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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2015  |  Volume : 26  |  Issue : 6  |  Page : 1289-1293
Membranous nephropathy and severe acute kidney injury following influenza vaccination


Division of Kidney Diseases and Hypertension, Department of Medicine, North Shore University Hospital and Long Island Jewish Medical Center, Hofstra North Shore-LIJ School of Medicine, Great Neck, NY, USA

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Date of Web Publication30-Oct-2015
 

   Abstract 

Immunization with influenza vaccine remains an important global health strategy to prevent outbreaks and epidemics of seasonal influenza. Influenza vaccine has rarely been associated with vasculitis, acute kidney injury (AKI) and nephrotic syndrome (NS). Glomerular diseases following influenza vaccination have also been rarely reported. We report a patient who developed acute-onset massive proteinuria with NS and severe AKI soon after receiving the 2009 H1N1 influenza vaccine. Kidney biopsy showed membranous nephropathy (MN) and acute interstitial nephritis (AIN). Optimal management of glomerular diseases or AIN following influenza vaccination is not known. Our patient responded well to an initial course of oral corticosteroid therapy with normalization of serum creatinine level but had a relapse of NS with AKI soon after completion of corticosteroid therapy. A repeat kidney biopsy revealed MN and resolved AIN. A subsequent prolonged course of oral corticosteroids resulted in complete clinical remission of the NS as well as normalization of renal function. Long-term response to corticosteroid therapy in such cases is not known. However, our patient continued to remain in clinical remission with normal renal function, five years after the initial treatment.

How to cite this article:
Patel C, Shah HH. Membranous nephropathy and severe acute kidney injury following influenza vaccination. Saudi J Kidney Dis Transpl 2015;26:1289-93

How to cite this URL:
Patel C, Shah HH. Membranous nephropathy and severe acute kidney injury following influenza vaccination. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2018 Dec 18];26:1289-93. Available from: http://www.sjkdt.org/text.asp?2015/26/6/1289/168676

   Introduction Top


Seasonal influenza is an acute respiratory illness caused by influenza A or B viruses. Immunization with influenza vaccine remains the mainstay of preventive efforts to reduce the substantial health burden from seasonal influenza. However, the safety of influenza vaccine has been the focus of research for many years. Minor transitory side-effects following influenza vaccination are common, while systemic complications are rarely reported. [1] Although uncommon, exposure to influenza vaccine has been associated with autoimmune diseases like Guillain-Barré (GB) syndrome [2] and vasculitis. [3] Both glomerular and tubular diseases have also been reported following influenza vaccination. Optimal management of glomerular diseases following influenza vaccination is unknown. We report a case of an adult patient who developed abruptonset nephrotic syndrome (NS) and severe acute kidney injury (AKI) soon after receiving the 2009 H1N1 influenza vaccine. Kidney biopsy revealed membranous nephropathy (MN) and acute interstitial nephritis (AIN). Our patient initially responded to a short course of corticosteroid therapy; however, she developed a relapse of the NS and AKI soon after the completion of corticosteroid therapy. A subsequent prolonged course of corticosteroid therapy resulted in complete remission of the NS and AKI. The patient remains in clinical remission of the NS with normal renal function several years after treatment with corticosteroids.


   Case Report Top


A 60-year-old African-American female with a past medical history of bronchial asthma was referred to the emergency room (ER) by her primary medical doctor (PMD) for evaluation of elevated serum creatinine level (10.3 mg/ dL). The patient was seen by her PMD one day before her ER visit for evaluation of worsening bilateral lower extremity edema. She had received the 2009 H1N1 influenza vaccine two weeks before her ER presentation. The patient said that she developed fever, intermittent nausea and vomiting and lower extremity edema soon after being immunized with the influenza vaccine. She had refused influenza vaccination in the past as her father died from GB syndrome after receiving influenza vaccine. Review of systems was negative for sore throat, dyspnea, gross hematuria, arthralgias or rash. There was no history of drug allergy. Her home medications included montelukast, albuterol and advair. She denied use of any other medications, including non-steroidal anti-inflammatory drugs and herbal medications. There was no history of diabetes, hypertension, hepatitis or blood transfusion. She denied smoking, alcohol or intravenous drug use.

