Beyond the Differences in Tonsillectomy in IgA Nephropathy: From Rationale To Indications in Patients

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© Springer Japan 2016

Yasuhiko Tomino (ed.)Pathogenesis and Treatment in IgA Nephropathy10.1007/978-4-431-55588-9_18

18. Beyond the Differences in Tonsillectomy in IgA Nephropathy: From Rationale To Indications in Patients

Yusuke Suzuki1   , Rosanna Coppo2  and Yasuhiko Tomino1

Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan

Nephrology, Dialysis and Transplantation, Regina Margherita Children’s University Hospital, Piazza Polonia 94, 10126 Turin, Italy
Yusuke Suzuki
 Contributed equally
In the special symposiums on IgA nephropathy (IgAN) (Symposium 3, IgAN Basic; Symposium 4, IgAN Clinical/KDIGO) at the last Asian Pacific Congress of Nephrology (APCN) 2014 in Tokyo, discussion by expert nephrologists from Asian and Western countries revealed how actual clinical practices in IgAN, including timing of renal biopsy and choices of treatments, are different, despite evidence-based guidelines. In particular, indication for tonsillectomy with or without steroid pulse therapy for IgAN patients is markedly different between Asian and European-American practices. The tonsillectomy is considered to be old-fashioned in Western countries, while it is still widely accepted in Asian countries such as Japan and China. The present chapter discusses rationale of tonsillectomy, with up-to-date understanding of IgAN pathogenesis, and summarizes the actual difference in the IgAN practice with respect to tonsillectomy with or without steroid pulse therapy, such as clinical stages at the intervention, based on some key papers from Asian and Western countries. In addition, we attempt to identify the medical and social causes behind these differences.

TonsillectomySteroid pulse therapyMucosal immunityGalactose-deficient IgARandomized clinical trial

1st and 2nd authors equally contributed to this work.

18.1 Introduction

The hallmark of IgA nephropathy (IgAN), well known to every medical student, is macroscopic hematuria, which is coincident with or immediately following acute tonsillitis [1]. This presentation is very common; therefore, patients with recurrence of such episodes receive a likely diagnosis of IgAN even without a renal biopsy detecting IgA in the mesangial area. Tonsillectomy was traditionally considered the treatment of choice for patients with IgAN, and reduction in the frequency of episodes of macroscopic hematuria is commonly observed when recurrent bacterial tonsillitis is cured via tonsillectomy [2]. However, it became clear that repeated episodes of gross hematuria do not represent a sign of progression and not a risk factor of IgAN [3]. Relentless progression is frequently associated with persistent heavy hematuria, particularly proteinuria [4]. This finding suggests that less clinical benefit of tonsillectomy is observed in IgAN patients than that expected. On the other hand, in Japan, only 10 % of IgAN patients are detected by episodic macroscopic hematuria, while 70 % IgAN patients are detected by chance microscopic hematuria in annual screening via urinalysis. This clinical fact clearly indicates that hematuria is an initial and essential manifestation of IgAN. However, the degree of proteinuria presents a greater risk for progressive IgAN than that of hematuria [4, 5]. These observations are reasonable because glomerular injury events leading to hematuria may precede those leading to persistent proteinuria in IgAN. Previous epidemiological studies assessing risk factors for CKD [6, 7] further support the idea that hematuria precedes proteinuria. Therefore, it is not surprising that proteinuria is a stronger predictor of IgAN progression than episodic macroscopic hematuria [5].
In addition to causing a debate over the clinical outcome of tonsillectomy, these observations had different effects on clinical practice all over the world. In Western countries, such as Europe and the USA, tonsillectomy is considered to be old-fashioned, while it is still widely used in Japan and China.

18.2 Comparison of Different Clinical Practices for Tonsillectomy in IgA Nephropathy

In the special symposiums on IgAN at the last Asian Pacific Congress of Nephrology (APCN) 2014 in Tokyo (President: Prof. Yasuhiko Tomino), Asian and European nephrologists discussed the differences in clinical practice of IgAN treatment in their respective countries as well as up-to-date understanding of IgAN pathogenesis. This discussion revealed how actual clinical practices, including timing of renal biopsy and choices of treatments, are different, despite evidence-based guidelines. Indication for tonsillectomy [often associated with steroid pulse therapy] is markedly different between Asian and European-American practices. This debate was followed by a blog discussion launched by NDT-Educational. Here we summarize the actual difference in the IgAN practice with respect to tonsillectomy and attempt to identify the medical and social causes behind this difference.

