Despite the improvement in survival after the introduction of the antiretroviral therapy, HIV-infected patients have an increased risk of developing kidney disease [1–2]. Along with the HIV-associated nephropathy, there have been described a wide spectrum of lesions that could involve each compartment of the kidney, the mechanisms involved being either the direct association with the HIV infection, the consequences of the superinfections and of the antiretroviral treatment and the systemic immune response to HIV infection [3–4].Furthermore, the spectrum of HIV-related kidney disease changed with the widespread use of effective antiretroviral therapy, with diseases like nephrotoxicity of antiretroviral therapy, focal segmental glomerulosclerosis not otherwise specified, arterionephrosclerosis of aging and hypertension, diabetic nephropathy and immune complex mediated glomerulonephritis having an increased prevalence in this population of patients in the last years [1, 2].Here, we report one case of true ANCA-associated vasculitis with renal and pulmonary involvement in a young patient with a history of well-controlled HIV infection.
The dysregulation of the B and T lymphocyte interaction, the molecular mimicry, viral triggers (like EBV (Epstein-Barr virus)), cytokine production (like TNFα (tumor necrosis factor-α)) and the polyclonal activation of B lymphocytes may favour the development of autoantibodies in HIV infection [5, 7–9, 12, 15, 17], infections usually having a critical role in the breakdown of tolerance and the appearance of autoreactivity [12]. As it was reported previously, the nonorgan-specific autoantibodies can also be detected as “false-positive” in healthy people, during infections or in neoplasia [5]; in HIV-infected patients several studies have reported the occurrence of autoantibodieswith a prevalence ranging from 20 to 83% [5–6] with few reports of clinically-relevant autoantibodies profiles that lead to true systemic autoimmune disease [7].
Most of the studies were conducted in the pre-antiretroviral therapy era with population of patients presenting at a more advanced disease stage, but in the last ten years have started to appear systematic investigations with the purpose to describe the prevalence of autoantibodies in the antiretroviral therapy era when higher proportion of patients have a good immunovirological status [5, 7, 18]. Iordache et al found in 92 HIV1-infected patients with a good immunovirological status an ANCA positivity of 13% [5] compared to the historical studies where the prevalences were up to 83% [6, 10, 12], suggesting that the viral replication may play a pivotal role in the development of autoantibodies in HIV infection. The study conducted by Meng supports this observation by demonstrating that the antiretroviral therapy supress the autoimmune manifestations by reducing the CD33 + CD11b + HLA-DR + myeloid-derived suppressor cells in vivo [18].
Another opposite hypothesis might be that the autoimmune diseases and HIV infection are coincidental pathologies and the autoimmune phenomena are possibly being modified in the context of immune deficiency secondary to HIV infection; in this situation, HAART (highly active antiretroviral therapy) might hasten the onset of autoimmune diseases [7]. Also, some autoimmune diseases as vasculitis, sarcoidosis and thyroid disease may also represent a form of immune reconstitution inflammatory syndrome secondary to initiation of HAART [7].
The incidence of vasculitis in HIV-positive patients is estimated to be less than 1%[7, 13].A study conducted by Gherardi in 1992 reported 148 patients with symptomatic HIV infection in whom have been performed muscle, nerve or skin biopsies. 34 of the patients (23%) presented inflammatory vascular diseases, with 30 patients presented exclusively small vessels involvement; there was no specification on ANCA status [17]. In these cases reported, small vessel-vasculitis had in more than half of the patients a clinical expression with cutaneous and neurologic involvement [17]. Another case of ANCA negative granulomatous necrotizing vasculitis was reported by Garcia-Garcia et al [19] based on the muscle biopsy; the patient had a poor controlled HIV, diagnosed in an advanced stage with a CD4 count of 175 cells/ul and a viral load of 120000 copies/ml. The treatment was based on cyclophosphamide, vincristine, adriamicin, corticosteroids and initiation of the antiretroviral therapy [19].