On physical examination, her blood pressure was elevated at 220/100 mm Hg and there was 3+ pitting edema of the lower extremities. She was afebrile in the ER. The rest of the examination was unremarkable.

At the time of ER presentation, the serum creatinine was elevated at 9.93 mg/dL and blood urea nitrogen was 77 mg/dL. The serum creatinine checked three months before presentation to the ER was 0.9 mg/dL. The serum total protein was 7.8 g/dL and serum albumin was low (2.3 g/dL). Because of the high globulin fraction, serum immunofixation was performed, which revealed polyclonal gammopathy but no monoclonal immunoglobulin was seen. Repeat laboratory testing performed subsequently revealed a total protein level of 4.5 g/dL and serum albumin of 2.2 g/dL. Aspartate aminotransferase was mildly elevated (49 U/L). Other liver enzymes were within normal limits. Complete blood count was normal. Urinalysis was significant for 20-30 WBC/hpf, 10-20 RBC/hpf and 3+ proteinuria. Her random urine total protein to creatinine (TP/CR) ratio was significantly elevated at 22. A 24-h urine collection revealed 20.5 g of protein. A non-contrast computed tomography (CT) scan of the abdomen and pelvis in the ER revealed no hydronephrosis or peri-nephric inflammatory changes. Chest X-ray was normal. Workup for secondary causes of the NS and AKI revealed non-reactive hepatitis C virus antibody and hepatitis B surface antigen. The antinuclear antibody, anti-neutrophil cytoplasmic antibodies (ANCA), cryoglobulins, anti-glomerular basement membrane antibody and human immunodeficiency virus (HIV) antibody were all negative. The serum complement levels were normal. A CT scan-guided kidney biopsy was subsequently performed.

Kidney biopsy findings

Eight glomeruli were identified on light microscopic examination of the kidney biopsy specimen. The glomeruli showed patent capillary loops and urinary spaces. The interstitium showed patchy edema and mild to moderate inflammatory cell infiltrate composed of mononuclear cells with many eosinophils [Figure 1].
Figure 1: Light photomicrograph of kidney biopsy specimen stained with hematoxylin and eosin stains under high-power view showing patchy interstitial edema and inflammatory cell infiltrate composed of mononuclear cells with many eosinophils (arrows).

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The arteries showed mild intimal sclerosis without vasculitis. Immunofluorescence showed scattered fine granular staining for IgG, C3, kappa and lambda light chains in the outer aspect of the glomerular capillary wall. Electron microscopy showed scattered electrondense deposits in the subepithelial and intramembranous locations [Figure 2]. Extensive effacement of the epithelial cell foot processes was seen [Figure 2]. The kidney biopsy findings were consistent with (stage 1) MN and AIN.
Figure 2: Electron photomicrograph showing subepithelial electron-dense deposits (arrow) and effacement of epithelial foot processes (arrow head).

