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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2018  |  Volume : 29  |  Issue : 3  |  Page : 714-718
Should antiviral monotherapy with nucleotide analogs be the primary treatment option for focal segmental glomerulosclerosis-related nephrotic syndrome in chronic hepatitis B infection?


1 Division of Nephrology, University Medicine Cluster; Department of Medicine, Yong Loo Lin School of Medicine, National University Hospital, Singapore
2 Division of Nephrology, University Medicine Cluster, National University Hospital, Singapore

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Date of Submission28-Mar-2017
Date of Acceptance26-Apr-2017
Date of Web Publication28-Jun-2018
 

   Abstract 

Renal involvement is the most common extrahepatic manifestation of chronic hepatitis B virus (HBV) infection. While membranous nephropathy is the most frequent, the association with focal segmental glomerulosclerosis (FSGS) is not as strong, and only a few cases have been described in the literature. In particular, the tip variant FSGS is extremely rare and to our knowledge has not previously been described in association with chronic HBV infection. The management of such cases can be challenging. Immunosuppression may lead to enhanced viral replication and flare-up of the hepatic disease. Antiviral treatment has been reported to induce remission in hepatitis B-associated glomerulonephritis in a few cases. However, their use is primarily restricted to the treatment of associated liver disease, and the current guidelines do not provide specific recommendations on HBV-mediated kidney disease in the absence of hepatic involvement. We describe a case of nephrotic syndrome due to secondary tip variant FSGS in a patient with chronic HBV infection who went into complete remission with antiviral therapy alone and present an argument for the use of oral antiviral agents as the primary treatment option for FSGS-related nephrotic syndrome in chronic HBV-infected patients without progressive liver disease.

How to cite this article:
Javaid MM, Khatri P, Subramanian S. Should antiviral monotherapy with nucleotide analogs be the primary treatment option for focal segmental glomerulosclerosis-related nephrotic syndrome in chronic hepatitis B infection?. Saudi J Kidney Dis Transpl 2018;29:714-8

How to cite this URL:
Javaid MM, Khatri P, Subramanian S. Should antiviral monotherapy with nucleotide analogs be the primary treatment option for focal segmental glomerulosclerosis-related nephrotic syndrome in chronic hepatitis B infection?. Saudi J Kidney Dis Transpl [serial online] 2018 [cited 2022 Jun 25];29:714-8. Available from: https://www.sjkdt.org/text.asp?2018/29/3/714/235166

   Introduction Top


Chronic hepatitis B virus (HBV) infection is a global health problem affecting around 248 million individuals worldwide.[1] In the United States, approximately two million people are chronic HBV carriers with 20,000–40,000 new cases diagnosed annually.[2] HBV-related nephro-pathy is one of the most common extrahepatic manifestations affecting 3%–5% of patients with chronic HBV infection.[3] Several morphological patterns of renal disease, including membranous nephropathy (MN), membrano-proliferative glomerulonephritis (MPGN), IgA nephropathy (IgAN), and focal segmental glomerulosclerosis (FSGS) have been described in association with chronic HBV infections.[4] While MN and MPGN are the well-recognized histological diagnosis, the association with other forms of glomerular diseases is not as strong, and only a few cases of FSGS related nephrotic syndrome have been reported in the literature.[5],[6],[7] In particular, the tip variant FSGS is extremely rare and to our knowledge has not previously been described in association with chronic HBV infection. In adults, spontaneous remission of HBV-mediated glomerulonephritis is rare, and the disease is usually progressive. Patients with nephrotic syndrome and abnormal liver function tests have the worst prognosis, with 50% progressing to end-stage renal disease.[8] Therapeutic intervention with immuno-suppression is often challenging and may lead to enhanced viral replication and flare-up of hepatic disease.[9] The treatment of chronic HBV infection with antiviral agents has been shown to be effective in MN. However, their use is primarily limited to the treatment of the hepatic disease. The current guidelines do not provide specific recommendations on HBV-mediated kidney disease in the absence of the evidence of hepatic involvement.[10],[11]

We describe a case of secondary nephrotic syndrome due to tip variant FSGS in a patient with chronic HBV infection. The patient went into complete remission with antiviral therapy alone. We also present a brief literature review and an argument for the use of oral antiviral agents as the primary treatment option for FSGS with nephrotic syndrome in chronic HBV-infected patients without progressive liver disease.


   Case Report Top


A 22-year-old Vietnamese female presented with a 4-week history of progressive bilateral lower limb edema. She was a known chronic HBV carrier, acquired through vertical transmission from her mother. In the past, her HBV-DNA had been undetectable, and she had not required antiviral treatment. On examination, she looked well. She had a blood pressure of 133/93 mm Hg, pulse rate of 77 beats per minute, and temperature of 37°C. She had bilateral pitting edema up to her knees. Examinations of respiratory, cardiovascular, and gastrointestinal systems were normal. She did not have any stigmata of chronic liver disease.

