|Year : 2019 | Volume
| Issue : 2 | Page : 520-525
|Lupus nephritis in a patient with retroviral infection
T Yashwanth Raj1, S Sujith1, ND Srinivasaprasad1, K Thirumal Valavan1, M Hema2, Anila Abraham Kurien3, Edwin Fernando1
1 Department of Nephrology, Stanley Medical College, Chennai, Tamil Nadu, India
2 Department of Rheumatology, Stanley Medical College, Chennai, Tamil Nadu, India
3 Center for Renal and Urological Pathology, Chennai, Tamil Nadu, India
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|Date of Submission||17-May-2018|
|Date of Decision||05-Jul-2018|
|Date of Acceptance||08-Jul-2018|
|Date of Web Publication||23-Apr-2019|
| Abstract|| |
A 38-year-old woman, diagnosed as Person Living with Human Immunodeficiency Virus (HIV) on Highly Active Antiretroviral Therapy (HAART) for three years, presented with features of fever, rashes, joint pain, dyspnea and pedal edema. On evaluation, a diagnosis of Systemic Lupus Erythematosus with Lupus Nephritis (LN) triggered by HIV infection was made based on clinical and serological evidence. She was continued on HAART, and immuno-suppressive therapy was co-administered resulting in the resolution of her symptoms. Lupus-like histopathological findings have been reported in patients with HIV-related kidney diseases. This case report is to highlight the co-existence of LN in a patient with HIV infection.
|How to cite this article:|
Raj T Y, Sujith S, Srinivasaprasad N D, Valavan K T, Hema M, Kurien AA, Fernando E. Lupus nephritis in a patient with retroviral infection. Saudi J Kidney Dis Transpl 2019;30:520-5
|How to cite this URL:|
Raj T Y, Sujith S, Srinivasaprasad N D, Valavan K T, Hema M, Kurien AA, Fernando E. Lupus nephritis in a patient with retroviral infection. Saudi J Kidney Dis Transpl [serial online] 2019 [cited 2020 Jun 5];30:520-5. Available from: http://www.sjkdt.org/text.asp?2019/30/2/520/256861
| Introduction|| |
The co-existence of Human Immunodeficiency Virus (HIV) infection and Systemic Lupus Erythematosus (SLE) is an unusual, yet interesting phenomenon. The pathogenesis regarding how HIV infection, a state of immunodeficiency, triggers SLE is intriguing. Diagnosing these two conditions as separate entities poses a great difficulty due to overlapping clinical features and, initiating immunosuppressive therapy in such patients requires in-depth knowledge regarding the interaction between HIV and SLE. We report the case of a 38-year-old female who was diagnosed to have SLE with lupus nephritis (LN) triggered by an underlying retroviral infection.
| Case Report|| |
A 38-year-old female, known Person Living with HIV (PLHIV) infection on Highly Active Antiretroviral Therapy (HAART) for three years, presented with a history of rashes over the legs, face, chest, and back for three months. This was associated with arthritis of knees and ankles bilaterally. She had sought indigenous medical therapy for the above complaints for about a month, but in vain. She further developed multiple oral ulcers along with facial puffiness and bilateral leg swelling extending up to her knees. She also noted significant photosensitivity. A week prior to presentation to us, she developed high-grade, intermittent fever associated with right lower-limb pain and dyspnea, for which she was treated with broad-spectrum antibiotics elsewhere for three days and referred to us in view of worsening of symptoms.
The patient had been diagnosed as PLHIV three years back, for which she had been on HAART (Tenofovir 300 mg, Lamivudine 300 mg, and Efavirenz 600 mg) since diagnosis, with good compliance and follow-up. The CD4 count at index presentation was 258 cells/ mm3. Subsequently with HAART, her disease had been under optimal control with serial documented CD4 counts above 500 cells/mm3, last being 609 cells/mm3, two months prior to presentation.
On arrival at our institute, the patient was conscious and oriented. She was moderately built and nourished. She was tachypneic and tachycardic and had a blood pressure of 180/100 mm Hg. General examination was significant for discoid rash over the face, ear lobes, sternal area, and right scapular region posteriorly. She also had facial puffiness with symmetrical hyperpigmented rash in the periorbital region. Oral cavity showed multiple small ulcers over the hard palate [Figure 1].
|Figure 1: (a) Symmetrical hyperpigmented rash in the periorbital region, cheeks, forehead, and nostril. (b) Discoid rashes over the back of the trunk. (c) Ulcers over the hard palate, (d) Rashes over the lower extremities.|
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Bilateral pitting pedal edema, right more than left, extending upto the knees with erythematous macular rash over the legs was seen. There was significant warmth and tenderness over the right leg, leading to a suspicion of cellulitis. Systemic examination revealed decreased breath sounds over the right lung base with elevated jugular venous pressure. Abdominal and neurological examinations were insignificant.
The differentials considered were autoimmune disorders such as SLE, systemic vasculitis (HIV related), infectious arthritis, and drug-induced rash. The possibility of an opportunistic pathogen-related infection was considered, but seemed less likely because her retroviral illness was under good control with stable CD4 counts above 500 cells/mm3.
