Tubulointerstitial nephritis complicating IVIG therapy for X-linked agammaglobulinemia
Patients with X-linked agammaglobulinemia (XLA) develop immune-complex induced diseases such as nephropathy only rarely, presumably because their immunoglobulin (Ig) G concentration is low. We encountered a patient with XLA who developed tubulointerstitial nephritis during treatment with intravenous immunoglobulin (IVIG).
A 20-year-old man was diagnosed with XLA 3 months after birth and subsequently received periodic γ-globulin replacement therapy. Renal dysfunction developed at 19 years of age in association with high urinary β2-microglobulin (MG) concentrations. A renal biopsy specimen showed dense CD3-positive lymphocytic infiltration in the tubulointerstitium and tubular atrophy, while no IgG4-bearing cell infiltration was found. Fibrosclerosis and crescent formation were evident in some glomeruli. Fluorescent antibody staining demonstrated deposition of IgG and complement component C3 in tubular basement membranes. After pulse steroid therapy was initiated, urinary β2-MG and serum creatinine concentrations improved.
Neither drug reactions nor collagen disease were likely causes of tubular interstitial disorder in this patient. Although BK virus was ruled out, IgG in the γ-globulin preparation might have reacted with a pathogen present in the patient to form low-molecular-weight immune complexes that were deposited in the tubular basement membrane.
KeywordsBruton agammaglobulin tyrosine kinase (BKT) gene Immune complexes Steroid therapy Tubular deposition Tubular atrophy
Intravenous immunoglobulin therapy
Burton agammaglobulin tyrosine kinase
Lymphocyte stimulation tests
In X-linked agammaglobulinemia (XLA), mutation involving the Bruton agammaglobulin tyrosine kinase (BTK) gene induces a B-cell maturation disorder that causes congenital immunodeficiency in which repeated bacterial infections reflect antibody production failure [1, 2]. Prognosis for survival is relatively favorable owing to immunoglobulin replacement therapy (intravenous immunoglobulin therapy, or IVIG) .
We encountered a patient with BTK gene mutation (p.Gln412X)-induced XLA who developed renal dysfunction associated with increased urinary β2-microglobulin during IVIG therapy. Renal histology indicated a tubular interstitial disorder. Glomerular immune complex deposition such as in membranous nephropathy  and membranoproliferative glomerulonephritis  occasionally has been reported in association with IVIG therapy for XLA. To our knowledge, however, tubulointerstitial nephritis (TIN) showing immune complex deposition in the tubular basement membrane has not previously been reported in XLA patients receiving IVIG therapy.
A 20-year-old man who was diagnosed with XLA 3 months after birth was treated periodically with IVIG. Mild renal dysfunction developed at 19 years. Serum creatinine (Cr) and blood urea nitrogen (BUN) were 1.5 and 30 mg/dL respectively, and urinary β2-microglobulin was elevated. The patient was admitted to our department for further evaluation and treatment.
Steroid therapy was administered including methylprednisolone pulse therapy followed by prednisolone (PSL). Urinary findings and renal function slowly improved, and progress continued after gradual dose reduction. Although the patient still is receiving IVIG therapy, urinary abnormalities and renal function deterioration have not recurred.
Immune-comples induced nephritis and complement-associated renal impairment are infrequent in XLA patients, most likely because of their very low IgG concentrations . We encountered a young man who developed tubulointerstitial nephritis (TIN) during IVIG for XLA. Glomerular immune complex deposition related to membranous nephropathy  and membranoproliferative glomerulonephritis  during the course of XLA have been reported occasionally. Nephrotic syndrome with TIN during IVIG therapy for secondary hypogammaglobulinemia during childhood has been described . However, the reporting authors concluded that TIN might have been caused by a local allergic reaction, considering a predominance of eosinophils among cells infiltrating the tubulointerstitum. To our knowledge, however, TIN induced by immune complex deposition in the renal tubules, such as that occurring in our patient, has not been reported previously.
In XLA, viral infections follow a normal course except for enterovirus infection, in which effective host defense requires antibodies. XLA patients are vulnerable to this infection, which may become persistent and progressive . In our patient, IgG and complement deposits were demonstrated in the tubular basement membrane by fluorescent antibody staining and electron microscopy, suggesting several possible pathogenetic mechanisms. Complement may have been activated locally after immune complex formation by interactions between an antigen present in the patient and the IgG contained in the γ-globulin preparation, inducing a tubular interstitial disorder. However, no specific infection could be identified in our patient. Although tubulointerstitial immune-complex nephritis is a very rare form of TIN, such nephritis can be caused by treatments such as nonsteroidal anti-inflammatory drugs , by autoimmune diseases such as lupus erythematosus , or IgG4-related diseases . However, our patient received no long-term drug treatment apart from IVIG, and had no collagen disease or IgG4-related disease according to repeated laboratory examinations.
Wegmuller et al.  reported that complement activation may occur in both healthy individuals and patients with congenital humoral immunodeficiency. A few B cells persist in XLA patients, producing a small amount of IgG in some patients . The exogenous, non-self IgG infused in IVIG might have induced autoantibody production against exogenous IgG with consequent nephropathy, but this mechanism cannot be proven in our patient; because to prevent fatal infection, he received periodic doses of IVIG, rendering measurement of self-produced IgG impossible. When type III allergy is involved in disease development and the antigen concentration exceeds the antibody concentration, immune complexes will have low molecular weight and may well be deposited outside the tubular basement membrane . Alternatively, antigen concentrations may be excessive in XLA patients, with low-molecular-weight immune complexes formed in the circulation possibly passing through the glomeruli to enter the urinary space and then deposited in the tubular basement membrane.
In patients with congenital humoral immunodeficiency patients, vigilance is needed to detect development of renal dysfunction during IVIG therapy. Not only glomerular disease but also TIN may occur, as occurred in our patient.
Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
We thank Ai Itoh for technical support in tissue staining and manuscript preparation. This study was partly supported by a Grant-in-Aid for Scientific Research from Morinaga Hoshikai to TT (2012-2013).
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