Investigations showed a hemoglobin of 14.5 g/dL, serum urea of 3.7 mmol/L, and serum creatinine of 56 umol/L. Liver transaminases were normal with aspartate transaminase of 28 U/L, alanine aminotransferase of 18 U/L, and alkaline phosphatase of 63 U/L. She had a normal international normalized ratio measuring 0.87. Serum albumin was low measuring 21 g/L. A 24-h urinary protein excretion measured 8.2 g/day. Antinuclear antibody, anti-double-stranded DNA and complement C3, C4 levels were within normal limits. HIV antigen and antibody and anti-hepatitis C antibody were negative. Hepatitis B surface and envelope antigens (HBsAg and HBeAg) were positive. Hepatitis B envelope antibody (anti-HBe) was nonreactive. HBV load was markedly elevated above 1 χ 109 copies/mL. An ultrasound of the abdomen did not show any significant hepatic or renal abnormality.

A renal biopsy was done which showed segmental sclerosis in 3/21 glomeruli with features consistent with a tip variant of FSGS [Figure 1] and [Figure 2]. Immunofluorescence showed a negative pattern. Although we were unable to identify HBV antigens in the biopsy material, the temporal relationship between the increased HBV load and development of nephrotic syndrome convinced us about the diagnosis of HBV-associated glomerulonephritis.
Figure 1: Hematoxylin and eosin stain showing tip variant FSGS.
FSGS: Focal segmental glomerulosclerosis.


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Figure 2: Silver stain showing tip variant FSGS.
FSGS: Focal segmental glomerulosclerosis.


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On account of our clinical diagnosis and high HBV load, treatment with glucocorticoids was not considered a suitable first-line therapy. A therapeutic trial with antiviral medication, Entecavir, alone was initiated in the first instance.

One month into the treatment, proteinuria started to improve. Urine protein excretion reduced to 2.2 g/day and serum albumin improved to 25 g/L. At the end of the 2nd month of therapy, proteinuria reduced further to 1.5 g/day, and serum albumin increased to 33 g/L. The patient went into complete remission of nephrotic syndrome after five months of therapy. Urine protein excretion reduced to 0.2 g/day and serum albumin levels improved to 45 g/L. HBV load decreased to 2.2 × 104 copies/mL. Eighteen months following initial presentation, the patient has continued to take Entecavir without any side effects. HBV load has reduced to 2.3 × 103 copies/mL. The patient has remained in complete remission of nephrotic syndrome. Urine protein excretion has reduced to 0.1 g/day and serum albumin has improved to 47 g/L. Renal and liver function tests have remained entirely normal.


   Discussion Top


The pathogenesis of glomerulonephritis in chronic HBV infection is not clearly understood. An immune complex-mediated injury is thought to play the central role.[3],[4],[9] While such mechanisms can explain the development of MN, MPGN, and IgAN; it might not be the primary underlying pathology in the development of HBV-associated FSGS.[6] Studies have shown that podocyte injury is the key event in the pathogenesis of FSGS.[5],[6] Zhong et al showed that the podocyte restricted expression of HIV-1 gene products is sufficient for the development of collapsing FSGS in the setting of susceptible genetic background.[12] Sakai et al postulated that similar mechanism might be responsible for the development of FSGS in HBV infections. HBV-DNA was identified in the podocytes using real-time PCR methods. Both FSGS and HBV-DNA in podocytes improved with the administration of antiviral agents.[5] We believe that our case might have similar underlying pathology. In both these cases, HBV antigens (HBsAg and HBcAg) were not identified in the renal biopsy specimens. The identification of HBV antigens in renal tissues in some reported cases might not be of clinical relevance and only represent the nonspecific trapping of these antigens in the damaged capillary walls.[6],[7] Alternatively, this disparity may reflect variation in the patho-physiological pathways, immunohistochemical methodology, or the host factors. Regardless, all the above-mentioned cases showed a response to treatment with antiviral agents, thus indicating a possible causal association between the viral infection and occurrence of nephrotic syndrome. The similar causal relationship has also been reported in other forms of glomerulonephritis in chronic HBV infection. Antiviral therapy led to the improvement in the renal function and proteinuria in a chronic HBV-infected patient with membranous nephropathy without the evidence of HBV in the kidney biopsy sample.[13] Clinical remission of minimal change disease with antiviral treatment has also been reported in children with HBV.[14]

