGN) triggered by infection is still one of the major causes of AKI. During the past century, poststreptococcal acute glomerulonephritis (PSAGN) that develops after the cure of group A Streptococcus (GAS) infection after a distinct latent period in children comprised the majority of AGN cases [2,3]. However, during the previous two Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. decades, there has been a major paradigm shift in the epidemiology of AGN. Probably This article is an open access article owing to the improvement in living environments and the adequate use of antibiotics, distributed under the terms and the incidence of PSAGN has decreased, particularly in developed countries. On the other conditions of the Creative Commons hand, adult AGN cases have been increasing, and those associated with nonstreptococcal Attribution (CC BY) license (https:// infections, particularly infection of Staphylococcus, are now as common as PSAGN. Fur- creativecommons.org/licenses/by/ thermore, in adult AGN patients, particularly older patients with comorbidities, infections 4.0/). are usually ongoing at the time when glomerulonephritis is diagnosed. This is why the

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term “infection-related glomerulonephritis (IRGN)” has recently been more commonly used instead of “post-infectious AGN” [3]. Notably, whereas most PSAGN in children resolve without any speciﬁc treatment, the prognosis of adult IRGN is poor, and older patients, particularly those with immunocompromised backgrounds, such as diabetes mellitus, malignancies, or alcoholism, are reported to be at high risk [4]. Thus, typical PSAGN in children is considered as a benign disease with a favorable prognosis that completely resolves without progression, in contrast to IRGN in adults, which often progresses into chronicity with an unfavorable renal prognosis. However, a long-term epidemiological study demonstrated that an episode of PSAGN in childhood is a strong risk factor for CKD and ESRD in adulthood, even after the complete remission of PSAGN [5–10]. Although the precise mechanism of the transition from AGN to CKD remains unknown, understanding it is important as it is expected to lead to the prevention of CKD and ESRD. In this review, we therefore focus primarily on the possible factors that may contribute to the progression of IRGN, which is a major cause of AKI, into CKD. As summarized in Table1 and Figure1, the following four factors are listed and discussed: 1. persistent infection, 2. genetic background of the host’s complement system, 3. tubulointerstitial changes, and 4. pre-existing histological damage due to old age and comorbidities. Among these factors, 2 of them (1 and 2) are associated with the pathogenic mechanism of IRGN, whereas the other 2 factors (3 and 4) are independent of IRGN itself.

Table 1. Factors affecting the progression of infection-related glomerulonephritis to chronic kidney disease.

Evaluation of the Involvement of Each Factor Potential Intervention Factor (Biomarkers) Histological staining for NAPlr and Use of antimicrobial agents 1. Persistent infection plasmin activity [11] Removal of indwelling device Serum complement levels, histological 2. Genetic background of the host’s Use of complement—regulating deposition of complement components, complement system [12] medications (in the future) genetic testing 3. Tubulointerstitial changes Interstitial staining for α-SMA Not yet determined 4. Pre-existing renal histological damage Adequate treatment for comorbidities, Histopathological evaluation due to comorbidities [4,13] such as hypertension and DM NAPlr: nephritis-associated plasmin receptor; α-SMA: alpha-smooth muscle actin; DM: diabetes mellitus. Numbers of related references are listed.

Some autoantibodies, such as the anti-neutrophil cytoplasmic antibody (ANCA), anti-nuclear antibody (ANA), anti-dsDNA antibody, and anti-factor B antibody have been reported to be detected in patients with IRGN [14–21]. Although these antibodies may contribute to the progression of IRGN, at present there is little data regarding their signiﬁcance on the prognosis of IRGN, and as their involvement remains controversial, we touched on this point but did not list the antibodies as possible factors associated with IRGN. Generally, clear evidence in this ﬁeld is very scarce because no large prospective clinical studies have been performed owing to the rarity of IRGN, and, furthermore, a reliable animal model has not been established to date, partly owing to the differences in the infectiveness of pathogens among different species. Therefore, a substantial portion of this review is based on detailed evaluations of case reports. Int. J.Int. Mol. J. Mol. Sci. Sci. 20212021, 22, 22, ,x 905 FOR PEER REVIEW 3 of 12 3 of 12

