Correspondence *Texas Tech Health Sciences Center at El Paso, Department of Internal Medicine, 4800 Alberta Avenue, El Paso, TX 79905, USA

Email german.hernandez@ttuhsc.edu

The case

A 32-year-old African American man was admitted with a 1-day history of hemoptysis; he estimated that he had coughed up half a gallon of blood in the form of clots and liquid. The patient had experienced shortness of breath for several months. He denied fever, chills or night sweats. He had been infected with HIV for 3 years, he had a CD4⁺-lymphocyte count of 0.78 10⁹/l (normal range 0.36–1.26 10⁹/l) and an HIV-1 RNA viral load of 56,000 copies/ml, and he was anti-retroviral-treatment naive. He had no history of opportunistic infections. Three years prior to his current presentation, he had a positive hepatitis C virus (HCV) antibody test, and he received an incomplete course of isoniazid for a positive tuberculin skin test. He reported a history of 'crack cocaine' and intravenous drug use, but not for a year before presentation. He was not taking any medications. Upon presentation, he was afebrile, his heart rate was 100 beats/min, his blood pressure was 128/76 mmHg, his respiration rate was 20 breaths/min, and the oxygen saturation was 99% while breathing ambient air. His nasal septum was eroded and erythematous, and he had cervical adenopathy. There was no active oropharyngeal bleeding. Coarse crackles were recorded at the left lung base. The heart, abdomen, extremities, skin, and nervous system were normal.

Results of laboratory tests, including serum creatinine, are shown in Table 1. A urinalysis showed 2+ protein; the sediment contained 0–2 leukocytes/high power field (hpf; normal range 0–3/hpf) and 10–20 non-dysmorphic erythrocytes/hpf (normal range 0–3/hpf) but no bacteria or casts. An ultrasound revealed kidneys of normal size and echogenicity. A chest radiograph revealed bilateral lower lobe patchy infiltrates. The patient was placed in respiratory isolation. Therapy for pneumonia was initiated on an empiric basis with ceftriaxone 1 g daily. Stains of three induced sputa were negative for acid-fast bacilli. Bronchoscopy revealed a trace amount of blood in the upper third of the trachea. Because of the HIV infection and the partial course of isoniazid, anti-tuberculosis therapy was initiated with rifampicin 600 mg daily, isoniazid 300 mg daily, pyrazinamide 1,500 mg daily, and ethambutol hydrochloride 1,400 mg daily.

Table 1 The patient's laboratory results at the time of presentation, and normal ranges.

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Renal function remained impaired and the hemoptysis, though diminished, continued. A renal biopsy was performed and immune-complex glomerulonephritis was diagnosed (Figure 1). Light microscopy showed increased mesangial matrix with hypercellularity and mild mononuclear interstitial inflammation. Immunofluorescence showed granular capillary loop staining for IgG and complement 3, and electron microscopy revealed numerous subepithelial deposits. The cause of the immune-complex glomerulonephritis was initially thought to be related to HCV, but the HCV RNA level was undetectable (<1,000 copies/ml).

Figure 1 Renal biopsy.

Light microscopy showing mesangial prominence and increased cellularity (periodic acid–Schiff stain).

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Several weeks later, the sputum cultures grew Mycobacterium tuberculosis. Anti-tuberculosis therapy was continued for a total of 12 months and, despite poor compliance with treatment, the hemoptysis did not persist. The patient did not receive specific treatment for the immune-complex glomerulonephritis. He was normotensive and did not require treatment with antihypertensive medications. His proteinuria increased from 3.6 g/day to 11.1 g/day, but he was not treated with angiotensin-converting-enzyme (ACE) inhibitors because of problems with hyperkalemia and poor compliance with all medications. The kidney disease progressed and hemodialysis was initiated 3 years after the patient's initial presentation.

Discussion of diagnosis

Interpretation of autoantibodies in the setting of HIV infection

Despite the lack of association between ANCA-associated glomerulonephritis and HIV or anti-GBM renal disease and HIV, the presence of autoantibodies in HIV infection has been widely reported. In 1990, Koderisch et al. were the first to report the presence of 'false-positive' ANCAs by indirect immunofluorescence and anti-myeloperoxidase antibodies by enzyme-linked immunosorbent assay in HIV-infected patients without any other evidence of vasculitis.⁷ In 1992, Klaassen et al. also reported the presence of atypical forms of ANCA that produce perinuclear staining (pANCA) as well as cytoplasmic staining with central accentuation (cANCA) among 20% and 10%, respectively, of patients with symptomatic HIV infection; the ANCAs were not specific to either proteinase 3 or myeloperoxidase.⁸ Savige et al. examined the sera of 105 HIV-positive patients with no evidence of vasculitis and found that 17% had ANCA by indirect immunofluorescence, and that 25% had anti-myeloperoxidase, 7% had anti-proteinase-3, and 17% had anti-GBM antibodies by specific enzyme-linked immunosorbent assay. Furthermore, among patients with anti-GBM antibodies, 67% also had ANCAs.⁹