A retrospective study conducted by Peraldi [20] included 92 HIV-positive patients with an episode of acute kidney injury, 60 of them having renal biopsies performed. No small vessel vasculitis was diagnosed in this subgroup of patients with HIV infection, acute kidney injury and a poor immunovirological status, as 82% of the patients had overt AIDS and the mean CD4 cell count was of 76/mm3. 80% of the patients were on at least one antiretroviral agent, with only 13% being on a three anti-retroviral protocol [20]. Vali et al [21] reported the results of the biopsies of 27 HIV-infected patients with renal dysfunction and almost half of them with nephrotic-range proteinuria (48% of the patients). The CD4 count of the patients ranged between 77 to 633/ul and 29.6% of the patients were on HAART. They reported only one case of pauciimune crescentic glomerulonephritis, without mentioning the ANCA status of the patients [21].
A review conducted by Reville in 2000 [22] that had the aim to describe the HIV-associated rheumatic disease reported in the literature, presented also their department experience. From the 458 patients reffered to rheumatology consultation during 6 years, only 4 patients( 1%) were diagnosed with vasculitis: 1 case of Wegener’s granulomatosis, 1 case of polyarteristis nodosa, 1 of central nervous system angiitis and 1 cutaneous vasculitis [22]. Another recent review focused on the autoimmune disease in HIV-positive patients published in 2014 by Iordache et al [7], reported also their retrospective experience consisting of 52 patients with autoimmune diseases and HIV infection. There were 11 cases of vasculitis (1 case of cutaneous vasculitis and 1 case of granulomatosis with polyangeitis), 9 of them having the CD4 > 200 mm3. Seven of them needed immunosupression and the treatment consisted of corticosteroids in 7 patients, cyclophosphamide in 1 patient, intravenous immunoglobulins in 1 patients, methotrexate in 2 patients and plasmapheresis in 1 patients; HAART was started in 9 patients. The patients had a good evolution, as 8 of them achieved complete remission [7].
ANCA positivity has been detected with a prevalence between 13 and 83%, without evidence of clinical vasculitis in most cases [6, 8–12].Some studies reported no correlation between ANCA positivity andopportunistic infection [11], hypergammaglobulinemia [5, 11, 16] and the stage of the disease [6, 11]. On the other hand, some studies seem to find a correlation between ANCA positivity and stage of the disease [5, 16, 23] (Table 1). One cross-sectional observational study conducted by Iordache et al [5] found an inverse association between the presence of more than one autoantibody and CD4 + lymphocyte count (p 0.03) [5].
There are some reports of true ANCA-associated vasculitis [8–9, 14–16]. The reported manifestations in HIV-positive patients with ANCA-associated vasculitis were renal [8–9, 14, 16], pulmonary [9, 15, 22],articular [8, 16], cutaneous [16], ophtalmological [8] and neurological [14]. The renal manifestations reported included acute kidney injury [8–9] and nephritic syndrome [8–9, 14] (Table 1). In our patient, a diagnosis of systemic ANCA-associated vasculitis with severe renal and pulmonary involvement was established; the patient presented with acute kidney injury and a nephrotic syndrome with active urinary sediment and the renal biopsy and the computer tomography confirmed the diagnosis in the context of ANCA positivity.
The treatment reported in patients with ANCA vasculitis in this category of patients was based on glucocorticosteroids [8–9, 14–16, 22], cyclophosphamide [9, 15], rituximab [8] and the initiation of HAART [9, 15], as some of the patients had a well controlled HIV infection [8], while others were detected with ANCA positivity at the moment of HIV infection diagnosis with a low CD4 count [9, 15, 24]. Also, there are two reports of Churg Strauss vasculitis in HIV-infected patients (25–26) with renal involvement in the case reported by Myugen (nephritic syndrome) [25]; in both cases the vasculitis was diagnosed simultaneously with the HIV infection. In both cases the treatment was based on corticosteroids [25–26]. Our patient that had a well controlled-HIV infection with undetectable viral load and CD4 count over 500 cells/mm3 ,was started on an induction immunosuppressive treatment regimen consisting of a combination of intravenous cyclophosphamide, rituximab and tapering corticosteroids with resolution of the diffuse alveolar hemorrhage and immunological remission, but with loss of her renal function with the need of initiation of dialysis. In this case, a correct antibiotic prophylaxis, prevented from infectious complications despite that the patient was under aggressive combined immunosuppresive therapy.