FigureFigure 1. Summary 1. Summary of the conceptof the concept of this review. of this Induction review. of IRGNInduction and its of outcome IRGN are and summarized. its outcome are summa- IRGNrized. may IRGN cure completely may cure or completely may progress or into may CKD. progress Four factors into that CKD. may contribute Four factors to the progres-that may contribute to sionthe of progression IRGN into CKD of are IRGN depicted. into Solid CKD arrow are indicatesdepicted. the So mainlid flow arrow of induction indicates of IRGNthe main and its flow of induction outcome.of IRGN While and dotted its outcome. arrow indicate While the dotted flow of patientsarrow indi withcate pre-existing the flow comorbidities of patients (Factor with 4). pre-existing NAPlr:comorbidities nephritis-associated (Factor plasmin4). NAPlr: receptor; nephritis-associated IRGN: infection-related plasmin glomerulonephritis; receptor; IRGN: PGN: pro- infection-related liferativeglomerulonephritis; glomerulonephritis; PGN: GN: proliferative glomerulonephritis; glomerulon C activation:ephritis; complement GN: glomerulonephritis; activation; MPGN: C activation: membranoproliferativecomplement activation; glomerulonephritis; MPGN: membranoprolifer MesPGN: mesangialative proliferative glomerulonephritis; glomerulonephritis; MesPGN: mesangial T-I:proliferative tubulo-interstitial; glomerulonephritis; C3-G: C3 glomerulopathy; T-I: tubulo-i PIGN:nterstitial; postinfectious C3-G: glomerulonephritis; C3 glomerulopathy; CKD: PIGN: chronicpostinfectious kidney disease. glomerulonephritis; CKD: chronic kidney disease. 2. Persistent Infection as a Possible Cause of the Progression of IRGN into CKD TheSome simplest autoantibodies, reason for the persistencesuch as the and progressionanti-neutrophil of IRGN cytoplasmic into CKD is antibody the (ANCA), persistenceanti-nuclear of the antibody causative (ANA), infection, anti-dsDNA resulting in theantibody, continuation and anti-factor of the pathogenic B antibody have been mechanism.reported to In thisbe detected setting, abnormalities in patients in with urinalysis, IRGN serum [14–21]. complement Although levels, these and antibodies may inflammation (ESR and CRP levels) continue, leading to disease progression into chronic glomerulonephritis.contribute to the Manyprogression factors, such of IRGN, as the strainat pres ofent pathogen there (variousis little data bacteria regarding and their signif- viruses),icance focuson the of infection, prognosis and of conditions IRGN, ofand the hostas th (immuneeir involvement competence, remains comorbidi- controversial, we ties,touched use of indwellingon this point devices, but etc.) did may not affect list thethe persistence antibodies of pathogens.as possible In termsfactors of associated with bacterialIRGN. strains, as described in the introduction, GAS infection tends to occur more fre- quentlyGenerally, in children and clear is usually evidence completely in this cured field before is very the scarce onset of because glomerulonephritis. no large prospective clin- Glomerular histological analysis in such a condition usually shows the so-called acute change,ical studies i.e., prominent have been endocapillary performed proliferation owing to mainlythe rarity by the of accumulationIRGN, and, furthermore, of infil- a reliable tratinganimal cells model [22,23 ].has On not the otherbeen hand,establishedStaphylococcal to dateIRGN, partly mainly owing affects to older the adults differences in the in- whofectiveness often have of comorbidities, pathogens and among the infection different is ongoing specie whens. Therefore, the glomerulonephritis a substantial portion of this developsreview [ 4is]. based Glomerular on detailed histological evaluations changes in such of case patients reports. with ongoing infection may

2. Persistent Infection as a Possible Cause of the Progression of IRGN into CKD The simplest reason for the persistence and progression of IRGN into CKD is the persistence of the causative infection, resulting in the continuation of the pathogenic mechanism. In this setting, abnormalities in urinalysis, serum complement levels, and inflammation (ESR and CRP levels) continue, leading to disease progression into chronic glomerulonephritis. Many factors, such as the strain of pathogen (various bacteria and viruses), focus of infection, and conditions of the host (immune competence, comorbidities, use of indwelling devices, etc.) may affect the persistence of pathogens. In terms of

