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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2022  |  Volume : 33  |  Issue : 1  |  Page : 210-215
Chronic Hepatitis B and Nephrotic Syndrome in Children: Treatment Outcomes


1 Department of Pediatrics, Maulana Azad Medical College and Associated Lok Nayak Hospital, New Delhi, India
2 Department of Pathology, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research, Delhi, India

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Date of Web Publication16-Jan-2023
 

   Abstract 


Hepatitis B-related glomerulonephritis (GN) is an uncommon but important cause of renal morbidity in children. While immunosuppressive therapy has been tried along with antivirals for treatment, some children may undergo spontaneous remission or achieve remission with antivirals alone. We retrospectively studied the outcomes of children with nephrotic syndrome (NS) and chronic hepatitis B infection treated at our nephrology clinic over a five years period; seven children were included of which six (86%) presented with NS and one with nephritic syndrome. Renal biopsy (done in 5 children) showed membranous GN in two (40%), membranoproliferative GN in one (20%), and focal segmental glomerulosclerosis in two (40%). Entecavir therapy was started in 6/7(86%) and four (57%) achieved remission after a median period of 2.7 months and achieved hepatitis B e-antigen seroconversion after mean duration of 1.2 years of treatment with entecavir; the remaining achieved remission with immunosuppression with calcineurin inhibitors.

How to cite this article:
Agrwal S, Mantan M, Agrawal A, Batra VV. Chronic Hepatitis B and Nephrotic Syndrome in Children: Treatment Outcomes. Saudi J Kidney Dis Transpl 2022;33:210-5

How to cite this URL:
Agrwal S, Mantan M, Agrawal A, Batra VV. Chronic Hepatitis B and Nephrotic Syndrome in Children: Treatment Outcomes. Saudi J Kidney Dis Transpl [serial online] 2022 [cited 2023 Jan 29];33:210-5. Available from: https://www.sjkdt.org/text.asp?2022/33/1/210/367818



   Introduction Top


Hepatitis B is an important public health problem and an important cause of morbidity and mortality in children. It is estimated that there are more than 240 million hepatitis B virus (HBV) carriers in the world.[1] India is an intermediate endemicity zone with about 4% population being infected with hepatitis B and chronic hepatitis B accounts for about 50% of chronic liver disease.[2] Extrahepatic manifestations of hepatitis B also occur as a result of immunological response of the host; circulating immune complexes are primarily responsible in most instances. Some common extrahepatic manifestations are glomerulonephritis (GN), arthritis, and vasculitis and can occur without overt hepatic involvement also.[3]

Hepatitis B-related GN is caused by deposition of immune complexes in the glomeruli.[3] The association of hepatitis B with glomerular disease was described as early as the 1970s.[4] While spontaneous remission is common in children with HBV-related GN with favorable prognosis, adults usually require treatment and up to 30% may develop end-stage renal disease.[5] The recommended treatment for glomerulopathy is same as for chronic hepatitis B infection and includes antivirals (interferon or nucleoside analogs).[6] Therapy with antivirals is often sufficient to induce sustained remission of the disease; combination treatment of antivirals with immunosuppressive agents has also been found successful without any adverse effect on viral proliferation.[5],[7],[8] In this case series, we describe the course and outcome of seven children identified with hepatitis-related glomerulopathy.


   Methodology Top


This study was done at a tertiary care teaching hospital located in the northern part of India. Records of all children (1–12 years) who presented to the hospital between 2014 and 2019 with nephrotic syndrome (NS) and evidence of chronic hepatitis B infection were retrieved. The clinical presentation, investigations, serology, biopsy features, treatment, and follow-up of these children were recorded in a detailed pro forma. The data were tabulated and analyzed using descriptive statistics of Microsoft excel.


   Results Top


Seven boys with mean [standard deviation (SD)] age of nine (2.1) years were identified with hepatitis B-associated nephropathy. The mean (SD) age of the onset of renal symptoms was seven (2.9) years. Six (85%) children presented with features of NS and had heavy proteinuria while one child had nephritic presentation (hematuria, hypertension). All of them presented with edema and oliguria while hypertension was present in one (15%). None of them had fever, jaundice, arthritis, bleeding manifestation, or encephalopathy. None of them had received blood transfusion or undergone any unsafe injection or surgery in the past and all were unimmunized for hepatitis B.