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Clinical follow-up

The patient was initially started on furosemide and metolazone for management of edema. She was also started on amlodipine and clonidine for management of hypertension. The BP was well controlled with the above medications. As our patient was responding well to the diuretic therapy and had no uremic symptoms, she was not dialyzed. After reviewing the results of the kidney biopsy, the patient was initiated on daily oral prednisone (0.75 mg/kg) with tapering doses over the next 2.5 months. The serum creatinine normalized (1.04 mg/dL) five weeks after initiation of oral prednisone. The serum albumin normalized (3.7 g/dL) after seven weeks, while spot urine TP/CR decreased dramatically to 1.3 after nine weeks of oral corticosteroid therapy. However, one week after completion of prednisone therapy, the patient presented to the office with bilateral lower extremity swelling and 30 pounds weight gain. Laboratory tests performed during that office visit revealed a low serum albumin level of 2.1 g/dL and an elevated serum creatinine level of 2.3 mg/dL. The total cholesterol (417 mg/dL) and triglyceride (608 mg/ dL) levels were also elevated. Her spot urine TP/CR increased significantly to 28. The patient was hospitalized for management of worsening edema. Repeat kidney biopsy performed during her hospital stay revealed rare subepithelial deposits on electron microscopy with a varied degree of translucency suggestive of resorption of previous deposits. There was no evidence of AIN on repeat kidney biopsy. The patient was reinitiated on daily oral prednisone (0.75 mg/kg) soon after reviewing the biopsy results. Prednisone was gradually tapered over the next four months. Two weeks after reinitiation of corticosteroids, her serum creatinine decreased to the normal range (0.88 mg/dL), her serum albumin increased to 3.5 g/dL and spot urine TP/CR decreased to 2.2. Serum albumin improved further to 4.1 g/dL after one month of oral prednisone therapy. Proteinuria continued to decline and spot urine TP/CR normalized (0.2) two weeks after completion of the second course of oral corticosteroid therapy. Since then, the patient has refused further influenza vaccinations. At the five-year follow-up, our patient continues to remain in complete clinical remission of the NS (spot urine TP/CR of 0.1) with normal renal function (serum creatinine: 0.9 mg/dL).


   Discussion Top


Immunization with influenza vaccine is known to be effective in lowering morbidity as well as severe complications associated with seasonal influenza. Most influenza vaccines are made from virus grown in chicken eggs. They are inactivated by formaldehyde and contain whole virus, split virus or purified hemagglutinin and neuraminidase protein of virus strain that are recommended annually by the World Health Organization. [4] In the US, influenza vaccination is recommended for all children ≥6 months, all adults ≥50 years, patients with chronic medical conditions, pregnant women and health-care workers. Two major types of influenza vaccines are comercially available, live attenuated strains and inactivated vaccines. [4] The influenza vaccine induces antibodies against the major surface glycoproteins, hemagglutinin and neuraminidase. The immune response peaks at two to four weeks after one dose of the vaccine.

The most common adverse reactions associated with the inactivated influenza vaccine include injection site soreness or redness and mild constitutional symptoms such as malaise or fever. [4] Influenza vaccine has been associated with rare autoimmune complications like the GB syndrome. [2] The swine flu vaccine, first administered in 1976, was particularly associated with an increased risk for the GB syndrome. [2] In subsequent years, influenza vaccines have been carefully monitored for this possible adverse effect and have shown a negligible risk.

To the best of our knowledge, only one case of biopsy-proven MN following influenza vaccination has been previously reported in the literature. [5] The patient was a 56-year-old man who developed influenza-like illness and acute-onset NS approximately 20 days after receiving the 2009 H1N1 influenza vaccine. Renal function however was normal. Kidney biopsy was consistent with MN. He was started on an angiotensin-converting enzyme inhibitor, a statin, acetylsalicylic acid and methylprednisolone. Both edema and proteinuria subsided and the steroid dose was gradually decreased and stopped completely in the following three months. [5] The renal function also remained stable throughout the course of his treatment.

Our patient presented with abrupt-onset NS with massive proteinuria and severe AKI two weeks after she had received the 2009 H1N1 influenza vaccine. Kidney biopsy revealed MN and AIN. Abrupt onset of NS following influenza vaccination, as in our case, suggests that there might be activation of the immune system, which is triggered by the vaccine. Optimal therapy of NS with AKI following influenza vaccination is not known. Soon after our patient was initiated on oral corticosteroid therapy, she had a complete resolution of NS and AKI. This response to oral corticosteroid therapy suggests that MN was secondary in nature as primary MN hardly responds to steroids alone. Our patient, however, relapsed soon after being tapered off corticosteroid therapy. It is not clear why our patient relapsed. The repeat kidney biopsy at the time of relapse showed MN and resolved AIN. It is likely that the duration of initial course of oral corticosteroids was not long enough to sustain a remission or the relapse occurred as a result of somewhat rapid tapering of initial oral corticosteroids. The patient however responded well to the second (four months) gradual tapering course of oral corticosteroids.