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bacterial strains, as described in the introduction, GAS infection tends to occur more frequently in children and is usually completely cured before the onset of glomerulonephritis. Glomerular histological analysis in such a condition usually shows the so-called acute change, i.e., prominent endocapillary proliferation mainly by the accumulation of infil- Int. J. Mol. Sci. 2021, 22, 905 4 of 12 trating cells [22,23]. On the other hand, Staphylococcal IRGN mainly affects older adults who often have comorbidities, and the infection is ongoing when the glomerulonephritis develops [4]. Glomerular histological changes in such patients with ongoing infection may also show endocapillary prolif proliferativeerative glomerulonephritis in the early phase of the disease course. However, However, as the disease duration afterafter the onsetonset ofof glomerulonephritisglomerulonephritis becomes longer,longer, glomerular changes appear to to make make a a gradual transition transition from from endocapillary endocapillary pro- pro- liferativeliferative glomerulonephritis to membranoproliferative glomerulonephritis (MPGN) or mesangial proliferative glomerulonephritis (MesPGN),(MesPGN), probablyprobablythrough through chronic chronic glomeru- glomer- ularlar endothelial endothelial damage damage and and gradual gradual transition transition from from the the accumulation accumulation of of infiltrating infiltrating cells cells to tothe the proliferation proliferation of mesangialof mesangial cells. cells.Staphylococcal Staphylococcalinfections infections in older in older patients, patients, particularly particu- larlydeep-seated deep-seated infections, infections, are frequentlyare frequently occult occu inlt nature in nature and and are are quite quite difficult difficult to detect.to detect.Therefore, Therefore, complicating complicating glomerulonephritis glomerulonephritis tends tends to be to detected be detected in its in chronic its chronic stages, stages, and andhistological histological analysis analysis often often shows shows a MPGN a MPGN or MesPGN or MesPGN pattern pattern with or wi withoutth or without crescent cres- for- centmation formation and IgA and deposition. IgA deposition. Typical examplesTypical exam of thisples condition of this condition have been have reported been reported in IRGN incaused IRGN by caused infective by endocarditisinfective endocarditis due to Staphylococcus due to Staphylococcus aureus and aureus caused and by ventriculoatrialcaused by ven- triculoatrialshunt infections shunt due infections to coagulase-negative due to coagulase-negativeStaphylococcus Staphylococcus epidermidis. epidermidis. For assessment assessment of of the the continuation continuation of of th thee pathogenic pathogenic mechanism mechanism due due to persistent to persis- infection,tent infection, the identification the identification of histological of histological biomarkers biomarkers is desired. is desired.In this respect, In this nephritis- respect, associatednephritis-associated plasmin receptor plasmin (NAPlr) receptor (NAPlr)and associated and associated plasmin plasminactivity activitymay be may useful be [11,24,25].useful [11 ,NAPlr24,25]. was NAPlr originally was originally isolated isolated from the from cytoplasmic the cytoplasmic fraction fractionof GAS as of a GAS candi- as datea candidate nephritogenic nephritogenic protein proteinof PSAGN, of PSAGN, and was and found was to found be the to same be the molecule same molecule as strepto- as coccalstreptococcal glyceraldehyde-3-phosphate glyceraldehyde-3-phosphate dehydrogenase dehydrogenase (GAPDH) (GAPDH) [24,25]. [Glomerular24,25]. Glomerular NAPlr depositionNAPlr deposition is frequently is frequently observed observed by immunofluorescence by immunofluorescence staining stainingin early stage in early PSAGN stage patientsPSAGN (Figure patients 2); (Figure all patients2); all patientswithin two within weeks two of weeks disease of onset disease are onset reported are reported to show NAPlrto show deposition NAPlr deposition [25]. The deposited [25]. The NAPlr deposited binds NAPlrwith plasmin binds withand maintains plasmin andits activity maintains its activity by protecting it from physiological inhibitors, and is considered to cause by protecting it from physiological inhibitors, and is considered to cause glomerular dam- glomerular damage directly by degrading extracellular matrix proteins and indirectly by age directly by degrading extracellular matrix proteins and indirectly by activating pro- activating pro-matrix metalloproteases. Additionally, glomerular plasmin activity can exert matrix metalloproteases. Additionally, glomerular plasmin activity can exert proinflam- proinflammatory functions by activating and accumulating inflammatory cells [11]. matory functions by activating and accumulating inflammatory cells [11].

Figure 2.2. Representative photomicrographs of of the histological st stainingaining for C3, nephritis-associatednephritis-associated plasmin receptor (NAPlr), and plasmin activity in the glomeruliglomeruli of aa post-streptococcalpost-streptococcal acuteacute glomerulonephritisglomerulonephritis (PSAGN) patient. ( (A–C)) Double immunofluorescence (IF) staining for NAPlr (fluorescein isothiocyanate, green) and complement C3 (Alexa Fluor Double immunoﬂuorescence (IF) staining for NAPlr (ﬂuorescein isothiocyanate, green) and complement C3 (Alexa Fluor 594, red). Both NAPlr (A) and C3 (B) were positive in the glomeruli, but they generally were not colocalized, as shown in 594, red). Both NAPlr (A) and C3 (B) were positive in the glomeruli, but they generally were not colocalized, as shown in the merged image (C). (D) Plasmin activity assessed by in situ zymography on a serial section was found to be positive, theand merged to have image a similar (C). distribution (D) Plasmin activityto the NAPlr assessed staining by in situin the zymography glomeruli. on Details a serial of sectionall staining was foundmethods to be have positive, been andde- toscribed have previously a similar distribution [11]. to the NAPlr staining in the glomeruli. Details of all staining methods have been described previously [11]. Recently, glomerular NAPlr deposition and associated plasmin activity were re- portedRecently, to be observed glomerular not NAPlronly in deposition patients with and associatedPSAGN but plasmin also in activitythose with were other reported glo- merularto be observed diseases, not in only whom in patientspreceding with streptoc PSAGNoccal but infection also in thosehad been with suggested other glomerular [26–31]. diseases, in whom preceding streptococcal infection had been suggested [26–31]. In fact, the preceding infection might be an infection other than GAS, because the GAPDH of various bacteria show cross-immunoreactivity to the anti-NAPlr antibody, and simultaneously show plasmin-binding function [32–34]. From these results, NAPlr and associated plasmin activity are presently considered as general biomarkers of IRGN [35]. Positive glomerular staining of these markers usually disappears within 30 days after the onset of PSAGN [25]. However, the prolonged positive glomerular staining of these markers (for more than half Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 5 of 12

