Treatment of HIV-Associated Lupus-like Membranous Nephropathy with Tacrolimus: A Case Report and Review of the Literature

Renal complications of HIV infection are common and histologically diverse. Besides HIV-associated nephropathy, which is the most well-defined glomerular disorder, immune-complex-mediated glomerulonephritis (HIVICK) is also encountered in the setting of HIV infection and may occasionally present with “lupus-like” features by light microscopy and immunofluorescence. Management of HIVICK remains controversial and mainly focuses on HIV viremia suppression with combined antiretroviral therapy. Immunosuppressive therapy may be used in order to mitigate the renal inflammation induced by the immune complex deposition. Data regarding the use of immunosuppressants in HIVICK are very limited, mostly including corticosteroids and mycophenolate acid analogues. Herein, we present the case of a 40-year-old HIV-infected Caucasian man with nephrotic syndrome, renal impairment, and a “lupus-like” membranous pattern in the kidney biopsy, who achieved a partial response of his proteinuria with a tacrolimus-based regimen in combination with antiretroviral therapy.


Introduction
A total of 38.4 million adults and children worldwide are currently living with human immunodeficiency virus (HIV) infection, according to the 2022 Joint United Nations Program on HIV/AIDS estimates [1]. Renal disease is an important cause of morbidity and mortality, affecting approximately 30% of HIV-positive patients [2,3]. A variety of renal manifestations have been described in patients with HIV infection, including HIVassociated nephropathy (HIVAN), immune complex glomerulonephritis (ICGN), thrombotic microangiopathy, and nephrotoxicity of antiretroviral therapy [4]. The introduction of highly active antiretroviral therapy (HAART) has resulted in increased life expectancy and a shift in the spectrum of renal diseases observed in HIV-infected patients (Table 1). Before the introduction of HAART, HIVAN was the leading cause of HIV-related renal disease and the most common cause of end-stage kidney disease (ESKD) in African American HIV patients. In the post-HAART era, sustained viral load suppression has led to a decline in the prevalence of HIVAN, while the incidence of ICGN and chronic kidney disease due to traditional risk factors, such as hypertension and diabetes mellitus (DM), has steadily increased [5,6].  ICGN in the setting of HIV infection (HIVICK) represents a heterogeneous group of glomerular diseases, such as IgA nephropathy, lupus-like proliferative glomerulonephritis, membranous nephropathy, and fibrillary glomerulonephritis [7]. Lupus-like nephritis is characterized by a "full-house" immunofluorescence pattern, defined by concurrent glomerular deposition of IgG, IgM, IgA immunoglobulins, C3, C1q complement components, in association with glomerular proliferative or membranous features by light microscopy. Extrarenal signs and symptoms of systemic lupus erythematosus (SLE), as well as serologic lupus antibody testing, are typically absent. [8].
Optimal treatment of patients with HIVICK is not yet established. Glucocorticoids have been used in patients with HIVAN with a favourable outcome [9][10][11][12]; however, data about immunosuppression therapy in HIVICK are limited. The use of HAART alone or in combination with immunosuppressive agents including mycophenolic acid analogues (MPAA) and glucocorticoids has been described in several cases with controversial results [13,14]. Furthermore, applying immunosuppressive therapy in already immunocompromised subjects raises concerns. Herein, we present a case of a patient with lupus-like nephropathy in the setting of HIV infection who was treated with tacrolimus and provide an overview of the current literature.

Case Presentation
A 40-year-old Caucasian man with a history of HIV and hepatitis C virus (HCV) infection, associated with intravenous drug use, presented to the emergency department reporting lower extremity oedema that had progressively developed over the past month. HIV infection was diagnosed 11 years ago, when he first received HAART, albeit with poor compliance over the last 2 years. HCV infection had been successfully treated with pegylated interferon-a (IFN-alpha) and the viral load was undetectable for the past three years. The patient had reportedly quit intravenous drug use five years ago. At presentation, the patient's blood pressure was 150/90 mmHg, the heart rate was 100 beats per minute, temperature 36.7 • C, respiratory rate 17 breaths per minute, and oxygen saturation was 98% on room air. Physical examination revealed mild bibasilar crackles, a palpable enlarged liver, and bilateral pretibial pitting oedema. There was no lymphadenopathy or skin rash. Chest radiography showed a small right pleural effusion and abdominal ultrasound showed liver enlargement (20 cm).