Compared with HIV-negative individuals, HIV-infected patients also have a higher prevalence of other autoantibodies, including rheumatoid factor, antinuclear antibodies, anticardiolipin antibodies, lupus anticoagulant, and cryoglobulins (Table 2).^{10, 11, 12} Early in the course of HIV infection, many individuals develop hypergammaglobulinemia, which is usually polyclonal. The polyclonal nature of the gammopathy could be explained by diminished or altered T-cell counter-regulation of B-cell activity. Alternatively, diminished T-cell surveillance might contribute to increased antigenic exposure through recurrent or persistent infectious pathogens (Figure 2). One example of this mechanism is Epstein–Barr virus, which has been shown to trigger clonal outgrowth of B cells in the peripheral blood of HIV-infected patients.¹³ Whatever the mechanism, this polyclonal activation probably contributes to the observed production of autoantibodies in the absence of clinical autoimmune disease.^{10, 14}

Figure 2 Possible mechanisms of autoantibody production in HIV-infected individuals without autoimmune disease.

(A) HIV—or other pathogens prevalent in immunocompromised patients—activates cells in the innate immune system (e.g. dendritic cells) through its interaction with Toll-like receptors. Increased production of cytokines, such as interleukin 6, in HIV-infected patients can trigger differentiation of B cells into antibody-producing plasma cells.^{13, 26} (B) T cells can facilitate differentiation by interacting directly with B cells that are presenting processed antigens from phagocytosis of pathogens. (C) High levels of interleukin 6 inhibit regulatory T cells that suppress the T-cell inputs in pathway B, which further potentiates B-cell activity.²⁷ Abbreviations: AFB, acid-fast bacilli; CMV, cytomegalovirus; EBV, Epstein–Barr virus; HCV, hepatitis C; IL, interleukin; TGF-, transforming growth factor ; TLRs, Toll-like receptors; TNF-, tumor necrosis factor .

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Table 2 Prevalence of positive autoantibodies in HIV-infected individuals.^{8, 9, 10, 12}

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Discussion of treatment

Treatment of the various glomerular diseases in the setting of HIV infection is guided by the results of the kidney biopsy. HIVAN is the most common glomerular disease in African American HIV-positive patients and, although no prospective trials have been undertaken, the standard treatment consists of highly active antiretroviral therapy, ACE inhibitors and, in select patients, corticosteroids.^{16, 17, 18} The choice of agents and doses of highly active antiretroviral therapy should be guided by the existing guidelines, including dose adjusting for renal impairment.¹⁹ The dose of ACE inhibitors should be maximized to reduce proteinuria and treat hypertension, as permitted by renal function and levels of serum potassium. Whether associated with HCV or not, immune-complex glomerulonephritis in HIV-infected patients has a poor prognosis and is very difficult to treat.^{20, 21} Regardless of the renal disease, HCV infection presents a dilemma in patients with HIV coinfection because of the rapid and severe course of HCV-related liver disease and the poor response to treatment with pegylated interferon and ribavirin.²²

Other types of glomerular lesions, most likely unrelated to the HIV infection, also occur in HIV-infected patients. Corticosteroids, ciclosporin, and mycophenolate mofetil are routinely considered in patients with minimal change disease, membranous nephritis, or lupus nephritis, respectively, but clinicians might be reluctant to use these agents in patients immunocompromised by HIV. Corticosteroids have been used safely for other indications in the setting of HIV-infection, however, such as Pneumocystis jiroveci pneumonia and idiopathic thrombocytopenic purpura. Interestingly, ciclosporin and mycophenolate mofetil have shown some promise in the treatment of HIV infection and have been used safely in the routine immunosuppression of HIV-infected solid organ transplant recipients.^{23, 24, 25}

Conclusion

Given the common presence of nonpathologic autoantibodies in individuals with HIV infection and the rare co-occurrence of ANCA-associated or anti-GBM disease and HIV, clinicians should order and interpret serologic tests with caution, paying special attention to the pre-test probability of autoimmune disease. A kidney biopsy should be performed to confirm a diagnosis before initiating aggressive immunosuppressive therapy in the setting of HIV infection.

Acknowledgments

We thank Dr Doug Hanks for providing the pathology slide.

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Subject areas under which this article appears: Glomerular diseases (glomerulonephritis, FSGS, cryoglobulinemia)