In fact, the preceding infection might be an infection other than GAS, because the GAPDH of various bacteria show cross-immunoreactivity to the anti-NAPlr antibody, and simultaneously show plasmin-binding function [32–34]. From these results, NAPlr and associated plasmin activity are presently considered as general biomarkers of IRGN [35]. Posi- tive glomerular staining of these markers usually disappears within 30 days after the onset of PSAGN [25]. However, the prolonged positive glomerular staining of these markers (for more than half a year) has been observed in some IRGN patients, suggesting persis- Int. J. Mol. Sci. 2021, 22, 905 tent infection and its pathogenic significance in these patients5 of 12 [26,27]. It is very important to shed light on the possible involvement of persistent infection in the pathogenic condition of glomerulonephritis, because this factor is potentially mod- a year) has been observed in some IRGN patients, suggesting persistent infection and its pathogenicifiable. signiﬁcanceUsing NAPlr in these and patients plasmin [26,27]. activity as biomarkers, the pathogenic involvement of persistentIt is very important infection to shed can light be on detected. the possible If involvement these biomarkers of persistent infection are persistently in positive, the most the pathogenic condition of glomerulonephritis, because this factor is potentially modiﬁable. Usingimportant NAPlr and therapeutic plasmin activity strategy as biomarkers, would the pathogenic be to er involvementadicate the of persistent persistent and pathogenic infec- infectiontion, which can be detected. may Ifresult these biomarkers in blocking are persistently the transi positive,tion the of most IRGN important to CKD. Indeed, Noda et al. therapeutic strategy would be to eradicate the persistent and pathogenic infection, which mayrecently result in reported blocking the transitionan interesting of IRGN to IRGN CKD. Indeed, case Noda caused et al. recentlyby asymptomatic reported sinusitis, which sug- angests interesting the IRGNimportance case caused of by asymptomaticdetecting the sinusitis, hidden which suggestsinfection the importance by histological staining of NAPlr ofand detecting plasmin the hidden activity. infection Eradication by histological stainingof the ofhidden NAPlr and but plasmin pathogenic activity. infection in this patient Eradication of the hidden but pathogenic infection in this patient resulted in clinical remissionresulted of thein diseaseclinical (Figure remission3)[36]. of the disease (Figure 3) [36].

FigureFigure 3. Photomicrographs 3. Photomicrographs of histological of histologic staining for C3,al staining NAPlr, and for plasmin C3, activityNAPlr, in and the plasmin activity in the glomeruli of a patient with infection-related glomerulonephritis (IRGN) induced by asymptomatic sinusitisglomeruli [36]. Although of a patient the infection with was infection-related clinically inapparent, glom doubleerulonephritis IF staining for NAPlr (IRGN) (ﬂuo- induced by asymptomatic resceinsinusitis isothiocyanate, [36]. Although green) and the C3 (Alexa infection Fluor 594, was red) clinically with nuclear inapparent, staining for DAPI double (blue) IF staining for NAPlr (fluo- showedrescein glomerular isothiocyanate, deposition of green) NAPlr andand C3 C3 (A). (Alexa Furthermore, Fluor glomerular 594, red) plasmin with activity nuclear staining for DAPI (blue) assessedshowed by inglomerular situ zymography deposition on a serial sectionof NAPlr demonstrated and C3 a similar(A). Furthermore, distribution as NAPlr glomerular plasmin activity deposition, providing histological evidence for the substantial involvement of bacterial infection in theassessed development by ofin glomerulonephritis situ zymography (B). on a serial section demonstrated a similar distribution as NAPlr deposition, providing histological evidence for the substantial involvement of bacterial infection in theThe development histological transition of glomerulonephritis from endocapillary (B proliferative). glomerulonephritis to MPGN is also observed in some cases of viral IRGN. Indeed, we encountered a patient in which the ﬁrst renal biopsy showed endocapillary proliferative glomerulonephritis typical ofThe AGN histological associated with transition parvovirus B19from (PVB19) endocapi infection,llary and inproliferative the second glomerulonephritis to biopsy, which was performed 4 years subsequently because of persistent proteinuria andMPGN prolonged is also low serum observed complement in some C3 level cases with positivityof viral for IRGN. the IgM Indeed, antibody forwe encountered a patient in PVB19which (persistent the first PVB19 renal infection), biopsy showed showed MPGN with endocapillary mesangial interposition proliferative and with glomerulonephritis typi- thickeningcal of AGN and double associated contours ofwith the glomerular parvovirus basement B19 membrane (PVB19) (GBM) infection, [37]. This and in the second biopsy, case provides lines of evidence that the transition from acute endocapillary proliferative glomerulonephritiswhich was performed to MPGN can 4 actually years occur subsequently during prolonged be infection.cause of persistent proteinuria and pro-

