Sex: F
Vaccine: FLUX(H1N1)
Symptoms: Joint stiffness, Microscopy, Nausea, Nephrotic syndrome, Oedema
Clinical narrative: This medically confirmed literature report (initial receipt 23-Feb-2016) concerns a 60-year old female patient who developed acute-onset massive proteinuria with NS (nephrotic syndrome) and severe AKI (acute kidney injury) soon after receiving the 2009 H1N1 influenza vaccine. The patient had medical history of bronchial asthma and there was no history of drug allergy. Her medications included montelukast, salbutamol and SERETIDE. 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. She 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 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. 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. 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 electron dense deposits in the subepithelial and intramembranous locations. Extensive effacement of the epithelial cell foot processes was seen. The kidney biopsy findings were consistent with (stage 1) MN and AIN. 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. She 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). Linked to case: 2016059464 (same reporter). Reporter comments: We present a 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. Sender's Comments: Company's evaluation and comment: Seriousness criterion/criteria: Medically significant. Listedness: Unlisted. Assessment according to the CCDS for CSL's H1N1 Influenza Vaccine, nephrotic syndrome and all other events are unlisted except fever, nausea and vomiting which are listed. Company Causality: Possible. There was a plausible temporal relationship of 2 weeks for onset of clinical signs and symptoms consistent with nephrotic syndrome.  No other risk causative or risk factors such as NSAIDS use, diabetes, hypertension, connective tissue disease and or HIV infection. Vasculitis with transient renal involvement is a known adverse event with Influenza vaccination in general including H1N1. In concurrence with the authors, although the exact pathogenesis of MN following influenza vaccination is not known, it is possible for autoimmune mediate damage to have occurred by either auto-antibody and or small circulating immune complex deposition in the glomerular basement membrane  induced as an immunologically mediated vaccination response.