The investigations revealed mean (SD) serum albumin and cholesterol levels of 1.7 (0.2) mg/dL and 314 (114) mg/dL respectively; mean serum creatinine levels were 0.67 (0.46) mg/dL with mean estimated glomerular filtration rate of 107 (43) mL/min/1.73 m2 using modified Schwartz formula. The mean alanine transaminase and aspartate transaminase levels were 53 (49) IU/L and 50.7 (38.7) IU/L and the prothrombin time was normal in all. The serology showed that 6/7 (85%) were positive for hepatitis B surface antigen (HBsAg) at presentation and five (71%) had positive hepatitis B e-antigen (HBeAg) and were negative for anti-HBeAg antibodies while one had already achieved HBeAg seroconversion (was negative for HBeAg and had anti-HBeAg antibodies). One patient had also achieved HBsAg seroconversion (HBsAg negative, HBeAg negative, and anti-HBeAg positive) at presentation. Anti-nuclear antibody and anti-neutrophil cytoplasmic antibody were negative for all. The details of biochemical and serological investigations are provided in [Table 1].
Table 1: Clinical details of the patients.

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The median HBV DNA levels of the patients were 3.1 million U/mL; one child had a value <2000 U/mL and another had undetectable DNA levels. The ultrasound of the abdomen revealed normal-sized liver and echogenicity in all except one who had evidence of chronic liver disease with coarsened echotexture with splenomegaly. Family screening for hepatitis B was negative in all.

All children were initially treated as idiopathic NS and started on steroids and later referred to us in view of positive HBsAg status. The renal biopsy was done in five children (2 patients did not give consent for biopsy); 2/5 (40%) showed features of membranous nephropathy (MN) with thickened basement membranes and spikes on silver methenamine stain [Figure 1]a and [[Figure 1]b, 1/5 (20%) had membranoproliferative changes [membranoproliferative GN (MPGN)] and 2/5 (40%) had features of focal segmental glomerulosclerosis (FSGS) [Figure 1]c and [Figure 1]d. Liver biopsy could be performed only in two children which showed features of chronic active hepatitis with mild activity.
Figure 1:(a and b) PAS and JMS stained sections of kidney biopsy of patient 4 showing thickened basement membranes with duplication and focal spikes (arrow) (×40), (c) PAS stained slides of patient 7 at low power showing glomeruli with segmental sclerosis and chronic parenchymal damage (×10), (d) PAS stained slides of patient 7 at high power showed the segmental sclerosed tuft (×20).
PAS: Periodic acid Schiff, JMS: Jones silver methenamine.


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Course on therapy

Treatment was initiated with entecavir in six (85%) children; after a mean (SD) duration of 1.2 (0.89) years all six (100%) had achieved HBeAg seroconversion (including one child who was already HBeAg negative), 2/6 had HBsAg surface antigen loss too and all except one had undetectable HBV DNA levels in blood. While on antiviral therapy none of these patients reported any entecavir-related side effects; four (66%) children achieved complete remission of proteinuria after a mean duration of 2.7 (range 1–4) months of treatment with entecavir. One child who did not achieve remission of proteinuria even after eight months of entecavir therapy had membranous GN (MGN) on biopsy. However, he had undergone HBeAg seroconversion with HBV DNA levels of <6 U/mL and his liver enzymes too normalized on therapy. Failure to undergo remission despite adequate control of HBV proliferation was a pointer towards idiopathic MGN and he was started on cyclosporine with prednisolone. The other child who was started on entecavir and did not achieve remission had FSGS on renal biopsy and he too was started on cyclosporine with prednisolone. Another patient had already seroconverted at presentation (did not receive antiviral therapy) and was started on tacrolimus for steroid-resistant nephrotic state. All three children who received calcineurin inhibitors (CNIs) achieved remission of nephrotic state after a mean duration of five months and CNI was continued for a total duration of two years. Overall, 4/7 (57%) patients could achieve remission of proteinuria with antiviral therapy alone thereby avoiding immunosuppressive therapy [Table 1]. Besides entecavir and immunosuppressants, all children received enalapril in doses of 0.2 mg/kg/day for reduction of proteinuria during the entire duration of treatment.