3.longed Genetic Backgroundlow serum of the complement Host’s Complement C3 level Regulatory with System positivity as a Possible for the IgM antibody for PVB19 Cause(persistent of the Progression PVB19 ofinfection), IRGN into CKD showed MPGN with mesangial interposition and with thick- eningThere and have double been several contours reports of patientsof the whoglomerular have acute nephritic basement syndrome membrane with (GBM) [37]. This case preceding streptococcal infection, diagnosed initially as having PSAGN, but owing to theprovides persistence lines of hypocomplementemia of evidence that and the urinary transiti abnormalities,on from genetic acute testing endocapillary of proliferative glo- themerulonephritis alternative complement to MPGN pathway wascan performed, actually and occur a genetic during abnormality prolonged in the infection.

3. Genetic Background of the Host’s Complement Regulatory System as a Possible Cause of the Progression of IRGN into CKD There have been several reports of patients who have acute nephritic syndrome with preceding streptococcal infection, diagnosed initially as having PSAGN, but owing to the

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complement regulatory system was eventually identified, leading to the final diagnosis of C3 glomerulopathy [38,39]. These cases suggest that in the presence of an abnormal genetic background of the host’s complement system, the pathogenic mechanism of glomerulonephritis associated with complement activation induced by infection continues, which may turn PSAGN into persistent smoldering nephritis causing C3 glomerulopathy, leading to the development of CKD without resolution. As the disease entity and the diagnostic criteria for both diseases (IRGN and C3 glomerulopathy) are not yet fully established, patients with a similar condition have also been reported as having atypical post-infectious glomerulonephritis (PIGN) [12]. In this previous report, 11 patients with so-called atypical PIGN were analyzed and 4 of them were found to have genetic abnormalities in the regulatory system of the alternative complement pathway (3 had a mutation in CFH, and 1 in CFHR5). In this setting, the pathogenic mechanism associated with complement activation inducing glomerulonephritis persists not because of persistent infection but because of the host’s characteristic genetic background regarding the complement regulatory system, and abnormalities in urinalysis and low serum complement levels continue without normalization, leading to the subsequent progression into chronic glomerulonephritis. Considering the rapid recent advances in the development of medications that con- trol complement activation, such as eculizumab and avacopan, this factor may also be potentially modifiable in the future, using appropriate complement-regulating medications.

4. Continuous Tubulointerstitial Changes Independent of Glomerular Changes as a Possible Cause of the Progression of IRGN into CKD In 1961, Jennings and Earle [40] reported that the degree of interstitial reaction is one of the main factors determining whether PSAGN becomes chronic or not. Similar findings have actually been reported more generally, i.e., the progression of glomerular disease correlates more closely with interstitial lesions than with glomerular lesions [41–44]. In association with these observations, there have been reports indicating that an increase in the number of interstitial alpha-smooth muscle actin (α-SMA)-positive cells, which are believed to be myofibroblasts, is a good marker of disease progression in various types of human glomerulonephritis, including IgA nephropathy [45], membranous nephropathy [46], and diabetic nephropathy [47]. We therefore analyzed the α-SMA expression immunohistochemically, using a monoclonal antibody against α-SMA and renal biopsy tissues sampled repeated from 6 PSAGN patients, 3 of whom progressed into CKD, and 3 who were cured. Glomerular mesangial cells have been reported to show an α-SMA-positive phenotype, with cell activation or proliferation in both experimental and human glomerulonephritis [48]. Consistent with the report, prominent glomerular α-SMA expression was observed in all six tissues of patients in the acute phase of PSAGN, irrespective of disease prognosis, whereas glomerular α-SMA expression was uniformly minimal or absent in tissues of patients in the convalescent phase (Table2, Figure4). Namely, there was no significant difference in glomerular α-SMA expression between those who progressed into CKD and those who were cured, both in the acute phase and in the convalescent phase. Interstitial α- SMA expression was also generally upregulated in acute phase tissues, but the expression was more prominent in tissues of patients who progressed into CKD than in the cured patients, and this tendency persisted in the convalescent phase. These data indicate that glomerular α-SMA expression appears to be a reversible and transient phenomenon, and levels return to the steady state irrespective of the disease prognosis. In contrast, interstitial α-SMA expression appears to be associated with the development of chronic disease. Int. J. Mol. Sci. 2021, 22, 905 7 of 12

Table 2. Alpha-smooth muscle actin staining scores of renal biopsy tissues sampled repeatedly from 6 PSAGN patients and their characteristics.

