Does tonsillectomy have a role in the treatment of patients with immunoglobulin A nephropathy?

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Immunoglobulin A nephropathy (IgAN) is an immune-complex mediated glomerulonephritis characterized by deposition of polymeric IgA (mainly IgA1) in the mesangium of the kidney [1]. It is the most common form of primary glomerulonephritis worldwide and is prevalent among all ages and racial demographics [2]. Its pathogenesis has been under investigation for the last several decades and one of the key players is the aberrant glycosylation pattern of IgA1. There is now convincing evidence that the hinge region of IgA1 heavy chain has defective glycosylation with a reduction in the galactose and or sialic acid residues [3]. As a result, the N-acetylgalactosamine in the IgA1 hinge region is exposed and recognized by IgG antibodies. This in turn leads to formation of IgG-IgA immune complexes and their deposition in the mesangium and renal injury that subsequently ensues [4–7]. It should be noted that aberrantly glycosylated IgA1 can also be seen in circulation in normal subjects following an immune response triggered by exposure to mucosal antigens such as food, bacteria or viruses. Thus, other factors, including genetic predisposition, are likely to influence the pathogenesis of IgAN [8]. The renal outcomes of IgAN vary significantly between individuals ranging from minimal proteinuria and stable renal function to development of end-stage renal disease (ESRD) in up to 50% of the cases [9]. Markers of poor prognosis include impaired kidney function at presentation, hypertension and persistent proteinuria >1 g/day in adults, and 0.5 g/day in children [10–12]. In addition, the recent Oxford classification has identified MEST (mesangial hypercellularity, endocapillary hypercellularity, segmental glomerulosclerosis, tubular atrophy/interstitial fibrosis) as an independent renal biopsy indicator of poor renal outcome [13]. Treatments aiming to block the angiotensin II system, the use of corticosteroids, either alone or in combination with cytotoxic medications have been used in patients with IgAN with variable success [14–18]. In some patients, renal disease progresses despite treatment and thus a search for additional forms of therapy have been carried out including the use of tonsillectomy. What is the rationale behind performing tonsillectomy in patients with IgA nephropathy? First, recurrent tonsillitis is the most common extrarenal clinical manifestation in IgAN and there is a clear recognition that in some patients episodes of macroscopic hematuria and proteinuria are often associated with tonsillitis (synpharyngitic hematuria) [19, 20]. In fact, studies have shown that episodes of macroscopic hematuria can be reduced following tonsillectomy [21, 22]. Second, tonsils provide the first line of defense against inhaled pathogens. The foreign antigens, particularly bacterial polysaccharides, activate the Toll-like receptors (TLRs) of the cells of innate immunity, which ultimately results in activation of tonsillar B-cells and production of immunoglobulins particularly polymeric IgA1. Third, tonsils from patients with IgAN have an increased number of polymeric IgA1 compared with controls [23]. Forth, the polymeric IgA1 deposited in the kidney are, in part, of tonsillar origin. This was based on the evidence that IgA1 eluted from the mesangium of patients with IgAN specifically bound the nuclear regions of tonsillar cells obtained from the same patient and the binding was completely inhibited by the addition of antihuman IgA sera [24]. Fifth, abnormal IgA-secreting cells which predominantly produce polymeric IgA1 are found in the tonsillar tissue of patients with IgAN in contrast to IgG-secreting cells that predominate in tonsils of patients without IgAN [20, 25–27]. Taken together, it has been postulated that chronic tonsillitis in a susceptible patient may lead to increased production of aberrantly glycosylated IgA1, formation of IgG-IgA immune complexes and their deposition in the glomeruli triggering an inflammatory response [28]. As such, tonsillectomy has been suggested as a possible treatment modality in patients with IgAN. Several retrospective studies have evaluated the efficacy of tonsillectomy in treatment of IgAN with conflicting results as shown in Table 1 [21, 22, 29–35]. Most of the studies, however, are from an era prior to routine use of renin-angiotensin system (RAS) blockade and/or concomitant corticosteroid therapy. Summary of non-randomized studies evaluating the efficacy of tonsillectomy in treatment of patients with IgAN CR, complete remission. aThis is for the entire group of patients which included 121 patients with mesangial glomerulonephritis in addition to those with IgAN. bThis is median with minimum and maximum range. Summary of non-randomized studies evaluating the efficacy of tonsillectomy in treatment of patients with IgAN CR, complete remission. aThis is for the entire group of patients which included 121 patients with mesangial glomerulonephritis in addition to those with IgAN. bThis is median with minimum and maximum range. In the only prospective non-randomized trial, Komatsu et al. found an increased rate of clinical remission in patients with IgAN when tonsillectomy was combined with pulse steroids suggesting a possible role for tonsillectomy [21]. Similarly in a meta-analysis by Wang et al. in which seven retrospective studies were included, there appeared to be a beneficial effect for tonsillectomy when it was combined with steroids [36]. Importantly, in some of these studies, the beneficial effect of tonsillectomy was not seen until 5–10 years after the procedure [22, 32]. Currently, even though tonsillectomy is not recommended as part of treatment of IgAN by Kidney Disease: Improving Global Outcomes Guidelines [12], tonsillectomy remains a common practice in Japan [37]. Given that tonsillectomy is not without risks, there has remained a definite need for a randomized clinical trial (RCT) to evaluate the role of tonsillectomy in treatment of IgAN. In the current issue of NDT, Kawamura et al. report the results of the first randomized controlled trial of tonsillectomy combined with pulse steroids in treatment of patients with IgAN [38]. Eighteen centers across Japan participated in this study and total of 80 patients were recruited. Patients were randomized into two groups and followed for 12 months. Group A underwent tonsillectomy in addition to pulse steroids (500 mg of intravenous methylprednisolone per day for 3 days at 1 and 3 weeks and then at 2 and 4 months in addition to oral prednisolone at a dose of 0.5 mg/kg for 6 months), whereas Group B only received steroid therapy similar to Group A. Patients with IgAN who presented with nephrotic syndrome, serum creatinine >1.5 mg/dL, or recent immunosuppressive therapy or contra-indications to surgery were excluded. Percentage decrease in urinary protein from baseline and clinical remission defined as disappearance of proteinuria and hematuria were primary end points. Doubling of serum creatinine and change in estimated glomerular filtration rate (eGFR) were secondary end points. There were equal numbers of males and females in the study with mean age of 38 years. The renal function was similar between the groups and well-preserved (mean eGFR of 72 mL/min/1.73 m2). The renal biopsies, however, suggested a relatively poor or a poor prognosis in 95% of the patients with a mean 24-h proteinuria of 1.6 g/day. Only half the patients were on treatment with renin-angiotensin inhibitor (RAS-I) at the time of randomization. At 12 months, patients who underwent tonsillectomy in Group A had a larger percentage decrease in proteinuria compared with Group B. The authors do not provide data on the absolute reduction in the amount of proteinuria in each group or the mean 24-h urinary protein in follow-up, which weakens interpretation of the results. In addition, even though the percentage decrease in the degree of proteinuria was statistically significantly higher in Group A, the actu

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