On admission, the patient's workup was remarkable for normocytic anemia (Hb: 9.7 g/dL), elevated ferritin levels (1.135 µg/L), polyclonal hypergammaglobulinemia (24 g/L), and a normal CRP value ( Table 2). Renal indices showed mild kidney function impairment with a serum creatinine level of 99.1 µmol/L, corresponding to an estimated glomerular filtration rate (eGFR) of 70 mL/min per 1.73 m 2 by CKD-EPI equation. He had nephrotic-range proteinuria (6.5 g/24 h) and a low serum albumin level (2.9 g/dL). Urine sediment examination revealed 25 to 30 erythrocytes of glomerular origin per high-power field. Ultrasonography displayed normal-sized kidneys. A percutaneous renal biopsy was performed. Light microscopic examination revealed six glomeruli, two of which were globally sclerosed. Mild mesangial hypercellularity and diffuse thickening of the glomerular basement membrane (GBM) was noticed ( Figure 1). In immunofluorescence examination, concomitant presence of IgG 3+, IgM 2+, IgA 1+, C3 3+, C1q 3+, kappa light chain 2+, and lambda light chain 3+ (0-3 + intensity scale) was observed, indicating a full-house pattern. The PLA2R staining was negative. Electron microscopy revealed numerous subepithelial and paramesangial deposits (Figure 2), as well as tubuloreticular inclusions ( Figure 3). Histologic findings were compatible with a diagnosis of membranous nephropathy with lupus-like features.     Anti-nuclear antibodies (ANA), double-stranded DNA antibodies (anti-ds-DNA) antibodies to extractable nuclear antigens (ENA), and phospholipase A2 receptor antibod ies (PLA2R) were negative. Serum C4 concentration was within the normal range whereas a low serum C3 concentration was observed (69 mg/dL). Further testing showed a low CD4+ lymphocyte count of 66 cells/mm 3 and an increased HIV RNA load of 3050 copies × 10 7 /mL.
In the absence of extrarenal and serological criteria of SLE, the diagnosis of lupus like membranous nephropathy in the setting of HIV infection was made [15].
Combined antiretroviral therapy with tenofovir alafenamide, emtricitabine, and ral tegravir was initiated. In addition, loop diuretics were added for oedema and co-trimox azole for PCP prophylaxis due to immune deficiency. An ACE inhibitor was also initially administered, which was later discontinued due to an increase in serum creatinine levels (221 μmol/L). He remained on HAART for 2 months without renal response. Due to per sistent nephrotic syndrome despite antiretroviral therapy, immunosuppressive treatmen initiation was decided. Immunosuppressive therapy consisted of three intravenou methylprednisolone pulses of 500 mg, followed by oral prednisone (1 mg/kg/d), which was gradually tapered to 5 mg by Month 4 and mycophenolic sodium at an initial dose o 1080 mg/d and titrated to 1440 mg/d after two weeks. The patient was followed regularly at the renal department and HIV clinic.
Six months after treatment initiation, the CD4+ lymphocyte count had increased to 100/mm 3 , and the HIV viral load was undetectable (157 copies/mL). The patient's ne phrotic syndrome persisted, however, and no improvement in his kidney function wa observed; serum creatinine levels were 141 μmol/L and urine protein levels were 5.5 g/d Moreover, due to mycophenolate acid-related leukopenia development, mycophenolate sodium was discontinued. Based on previous experience with calcineurin inhibitor (CNIs) in nephrotic syndrome, particularly primary membranous nephropathy, we de Anti-nuclear antibodies (ANA), double-stranded DNA antibodies (anti-ds-DNA), antibodies to extractable nuclear antigens (ENA), and phospholipase A2 receptor antibodies (PLA2R) were negative. Serum C4 concentration was within the normal range, whereas a low serum C3 concentration was observed (69 mg/dL). Further testing showed a low CD4+ lymphocyte count of 66 cells/mm 3 and an increased HIV RNA load of 3050 copies × 10 7 /mL.