Acute Phase: Convalescent Phase: Glomerular Staining Score Interstitial Staining Score Patient Age Duration between Duration between Second Second (Years) Onset to First Onset to Second First Biopsy First Biopsy Biopsy (Days) Biopsy (Years) Biopsy Biopsy Progression into CKD 39.3 ± 6.0 19.7 ± 9.9 3.0 ± 1.0 2.7 ± 1.2 0.7 ± 0.6 3.7 ± 0.6 3.0 ± 1.0 (n = 3) Cured 35.7 ± 7.8 23.3 ± 12.1 5.1 ± 4.5 3.0 ± 1.0 0.7 ± 0.6 2.7 ± 0.6 1.7 ± 0.6 (n = 3) PSAGN: poststreptococcal acute glomerulonephritis; CKD: chronic kidney disease. Data are expressed as the mean ± SD. Sections stained Int. J. Mol. Sci.for 2021α-SMA, 22 as, x described FOR PEER in Figure REVIEW4 were evaluated as follows. Glomerular staining intensities were semiquantitatively graded as 0 to 4, 7 of 12 as previously reported by Alpers et al. [48], whereas interstitial staining intensities were graded semiquantitatively as 1 to 4 using the following scale: 1 = positive area < 10%; 2 = 10% to 20%; 3 = 20% to 30%; 4 ≥ 30%.

FigureFigure 4. Immunoperoxidase 4. Immunoperoxidase staining staining fo forr alpha-smoothalpha-smooth muscle muscle actin actin (α-SMA) (α-SMA) with methyl with methyl green counterstaining green counterstaining in in re- peatedrepeated renal biopsy renal biopsy sections sections from from the the acute phase phase and and the the convalescent convalescent phase ofphase a PSAGN of a patientPSAGN who patient developed who chronic developed chronic kidneykidney disease disease (CKD), (CKD), and and a a PSAGN PSAGN patient patient who who was was cured. cured. Strong Strong positive positive staining ofstainingα-SMA inof theα-SMA mesangial in the area mesangial of area of the glomerulithe glomeruli was was observed observed in in tissues of of PSAGN PSAGN patients patients in the in acute the phaseacute irrespective phase irresp of diseaseective prognosis,of disease and prognosis, this and this glomerularglomerular staining staining diminished diminished uniformly in in the the convalescent convalescent phase phase irrespective irresp ofective disease of prognosis. disease Interstitialprognosis.α-SMA Interstitial α-SMA stainingstaining was wasmore more intense intense in in the the PSAGN patient patient who who developed developed CKD than CKD in thethan patient in the who pa wastient cured, who both was in cured, the acute both in the acute phasephase and andin the in the convalescent convalescent phase.phase. For For the th indirecte indirect immunoperoxidase immunoperoxidase staining for stainingα-SMA, a for mouse α-SMA, monoclonal a mouse antibody monoclonal antibody (clone(clone 1A4) 1A4) was was used used as the as primary the prim antibody,ary antibody, and a peroxidase-conjugated and a peroxidase-conjugated goat anti-mouse goat IgG antibody anti-mouse was used IgG as antibody the was used secondary antibody. as the secondary antibody. Thus, from the view of long-term renal prognosis, it is obvious that tubulointerstitial Table 2. Alpha-smooth musclechanges actin arestaining more importantscores of renal than glomerularbiopsy tissues changes sampled in PSAGN. repeatedly However, from although6 PSAGN patients and their characteristics. PSAGN is clearly a glomerular disease, the precise mechanism as to how tubulointerstitial changes develop in PSAGN has not been fully elucidated. Regarding this point, results fromAcute our Phase: previous Convalescent study on proliferating Glomerular cells in PSAGN Staining tissues Score is informative Interstitial [23]. Staining In Score thisDuration previous study,Phase: we foundDuration a prominent increase in proliferating cell nuclear antigen Patient Age between(PCNA)-positive Onset between cells in kidney Onset tissues of PSAGN patients, but the distribution of the (years) First Biopsy Second Biopsy First Biopsy Second Biopsy toPCNA-positive First Biopsy cellsto was Second irregular (Figure5). This suggested that in PSAGN, locally produced growth factors, rather than circulating factors, act on the glomerular cells and (days) Biopsy (years) subsequently the adjacent tubular epithelial cells of the nephron. This means that speciﬁc Progression into 39.3 ± 6.0 factors 19.7 produced± 9.9 in the 3.0 glomeruli ± 1.0 ﬁltrate 2.7 into ± 1.2 the urine and 0.7 damage ± 0.6 the tubular 3.7 ± epithelial0.6 3.0 ± 1.0 CKD (n = 3) Cured 35.7 ± 7.8 23.3 ± 12.1 5.1 ± 4.5 3.0 ± 1.0 0.7 ± 0.6 2.7 ± 0.6 1.7 ± 0.6 (n = 3) PSAGN: poststreptococcal acute glomerulonephritis; CKD: chronic kidney disease. Data are expressed as the mean ± SD. Sections stained for α-SMA as described in Figure 4 were evaluated as follows. Glomerular staining intensities were semiquantitatively graded as 0 to 4, as previously reported by Alpers et al. [48], whereas interstitial staining intensities were graded semiquantitatively as 1 to 4 using the following scale: 1 = positive area < 10%; 2 = 10% to 20%; 3 = 20% to 30%; 4 = > 30%. Thus, from the view of long-term renal prognosis, it is obvious that tubulointerstitial changes are more important than glomerular changes in PSAGN. However, although PSAGN is clearly a glomerular disease, the precise mechanism as to how tubulointerstitial changes develop in PSAGN has not been fully elucidated. Regarding this point, results from our previous study on proliferating cells in PSAGN tissues is informative [23]. In this previous study, we found a prominent increase in proliferating cell nuclear antigen (PCNA)-positive cells in kidney tissues of PSAGN patients, but the distribution of the PCNA-positive cells was irregular (Figure 5). This suggested that in PSAGN, locally produced growth factors, rather than circulating factors, act on the glomerular cells and subsequently the adjacent tubular epithelial cells of the nephron. This means that specific factors produced in the glomeruli filtrate into the urine and damage the tubular epithelial cells from the apical side. The damaged and activated PCNA-positive tubular epithelial cells may then affect the interstitial cells.