   Discussion Top


Renal diseases attributed to hepatitis B commonly are MGN, MPGN, and vasculitis; others being mesangioproliferative GN, IgA nephropathy, and amyloidosis.[3] Evidence for association of these renal lesions with hepatitis B comes from the fact that the prevalence of these lesions, especially MGN, closely follows that of hepatitis B and widespread immunization with hepatitis B has led to a reduction in the occurrence of MGN.[9],[10]

Hepatitis B-related GN is an important cause of renal morbidity, especially in regions with high endemicity. MN is the most common histopathology seen with hepatitis B in children and usually presents as NS.[9] In our series too most patients presented as NS.

Of the five children biopsied in the present study, MN was seen in 40% and FSGS in another 40% and also it was observed that the condition had male predominance (all patients enrolled were boys). Wiggelinkhuizen et al in 1983 reported HBsAg positivity in 34 (30%) out of 114 children with GN and of these 25 had MN; the condition occurred predominantly in boys.[11] Later in 1985, Cadrobbi et al reported a three years old boy with hepatitis B-related chronic active hepatitis who developed MGN which resolved with HBsAg seroconversion.[12] Ozdamar et al reported 14 Turkish children with HBV-related GN; six of them had MGN, while others had MPGN or IgA nephropathy. Spontaneous remission occurred in four while the overall remission rate was 71%.[13] A study from India on 181 adults with hepatitis B infection showed that 10 also had GN and renal biopsy showed the presence of hepatitis B antigen deposition in the basement membrane and mesangium in a majority.[14] FSGS is rarely associated with hepatitis B; of the two patients with FSGS on biopsy in the present study, one had evidence of chronic hepatitis B carrier state while the other child had already seroconverted at presentation suggesting that the renal lesion may not be related to hepatitis B and both of them also responded to immunosuppression.

Diagnosis of hepatitis B-related GN is made by the presence of circulating HBsAg, characteristic histology with exclusion of other causes of GN, and presence of hepatitis B antigen in renal biopsy.[5] Our patients too had circulating antigens, elevated HBV DNA levels and characteristic biopsy findings, however staining for hepatitis B antigen in the renal tissue could not be done.

The primary aim of therapy for HBV infection is to achieve long-term viral DNA suppression. The decision to treat depends on the HBV DNA levels, liver enzymes, and liver histology. The presence of extrahepatic manifestation is indication for starting the antiviral therapy.[1] The Kidney Disease Improving Global Outcomes guidelines recommend treatment of hepatitis B-related GN with interferon or nucleoside analogs as per the recommendations for the treatment of chronic hepatitis B infection.[6] Four of our patients responded to antiviral therapy with entecavir alone while three required further immunosuppression with steroids and CNIs for remission of proteinuria while seroconversion for HBV was achieved for all with entecavir. Immunosuppressive therapy is required for treatment of idiopathic MGN while control of the underlying disease is usually sufficient to treat true secondary MGN. The mean duration of response to proteinuria with entecavir for our patients was 2.7 months. There are reports of complete remission of hepatitis B-related MN with entecavir in children as well as in adults.[9],[15] A meta-analysis concluded that the treatment with antivirals significantly increased the chances of complete remission in HBV-MGN and no difference was found between interferon and entecavir therapy.[16] Another meta-analysis by Zhang et al showed that therapy with antivirals but not with steroids was significantly associated with remission of proteinuria and with HBeAg clearance.[17]

Although the data suggest that the antivirals are sufficient for the treatment of HBV-GN, there is a concern regarding uncertain duration of therapy with nucleoside analogs and chances of disease progression.[5] This led to trial of combination therapies with antivirals and immunosuppression. Ochi et al reported an adult with HBV-MGN treated with steroids and cyclosporine; no worsening of viral replication was observed while on therapy.[8] Tacrolimus has been shown to reduce HBV replication by inhibiting HBV receptor on hepatocytes. Wang et al reported 42 adult patients with HBV-MGN who were treated either with tacrolimus and entecavir combination therapy or entecavir alone with better remission rates in combination group with no viral reactivation during therapy.[5] We too observed that there was no reactivation of HBV during a mean follow-up of two years in our patients treated with CNIs. While there is some information on treatment of adults with hepatitis B nephropathy with immunosuppressants the information on children is relatively scant.