Other investigations revealed hemoglobin of 6.2 g/dL, total count of 5000 cells/mm3; differential count showed 73% polymorphs and 27% monocytes and platelet count was 1.25 lakh/mm3. Peripheral smear revealed microcytic anemia. Urine dipstick showed proteinuria (2+) and blood 2 (+), 24-h urine protein was 1.6 g, serum creatinine was 1.1 mg/dL, and liver function tests were normal. Computerized tomography of the thorax showed bilateral pleural effusion, right more than left, with bilateral lower-lobe consolidation. Echocardiogram showed moderate pericardial effusion with no tamponade.
Serological investigations revealed significantly high titers of antinuclear antibody (ANA) speckled (1/1000 titer by immunoflourescence), positive dsDNA and weakly positive anti-Sm antibody, with low complements [C3 – 16 mg/dL (90–180) and C4 – 3.4 mg/dL (10–40)]. Direct Coomb’s test was negative. Erythrocyte sedimentation rate (66 mm at 1 h) and C-reactive protein (74 mg/L) were elevated. The CD4count was 155 cells which can be low in the setting of an acute bacterial infection.
The patient had acutely presented with fever and had clinical features of right-leg cellulitis. Hence, she was treated with appropriate parenteral antibiotics. Her clinical and laboratory evaluation was consistent with SLE. In view of nonnephrotic proteinuria, hematuria, and hypertension, a clinical diagnosis of acute nephritic syndrome was made, and a kidney biopsy was performed. Kidney biopsy on light microscopy showed 11 glomeruli. There was an increase in mesangial and endocapillary cellularity with focal double contours on the glomerular basement membrane. Wire-loop lesions and hyaline thrombi were seen in two glomeruli. There was no collapse of capillary tuft, segmental sclerosis, or microcystic dilatation of the tubules [Figure 2].
|Figure 2: (a) Diffuse and global increase in cellularity in mesangial matrix(PAS, ×200). (b) Silver stain demonstrates the double contouring on the glomerular basement membrane (PASM, ×1000). (c) “Wire-loop lesions” which are massive subendothelial immune complex deposits are highlighted by the trichrome stain (Massons Trichrome, ×400). (d) “Full-house” positivity on IF, with deposits on capillary loops, mesangium, and tubular basement membranes.|
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There was no significant interstitial fibrosis or tubular atrophy. Immunofluorescence staining showed 15 glomeruli with full-house pattern – IgG, IgM, IgA, C3, and C1q were all (3+) positive over the glomerular capillary wall, mesangium, and tubular basement membrane. No light chain restriction was seen. The biopsy picture was that of a diffuse prolife-rative glomerulonephritis.
In this patient with retroviral positivity, the possibilities considered were Class IV LN and lupus-like nephritis associated with HIV. “Lupus-like” nephritis is characterized by histologic, immunohistologic, and ultrastructural features resembling LN, but occurring in patients without serological evidence of SLE. Lupus-like nephritis has been associated with HIV as a syndrome of immune dysregulation that is poorly understood, usually occurring in patients with low CD4 counts and high HIV viral load. As our patient had well-controlled disease with HIV-1 quantitative polymerase chain reaction detecting <20 copies of HIV-1 RNA/mL, this possibility was considered less likely. Based on clinical and laboratory criteria, the patient fulfilled nine out of 17 Systemic Lupus International Collaborating Clinics (SLICC) criteria, firmly establishing the diagnosis of SLE with Class IV LN. Electron microscopic analysis was not performed as it would not help differentiate LN from lupuslike nephritis because tubulo-reticular inclusions may be seen in association with both HIV infection and SLE. Furthermore, there were no features of HIV-associated nephropathy (HIVAN) in our patient. After being treated with parenteral antibiotics for cellulitis and pneumonia, she was treated with parenteral Methylprednisolone 500 mg for three days, followed by tablet Prednisolone 0.5 mg/ kg/day and tablet Mycophenolate Mofetil 250 mg twice daily, leading onto gradual resolution of the symptoms over three months. She is being regularly monitored as an outpatient.
Informed consent was obtained from the patient before reporting the case.
| Discussion|| |
The co-existence of cases of SLE and HIV infection has been rarely reported worldwide. Since the first case reported in 1988 by Kopelman and Zolla-Pazner, only a few cases of concurrent SLE and HIV infection have been reported to date. These sporadically reported cases have attracted increasing attention to the potential association of SLE and HIV infection. In addition, HIV and SLE share multiple overlapping clinical features, posing a great challenge to the diagnosis of these concurrent entities. Autoimmune diseases reported in the setting of HIV infection include SLE, anti-phospholipid syndrome, autoimmune thrombocytopenia, vasculitis, polymyositis, Graves’ disease, and primary biliary cirrhosis. SLE is a condition where cells undergo damage mediated by autoantibodies and immune complexes. The pathogenesis of SLE involves interactions between genetic and environmental factors, resulting in abnormal immune responses. These include activation of innate immunity by viral DNA or RNA, and protein self-antigens, lowered activation thresholds in adaptive immunity cells, ineffective regulatory CD4+ and CD8+ T cells, and reduced clearance of immune complexes and apoptotic cells.