Int. J. Mol. Sci. 2021, 22, 905 8 of 12

Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 8 of 12 cells from the apical side. The damaged and activated PCNA-positive tubular epithelial cells may then affect the interstitial cells.

Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 8 of 12

FigureFigure 5. Immunoperoxidase 5. Immunoperoxidase staining for staining proliferating for cell proliferatin nuclear antigeng (PCNA)cell nuclear and counter- antigen (PCNA) and counter- stainingFigure 5. with Immunoperoxidase methyl green in staining a renal biopsy for proliferatin tissue fromg cell a PSAGNnuclear patientantigen (original(PCNA) and magnification, counter- stainingstaining with with methyl methyl green in agreen renal biopsy in a tirenalssue from biopsy a PSAGN tissue patient from (original a PSAGN magnification, patient (original magnification, ×100) [23]. Prominent expression of PCNA in the glomerulus and tubular epithelial cells was ob- ×100)×100) [23]. [23]. Prominent Prominent expression expression of PCNA in the of glomerulus PCNA inand the tubular glomerulus epithelial cells and was tubularob- epithelial cells was observed. The distribution of PCNA-positive cells was variable; i.e., there was a considerable difference served.served. The The distribution distribution of PCNA-p ofositive PCNA-p cells wasositive variable; cells i.e., there was was variable; a considerable i.e., differ- there was a considerable differ- inence the in number the number of PCNA-positive of PCNA-positive cells cells between between each each glomerulus glomerulus and and between between different different parts parts of theofence the tubules. tubules. in the number of PCNA-positive cells between each glomerulus and between different parts of theAlternatively, tubules. interstitial inflammation developing from the vascular pole of the Alternatively, interstitial inflammation developing from the vascular pole of the glo- glomeruli via the spread of massive glomerular inflammation may affect the adjacent meruli via the spread of massive glomerular inflammation may affect the adjacent tubular tubular epithelial cells, inducing PCNA in the damaged tubules, as shown in Figure6. epithelialAlternatively, cells, inducing PCNA interstitial in the damaged inflammation tubules, as shown developing in Figure 6. from the vascular pole of the glomeruli via the spread of massive glomerular inflammation may affect the adjacent tubular epithelial cells, inducing PCNA in the damaged tubules, as shown in Figure 6.

FigureFigure 6.6. StainingStaining ofof infiltratinginfiltrating cells and PCNA in serial sections of renal biopsy tissue tissue from from a a pa- patient with PSAGN. Double staining for neutrophils (chloroesterase staining: blue) and macro- tient with PSAGN. Double staining for neutrophils (chloroesterase staining: blue) and macrophages phages (immuno-alkaline phosphatase staining for CD11c: red) demonstrated extensive glomeru- (immuno-alkaline phosphatase staining for CD11c: red) demonstrated extensive glomerular infil- lar infiltration of both cell types, which spread out from the vascular pole (circled region) (A). Tub- trationular epithelial of both cells cell types,of the same which region spread (circled out from) showed the vascular positive polePCNA (circled staining region) (immunoperoxi- (A). Tubular epithelialdase staining: cells brown) of the sameon a serial region section (circled) (B). showed Details of positive all the PCNAstaining staining methods (immunoperoxidase have been de- staining:scribed previously brown) on [22]. a serial section (B). Details of all the staining methods have been described previously [22]. Tubulointerstitial changes that develop in this manner persist in the absence of glo- merularFigureTubulointerstitial inflammation, 6. Staining changesandof infiltrating may thatcontribute develop cells to the in and thisprogression PCNA manner inof persist PSAGN.serial in sections the absence of ofrenal biopsy tissue from a glomerularpatientThe abovewith inflammation, PSAGN.findings andare Double somewhat may contribute staining consistent to thefor progression withneutro the philsrecent of PSAGN. (chloroesterase reports on the im- staining: blue) and macro- portancephages of (immuno-alkaline proximal tubular injury phosphat and its limitedase staining regenerative for propertiesCD11c: red)on the demonstrated transi- extensive glomeru- tion of AKI into CKD [49–51]. lar infiltrationIt may be possible of both to assess cell the types, involvement which of spre this adfactor, out tubulointerstitial from the vascular changes, pole (circled region) (A). Tub- byular the epitheliallevel of interstitial cells ofα-SMA the expression;same region however, (circled at present,) showed there positiveare no established PCNA staining (immunoperoxi- therapeuticdase staining: strategies brown) that potentially on a serial modify section this factor. (B). DetailsThe development of all the of medicationstaining methods have been de- that modifies interstitial fibrosis, the final common pathway, are expected in the future. scribed previously [22].

