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Invited Commentary
Nephrology
May 31, 2019

Tonsillectomy for the Management of Immunoglobulin A Nephropathy

Author Affiliations
  • 1Department of Pediatrics, Division of Nephrology, NYU Langone Health, New York, New York
JAMA Netw Open. 2019;2(5):e194755. doi:10.1001/jamanetworkopen.2019.4755

Considering the global burden of disease associated with IgA nephropathy, it is striking how little data are available about effective therapies for patients. Originally, IgA was seen as a benign entity and the mesangial deposits of IgA that characterize the disease were considered an immunological curiosity. But extended clinical observation confirmed that nearly 30% of affected patients will progress to end-stage kidney disease over 20 to 25 years of follow-up. Immunoglobulin A nephropathy initially requires a genetic predisposition toward the synthesis of IgA 1 molecules with deficient galactosylation of the hinge region of the antibody. This triggers production of autoantibodies, formation of immune complexes, deposition in the glomerular mesangium, and initiation of inflammation.1

Based on this understanding of disease pathogenesis, immunosuppressive medications have been a staple in the treatment of patients with IgA nephropathy. However, despite numerous attempts to address the question, the efficacy of corticosteroids and other immunosuppressive drugs remains unproven.1 Tonsillectomy has lurked in the background as a potential treatment to reduce mucosal production of the aberrant IgA 1. There have been trials and a meta-analysis that support the value of this operation.2 However, there were flaws in all these studies and the role of tonsillectomy in the management of IgA nephropathy remains an unsettled question.

Hirano et al3 report a retrospective analysis of outcomes in Japanese adults with IgA nephropathy who underwent a tonsillectomy within a year of the renal diagnosis and compared the course of disease to patients who did not undergo surgery. They took advantage of a national retrospective cohort study of IgA nephropathy and the remarkably high rate of tonsillectomy in Japan. The primary outcome was a combination of either a 1.5-fold increase in serum creatinine level or the initiation of renal replacement therapy. There were 1065 patients in the registry with IgA nephropathy with a diagnostic biopsy performed between 2002 and 2004, of whom 252 underwent tonsillectomy. The median follow-up period was 5.8 years. Several matching protocols were used to achieve balanced clinical features among those who did and did not undergo tonsillectomy. The main finding was that the hazard ratio for the primary outcome, progression of kidney disease, was 0.37 in the tonsillectomy group. In addition, there was a significantly reduced likelihood of prescribing a new renin-angiotensin aldosterone system inhibitor (RASi) or corticosteroid therapy to patients who underwent the procedure. The benefit of tonsillectomy was confirmed in the complete cohort and was independent of baseline characteristics, including estimated glomerular filtration rate (eGFR), proteinuria, degree of hematuria, or prior use of RASi therapy. A key strength of the study was the detailed accounting for administration of corticosteroid use and confirmation of the benefit associated with the procedure regardless of whether patients were treated with oral or intravenous corticosteroids during the follow-up period.

This well-conceived study makes optimal use of a comprehensive registry to assess the benefits associated with a therapeutic intervention. It is not a randomized clinical trial, but the results are clear cut and clinically meaningful. There are some concerns that readers should keep in mind. The primary end point is composed of 2 vastly different events, namely, a modest change in eGFR and initiation of renal replacement therapy. To be sure, in a subgroup analysis, the benefits of tonsillectomy were confirmed in a smaller group of patients (n = 56) who progressed to end-stage kidney disease. The authors do not describe the analytic method(s) used to measure serum creatinine and the procedures that they used to verify the accuracy of the 1.5-fold increment in serum creatinine concentration. Finally, there are no data on the distribution of eGFR or proteinuria to gain a more complete picture of the study cohort.

The period during which the patients were identified is prior to recognition of the need to implement an extended trial of maximum tolerated dose of RASi therapy as first-line treatment of proteinuria.4 Therefore, the impact of tonsillectomy may be blunted in patients treated according to current guidelines. In fact, although the authors assert that tonsillectomy was beneficial regardless of whether patients were prescribed RASi therapy, the magnitude of the benefit was diminished in those already taking these drugs, suggesting that taking stock of what treatment the patient is receiving may influence the recommendation for or against tonsillectomy.

The authors assert that the patient population had mild disease compared with the European Validation Study of the Oxford Classification of IgAN (VALIGA) cohort based on the lower levels of proteinuria and mean arterial pressure.4 However, this is not definitive because the Japanese cohort had a fairly low baseline eGFR and a high percentage of participants reached the primary end point within 6 years of diagnosis. This suggests that the disease severity was not as mild as the investigators claim. More work is required to determine the efficacy of tonsillectomy along the spectrum of disease severity in patients with IgA nephropathy. The introduction of the Oxford classification MEST scoring system (mesangial hypercellularity, endocapillary proliferation, segmental glomerulosclerosis, and tubular atrophy/interstitial fibrosis) to assess histopathological disease severity has greatly improved the stratification of patients with IgA nephropathy.5 Moreover, this instrument adds significant information in formulating a prognosis for individual patients with this primary glomerular disease. It would be useful to assess the impact of tonsillectomy in patients categorized by MEST histopathology categories.

