Our patient is a 67-year-old Spanish-speaking male with history of hypertension, hyperlipidemia, and chronic bilateral osteoarthritis of the knees, who was admitted to our hospital for anasarca and shortness of breath. Over the 3 months prior to initial presentation, he noticed worsening bilateral lower extremity pitting edema, abdominal swelling, and orthopnea. He also endorsed having nausea, vomiting, and diarrhea. Furthermore, he reported making less urine than before, accompanied by urine frothiness.
On initial examination, his blood pressure was 168/67 mm Hg. He had notable anasarca and a brain natriuretic peptide in the 2000s. There was 4+ pitting edema of his lower extremities up to the thighs. His lungs were clear and there was no respiratory distress. Initial urinalysis showed elevated urine protein of >500 mg/dL with 5 to 10 white blood cells/high power field (WBC/HPF) and 20 to 30 granular casts/HPF. His baseline serum creatinine (SCr) in 2018 was 0.5 to 0.6 mg/dL, but his SCr on initial admission was 2.1 mg/dL. Albumin was 2.0 g/dL, and urine protein:creatinine ratio (UPCR) was 6132 mg/g. Extensive proteinuria workup was done, revealing of 7 g protein/24 h, 3600 mg/24-h albuminuria. The proteinuria was mostly albuminuria nearly 60% with 40% of proteinuria being non-albumin proteinuria.
Further workup, including HIV, hepatitis B, hepatitis C, antinuclear antibody, rapid plasma reagin, anti-Rho, double-stranded DNA, and complements C3 and C4, was all negative or within normal limits. Serum and urine protein electrophoresis showed no monoclonal spikes. Renal ultrasound demonstrated normal cortical echogenicity and contour for both kidneys, with right measuring 13.2 cm and left measuring 13.0 cm.
A percutaneous sonographic guided renal biopsy was done and was composed of renal cortex and contained at least 33 non-sclerotic glomeruli. The glomerular capillary loops were mildly thickened and exhibited segmental subtle spikes and pinholes. Podocytes appeared reactive. There was no mesangial or endocapillary hypercellularity. There were no large endocapillary deposits, necrotizing lesions, segments of sclerosis, or crescents. There was patchy acute tubular injury associated with mild patchy interstitial inflammation associated with foci of tubulitis and scattered eosinophils. There was mild interstitial fibrosis/tubular atrophy (~15%). Immunofluorescence studies demonstrated segmental granular glomerular capillary wall staining with immunoglobulin G (IgG, trace), immunoglobulin M (IgM, trace), C1q (trace-1+), kappa (trace), and lambda (trace) light chains. There was no extra-glomerular staining. The M-type phospholipase A2 receptor (PLA2R) stain was negative. Electron microscopic analysis demonstrated diffuse podocyte foot process effacement with frequent microvillous transformation and condensation of actin cytoskeletal filaments. Glomerular basement membranes were variable thickening with segmental subepithelial and intramembranous electron lucencies and subepithelial remodeling (spike/pinholes) and showed rare small granular subepithelial and intramembranous deposits. Minimal mesangial electron densities were present. No deposits displayed any significant fibrillary or microtubular substructure. There were no tubuloreticular inclusions or immune complex-type deposits present in any other location (see Figure 1).
Diagnosis of MN (stage IV of IV) and mild AIN was rendered. Because the degree of podocyte foot process effacement was felt to be more extensive than would be expected given the somewhat segmental and low-grade MN, the possibility of a superimposed podocytopathy (MCD) was raised. The time course of the worsening proteinuria was also felt to be incompatible with the relatively chronic stage of the MN. The constellation of biopsy findings raised the suspicion for an underlying allergic/drug-induced etiology.
In light of this biopsy-proven diagnosis of MN, PLA2R [Anti Phospholipase A2 Receptor Antbiody] serology, anti-THSD7A [Anti Thrombospondin Type 1 Domain Contaning 7A Antibody], and anti-NELL [Anti Neural Epidermal Growth Factor-Like 1 Protein Antibody] were sent, and anti-PLA2R and anti-THSD7A came back negative.   Anti-NELL was sent, but after discussion with the Mayo Clinic laboratory, it could not be performed due to a lack of current approval as a commercially approved assay. The patient had no signs of systemic lupus erythematosus, no indications of malignancy (on recent computed tomography (CT) imaging studies and colonoscopy), and no evidence of chronic infections or sarcoidosis to suggest any other etiologies for a secondary MN. Lyme IgG and IgM were sent to investigate Lyme nephritis and were not detected, as Lyme disease has been reported to cause a diverse spectrum of glomerular disease.
Given the concern for a potential drug-induced MN, lack of serologic evidence for a primary form, and its low-grade chronic nature, immunosuppressants such as cyclophosphamide or rituximab were not pursued. The patient was further diuresed with metolazone 5 mg and furosemide 80 mg IV (intravenous) twice a day with improvements to his urine output and edema. Prednisone 10 mg daily was also started for his worsening SCr, which peaked at 5.6 mg/dL about 1 month after initial presentation. When the patient came to our clinic a month later, his symptoms had drastically improved. The patient lost around 24 pounds of water weight with noticeable improvements to his edema. Upon further investigation at that time, the patient finally recalled that he had been frequently taking ibuprofen 9 months prior to symptom manifestation. He was taking 400 mg of ibuprofen three to four times a day; he had no heavy metal exposure, industrial exposure, or new vaccines in the time prior to development of anasarca. He had been using over-the-counter ibuprofen at lower doses (once a day) nearly daily for his chronic knee pain for 10 months prior to his intensification of therapy years before stopping due to inefficacy and advice of nephrologists regarding NSAID nephrotoxicity.
The findings suggesting NSAID-induced injury were tempered by finding of elevated urine copper levels. A 24-h urine panel for heavy metals showed undetectable levels of arsenic, zinc, cadmium, mercury, and lead. Copper levels were elevated at 27.1 microg/dL (upper limit of normal value 3.2 microg/dL) with a caveat that this is known to occur in high-grade proteinuria and with cirrhosis which the patient had. The patient also underwent workup for cirrhosis, including exclusion of Wilson's disease; the patient ceruloplasmin level was within normal limits at 27 mg/dL. Eye examination did not reveal Kayser Fleischer rings as well. The liver findings were attributed by hepatology to non-alcoholic fatty liver disease (NAFLD). Unfortunately, given the patient's financial status and insurance status, hair sampling for heavy metal toxicity was not financially viable or practical in this particular situation.