In the absence of extrarenal and serological criteria of SLE, the diagnosis of lupus-like membranous nephropathy in the setting of HIV infection was made [15].
Combined antiretroviral therapy with tenofovir alafenamide, emtricitabine, and raltegravir was initiated. In addition, loop diuretics were added for oedema and co-trimoxazole for PCP prophylaxis due to immune deficiency. An ACE inhibitor was also initially administered, which was later discontinued due to an increase in serum creatinine levels (221 µmol/L). He remained on HAART for 2 months without renal response. Due to persistent nephrotic syndrome despite antiretroviral therapy, immunosuppressive treatment initiation was decided. Immunosuppressive therapy consisted of three intravenous methylprednisolone pulses of 500 mg, followed by oral prednisone (1 mg/kg/d), which was gradually tapered to 5 mg by Month 4 and mycophenolic sodium at an initial dose of 1080 mg/d and titrated to 1440 mg/d after two weeks. The patient was followed regularly at the renal department and HIV clinic.
Six months after treatment initiation, the CD4+ lymphocyte count had increased to 100/mm 3 , and the HIV viral load was undetectable (157 copies/mL). The patient's nephrotic syndrome persisted, however, and no improvement in his kidney function was observed; serum creatinine levels were 141 µmol/L and urine protein levels were 5.5 g/d. Moreover, due to mycophenolate acid-related leukopenia development, mycophenolate sodium was discontinued. Based on previous experience with calcineurin inhibitors (CNIs) in nephrotic syndrome, particularly primary membranous nephropathy, we decided to

Discussion
Renal dysfunction remains a frequent consequence of HIV infection, occurring in up to 30% of affected patients. Acute or chronic kidney disease may occur as a direct complication of HIV infection or as a result of combined antiretroviral therapy and other chronic comorbid conditions, including hypertension and type 2 diabetes mellitus. Despite the introduction of HAART, the prevalence of end-stage kidney disease (ESKD) continues to increase, affecting approximately 35% of patients with HIV-associated chronic kidney disease (CKD) [16]. On account of the increased risk for CKD among HIV patients, regular screening for renal impairment, especially in the African American population, is advised. Many potential reasons have been proposed, such as differences in patient preferences, environmental factors, and genetics. Acute kidney injury is present in 6% of hospitalized patients with HIV infection, and it is associated with a mortality rate of 27% [17,18]. Furthermore, HIV-infected patients may develop various glomerular disorders. The spectrum of glomerular lesions depends on race, accompanying infections, and response to HIV treatment [19].
Three HIV-associated histologic patterns of glomerular injury are more commonly observed: thrombotic microangiopathy (TMA), HIV immune complex kidney disease (HIVICK), and HIV-associated nephropathy (HIVAN). HIV-related thrombotic microangiopathy is associated with hematuria and proteinuria. The pathophysiological mechanism has not been fully elucidated but seems to be associated with ADAMTS-13 levels. [20,21]. Plasma exchange or plasma infusion appears to be an effective treatment option. The reported prevalence of HIVICK varies worldwide, which might, in part, reflect genetic differences worldwide. While HIVAN, a collapsing variant of focal segmental glomerulosclerosis (FSGS), is more commonly observed in African Americans patients, HIV-ICK seems to predominantly affect Caucasian and Asian populations according to recent studies [22]. Data from a large kidney biopsy series revealed that patients with HIVICK tend to have hypertension, increased CD4+ T cells, lower viral load, a higher estimated glomerular filtration rate, and a lower degree of proteinuria than HIVAN patients at the time of biopsy. They are also more likely to have hepatitis B or C virus coinfection and to

Discussion
Renal dysfunction remains a frequent consequence of HIV infection, occurring in up to 30% of affected patients. Acute or chronic kidney disease may occur as a direct complication of HIV infection or as a result of combined antiretroviral therapy and other chronic comorbid conditions, including hypertension and type 2 diabetes mellitus. Despite the introduction of HAART, the prevalence of end-stage kidney disease (ESKD) continues to increase, affecting approximately 35% of patients with HIV-associated chronic kidney disease (CKD) [16]. On account of the increased risk for CKD among HIV patients, regular screening for renal impairment, especially in the African American population, is advised. Many potential reasons have been proposed, such as differences in patient preferences, environmental factors, and genetics. Acute kidney injury is present in 6% of hospitalized patients with HIV infection, and it is associated with a mortality rate of 27% [17,18]. Furthermore, HIV-infected patients may develop various glomerular disorders. The spectrum of glomerular lesions depends on race, accompanying infections, and response to HIV treatment [19].
