Case 6: Diagnosis & Conclusions -

Case Published: July 2018

Diagnosis: IgA Nephropathy (IgAN)

Case Summary: Well done! Let’s start back at the beginning and walk through this case. Our patient is a relatively young gentleman with an incidental finding of asymptomatic microscopic hematuria, or red blood cells (RBCs) in the urine. The remainder of his history and exam are relatively unremarkable, other than his weight and elevated blood pressure. Though not described in this case, patients with IgAN may present after experiencing gross hematuria after an acute upper respiratory tract illness (“synpharyngitic hematuria”).

The first step in the evaluation of hematuria is confirmation of hematuria with a repeat urinalysis, followed by investigation of whether the hematuria originates from the glomerulus (suggesting a glomerulonephritis) or elsewhere in the genitourinary tract (i.e. renal cell carcinoma, bladder cancer, vascular disorders, hemorrhagic cystitis, bleeding disorders). The presence of dysmorphic RBCs in more than 25% of the high power (hpf) microscope field is specific, though not sensitive, for glomerulonephritis. In other words, the absence of dysmorphic RBCs does not “rule out” glomerulonephritis, but their presence makes us fairly confident this is a glomerular issue. Glomerular diseases also often present with both hematuria and proteinuria (as in our patient), rather than hematuria alone.

Now that we are looking for a glomerulonephritis with dysmorphic RBCs, let’s think about our differential. The extent of dysmorphic RBCs make a nephrotic syndrome less likely (i.e. membranous nephropathy, HIV nephropathy, diabetic nephropathy, focal segmental glomerulosclerosis).

Primary and secondary glomerular diseases can be categorized as those more likely to present as nephritic vs nephrotic syndrome.

Those more likely to present with nephritic rather than nephrotic syndromes include:

IgA nephropathy (Berger’s disease)
Systemic lupus erythematosus (SLE) nephritis
Rapidly progressive glomerulonephritis (pauci-immune, anti-GBM, or immune-complex mediated)
Post-infectious glomerulonephritis
Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome
Membranoproliferative glomerulonephritis

Though some additional testing can help us narrow down our differential, ultimately a kidney biopsy is needed to make the diagnosis. Our biopsy shows us mesangial matrix expansion and relatively mild disease. The pathology of IgAN is a spectrum, and can present with various levels of severity – with the most severe disease revealing significant mesangial hypercellularity, endocapillary hypercellularity, glomerular sclerosis, crescents, and tubular atrophy/interstitial fibrosis on biopsy. In fact, IgAN can present as an immune-complex mediated RPGN with crescents!

The Oxford Classification (based on pathology) can be used for prognosis of IgAN:

Mesangial hypercellularity

– Mesangial cells are counted per mesangial area, a score of 0 – 3 is assigned for each glomerulus and all scores are averaged:
0 = less than 4 cells/area
1 = 4-6 cells/area
2 = 7-8 cells/area
3 = more than 8 cells/area
A score of M1 indicates a mean score of more than 0.5, or M0 if it is less than 0.5:

Endocapillary hypercellularity

E1 indicates presence of hypercellularity within the glomerular capillary lumens. If there isn’t any, the score is E0.

Segmental glomerulosclerosis

If ANY part of the glomerular tuft is involved in sclerosis, the score is S1. Otherwise, it’s S0.

Tubular atrophy/interstitial fibrosis (IF/TA)

This score quantifies the proportion of the cortex that has IF/TA.
T0 = 0-25%
T1 = 26-50%
T2 = > 50%

Crescents

No crescents? C0. If you see them in at least one glomerulus, it’s a C1. And if they’re present in at least 25% of glomeruli, the score is C2. Here’s a cellular crescent below, made up of proliferating extracapillary cells that collapse the capillary loops (seen within the navy blue circle).

We confirm our diagnosis of IgAN by looking for mesangial deposits on EM and subsequent mesangial IgA staining on IF – both of which we see here.

Briefly, the pathogenesis of IgAN is thought to be related impaired glycosylation of IgA1 due to a galactose deficiency in the hinge regions of the antibody. Treatment consists of blood pressure control as well as renin-angiotensin-aldosterone system (RAAS) blockade with angiotensin converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs) to minimize proteinuria (goal < 1 g/day). Fish oil has been also been used, though evidence on its efficacy show mixed results. Glucocorticoids and cyclophosphamide can be used in patients with crescentic glomerulonephritis and significant decline of their kidney function – and many other agents continue to be tested for this disease.

Of note, IgA deposits have been incidentally found in the mesangial spaces of individuals without kidney disease – so they may not always be pathologic!

For more, take a look at the references below:

Case 6 Index
Case 6 Introduction
Case 6 Physical Exam
Case 6 Diagnostic Testing
Case 6 Pathology
Case 6 Additional Pathology
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