18.3 The Rationale for Tonsillectomy in IgA Nephropathy Is Debated

One can speculate that tonsillectomy represents an easy means to eliminate a pathogen source. However, several studies suggest that abnormalities of the mucosal-associated lymphoid tissue (MALT) are critical for the development of IgAN, with infections representing the simple role of triggering an event [1]. Experimental IgAN can be produced in animals after abrogation of the natural process of mucosal tolerance, which favors the host defense against pathogens [8]. In this context, IgAN is likely to develop because of a failure of mucosal antigen elimination and altered IgA synthesis, leading to the production of nephritogenic IgA. On the other hand, studies with experimental IgAN also demonstrated that chronic mucosal infection is not required for nephritogenic IgA production [9]. Moreover, transient mucosal activation of a pattern recognition receptor (PRR), such as Toll-like receptor (TLR), by pathogen-associated molecular patterns in IgAN-prone mice is sufficient to exacerbate this disease with rapid serum elevation of IgA [9, 10]; this suggests that preexisting mucosal B-cell clones produce nephritogenic IgA. Palatine tonsils have a unique cellular composition in the reticulated subepithelium, which is ideal for productive antigen sampling. One of the most important characteristics of the palatine tonsils is that very rich B-cell lymphoid follicles at the subepithelial space foster the development of memory B cells and plasma cells. This is very different from other tonsils in Waldeyer’s ring. Japanese nephrologists and otolaryngologists are aware that the beneficial effect of tonsillectomy in IgAN patients is independent of the size of the palatine tonsils and the presence of abscesses. Therefore, if the responsible B cells producing nephritogenic IgA are localized in the palatine tonsils, tonsillectomy may abrogate mucosal antigen encounters to such B cells, even if not chronic, leading to acute elevation of nephritogenic serum IgA [9, 10] and their clonal expansion [11].
It is now accepted that galactose-deficient IgA1 (GdIgA1) and GdIA1 and immune complexes (IC) with endogenous antiglycan antibodies are essential nephritogenic molecules initiating IgAN [12, 13]. Although there is no study clearly demonstrating the type of mucosal B cells involved, the recent studies revealed that the palatine tonsils are, at least in part, delivery sources of GdIgA1 under abnormal cytokine conditions [1418]. Total IgA is decreased by 10 % on average after tonsillectomy alone in IgAN patients; because patients who showed tonsillar activation of innate immunity and a large decrease of serum IgA after the tonsillectomy had a better clinical outcome, it was thought that the palatine tonsils may be the major delivery source of nephritogenic IgA [19]. One recent study directly demonstrated that tonsillectomy alone rapidly decreased serum levels of GdIgA1 in patients who showed rapid improvement of hematuria after this therapy [20].
However, when considering tonsillectomy for reducing MALT surface, we should consider that tonsils represent only 0.5 m2 of the entire 400 m2 of the total mucosal surface in humans. In a recent study [21], IgAN patients who underwent tonsillectomy showed a long-term reduction, but not normalization, of GdIgA1, signs of persistently activated MALT, ongoing oxidative stress, and increased expression of TLR4. The ligand of TLR4 is lipopolysaccharide (LPS), produced by gram-negative intestinal bacteria. Notably, a correlation was found between progressive cases of IgAN and genetic polymorphism of the membrane receptor for LPS (CD14–159). A renewed interest toward intestinal immunity has been recently raised by a genetic-wide association study (GWAS), showing a strong association between IgAN and genes of intestinal MALT response [22]. These recent data, together with past reports on the role of dietary antigens in IgAN [23], tend to limit the extent of the rationale for tonsillectomy in patients with IgAN.
In contrast, other studies further supported tonsillectomy in nephropathy because serum levels of IgA and GdIgA1 were found to be correlated with tonsillar TLR9 overexpression [19, 20], and the TLR9 genotype was strongly associated with histological severity of IgAN [9]. Patients who did not show a decrease in GdIgA1 after tonsillectomy did so after the first additional steroid pulse therapy with improvement of hematuria, indicating GdIgA1 production outside the tonsils [20]. This finding suggests that some parts of the responsible cells producing GdIgA1 in such patients may be disseminated to MALT other than the tonsils and other lymphoid organs such as the bone marrow or spleen [24, 25]. It is known that tonsillectomy with steroid pulse therapy (TSP) leads to a better clinical outcome than tonsillectomy alone [26]. These clinical and experimental findings suggest that additional steroid pulse therapy on tonsillectomy may target these disseminated extratonsillar responsible cells [27].

18.4 The Clinical Effects of Tonsillectomy in IgA Nephropathy Are Difficult to Assess Using Randomized Controlled Trials

In the absence of large series studies or randomized clinical trials (RCTs), nephrologists in Western countries tend to consider tonsillectomy in IgAN as a procedure to be performed only in patients with macroscopic hematuria and clinically evident recurrent tonsillitis. However, in eastern countries tonsillectomy continues to be regularly performed. In 2003, a breakthrough report by Xie et al. from Japan resurrected the interest for tonsillectomy in IgAN because for the first time, the procedure was associated with a better outcome at long-term follow-up [28]. A Japanese retrospective analysis of 118 patients reported a significant effect of tonsillectomy on survival from dialysis.
Here, the scientific conflict regarding the benefits of tonsillectomy between Western and Asian countries began. In Europe, retrospective analyses of single medical centers showed negative results in tonsillectomy [29, 30]. However, reports from Japan showed a benefit of tonsillectomy, particularly with steroid pulse therapy versus steroid therapy alone [3133]. A benefit of tonsillectomy was also shown in IgAN recurrent in grafted kidneys while receiving a standard immunosuppressive regimen [34].
A recent RCT including 72 cases of IgAN in Japan was conducted. The patients received methylprednisolone pulse alone or in combination with tonsillectomy; some positive effects in reducing proteinuria at 1-year follow-up were observed [35

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