Three HIV-associated histologic patterns of glomerular injury are more commonly observed: thrombotic microangiopathy (TMA), HIV immune complex kidney disease (HIVICK), and HIV-associated nephropathy (HIVAN). HIV-related thrombotic microangiopathy is associated with hematuria and proteinuria. The pathophysiological mechanism has not been fully elucidated but seems to be associated with ADAMTS-13 levels. [20,21]. Plasma exchange or plasma infusion appears to be an effective treatment option. The reported prevalence of HIVICK varies worldwide, which might, in part, reflect genetic differences worldwide. While HIVAN, a collapsing variant of focal segmental glomerulosclerosis (FSGS), is more commonly observed in African Americans patients, HIVICK seems to predominantly affect Caucasian and Asian populations according to recent studies [22]. Data from a large kidney biopsy series revealed that patients with HIVICK tend to have hypertension, increased CD4+ T cells, lower viral load, a higher estimated glomerular filtration rate, and a lower degree of proteinuria than HIVAN patients at the time of biopsy. They are also more likely to have hepatitis B or C virus coinfection and to use intravenous drugs [23]. Suppression of plasma viremia with HAART has been shown to improve kidney function in patients with HIVAN but does not appear to affect disease progression in HIVICK [24,25]. The spectrum of HIV nephropathy has changed with the introduction of HAART regimens. Notably, antiretroviral therapy can contribute to renal dysfunction either directly by inducing acute tubular necrosis, acute interstitial nephritis, crystal nephropathy, and renal tubular disorders or via drug interaction. Therefore, a systematic screening for kidney injury in all HIV patients on a regular basis is advised. However, potential renal side-effects of antiretroviral medication should not prevent clinicians from introducing HAART treatment in patients with kidney dysfunction, but close monitoring of renal function and early detection of risk factors are required.
HIV-associated lupus-like nephropathy is included in the spectrum of HIVICK and has been described in patients with renal biopsy features that share proliferative lupus nephritis features by light microscopy and immunofluorescence in the absence of clinical or serologic evidence of SLE. Light microscopic examination of renal tissue reveals a wide spectrum of findings including focal or diffuse mesangial hypercellularity and endocapillary proliferative lesions, fibrinoid necrosis and crescents, wire loops, spiky thickening of the glomerular basement membrane, tubular injury, microcysts filled with periodic acid-Schiff-positive casts, oedema, and inflammatory infiltrates of the interstitium. A "full-house" pattern is present on immunofluorescence, with concurrent IgG, IgM, IgA, C3, and C1q expression. Electron microscopy findings include large mesangial or subendothelial intra-membranous and subepithelial deposits and tubuloreticular inclusion bodies [26][27][28].
A literature search for relevant articles using PubMed, Medline, and Scopus was performed. No date limits were applied, and the last update was in January 2022. The keywords "lupus-like glomerulonephritis", "lupus-like nephropathy", "HIV-patients", and "HIV-infection" were used. Search fields were restricted in the "Title/ abstract" and in human species.
