Case 7: Diagnosis & Conclusions -

Case Published: July 2018

Diagnosis: Systemic Lupus Erythematosus (SLE) Nephritis, Class IV

Case Summary:

This is a young woman presenting with two weeks of intermittent fevers, fatigue, peripheral edema, and joint pain/swelling of the wrists and ankles. Her initial laboratory studies are remarkable for pancytopenia (low levels of platelets, white blood cells, and hemoglobin/hematocrit), as well as an elevated blood urea nitrogen (BUN) and creatinine – increased from normal 3 months ago. We subsequently find evidence of both hematuria and proteinuria on her urinalysis, with red blood cell (RBC) casts in the urine sediment.

These findings raise concern for a rapidly progressive glomerulonephritis (RPGN), given the decrease in estimated glomerular filtration rate of more than 50% over a short period of time. This patient may have an underlying inflammatory, infectious, or possibly even neoplastic process. Regardless of our clinical suspicions, we should approach RPGN in a systematic way to avoid missing anything!

Classification of RPGN

Anti-glomerular basement membrane disease

Also known as Goodpasture’s disease, typically affects the small vessels of the kidney and lung and can be diagnosed by biopsy and an elevated anti-GBM antibody titer.

Immune-complex mediated

Can be secondary to wide variety of immune-complex mediated disease including systemic lupus erythematosus (SLE), hepatitis C virus, IgA nephropathy, post-infectious glomeruonephritis, etc.

Pauci-immune

Usually ANCA associated, and named because of the absence of immune complex deposition (absence of deposits on electron microscopy and negative immunofluorence)

With our working differential for RPGN, we now utilize serologic testing and ultimately kidney biopsy to make the diagnosis. In this case we find hypocomplementemia, with low levels of both C3 and C4. This finding helps narrow our differential to immune-complex mediated disease. In particular, the low levels of both C3 and C4 in the setting of a markedly elevated anti-nuclear antibody (ANA) titer are suggestive of lupus nephritis (LN). We would also expect anti-double stranded DNA (anti-dsDNA) to be positive in the presence of LN. In fact, it has been shown that there is a correlation between anti-dsDNA levels and active kidney involvement in lupus.

So in this patient with such a high suspicion for systemic lupus erythematosus (SLE) nephritis, why bother with a kidney biopsy? Histopathology is needed for classification of lupus nephritis (LN), which is crucial for treatment planning and prognostication.

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 our biopsy findings in this patient of proliferation of the endocapillary cells, “wire loop” capillaries due to subendothelial immune-complex deposits within the basement membrane, and crescents (proliferation of extracapillary cells), this patient would be classified as Class III or Class IV LN. As proliferation was seen in more than half of the glomeruli, our patient has Class IV.

On electron microscopy and immunofluorescence, LN has particular characteristics. The “full house” IF staining, or granular basement membrane/mesangial staining of IgG, IgA, IgM, C3, and C1q, is classic. Another clue is the presence of tubuloreticular inclusions (TRI) seen within the endothelial cell. TRIs are thought to arise from the endoplasmic reticulum (see below) and induced by interferons. They are seen in autoimmune and infectious processes including LN, HIV, and hepatitis C virus (and many others!).

Labele TRI

Finally, treatment regimens for LN vary depending on the both patient and disease characteristics. The 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 more, take a look at the references below:

Case 7 Index
Case 7 Introduction
Case 7 Physical Exam
Case 7 Diagnostic Testing
Case 7 Pathology
Case 7 Additional Pathology
NephSim