Case 5: Diagnosis & Conclusions

Diagnosis: Systemic lupus erythematosus (SLE) nephritis (lupus membranous nephropathy)

Case Summary:

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.

What is the differential diagnosis for nephrotic syndrome?
Primary causes of nephrotic syndrome
Focal segmental glomerulosclerosis (FSGS)
Membranous nephropathy
Minimal change disease
Secondary causes of nephrotic syndrome
Diabetes mellitus (most common)
Systemic lupus erythematosus (SLE)
Hepatitis B or C (more commonly HBV)
Nonsteroidal anti-inflammatory drugs
Multiple myeloma

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%.

What about secondary causes?
The differential includes:
 Malignancy, typically solid tumors
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
Let’s review the classic histopathological findings seen in membranous nephropathy (primary or secondary):
Light Microscopy
Diffuse thickening of the glomerular basement membrane (GBM), best seen on the Periodic-Acid Schiff or PAS stain.
Jones Silver Stain
Jones silver stain (below) stains collagen and the basement membrane a dark color, but does not stain immune-complex deposits. Thus, “spikes” of basement membrane can be seen around the basement membrane deposits.
Electron Microscopy (EM)
In either primary or secondary MN, subEPIthelial dense deposits are found within the basement membrane that are visualized closer to the podocyte (podocyte = visceral EPIthelial cell). Mesangial deposits (and less commonly subendothelial deposits) may also be seen with certain secondary causes of membranous nephropathy.
Immunofluorescence (IF)
Granular pattern staining of IgG and C3

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.

Lupus nephritis (LN) can be classified in six classes, based on histopathology. Here’s a brief description of each one:
Class I: Minimal mesangial LN
We’re unlikely to find class I disease on a kidney biopsy, as these patients have normal kidney function, minimal proteinuria, and normal light microscopy. However, we would find mesangial deposits on electron microscopy 
Class II: Mesangial proliferative LN
To the class I findings, add mesangial hypercellularity (proliferation of the mesangial cells, look for more nuclei) or expansion of the mesangial matrix (look for more areas of pink or purple on a PAS stain).  Normally, we should see no more than 2-3 mesangial cells between the capillary loops.
Class III: Focal lupus LN
Now, let’s add proliferation of the endocapillary or extracapillary cells to class II.  In addition to mesangial deposits/matrix expansion, we’ll see subENDOthelial deposits (within the basement membrane, closer to the ENDOthelial cell) If proliferation is seen in less than 50% of the glomeruli, we call this “focal” LN. Immune-complex deposits within the basement membrane may make the capillary loops appear very thick like “wire loops” on the PAS stain. Crescents, or proliferation of the extracapillary cells, may be seen. Hematuria and proteinuria are likely to be present.
Class IV: Diffuse LN
If you see proliferation as described above in more than 50% of glomeruli, that’s “diffuse” LN.
Class V: Lupus membranous nephropathy
 Let’s take a break from proliferation, this class is secondary membranous nephropathy. We’ll find subepithelial deposits, sometimes with mesangial involvement. Unlike classes III and IV, patients with class V may present without other clinical signs or serological evidence of lupus. Can a patient with LN nephritis have diffuse proliferation of endocapillary cells AND membranous nephropathy? Definitely – we can call that class IV + class V LN.
Class VI: Advanced sclerosing LN
The final LN class is characterized by global sclerosis of almost all glomeruli, and no active glomerulonephritis should be seen. It’s probably time for renal replacement therapy.

(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 are 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:

  1. Seitz-Polski B, Lambeau G, Esnault V: [Membranous nephropathy: Pathophysiology and natural history]. Nephrol. Ther. 13 Suppl 1: S75–S81, 2017
  2. Ronco P, Debiec H: Pathophysiological advances in membranous nephropathy: time for a shift in patient’s care. The Lancet 385: 1983–1992, 2015
  3. Almaani S, Meara A, Rovin BH: Update on Lupus Nephritis. Clin. J. Am. Soc. Nephrol. CJN.05780616, 2016
  4. Kodner C: Diagnosis and Management of Nephrotic Syndrome in Adults. Am. Fam. Physician 93: 479–485, 2016
  5. 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

Case 5 Index
Case 5 Introduction
Case 5 Physical Exam
Case 5 Diagnostic Testing
Case 5 Pathology
Case 5 Additional Pathology