Introduction

Staphylococci have been identified as causative agents in the genesis of glomerulonephritis (GN). Most published reports linking staphylococcal infection to GN have emphasized two clinical settings: Staphylococcus epidermidis bacteremia with a ventriculoatrial (VP) shunt [1] and S. aureus bacteremia with endocarditis [2]. A third type of GN related to methicillin-resistant S. aureus (MRSA) infection, named MRSA-GN, was reported in Japan in 1995 [3] and is on the rise [4–10]. In adult patients, MRSA-GN is characterized by rapidly progressing GN and/or nephrotic syndrome, with various degrees of proteinuria developing after MRSA infection, and by elevated serum levels of immunoglobulin A (IgA) and immunoglobulin G (IgG). However, we reviewed the literature and failed to find any mention of pediatric patients with MRSA-GN.

Herein, we report the case of the youngest patient to date with MRSA-GN, which was successfully treated by antimicrobial therapy.

Case report

The patient was a 6-year-old Japanese girl of healthy unrelated parents. Her perinatal history and past medical history were remarkable for pre-term delivery (gestational age 34 weeks and 1 day), very low birth weight (birth weight 1,188 g), and multiple malformations (microcephaly, anophthalmia, jejunal atresia, congenital tracheal stenosis). Although her kidneys were small in size, her renal function was normal. Radical surgery to repair her jejunal atresia and a tracheotomy for tracheal stenosis were performed at 2 days of age. These findings prompted us to determine if there was a chromosomal abnormality or intrauterine infection with a fetopathogenic virus, but no positive results were obtained. Proteinuria had never been detected by regular urinalysis during the 15 months that she had been hospitalized.

This patient was referred to our hospital due to the presence of a persistent cough for 6 weeks and fever for 1 week. A presumptive diagnosis of acute bacterial bronchitis was made, and 9 mg/kg of cefcapene pivoxil was prescribed. Despite antibiotic therapy, her cough and fever did not disappear, and she came back 7 days later and was admitted for further evaluation.

Physical findings on admission revealed severe stunted growth, with a height of 57 cm [−11.9 standard deviation (SD)], weight of 4.94 kg (−4.6 SD), and head circumference of 31.2 cm (−14.8 SD). Her development was also severely delayed as she reached the developmental milestone of 8 months of age. While edema was noted, her blood pressure was normal (98/42 mmHg). Chest auscultation revealed moist rales in the right lower lung field; these were consistent with the findings of consolidation on the X-ray. Ultrasound examination revealed hyperechoic small kidneys, with the right and left kidneys having a length of 41 and 40 mm, respectively.

Laboratory blood and urine tests revealed massive proteinuria with abnormal renal function, hypoalbuminemia, and increased C-reactive protein (CRP). The following results were obtained: urinary protein/creatinine ratio (UP/UC), 9.6 g/g creatinine; urine occult blood by dipstick, negative; urinary β2-microglobulin, 476 μg/L (normal range 0–250); serum protein, 5.5 g/dL; serum albumin, 1.3 g/dL; serum creatinine, 0.38 mg/dL; estimated glomerular filtration rate [11], 61.6 mL/minute/1.73 m2; total cholesterol, 225 mg/dL; blood urea nitrogen, 12 mg/dL; CRP, 7.9 mg/dL. The serum levels of immunoglobulins (Ig) were not decreased despite the nephrotic state, and the levels of complement proteins were within the normal ranges: IgG, 1,188 mg/dL; IgA, 262 mg/dL; IgM, 221 mg/dL; C3, 121 mg/dL; C4, 31 mg/dL; CH50, 59 U/mL. Autoantibodies, such as anti-nuclear antibody and rheumatoid factor, were not detected. Toxic shock syndrome toxin-1 (TSST-1)-producing MRSA was cultured from the sputum obtained via the tracheotomy tube, although it was not detected in the urine. These findings suggested the diagnosis of MRSA-GN based on the massive proteinuria of the patient and prompted us to explore the activation of Vβ2+ T cells among CD4+ cells reactive to TSST-1. We found that the percentage of Vβ2+ T cells expressing CD45RO, a marker of activated T cells, among CD4+ cells was increased (49%: normal <11.1% [12]).