Tubulointerstitial changes that develop in this manner persist in the absence of glomerular inflammation, and may contribute to the progression of PSAGN. The above findings are somewhat consistent with the recent reports on the importance of proximal tubular injury and its limited regenerative properties on the transition of AKI into CKD [49–51]. It may be possible to assess the involvement of this factor, tubulointerstitial changes, by the level of interstitial α-SMA expression; however, at present, there are no established therapeutic strategies that potentially modify this factor. The development of medication that modifies interstitial fibrosis, the final common pathway, are expected in the future.

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The above findings are somewhat consistent with the recent reports on the importance of proximal tubular injury and its limited regenerative properties on the transition of AKI into CKD [49–51]. It may be possible to assess the involvement of this factor, tubulointerstitial changes, by the level of interstitial α-SMA expression; however, at present, there are no established therapeutic strategies that potentially modify this factor. The development of medication that modifies interstitial fibrosis, the final common pathway, are expected in the future.

5. Pre-Existing Kidney Injury as a Possible Cause of the Progression of IRGN into CKD This factor represents adults with pre-existing comorbidities, such as nephrosclerosis or diabetic kidney disease, which may prevent them from achieving a complete recov- ery [4,13]. In fact, these cases should not be regarded as a transition from IRGN to CKD, because CKD actually exists before the onset of IRGN as a hidden condition. In addi- tion, the onset of IRGN demonstrates the existing but hidden condition of CKD. As this factor is also potentially modiﬁable, doctors should focus on controlling the pre-existing comorbidities.

6. Detection of Autoantibodies in IRGN Patients ANCA, especially PR3-ANCA, has been reported to be detected in patients with IRGN, particularly that caused by infective endocarditis [14–17]. There have also been reports of lupus-like symptoms in patients with some viral IRGN, such as parvovirus B19 [18,19] and CMV IRGN [20], with the appearance of ANA and anti-dsDNA antibodies. Furthermore, the presence of anti-factor B autoantibodies has recently been reported in patients with acute PIGN [21]. However, these were mostly reports of a small number of cases, and analyses of a large number of cases or prospective studies have not been reported to date. Furthermore, there appears to be a marked difference in outcomes depending on the report regarding the association between the appearance of autoantibodies and the prognosis of IRGN. Thus, the effect of the presence of autoantibodies on the prognosis of IRGN remains unclear, and is a matter of future investigation.

7. Concluding Remarks IRGN is still considered to be one of the major causes of AKI, and the transition from IRGN to CKD has consistently been a focus of attention. In this review, we therefore summarized the possible factors contributing to the transition from IRGN to CKD. Regarding the persistence of infection, positive glomerular staining for NAPlr and associated plasmin activity can be used as general histological markers. If these markers are persistently positive, eradication of the infection is the most important therapeutic strategy to stop the transition of IRGN to CKD. Understanding the possible involvement of the genetic background of the host’s complement system and pre-existing comorbidities is also important, because both factors are potentially modiﬁable. Regarding the tubulointerstitial changes, interstitial α-SMA staining was suggested to be useful for its assessment in IRGN patients. However, the precise mechanism underlying the association of glomerular damage and tubulointerstitial changes with α-SMA expression remains unknown. Furthermore, it is not known how tubulointerstitial change can be modiﬁed, and this is an important matter for future investigation.

Author Contributions: T.O. wrote the ﬁrst draft. N.Y. contributed by critically reviewing and revising the manuscript. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Informed consent was obtained from all subjects involved in the study. Int. J. Mol. Sci. 2021, 22, 905 10 of 12

Data Availability Statement: The data presented in this study are available upon request. Conﬂicts of Interest: The authors declare that they have no conﬂict of interest associated with this manuscript.

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