Table 1
ANCA Positivity Reported in the Literature in HIV-Infected Individuals
Study | Type of study | Number of patients | Immunovirological status | ANCA positivity | Clinical manifestations | Correlation with the stage of the disease | Treatment |
Evans [8] | Case report | 1 | CD4 > 400cells/mm3 UndectableVL (under Ritonavir and Darunavir) | pANCA > 100 IU/ml | Renal (Acute kidney injury, nephritic syndrome), articular, opthalmological | No | Glucocorticosteroids, rituximab |
Romano [24] | Case report | 1 | CD4 27 cells/mm3 VL-NR Untreated before | cANCA 251–736 UA/ml | No clinical vasculitis | At diagnosis | - |
Mirsaedi [9] | Case report | 1 | CD4 146 cells/mm3 VL- 91469 c/ml Untreated before | pANCA 68 U/ml | Renal (Acute kidney injury, nephritic syndrome), pulmonary | At diagnosis | glucocorticosteroids,cyclophosphamide, HAART |
Mohapatra [15] | Case report | 1 | CD4 0.9/ul Viral load- NR Untreated before | cANCA- titre NR | Pulmonary | At diagnosis | Glucocorticosteroids, Cyclophosphamide, HAART |
Jansen [10] | Case report | 1 | CD4 18x106/l Untreated before | cANCA 1/320 | No clinical vasculitis | At diagnosis | HAART |
Davenport [14] | Case report | 1 patient | CDC grade 4 disease -at diagnosis | Perinuclear with some focal intracytoplasmatic positivity (IF) | Renal (intermittent hematuria and proteinuria) and neurologic (peripheral neuropathy) | - | Corticosteroids |
Reville [22] | Review (1 case report) | 1 patient | NR | cANCA positivity titre NR | Severe sinusitis and pulmonary involvement (infiltrates) | NR | Corticosteroids |
Klassen [16] | Case report Cross-sectional | -82 pt. +: -1 index pt. presented separately -1 pt. presented separately | VL-not reported Treatment- NR − 21 asymptomatic HIV+ (CD4 > = 0.5x109/l -26 asymptomatic HIV+( CD4 < 0.5x109/l -26) -10 pt. with ARC (CDC group IV A) -14 pt. with AIDS-OI -11 pt. with AIDS- MAL | -5 ANCA+/10 ARC -2 ANCA+/14 AIDS-OI -4 ANCA+ /11-AIDS-MAL -No ANCA positivity in asymptomatic HIV; pANCA-3 pt. cANCA- 8 pt | Index patient-articular, cutaneous 1 Dutch pt.- renal involvement 48 pt. -No clinical vasculitis | Corelation with disease stage- “The occurrence of ANCA was limited to the symptomatic stages of HIV infection with the exception of the index pt.” | Corticosteroids |
Cornelly [11] | ObservationalProspective | 199 | Median CD4 80/ul VL-NR 77%-AIDS 76% on ART | 20% ANCA + (IF) Atypical ANCA 67%, pANCA 33% | No clinical vasculitis | No corelation with the stage of the disease. | - |
Sorrentino [23] | Observational | 88 | VL, CD4-NR Treatment-NR ( 49-asymptomatic HIV; 39- symptomatic HIV) | ANCA positivity: 21/39 (53.8%)-symptomatic HIV 2/49 (4.1%)- asymptomatic HIV | No clinical vasculitis | Corelation with disease stage | - |
Iordache [5] | Cross-sectional | 92 pt. | HAART 85% Median mean CD4 611/mm3 VL undetectable in 74% of pt. | At least 1 Ab (45%) ANCA-13% | 12% from the whole cohort had > = 1 clinically relevant Ab | Ab presence is associated with CD4 count. | - |
Savige [12] | Observational | 105 pt. | 55 pt. were treated with Zidovudine and 34 were not. CD4 counts < 400/ul in 78 pt.; >400/ul in 11 pt. Asymptomatic infection- 37 pt. ARC − 32 pt. AIDS-36 pt. | ANCA+-18 pt. cANCA-4 pANCA-4 atypical-10 | No clinical vasculitis | There was no significant correlation between ANCA and immunological status. | - |