This leads to increased secretion of pro-inflammatory cytokines where interferon (IFN) is the genetic “signature” in peripheral blood cells of 50%–60% of SLE patients. The decreased production of interleukin-2 and transforming growth factor-beta necessary to induce and sustain regulatory CD4+ and CD8+ T cells also contributes to SLE. Most of the SLE patients have auto-antibodies for a period of three years or more before the onset of the first symptom of disease.
A possible viral etiology for SLE was suspected due to the presence of virion-like tubuloreticular structures in endothelial cells and lymphocytes with demonstration of increased concentration of type 1 IFN in LN. The viruses usually implicated in the etiology of SLE are Epstein-Barr virus, retroviruses, paramyxovirus, cytomegalovirus, and parvovirus B19. They contribute to the pathogenesis ofSLE by triggering autoimmunity via structural or functional molecular mimicry.
With regard to HIV, there is a wide range of structural, functional, and immunological similarities between HIV-1 gp120 envelope protein and host proteins. Furthermore, a mimicking epitope between lupus autoantigen, Sm, and HIV-1 p24 gag has been defined, based on cross-reactivity with monoclonal antibody 4B4.
The HIV-1 tat gene upregulates a protein called Rab4, producing functional mimicry (like that of an anti-apoptotic protein) by causing downregulation of CD4 receptors in T helper cells, thus protecting them from the effect of cytotoxic T cells, enhancing the viral replication and survival. Following this, there is an increased production of pathogen-associated molecular patterns such as the viral DNA or RNA which cause excessive activation of toll-like receptors (TLRs) present on the surface of plasmacytoid dendritic cells. This causes increased production of IFNs, leading to the release of pro-inflammatory cytokines, triggering auto-immunity. Animal models of LN have shown the presence of TLR3 and TLR9, specifically immuno-localized in the kidney. The HIV virus also causes polyclonal B-cell activation producing polyclonal antibodies, which is an early step in the pathogenesis of SLE.
HIV infection induces a shift from Th1 to Th2 cytokine profile where Th1 cytokines protect against apoptosis and Th2 cytokines promote apoptosis. The HIV tat protein increases the oxidative stress leading to increased surface expression of Fas ligand-accelerating apoptosis. Furthermore, cleavage of bcl2 by HIV protease exposes cells to apoptotic signals. These necrotic and apoptotic cells release materials, which combine with immunoglobulins, forming immune complexes, which induce the production of IFN-a from plasmacytoid dendritic cells, provoking autoimmunity.
An expanding spectrum of clinical autoimmunity is seen among individuals with HIV infection. These include polyclonal hyper-gamma-globulinemia and a host of autoanti-bodies that include ANAs, IgG and IgA, rheumatoid factor, and antiphospholipid-, anti-platelet-, anti-red blood cell-, and antilymphocyte surface antigen-associated antibodies, causing diagnostic difficulties. When HIV and SLE coexist, active SLE can be difficult to distinguish from the primary or secondary manifestations of HIV infection. However, the presence of antibodies to double-stranded DNA and hypo-complementemia, neither of which is typically seen with HIV infection, might be helpful to ascertain the presence of active SLE.
In our patient, in the setting of HIV infection that is controlled by protease inhibitors and other antiretroviral agents, the immune system is no longer deficient. There is immune restoration and functional T-cell reconstitution so that a genetically predisposed host can develop autoimmunity.
In a study conducted by Haas et al in relation to patients with HIV-associated immune complex glomerulonephritis, out of the total 77 native renal biopsies from HIV-positive patients, the most common diagnosis was HIVAN, accounting for 31 cases (40%). Twenty-six (34%) biopsies showed immune complex glomerulonephritis, of which 14 biopsies (18% of total) showed features of lupus-like glomerulonephritis, with the patients having a negative or a weakly positive ANA (titer <1:80) with negative anti-dsDNA. Six had concurrent HIVAN. Only one patient had LN with serologic findings of SLE.
Active HIV infection appears to have a favorable impact on the clinical course of SLE. On the other hand, immunosuppressive therapy given for SLE activity has been associated with worsening of HIV infection. The efficacy and safety of immunosuppressant treatment for SLE in the context of HIV infection needs to be assessed. For SLE patients with confirmed HIV infection, anti-HIV therapy should be considered before immunosuppressive treatment. Moreover, monitoring of CD4 T-cell count is strongly recommended in terms of determining the appropriate immunosuppressant dose.
While reporting this case, we would also like to stress on the importance of doing a serological screening to rule out HIV infection in cases of suspected autoimmune disease. HIV is a “great mimicker” and it would be warranted to screen for HIV more often than is generally done.
| Declaration of patient consent|| |
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that her name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.
Conflict of interest: None declared.
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T Yashwanth Raj
Department of Nephrology, Stanley Medical College, Chennai, Tamil Nadu
[Figure 1], [Figure 2]
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