Hepatitis B–Associated Lupus-Like Glomerulonephritis Successfully Treated With Antiretroviral Drugs and Prednisone: A Case Report and Literature Review

Introduction

Kidney involvement with hepatitis B virus (HBV) is varied and mostly limited to nephrotic syndrome with membranous nephropathy (MN) and nephritic syndrome with membranous proliferative glomerulonephritis (MPGN). Hepatitis B Virus nephropathy (HBVN) most commonly presents as MN which usually has subepithelial deposits. The subendothelial glomerulonephritis (GN) condition, although reported to be associated with hepatitis C virus (HCV), is quite uncommon in patients with hepatitis B. Here we have a unique situation of a young male patient presenting with nephrotic range proteinuria and found to have hepatitis B–associated lupus-like GN with subendothelial electron-dense deposits. In this discussion, we would like to elaborate on the pathophysiology of common types of HBVN and approach a case that poses a diagnostic dilemma when the glomerular pathology is suggestive of lupus nephritis with negative lupus serology and lack of clinical features seen in lupus. Our case is unique and broadens the type of kidney disease which can occur with hepatitis B infection.

Case Report

A 46-year-old Caucasian gentleman with a past medical history of tetralogy of Fallot with multiple prior cardiac procedures, essential hypertension, and heart failure with preserved ejection fraction walked into the emergency department (ED) with symptoms of gradual worsening shortness of breath and generalized weakness. This was accompanied by progressive swelling of the ankles along with low-grade fever, petechial rashes of bilateral lower extremities for the last 2 weeks. In the ED, vital signs measured recorded a blood pressure of 176/86 mm Hg, heart rate of 83 beats/min, temperature 38° Celsius, and pulse oxygen saturation of 97% on 2-liter oxygen. Physical examination revealed grade 4/6 systolic ejection murmur at the neo-aortic area, bilateral nonpitting 1 + pedal edema, and non-blanching petechial rashes in both lower extremities. The rest of the systemic physical examination findings were unremarkable. Laboratory tests are as follows in Table 1. Of note, his creatinine was normal at 1.1 mg/dL at outpatient labs done 3 months ago. Urine analysis revealed large amount of blood with 3 + protein. The urine protein creatinine ratio was elevated at 3.2 gm/g (grams/gram). Brain natriuretic peptide (BNP) was elevated. Chest x-ray did suggest congestion cardiomegaly with diffuse interstitial infiltrates bilaterally (Figure 1). Computed tomography (CT) abdomen pelvis without contrast revealed incidental detection of absent left kidney, mild nonspecific enlargement of right kidney but otherwise no stones or hydronephrosis. The initial working diagnosis was cardiorenal syndrome with possible acute GN. Despite aggressive diuresis with furosemide 80 mg 3 times daily, he did not make much progress with urine output and his creatinine continued to stay elevated and went up to 5.1 mg/dL. An echocardiogram done suggested an ejection fraction of 50% to 55% with normal left ventricular diastolic function. Blood cultures returned negative. Because of low white blood cell count on presentation, recurrent low-grade fever at home, and petechial rash with acute kidney, initially, the diagnosis was thought to be infectious etiology of unknown origin with infective endocarditis in the differential. He was continued on intravenous vancomycin and piperacillin/tazobactam for broad-spectrum coverage. A transesophageal echocardiogram was done as per infectious disease recommendation which returned negative for any vegetations. Serological workup for GN revealed low Complement 4 (C4) level, normal C3 level, positive antinuclear antibody (ANA), negative anti-double-stranded DNA (dsDNA), and negative anti-neutrophilic cytoplasmic antibody (ANCA) level. Interestingly, his HBV workup came positive for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody negative, hepatitis B core antibody positive. Hepatitis C antibody and HIV were negative. Subsequently, his hepatitis Be antigen was positive, IgM anti-hepatitis B core antibody was negative, and HBV DNA PCR was positive with 42 000 international units/mL. He was not responding with intravenous antibiotics despite the initial thought of infectious etiology being the root cause. He underwent a high-risk kidney biopsy through the right internal jugular vein on day 6 of hospitalization. Because of his solitary kidney and thrombocytopenia, kidney biopsy was considered high risk and thus was delayed. Kidney biopsy revealed hepatitis B positive lupus-like GN. Light microscopy revealed severe diffuse endocapillary hypercellularity along with severe interstitial inflammatory infiltrates without any crescents (Figures 2 and 3). Immunofluorescent microscopy revealed granular mesangial and focal subendothelial staining with Immunoglobulin (Ig) G, Ig A, Ig M, C1q, C3 among others suggestive full-house effect as seen in lupus (Figures 4 and 5). Electron microscopy revealed subendothelial glomerular deposits and mesangial plus loop deposits (Figures 6 and 7). He was started on treatment for hepatitis B with tablet entecavir 0.5 mg once daily along with a high dose of oral prednisone 60 mg daily with the tapering plan. He did not need any lupus nephritis–specific immunosuppressants such as mycophenolate or cyclophosphamide. He responded well to therapy with defervescence of fever in 2 days along with improvement of creatinine down to 2.7 mg/dL in 7 days.

