A 38-year-old woman with a history of Crohn’s disease and a recent diagnosis of biopsy-proven membranous nephropathy with left renal vein thrombosis, presented with severe, non-oliguric acute kidney injury and volume overload.
Four months prior to the current presentation, the patient went to the emergency department with left flank pain and bilateral lower extremity edema. Investigations at that time revealed left renal vein thrombosis (diagnosed via Doppler ultrasonography) along with nephrotic range proteinuria (urine albumin-to-creatinine ratio [UACR] 7900 mg/g) and hypoalbuminemia (2.3 g/dL) but with preserved kidney function (serum creatinine 0.76 mg/dL, estimated glomerular filtration rate [eGFR] 100 mL/min/1.73m2). She was started on therapeutic anticoagulation, irbesartan, and furosemide and was referred for urgent outpatient nephrology evaluation. At the nephrology visit one week later, urine microscopy revealed no microscopic hematuria or cellular casts. Serologic evaluation included normal C3 and C4; negative antinuclear antibody (ANA), ANCA, anti-GBM, and PLA2R antibody titers; serum and urine protein electrophoresis with no monoclonal bands; and negative human immunodeficiency virus (HIV), hepatitis B, and hepatitis C serologies. The patient denied any non-steroidal anti-inflammatory drug (NSAID) use.
The following week, the patient underwent a kidney biopsy (Fig. 1). Specific details regarding the microscopy methods are listed within the Supplementary Appendix. Light microscopy showed 1/21 glomeruli globally sclerosed with the remaining glomeruli having thickened and rigid capillary walls. There was no significant interstitial fibrosis or tubular atrophy, and no crescents were seen. Immunofluorescence demonstrated granular staining in the capillary loops for C3, IgG, kappa, and lambda; IgA and IgM were negative. Electron microscopy revealed numerous subepithelial electron dense deposits with diffuse overlying foot process effacement and no significant mesangial deposits. PLA2R staining on the biopsy was negative. A diagnosis of membranous nephropathy was made. Based on the diagnosis of non-PLA2R-mediated membranous nephropathy, a malignancy work-up was then performed which included computed tomography scans of the chest, abdomen, and pelvis along with mammography and Pap testing all of which were unremarkable. With no secondary causes identified, her case of membranous nephropathy was deemed primary in nature. Despite the associated venous thromboembolism, the decision was made to proceed with a six month observation period (while maintained on irbesartan, furosemide, and warfarin) prior to starting immunosuppression as the patient’s condition in regard to volume overload improved and her eGFR remained normal.
Four months later, the patient returned to the emergency department after two weeks of low-grade fever, cough, dyspnea, and green-tinged sputum. Chest X-ray revealed diffuse airspace disease suggestive of pneumonia. Sputum and blood cultures were collected only after antibiotics and demonstrated no growth. She was treated for community acquired pneumonia with moxifloxacin. Her symptoms gradually improved over the next week. However, over the subsequent two weeks, she developed rapidly worsening dyspnea, hypoxia, and volume overload with a 17 pound weight gain. She was admitted to the hospital where her serum creatinine had increased to 4.01 mg/dL though she remained non-oliguric. She was also increasingly proteinuric (UACR 21,430 mg/g) and hypoalbuminemic (1.9 g/dL). Urine microscopy now revealed dysmorphic red blood cells with a few red blood cell casts. Serologic evaluation now demonstrated a low C3 level (0.32 g/L; reference range 0.90–1.80 g/L) while the C4 level remained normal. ANCA, anti-GBM, and PLA2R antibody titers remained negative. Streptozyme testing was negative. Blood, urine, and sputum cultures were negative. Doppler ultrasonography showed patent bilateral renal veins with resolution of the prior left renal vein thrombosis (notably, this could not definitively rule out residual renal vein thrombosis the given limited sensitivity and specificity of ultrasonography) [8]. A ventilation/perfusion scan was low probability for a pulmonary embolism. Her hypoxia and volume overload were refractory to aggressive intravenous diuresis with concurrent intravenous hypertonic albumin administration, and she was started on hemodialysis. Given her atypical clinical course and suspicion for the development of a rapidly progressive glomerulonephritis, a repeat kidney biopsy was pursued.
The repeat biopsy (Fig. 2) demonstrated the following set of findings overlaying a background of membranous nephropathy: endocapillary hypercellularity with a neutrophil predominance, mesangial proliferation, endothelial cell swelling, and active cellular crescents in 6/32 glomeruli. Zero of 32 glomeruli were globally sclerosed with no significant tubular atrophy. The immunofluorescence pattern was unchanged with granular staining in the capillary loops for C3, IgG, kappa, and lambda; IgA and IgM were negative. Electron microscopy now showed numerous subepithelial and scattered mesangial electron dense deposits along with several ‘hump’ lesions. Based on these findings, a diagnosis of post-infectious glomerulonephritis (PIGN, presumed to be related to her recent pneumonia) superimposed upon membranous nephropathy was made.
Due to the combination of a lack of improvement of membranous nephropathy during the observation window and the thought that the anti-inflammatory effects of corticosteroids may provide benefit during her acute presentation, treatment was started using the ‘modified Ponticelli’ regimen with corticosteroids and cyclophosphamide (dosed daily at 1.5 mg/kg rather than cyclical). Within two weeks of starting immunosuppression, she was no longer dialysis dependent and her volume status improved while gradually tapering off diuretics. One month post-discharge, her serum creatinine had improved to 1.36 mg/dL, UACR had improved but remained in a nephrotic range at 11,044 mg/g, and serum albumin had increased to 3.1 g/dL. One year post-discharge (and 6 months after completing immunosuppression), her serum creatinine had normalized at 0.72 mg/dL, UACR had declined to a non-nephrotic range at 429 mg/g, and serum albumin had normalized at 4.2 g/dL.