Case Published: June 2018
Diagnosis: Systemic lupus erythematosus (SLE) nephritis (lupus membranous nephropathy)
In this case, we find a woman who presents with progressive lower extremity edema and pruritis (itching) over a period of months, accompanied by the concerning symptom of “frothy” urine. This constellation of symptoms can often be a sign of proteinuria, and as we soon discover on urinalysis, this patient has 4+ protein on dipstick. It is crucial to quantify the proteinuria, as the dipstick gives us only an estimate and only detects albuminuria. Our patient has a urine protein:creatinine ratio of 8700mg/g, or nephrotic range proteinuria.
Nephrotic range proteinuria is defined as greater than 3 to 3.5 grams of protein in a 24-hour urine collection, or a urine protein:creatinine ratio of greater than 3000 to 3500 mg/g. Together, proteinuria, significant edema, hypoalbuminemia, and often hyperlipidemia/lipiduria (lipids in the urine) comprise nephrotic syndrome. Our patient meets criteria for nephrotic syndrome.
Minimal change disease
Systemic lupus erythematosus (SLE)
Hepatitis B or C (more commonly HBV)
Nonsteroidal anti-inflammatory drugs
Now that we have established a broad differential for nephrotic syndrome, let’s try to determine which etiology is most likely in our patient. Her clinical presentation, basic laboratory studies, and urinalysis are consistent with nephrotic syndrome but are otherwise unrevealing. The elevated ANA titer suggests SLE nephritis, but we must move to a kidney biopsy to confirm our diagnosis.
Light microscopy and electron microscopy show us thickening of the basement membrane and subepithelial deposits – together, these findings raise suspicion for membranous nephropathy (MN). With focal segmental glomerulosclerosis (FSGS), we would look for areas of sclerosis in some glomeruli. Minimal change disease is not the diagnosis here, as we would except only podocyte effacement on electron microscopy without light microscopy changes or immune-complex deposits.
MN, like many glomerular diseases can be primary or secondary (caused byanother underlying disease). Distinguishing between primary and secondary glomerular diseases is critical, as this will determine the treatment. We can use the patient’s clinical history, serologic testing, and immunofluoresence (IF) to try to tell the difference.
In primary MN, we would likely find granular pattern basement membrane staining of IgG and C3 on IF, and the presence of the phospholipase A2 receptor antigen (PLA2R) or thrombospondin type-1 domain-containing 7A (THSD7A) within immune deposits (with PLA2R being more common). PLA2R antibodies can be detected in the serum of primary MN patients, with specificity being near 100%.
Systemic lupus erythematosus (SLE) nephritis
Drugs (i.e. penicillamine, anti-tumor necrosis factor (TNF) antibodies, nonsteroidal anti-inflammatory drugs (NSAIDs))
Hepatitis C virus, Hepatitis B virus (HBV more common)
Immunoglobulin-G4 (IgG4) disease
Though the patient’s clinical history and serologic testing can sometimes provide helpful clues, what clinches the diagnosis here is the “full house” immunofluorescence staining, or granular basement membrane staining of IgG, IgA, IgM, C3, and C1q – this pattern is staining is classically seen in lupus nephritis (LN), making the most likely diagnosis here lupus membranous nephropathy. Further, we are not given any clues to suggest other etiologies of secondary MN in this case.
(Find more on classification, including definitions of “active” and “chronic lesions” here)
Based on the above LN classification, our patient’s presentation suggests class V LN.
Before we wrap up…one final clue that this is a case of LN is the tubuloreticular inclusion (TRI) seen within the endothelial cell and is thought to arise from the endoplasmic reticulum (see below). TRIs are thought to be induced by interferons, and are seen in autoimmune and infectious processes including LN, HIV, and hepatitis C virus (and many others!)
Though treatment regimens for LN vary depending on the both patient and disease characteristics, the arsenal of immunosuppressive agents that are most commonly used include glucocorticoids, mycophenolate mofetil (MMF), azathioprine, cyclophosphamide, and calcineurin inhibitors. Rheumatologists and nephrologists often work together to find the optimal treatment regimen for the lupus patient.
For a deeper dive, take a look at the references below:
- Seitz-Polski B, Lambeau G, Esnault V: [Membranous nephropathy: Pathophysiology and natural history]. Nephrol. Ther. 13 Suppl 1: S75–S81, 2017
- Ronco P, Debiec H: Pathophysiological advances in membranous nephropathy: time for a shift in patient’s care. The Lancet 385: 1983–1992, 2015
- Almaani S, Meara A, Rovin BH: Update on Lupus Nephritis. Clin. J. Am. Soc. Nephrol. CJN.05780616, 2016
- Kodner C: Diagnosis and Management of Nephrotic Syndrome in Adults. Am. Fam. Physician 93: 479–485, 2016
- Fogo AB, Lusco MA, Najafian B, Alpers CE: AJKD Atlas of Renal Pathology: Membranous Nephropathy. Am. J. Kidney Dis. Off. J. Natl. Kidney Found. 66: e15-17, 2015