MN is an immunologically mediated renal disease and is one of the most common causes of NS in adults, accounting for about 20% of the cases. [6] Most cases are considered primary where autoantibodies react with one or more podocyte antigens like M-type phospholipase A2 receptor to form subepithelial deposits causing uniform thickening of the glomerular basement membrane. [7] However, in about 25% of the cases, a secondary cause can be found, including autoimmune diseases, cancer, infections and medications. Hepatitis B antigen, hepatitis C virus, tumor antigens, thyroglobulin and DNA-containing material have been detected in the sub-epithelial deposits in patients with secondary MN. [8] These antigens might have been trapped in the glomerular basement membrane as a result of physicochemical properties. Alternatively, small circulating immune complexes containing these antigens could be deposited in the glomerular basement membrane. [8] The exact pathogenesis of MN following influenza vaccination is not known; however, it is plausible for immune complexes to form or deposit in the subepithelial space as a result of interaction between influenza vaccine antigen and native antibodies, initiating the pathologic process.


   Conclusion Top


In conclusion, we present an interesting case of MN and severe AKI following the 2009 H1N1 influenza vaccination. Optimal therapy of influenza vaccine-associated glomerular diseases including MN is unknown. Our patient remains in clinical remission with normal renal function, five years after completion of corticosteroid therapy. Based on our experience, one can consider corticosteroid therapy in patients with MN and AIN following influenza vaccination. However, further studies are required to investigate the exact pathogenesis of influenza vaccine-induced MN.


   Acknowledgment Top


The authors would like to thank Dr. Michael Esposito (pathologist) for providing the renal pathology pictures.

Conflict of interest: None declared.

Disclaimer: This case was presented (as a poster presentation) at the American Society of Nephrology Kidney Week 2013 in Atlanta, GA, USA in November 2013.

 
   References Top

1.
Kelso JM. Safety of influenza vaccines. Curr Opin Allergy Clin Immunol 2012;12:383-8.  Back to cited text no. 1
    
2.
Lehmann HC, Hartung HP, Kieseier BC, Hughes RA. Guillain-Barré syndrome after exposure to influenza virus. Lancet Infect Dis 2010;10:643-51.  Back to cited text no. 2
    
3.
Mader R, Narendran A, Lewtas J, et al. Systemic vasculitis following influenza vaccination - Report of 3 cases and literature review. J Rheumatol 1993;20:1429-31.  Back to cited text no. 3
    
4.
Fiore AE, Bridges CB, Cox NJ. Seasonal influenza vaccines. Curr Top Microbiol Immunol 2009;333:43-82.  Back to cited text no. 4
    
5.
Kutlucan A, Gonen I, Yildizhan E, Aydin Y, Sav T, Yildirim U. Can influenza H1N1 vaccination lead to the membranous glomerulonephritis? Indian J Pathol Microbiol 2012;55: 239-41.  Back to cited text no. 5
[PUBMED]  Medknow Journal  
6.
Glassock RJ. The pathogenesis of idiopathic membranous nephropathy: A 50-year odyssey. Am J Kidney Dis 2010;56:157-67.  Back to cited text no. 6
    
7.
Beck LH Jr, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med 2009;361:11-21.  Back to cited text no. 7
    
8.
Ronco P, Debiec H. Pathogenesis of membranous nephropathy: Recent advances and future challenges. Nat Rev Nephrol 2012;8: 203-13.  Back to cited text no. 8
    

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Correspondence Address:
Hitesh H Shah
Division of Kidney Diseases and Hypertension, North Shore University Hospital and Long Island Jewish Medical Center, Hofstra North Shore-LIJ School of Medicine, Great Neck, NY 11021
USA
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DOI: 10.4103/1319-2442.168676

PMID: 26586075

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    Abstract
   Introduction
   Case Report
   Discussion
   Conclusion
   Acknowledgment
    References
    Article Figures
 

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