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Table 1.

Laboratory Values on Admission.

Lab parameters	Value	Reference
Hemoglobin	11.4 gm/dL	12.5-14.5 gm/dL
Hematocrit	31.9%	39%-51%
White blood cells	3.1 × 103/microliter	4-11 × 103/microliter
Platelet counts	56 × 103/microliter	150-450 × 103/microliter
Serum sodium	134 mEq/L	135-145 mEq/L
Serum potassium	5 mEq/L	3.5-5.1 mEq/L
Bicarbonate	19 mEq/L	24 mEq/L
Blood urea nitrogen	46 mg/dL	<10 mg/dL
Creatinine	4.2 mg/dL	< 1.1 mg/dL
Albumin	2.5 gm/dL	3.5-5 gm/dL
Total bilirubin	0.8 mg/dL	<1.2 mg/dL
Aspartate aminotransferase	25 IU/L	<40 IU/L
Alanine aminotransferase	32 IU/L	<40 IU/L
Alkaline phosphatase	56 IU/L	40-129 IU/L
Brain natriuretic peptide	1153 pg/mL	< 300 pg/mL
International normalized ratio	1.2	<1.1

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Figure 1.

Chest x-ray showing enlarged heart and vascular congestion.

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Figure 2.

Hematoxylin and eosin-stained light microscopy showing neutrophilic debris in glomeruli.

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Figure 3.

Periodic acid-Schiff-stained light microscopy showing endocapillary hypercellularity.

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Figure 4.

Immune microscopy demonstrating Ig M deposits.

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Figure 5.

Immune microscopy demonstrating C 3 deposits.

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Figure 6.

Electron microscopy showing subendothelial deposits.

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Figure 7.

Electron microscopy showing mesangial deposits.

He was subsequently discharged with outpatient follow-up every 2 months. He did well for 8 months thereafter when his outpatient creatinine stayed in the range 2.7 to 3.0 mg/dL with Glomerular Filtration Rate from 22% to 26%. His proteinuria subsided completely too. He finished a tapering course of prednisone in 4 months and was continued on entecavir daily. However, one year later, he succumbed to a massive cerebrovascular accident from uncontrolled hypertension and cardiac complications related to his tetralogy of Fallot.

Discussion

Chronic HBV infection is prevalent in 240 million people in the world which constitutes approximately 5% to 6% of world population. Commonly, it refers to persistent HBsAg circulating in the bloodstream. In the United States, nearly 2 million people are chronic HBV carriers and 20 000 to 40 000 new cases of annual exposure to HBV occur. In all, 3% to 5% of chronic HBV carriers develop renal disease. ¹

In comparison with renal diseases from Parvovirus B19 virus, Epstein-Barr Virus or Cytomegalovirus which cause nephropathy by acute or subacute viral infection, immune-complex nephropathy caused by HBV usually occurs secondary to a lengthy carrier state. This contrasts with post-infectious GN seen in pharyngeal or cutaneous streptococcal infection which cause GN after a period of latency following resolved active infection. Demonstration of HBV antigen-antibody complexes in renal lesions via immunofluorescence microscopy has shown to document the pathogenesis of HBVN. ² The histopathological manifestations of HBVN can be classified as either immune-complex-related vasculitis, for example, polyarteritis nodosa (PAN) or as immune-complex-mediated GN like membranoproliferative GN (MPGN), membranous GN, and IgA nephropathy. HBVN is commonly seen in children than in adults and more in men than in women. ³ The most common type of GN in humans is MN and is frequently seen in children. By contrast, MPGN is commonly seen in adults. ⁴

On electron microscopy, the appearance of HBV membranous nephropathy (HBVMN) is indistinguishable from idiopathic MN with both demonstrating immune-complex deposits in subepithelial space. ⁵ All 3 potential viral components, namely, HBeAg, HBcAg, and HBsAg, can act like antigens within the immune deposits found with HBVMN. ⁵ The HBeAg is the most likely responsible antigen for the immunologic injury in HBVMN. ⁶ De novo deposit formation characterized by deposition of circulating antigen in basement membrane concluded that deposition of antibody on it can occur or an immune mediated complex between IgG with any of the stated types of antigens can lead to deposits. ⁷ The HBeAg is detected from the glomerulus of nearly 90% of patients with biopsy proven HBVMN and measurable circulating HBeAg is found in >95% of these patients.