Genetic factors that are unique to an Asian population may influence response to the surgical intervention.6 Mutational analysis of genes related to the alternate pathway of complement that are linked to IgA nephropathy might shed light on which patients are more likely to benefit from tonsillectomy. The authors attribute the benefit of tonsillectomy to a decreased mucosal production of abnormally galactosylated IgA 1 molecules. Although the bacterial composition of the tonsillar crypts is similar in patients with IgA nephropathy and recurrent pharyngitis,7 the composition of the oral subgingival microbiome may be associated with risk of developing IgA nephropathy.8 Tonsillectomy may modify the bacterial environment and act locally to diminish the risk of disease progression in IgA nephropathy. The authors provide no information about the histopathology of the tonsillectomy specimens. The role of tonsillectomy in reducing upper respiratory tract infections and modifying the gut microbiome warrants further study.

However, all that said, the authors should be congratulated on an ingenious approach to assessing the association of tonsillectomy with the progression of IgA nephropathy. Their findings underscore the role of the gastrointestinal mucosa–kidney axis in the pathogenesis of IgA nephropathy and raise the question of where along the gut to target a mucosal intervention. Delivery of budesonide to the distal ileum is associated with reduced proteinuria in patients with IgA nephropathy.9 The tonsils are more accessible and their safe removal may yield a sustained reduction in mucosal IgA 1 production. Tonsillectomy, with or without adenoidectomy, remains one of the most common operative procedures in children. In pediatrics, the indications for tonsillectomy remain controversial. The American Academy of Pediatrics guidelines recommend that obstructive sleep apnea syndrome with adenoidal hypertrophy, malignancy, and recurrent hemorrhage are absolute indications, while recurrent tonsillitis or recurrent peritonsillar abscess are relative indications.10 There is no mention of kidney disease. Should IgA nephropathy be added to this list of relative indications? Tonsillectomy is performed infrequently in adults and there is little literature on its proper use. Should the Boards of Internal Medicine and Otorhinolaryngology weigh in on this topic? The study by Hirano et al3 offers important new evidence to include in these discussions.

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Article Information

Published: May 31, 2019. doi:10.1001/jamanetworkopen.2019.4755

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Trachtman H. JAMA Network Open.

Corresponding Author: Howard Trachtman, MD, Department of Pediatrics, Division of Nephrology, NYU Langone Health, 403 E 34th St, Room 1-02, New York, NY 10016 (howard.trachtman@nyulangone.org).

Conflict of Interest Disclosures: Dr Trachtman reported participation on data monitoring committees for trials for Otsuka and ChemoCentryx, serving as a consultant for clinical trial development for Goldfinch Bio and Retrophin, and participating in discussions with Pfizer about a consultancy to assist in trial design.

Additional Contributions: Laura Malaga-Dieguez, MD, PhD, and David Goldfarb, MD, both of NYU Langone Health, assisted in reviewing this article. They were not compensated.

References
1.
Lafayette  RA, Kelepouris  E.  Immunoglobulin A nephropathy: advances in understanding of pathogenesis and treatment.  Am J Nephrol. 2018;47(suppl 1):43-52. doi:10.1159/000481636PubMedGoogle ScholarCrossref
2.
Duan  J, Liu  D, Duan  G, Liu  Z.  Long-term efficacy of tonsillectomy as a treatment in patients with IgA nephropathy: a meta-analysis.  Int Urol Nephrol. 2017;49(1):103-112. doi:10.1007/s11255-016-1432-7PubMedGoogle ScholarCrossref
3.
Hirano  K, Matsuzaki  K, Yasuda  T,  et al.  Association between tonsillectomy and outcomes in patients with immunoglobulin A nephropathy.  JAMA Netw Open. 2019;2(5):e194772. doi:10.1001/jamanetworkopen.2019.4772Google Scholar
4.
Ji  Y, Yang  K, Xiao  B,  et al.  Efficacy and safety of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker therapy for IgA nephropathy: a meta-analysis of randomized controlled trials.  J Cell Biochem. 2019;120(3):3689-3695. doi:10.1002/jcb.27648PubMedGoogle ScholarCrossref
5.
Coppo  R, Troyanov  S, Bellur  S,  et al; VALIGA study of the ERA-EDTA Immunonephrology Working Group.  Validation of the Oxford classification of IgA nephropathy in cohorts with different presentations and treatments.  Kidney Int. 2014;86(4):828-836. doi:10.1038/ki.2014.63PubMedGoogle ScholarCrossref
6.
Neugut  YD, Kiryluk  K.  Genetic determinants of IgA nephropathy: Western perspective.  Semin Nephrol. 2018;38(5):443-454. doi:10.1016/j.semnephrol.2018.05.014PubMedGoogle ScholarCrossref
7.
Watanabe  H, Goto  S, Mori  H,  et al.  Comprehensive microbiome analysis of tonsillar crypts in IgA nephropathy.  Nephrol Dial Transplant. 2017;32(12):2072-2079. doi:10.1093/ndt/gfw343PubMedGoogle Scholar
8.
Cao  Y, Qiao  M, Tian  Z,  et al.  Comparative analyses of subgingival microbiome in chronic periodontitis patients with and without IgA nephropathy by high throughput 16S rRNA sequencing.  Cell Physiol Biochem. 2018;47(2):774-783. doi:10.1159/000490029PubMedGoogle ScholarCrossref
9.
Fellström  BC, Barratt  J, Cook  H,  et al; NEFIGAN Trial Investigators.  Targeted-release budesonide versus placebo in patients with IgA nephropathy (NEFIGAN): a double-blind, randomised, placebo-controlled phase 2b trial.  Lancet. 2017;389(10084):2117-2127. doi:10.1016/S0140-6736(17)30550-0PubMedGoogle ScholarCrossref
10.
Gigante  J.  Tonsillectomy and adenoidectomy.  Pediatr Rev. 2005;26(6):199-202. doi:10.1542/pir.26-6-199PubMedGoogle ScholarCrossref
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