To conclude hepatitis B-associated nephropathy while uncommon in children may respond to viral suppression with antiviral alone or further addition of immunosuppressive therapy along with antivirals which may be added after achieving seroconversion for hepatitis B.

Conflict of interest: None declared.



 
   References Top

1.
European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol 2012;57:167-85.  Back to cited text no. 1
    
2.
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[PUBMED]  [Full text]  
3.
Shah AS, Amarapurkar DN. Spectrum of hepatitis B and renal involvement. Liver Int 2018;38:23-32.  Back to cited text no. 3
    
4.
Combes B, Shorey J, Barrera A, et al. Glomerulonephritis with deposition of Australia antigen-antibody complexes in glomerular basement membrane. Lancet 1971;2:234-7.  Back to cited text no. 4
    
5.
Wang L, Ye Z, Liang H, et al. The combination of tacrolimus and entecavir improves the remission of HBV-associated glomerulonephritis without enhancing viral replication. Am J Transl Res 2016;8:1593-600.  Back to cited text no. 5
    
6.
Kidney Disease Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl 2012;2: 139-274.  Back to cited text no. 6
    
7.
Zheng XY, Wei RB, Tang L, Li P, Zheng XD. Meta-analysis of combined therapy for adult hepatitis B virus-associated glomerulonephritis. World J Gastroenterol 2012;18:821-32.  Back to cited text no. 7
    
8.
Ochi A, Ishimura E, Ichii M, et al. Successful treatment of hepatitis B virus-associated membranous nephropathy with entecavir and immunosuppressive agents. Asian Pac Soc Nephrol 2014;9:595-6.  Back to cited text no. 8
    
9.
Mahajan V, D'Cruz S, Nada R, Sachdev A. Successful use of entecavir in hepatitis B-associated membranous nephropathy. J Trop Pediatr 2018;64:249-52.  Back to cited text no. 9
    
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Berchtold L, Zanetta G, Dahan K, et al. Efficacy and safety of rituximab in hepatitis B virus-associated PLA2R-positive membranous nephropathy. Kidney Int Rep 2018;3:486-91.  Back to cited text no. 10
    
11.
Wiggelinkhuizen J, Sinclair-Smith C, Stannard LM, Smuts H. Hepatitis B virus associated membranous glomerulonephritis. Arch Dis Child 1983;58:488-96.  Back to cited text no. 11
    
12.
Cadrobbi P, Bortolotti F, Zacchello G, Rinaldi R, Armigliato M, Realdi G. Hepatitis B virus replication in acute glomerulonephritis with chronic active hepatitis. Arch Dis Child 1985; 60:583-5.  Back to cited text no. 12
    
13.
Ozdamar SO, Gucer S, Tinaztepe K. Hepatitis-B virus associated nephropathies: A clinicopathological study in 14 children. Pediatr Nephrol 2003;18:23-8.  Back to cited text no. 13
    
14.
Amarapurkar DN, Kirpalani A, Amarapurkar A. Role of hepatitis in glomerulonephritis. Bombay Hosp J 2001;43:128-34.  Back to cited text no. 14
    
15.
Yang YF, Xiong QF, Zhao W, Zhong YD. Complete remission of hepatitis B virus-related membranous nephropathy after entecavir monotherapy. Clin Res Hepatol Gastroenterol 2012;36:e89-92.  Back to cited text no. 15
    
16.
Yang Y, Ma YP, Chen DP, Zhuo L, Li WG. A meta-analysis of antiviral therapy for hepatitis B virus-associated membranous nephropathy. PLoS One 2016;11:e0160437.  Back to cited text no. 16
    
17.
Zhang Y, Zhou JH, Yin XL, Wang FY. Treatment of hepatitis B virus-associated glomerulonephritis: A meta-analysis. World J Gastroenterol 2010;16:770-7.  Back to cited text no. 17
    

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Correspondence Address:
Mukta Mantan
Department of Pediatrics, Maulana Azad Medical College and Associated Lok Nayak Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1319-2442.367818

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