The MPGN is the second most common type of nephropathy in HBV carriers and is characterized by splitting of the basement membrane and typical lobular pattern of the glomerulus with mesangial and subendothelial deposits. These glomerular deposits consist mainly of IgG and C3. ⁸ The most common glomerular antigen deposited in the subendothelial space is HBsAg. ⁹ Chronic HBV carriers can have both type 1 and type 3 MPGN. Their clinical presentation matches idiopathic MPGN with characteristic nephritic syndrome accompanied with or without nephrotic range proteinuria along with drop in levels of classic complement pathway C3 and C4. ¹⁰

In the 1980s, commonest etiology of PAN was HBV in more than 80% of the cases. With time, due to the global HBV vaccination, the prevalence of HBVN has reduced significantly along with the cases of PAN from HBV, which now contribute to <20% of total cases. PAN occurs in medium-size blood vessels as a result of HBsAg antibody immune complexes causing vasculitis leading to renal infarction and ischemia causing Acute Kidney Injury (AKI). ¹¹

In patients with IgA nephropathy and renal mesangial cells of patients with FSGS, HBV viral transcripts have been noted suggesting HBV as a possible etiology in anecdotal cases substantiating the possible causative role of HBV in a select group of Focal Segmental Glomerulosclerosis (FSGS) and Ig A patients. ¹² Case report of minimal change disease with HBV has also been documented. ¹³

Biopsy findings of tubulo reticular inclusions (TRIs) on electron microscopy, along with immunofluorescent microscopy demonstrating polytypic and polyclonal complement immune complexes “full-house” findings, appear to be highly suggestive of Lupus nephritis.^14,15 In some cases of HBVN, immune depositions of polyclonal immuno-globulins associated with polytypic complements in glomeruli have been noted.^15-17 The TRIs are commonly seen in systemic lupus erythematosus and HIV-associated renal disease and now also been seen in HCV- and HBV-related glomerular lesions. ¹⁸ TRIs are seen with upregulation of endogenous interferons associated with viral illness and their presence makes the diagnosis of idiopathic etiology of MN less likely and more likely due to infectious or autoimmune in origin.

In demographics where HBV infection is endemic, “full house” immuno-reactant glomerular pattern can also suggest HBVMN is an alternative possibility in addition to lupus nephritis.^9,15,16 Such a pattern in HBVN has also been reported in non-endemic areas. ² The diagnosis of lupus membranous nephritis (LMN) is clear when this “full-house” pattern is accompanied by diffuse proliferative GN, because such a lesion is rarely, if ever, a form of HBVN.^2,15,16, However, it is challenging to differentiate between HBVN and LMN at the time of biopsy when clinical features of SLE are not present.^2,17 SLE and lupus nephritis have a female predominance and attributed to hormonal and genetic factors, although no specific genetic markers have been recognized so far.^17,19,20 In contrast to lupus nephritis, HBVMN has a strong predilection in men as was noted in our case. Just a positive serum HBsAg does not always link HBV with the underlying glomerulopathy, as close to >50% with primary glomerulopathy with positive serological evidence of the virus do not always demonstrate glomerular viral antigens. ²¹

As for treatment choices, Kidney Disease Improving Global Outcomes (KDIGO) recommends Interferon-alpha (IFN) or oral antiviral agents representing either nucleoside (entecavir, telbivudine, lamivudine) or nucleotide reverse transcription inhibitors (adefovir, tenofovir) for HBVMN. ²² The most used agent associated with complete resolution of the MN lesion and initial remission of viremia in 75% to 80% of patients are lamivudine. However, because of a somatic mutation of the HBV reverse transcription gene, this drug is meeting with a resistance rate of 20% yearly. ²³ Therefore, either tenofovir or entecavir have become the first-line therapy due to absence of clinical resistance so far. ²⁴ As a therapeutic trial, corticosteroids can be given for a period of <6 months for symptomatic relief of proteinuria without much significant effect on HBV viremia, liver disease, or overall morbidity or mortality if used concomitant with antiviral therapy. ²⁵

Lastly, our discussion would be incomplete without mentioning transjugular renal biopsy briefly. This is mainly performed in situations where percutaneous kidney biopsy might be risky such as cases of coagulopathy, solitary kidney, too small kidneys bilaterally, or where very high body mass index precludes patients’ lying down in prone position. With the patient lying in a supine position, transjugular renal biopsy is approached mainly with a guidewire running through the right internal jugular vein into the inferior vena cava and then to the right renal vein. Thereafter, sample is obtained through one of the subcortical veins through a trucut needle in a flexible sheath. ²⁶

Conclusion

The HBVMN and HBV MPGN are the commonly reported renal pathologies. Incidence of lupus-like HBV-related nephropathy has rarely been reported. The treatments for lupus-like nephropathy and lupus nephropathy are different and physicians should be aware of this rare association to facilitate timely recovery from this glomerular pathology with appropriate antiretroviral therapy.