The diagnosis of acute pneumonia caused by MRSA complicated by MRSA-GN was made, and the administration of a daily dose of 100 mg/kg of panipenem/betamipron (PAPM/BP) was initiated; this treatment led to a drastic improvement of her symptoms with a concomitant decrease in the serum level of CRP. The amount of urinary protein, assessed by the UP/UC, also decreased concurrently, but the test results did not become negative.

The patient was discharged 1 month later because her hypoalbuminemia had improved. In the outpatient clinic, a significant level of proteinuria was continuously detected even though she remained well. Based on the reports of successful treatment for MRSA-GN [13], prednisolone was given at a dose of 1 mg/kg/day without a significant reduction in the urinary protein level. MRSA had also been continuously cultured from her sputum for 8 months. Therefore, antimicrobial therapy using sulfamethoxazole/trimethoprim (SMX/TMP), drugs that her MRSA strain was confirmed to be sensitive to, was initiated. A daily oral dose of 160 mg of SMX containing 32 mg of TMP eradicated MRSA from her sputum in 2 months and concomitantly decreased the level of urinary protein.

Discussion

It is currently known that Staphylococcal infection can cause three types of GN, i.e., VP shunt-associated GN (shunt nephritis), immune complex (IC)-mediated GN, and MRSA-GN. These conditions are usually associated with S. epidermidis bacteremia with a VP shunt [1], S. aureus bacteremia with endocarditis [2], and chronic MRSA infection producing staphylococcal enterotoxins acting as superantigens, respectively (Table 1).

Table 1 Staphylococcus infection-associated glomerulonephritis
Full size table

Since first being described by Koyama et al. [3], several cases of MRSA-GN have been reported in adult patients, mostly from Japan [4–10]. MRSA-GN is clinically characterized by rapidly progressing GN and/or nephrotic syndrome, with various degrees of proteinuria developing after MRSA infection; it resembles primary IgA nephropathy in terms of histology [10]. Although the pathogenesis of MRSA-GN remains unknown, the following has been speculated. Persistent infection with MRSA leads to the production of staphylococcal enterotoxins, which act as superantigens. Superantigens can bind directly to major histocompatibility complex class II proteins on antigen-presenting cells and are recognized by T cell receptors (TCR) [14]. They bind only to specific Vβ chains of the TCR and cause the massive activation of T cells and the subsequent release of T cell-derived cytokines, such as interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α) and interferon gamma (INF-γ) [14]. The released cytokines induce not only kidney injury but also polyclonal B cell activation, resulting in the formation of immune complexes [3, 5–7]. In fact, MRSA-GN is characterized by elevated serum levels of IgG, IgA, and inflammatory cytokines, such as IL-2, TNF-α, INF-γ, IL-1β, IL-6, and IL-8. The selective activation of the TCR Vβ repertoire in the peripheral blood is also reported to be diagnostic [5].

Although a renal biopsy was planned to confirm the diagnosis of MRSA-GN, we decided against this procedure due to the small kidneys and multiple other anomalies in this sick child. As shown in Table 1, however, we believe that our patient suffered from MRSA-GN because (1) the clinical manifestation was nephrotic syndrome with elevated serum IgG and IgA levels, which are rarely observed in idiopathic nephrotic syndrome; (2) corticosteroid failed to reduce the amount of proteinuria, and only the eradication of MRSA using appropriate antibiotics was successful; (3) CD45RO, a potential marker for T cell activation, was overexpressed on the patient’s Vβ2+ T cells, which are known to be reactive to TSST-1 [12]. These results suggest that TSST-1 produced by MRSA activated the Vβ2+ T cells, which then produced an excessive amount of cytokines, resulting in kidney injury. It has been reported that the prognosis of MRSA-GN is relatively good if the MRSA infection is treated appropriately [3, 5, 7, 15]. Corticosteroid treatment can be an alternative in the uncommon situation of persistent active renal disease or in the case suggesting IC formation, such as hypocomplementemia despite a clearly successful treatment of infection [9, 15].

In summary, there should be a high index of suspicion for MRSA-GN, even in the very young, to avoid the unnecessary use of immune suppressants in this context.