Koderisch [6] | Observational | 29 patients (45 sera) | VL-NR Median T4/T8 ratio 0.43 3-asymptomatic 16- lymphadenopathy syndrome 5- ARC 5-AIDS (2-KAPOSI) | 31 sera/24 patients- faint homogenous cytoplasmatic staining of neutrophils (IF) 4 sera/3 patients-faint cANCA 0-pANCA; 9sera/5 pt.-borderline + ANCA-ELISA 3 pt- mpo-ELISA + | No clinical vasculitis | No correlation between ANCA and stage of disease. | - |
Iordache [7] | Retrospective descriptive | 52 patients -> 1 case of granulomatosis with poliangeitis | Good imunovirological status | Transiently cANCA + | GPA confirmed histological | - | Immunosupresant treatment (the drugs NR) |
AIDS- acquired immunodeficiency syndrome, AIDS-OI- AIDS and opportunistic infections; AIDS-MAL- AIDS and secondary malignancies, ARC-AIDS-related complex; HIV-human immunodeficiency virus, Ab-antibody,VL-viral load, pANCA-perinuclear anti-neutrophil cytoplasmic antibody ,cANCA- cytoplasmic anti-neutrophil cytoplasmic antibody, NR-not reported, ART- antiretroviral therapy, HAART-highly active antiretroviral therapy; IF-immunofluorescence; pt-patients; GPA-granulomatosis with polyangiitis; ELISA- enzyme-linked immunosorbent assay
The KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases [27] recommend for the initial treatment of new-onset ANCA-associated vasculitis, administration of glucocorticoids in combination with cyclophosphamide or rituximab; also in the cases presenting with markedly reduced or rapidly declining glomerular filtration rate (serum creatinine > 4mg/dl), a combination of rituximab and cyclophosphamide can also be considered [27], as we have also tried in our case. The KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases [27] also states that plasma exchange can be considered in patients with a serum creatinine > 5.7 mg/dl or in those with alveolar haemorrhage with hypoxemia, although the PEXIVAS trial showed no benefit with the addition of plasma exchange regarding the incidence of death or end stage kidney disease in patients with ANCA vasculitis presenting with GFR < 50 ml/min/1.73 m2 or alveolar haemorrhage [28].
For HIV-related kidney disease, there is no consensus regarding the immunosuppressant treatment in addition to antiretroviral therapy [27]. The immunosuppressive drugs can favour the development of opportunistic infections in HIV-positive patients [29] and as there are no controlled clinical trials, each case needs to be discussed in an multidisciplinary team; corticosteroids should be administered in patients with potentially life threatening vasculitis and cytotoxic agents should be tried with caution in resistant case [22, 29]. In their case based review of 52 HIV patients with autoimmune disease, Iordache and co-authors concluded that positivity for HIV should not limit the use of immunosuppresive therapy, as this was well tolerated by these patients [7].
In conclusion, although it is not clear whether HIV infection and ANCA-associated vasculitis are causally or coincidentally related, the possible systemic autoimmune phenomena should be acknowledged by physicians in order to establish the correct diagnosis and treat accordingly the disease by keeping a balance between the risks and benefits of immunosuppression in this category of patients, with the treatment decisions being taken in a multidisciplinary team in centre’s with experience in ANCA-associated vasculitis.