Both interferon-α and oral nucleotide analogs including lamivudine, adefovir, telbivudine, entecavir, and tenofovir have been widely used for the treatment of chronic HBV infections.[10] Nucleotide analogs have several advantages over interferon. They work by suppressing HBV replication through their inhibitory effect on viral DNA polymerase. They have the convenience of administration and higher tolerability, but the treatment is long term.[9] Lamivudine has been the most commonly used agent in the nephrotic patients with MN and FSGS with good clinical response.[6],[7],[13] However, lamivudine monotherapy can lead to somatic mutation of HBV resulting in the development of resistance.[4],[13] For this reason, newer agents entecavir and tenofovir are now preferred as the first-line therapy as neither is associated with significant HBV resistance.[4],[9] Tenofovir, on the other hand, has been associated with renal dysfunction and proximal tubular defect. Adefovir too have similar problems with proximal tubular defects and renal impairment. In addition, primary ade-fovir resistance has also been described in a few cases.[13] Entecavir seems to be the most suitable agent for use in patients with renal problems.

In conclusion, chronic HBV infection can be associated with different variants of FSGS. The diagnosis should be considered in HBV positive patients with serological evidence of active viral replication (positive HBeAg, negative anti-HBe, and high-HBV-DNA count) who present with nephrotic syndrome and have FSGS on renal biopsy. Antiviral therapy with nucleotide analogs can be considered as a first-line treatment and may lead to remission of renal disease. However, we acknowledge that we cannot be completely confident that our intervention definitely led to the remission of nephrotic syndrome, although the temporal relationship is highly suggestive [Figure 3]. Our case should be looked on as hypothesis generating rather than practice-changing. We would advocate a multi-center randomized trial looking at the role of antiviral agents in such patients so that this question can be answered definitively.
Figure 3: Schematic relationship between HBV load, proteinuria, and serum albumin.
HBV: Hepatitis B virus.


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Conflict of interest: None declared.

 
   References Top

1.
Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: New estimates of age-specific HBsAg seroprevalence and endemicity. Vaccine 2012; 30:2212-9.  Back to cited text no. 1
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2.
Zampino R, Boemio A, Sagnelli C, et al. Hepatitis B virus burden in developing countries. World J Gastroenterol 2015;21: 11941-53.  Back to cited text no. 2
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3.
Gupta A, Quigg RJ. Glomerular diseases associated with hepatitis B and C. Adv Chronic Kidney Dis 2015;22:343-51.  Back to cited text no. 3
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4.
Kupin WL. Viral-associated GN: Hepatitis B and other viral infections. Clin J Am Soc Nephrol 2017;12:1529-33.  Back to cited text no. 4
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5.
Sakai K, Morito N, Usui J, et al. Focal segmental glomerulosclerosis as a complication of hepatitis B virus infection. Nephrol Dial Transplant 2011;26:371-3.  Back to cited text no. 5
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6.
Khaira A, Upadhyay BK, Sharma A, et al. Hepatitis B virus associated focal and segmental glomerular sclerosis: Report of two cases and review of literature. Clin Exp Nephrol 2009;13:373-7.  Back to cited text no. 6
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7.
Sakallioglu O, Gok F, Kalman S, et al. Hepatitis B complicated focal segmental glomerulosclerosis. J Nephrol 2005;18:433-5.  Back to cited text no. 7
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8.
Appel G. Viral infections and the kidney: HIV, hepatitis B, and hepatitis C. Cleve Clin J Med 2007;74:353-60.  Back to cited text no. 8
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9.
Kiperova B. Glomerular diseases associated with HBV and HCV infection. Acta Med Med 2014;53:58-64.  Back to cited text no. 9
    
10.
Terrault NA, Bzowej NH, Chang KM, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology 2016;63:261-83.  Back to cited text no. 10
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11.
KDIGO Glomerulonephritis Work Group. Kidney disease: Improving global outcomes. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl 2012;2:200-8.  Back to cited text no. 11
    
12.
Zhong J, Zuo Y, Ma J, et al. Expression of HIV-1 genes in podocytes alone can lead to the full spectrum of HIV-1-associated nephropathy. Kidney Int 2005;68:1048-60.  Back to cited text no. 12
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13.
Das P, Vivek V, Ford M, Kingdon E, Holt S. Hepatitis B virus related membranous glome-rulonephritis and proteinuria treated with lamivudine and tenofovir. BMJ Case Rep 2011; 2011. pii: bcr0520114287.  Back to cited text no. 13
    
14.
Zhou TB, Jiang ZP. Is there an association of hepatitis B virus infection with minimal change disease of nephrotic syndrome? A clinical observational report. Ren Fail 2015;37: 459-61.  Back to cited text no. 14
[PUBMED]    

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Correspondence Address:
Dr. Muhammad M Javaid
Division of Nephrology, University Medicine Cluster, National University Hospital, 119228
Singapore
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-2442.235166

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    Figures

  [Figure 1], [Figure 2], [Figure 3]

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