Since 1993, 83 patients with lupus-like nephritis and HIV infection have been reported worldwide (Table 3). In 1993, Nochy et al. reported that 22 of 60 (37%) French HIV-positive patients who underwent renal biopsy had some form of immune complex glomerulonephritis, with or without concurrent HIVAN, and 10 of these 22 biopsies showed histologic, immunofluorescence, and electron microscopic features resembling diffuse proliferative lupus nephritis [29]. In 1999, Casanova et al. reported the results of renal biopsies performed in 26 Italian HIV-positive patients, all Caucasian [30]. Twenty of these patients had immune complex glomerulonephritis, none had HIVAN. A total of 3 of the 20 cases with immune complex deposits showed proliferative glomerulonephritis with lupus-like features, with subendothelial deposits in all three cases and hyaline thrombi and "wire loops" in two cases, although immunofluorescence studies were not performed in one case. The largest and most recent cohort comes from Columbia University. It is a retrospective histopathologic analysis of all HIV-positive patients with kidney biopsy interpreted at Columbia University from 2010 to 2018 by Kudose et al. [22]. They reported 437 renal biopsies in HIV patients, identifying 59 cases of classic HIVAN, 66 HIVICK, and 9 lupus-like nephritis. To be noted, no data for treatment or clinical outcomes are reported in these case series. were more likely to ultimately require hemodialysis (69.8% vs. 11.1% p < 0.0001) and had significantly worse survival than patients with HIVICK [33]. The optimal management of immune complex glomerulonephritis in the context of HIV infection is not clear. The role of immunosuppression has not been established yet. Single HIVICK cases, including patients with lupus-like features, where corticosteroids have been used, showed little benefit [34,35]. MPAA is the standard of care for induction and maintenance therapy in proliferative lupus nephritis with a favourable efficacy and tolerability profile. MPAA seems to modulate glomerular inflammation induced by immune complex deposition, thereby mitigating kidney injury. In HIVICK, HIV immune complexes circulating in the bloodstream are deposited in the kidneys. These circulating immune complexes trigger immune-mediated inflammatory kidney injury, which explains, in part, why HIV-associated glomerulonephritis shares similar histopathologic lesions with LN. These observations led Tiong et al. to suggest that patients with HIV-associated lupus-like nephritis may respond to therapies traditionally used in primary LN, which is why they were the first to use MPAA [13]. In line with the above, Kalyan et al. described the use Life 2023, 13, 641 9 of 11 of rituximab in an HIV patient with lupus-like membranous nephropathy who achieved partial remission [14]. Among the various case reports [36][37][38][39][40], two cases show interesting results in terms of therapeutic modalities. Matignon et al. [41], in 2005, and Yang et al. [39], in 2014, described two cases in which complete remission was achieved only using HAART therapy, while a case report by Chandran et al. [42] described a kidney transplant HIV patient with recurrent HIV-associated lupus-like nephritis whose kidney function has remained stable, even though no specific therapy was instituted.
The benefit of calcineurin inhibitor (CNIs) in patients with nephrotic syndrome is well established. A dose-dependent increase in renal vascular resistance at the level of the afferent arteriole leading to a reduction in renal blood flow, glomerular filtration pressure, and ultimately the amount of albumin filtered is a principal mechanism for CNI-induced proteinuria reduction. Additionally, studies have shown that CNIs exert a protective effect on synaptopodin phosphorylation, which is critical for the integrity of the podocyte actin cytoskeleton. Considering the aforementioned studies, CNIs seem to stabilize the actin cytoskeleton, which is disrupted in patients with foot process effacement, improving the podocyte function [43][44][45][46][47]. Our patient presented with nephrotic syndrome and mild renal impairment in the setting of HIV infection. The renal biopsy revealed membranous nephropathy features with a "full-house" pattern by immunofluorescence. Based on the above literature for HIV-associated "lupus-like" nephropathy, we decided to treat him initially with HAART alone and, afterwards, in combination with MPAA and prednisone, with no improvement in his proteinuria. Considering the well-established antiproteinuric effect of CNIs, he was subsequently treated with tacrolimus, achieving partial remission of his proteinuria, and avoiding MPAA-associated adverse events.

Conclusions
This case highlights the important role of renal biopsy in HIV-infected patients for diagnosing and differentiating HIVICK from HIVAN and other glomerular diseases. No consensus for the management of HIVICK has yet been reported due to the limited existing data. The safety of immunosuppressive treatment in patients already at risk for opportunistic infections and the potential interactions with HAART raise concerns regarding the optimal treatment approach for HIV-associated immune complex glomerulonephritis. To our knowledge, this the first case of HIVICK that was treated with tacrolimus in combination with antiretroviral therapy. Based on our experience, calcineurin inhibitors may be considered as an additional safe therapeutic option in order to ameliorate proteinuria in patients with HIVICK. Funding: This research did not receive any specific grants.

Informed Consent Statement:
Written informed consent has been obtained from the patient to publish this paper.

Data Availability Statement:
The data that support the findings of this study are available from the corresponding author, upon reasonable request.