Nephrotic syndrome key characteristics
- Common findings include:
- Proteinuria (frothy urine)
- Results from injury and disruption of podocytes and their foot processes.
- When podocytes lose their foot processes their special structure or detach completely, there is exposed basement membrane and free filtration of albumin and other plasma proteins.
- Nephrotic range proteinuria is >3.5g in 24 hours.
- On urine microscopy: It generally looks normal! If you’re lucky you can see oval fat bodies (tubular cells that have taken up large amounts of filtered lipid) with the Maltese cross sign (seen only with polarized light microscopy).
Common and testable causes of nephrotic proteinuria (you will get pimped on this by your IM attendings!)
Minimal Change Disease
- Most common cause of nephrotic syndrome in children, perhaps following a URI.
- High-yield for your pediatric clerkship!
- There is a secondary form: usually due to certain drugs (NSAIDS), cancers (leukemia, lymphoma), or infections (HIV, syphilis).
- On biopsy, H&E stained glomeruli look completely normal: “minimal change!”
- However, there is effacement of foot processes/podocytes on EM.
- Seen in patients with long standing diabetes.
- Presents first as mild albuminuria, which progressively worsens over time.
- As GFR declines, it can reach nephrotic-range proteinuria.
- Non-enzymatic glycosylation of vascular basement membrane leading to hyaline arteriosclerosis of efferent arteriole
- A hypothesis that has been proposed to explain the progressive kidney injury in diabetes is via excessive proximal tubular sodium and glucose reabsorption (via SGLT transporters) leads to reduced distal sodium delivery to the macula densa, which then leads to increased renin secretion and afferent arteriole vasodilation. This is inappropriate chronic hyperfiltration.
- After many years, the chronic hyperfiltration injury leads to podocyte injury, glomerulosclerosis, and proteinuria.
- Classic pathologic finding: mesangial sclerosis with Kimmelstiel-Wilson nodules
Focal Segmental Glomerulosclerosis (FSGS)
- This one is confusing because we can say this to refer to the primary/idiopathic disease (which we don’t fully understand) or the pathologic lesion that is secondary to another disease process.
- Either way, something is happening that leads to podocyte injury, detachment, and then sclerosis in parts of the glomeruli.
- When it’s primary/idiopathic: we don’t have a clear answer for it yet.
- There are genetic causes of FSGS, some known and some unknown. Always ask about family history with this disease!
- When FSGS is secondary, it can be from chronic urinary tract obstruction, obesity, sickle cell disease, and infections (especially HIV, which has its own name called HIV-associated nephropathy or HIVAN).
- On H&E staining, we see focal segmental sclerosis: large pink areas of scar in otherwise normal appearing glomerulus.
- On EM, we see effacement of podocyte foot processes. No deposits are seen.
- Negative IF (no immune complex deposition)
- Typically presents with sudden-onset nephrotic syndrome.
- Membranous is either Primary or Secondary in etiology.
- Primary is an autoimmune disease, 80% of patients with this have autoantibodies to the phospholipase A2 receptor (a glomerular antigen). So, the test for Anti-PLA2R antibody is positive.
- Secondary Membranous is due to some other disease: a solid organ malignancy (lung or colon), infections like Hepatitis B or C, and even Lupus can cause athe membranous lesion (known as Class V Lupus Nephritis).
- On Pathology, the GBM looks thickened. On EM, the GBM is characterized by Subepithelial (under the Podocyte) deposits with a “Spike & Dome.” The “domes” are electron dense deposits of Immune complexes, with “spikes” of GBM forming around them.
- On Immunofluorescence, there is Granular staining for IgG.
- Proteins start accumulating in tissues and they are aggregating into beta-pleated sheets. This leads to deposition of tiny fibrils in tissues. The fibrils are difficult to clear and eventually this leads to organ failure.
- Amyloid can affect any tissue/organ: typically skin, heart, kidney, liver, spleen, and blood vessels.
- When amyloid affects the kidney, the fibrils tend to accumulate in the mesangium and capillary loops/podocytes. This damage leads to foot process effacement, loss of filtration barrier, and typically the nephrotic syndrome.
- Amyloidosis can be due to AL amyloid: excess production of monoclonal light chain immunoglobulins (usually from multiple myeloma or other plasma cell dyscrasia).
- Rarely, amyloidosis can be due to AA amyloid: excess production of Serum Amyloid A protein, which is released in chronic inflammatory states. With chronic inflammation, this protein can mis-fold, accumulate in tissues, and form the amyloid fibrils.
- On kidney biopsy H&E staining, amyloidosis expands the mesangium with acellular, amorphous pale pink material. It sort of looks like cotton candy.
- The Congo red stain is positive: bright apple-green colorin areas of amyloid fibrils.
- In AL amyloid, immunofluorescence stains chains will be heavily positive for EITHER kappa or lambda light chains.
Check out NephSim for some practice cases!
Danae Olaso, MS2