Nephrotic Syndrome & Key Pathologies

Nephrotic Syndrome

Nephrotic syndromes are characterized damaged glomerular filtration membranes and high proteinuria.

Review of the glomerulus and filtration membranes, physiologic roles in filtration.

Glomerular Filtration Membrane

Filtration membrane:
Capillaries, which are lined with endothelial cells.
Glomerular basement membrane.
Podocytes, which are specialized epithelial cells with foot processes that interdigitate to form the slit diaphragm, and prevent proteins from leaving the blood.

DIAGNOSIS

Urinalysis - look for proteins Blood tests - look for hypoalbuminemia and altered levels of creatinine and BUN) Renal biopsies

Proteinuria Most glomerular disorders are associated with some degree of proteinuria and hematuria; however, it's helpful to remember that nephrotic syndromes are associated with high proteinuria, whereas nephritic syndromes are associated with hematuria.

Glomerular disorders can co-exist with tubular, interstitial, and vascular renal pathologies.

PATHOPHYSIOLOGY

Nephrotic syndrome is the result of podocyte injury, which can be caused by toxins, viral infections, antigens to podocyte antigens, and other factors.

Podocyte damage, effacement, and detachment from the basement membrane allows proteins to leak through the filtration membrane and enter the urine.

SIGNS AND SYMPTOMS

Protein leakage leads to a predictable series of signs and symptoms:

High proteinuria with greater than 3.5 g/day; we show that the urine appears "foamy" or "frothy" because of the protein content.
Loss of proteins, particularly albumin, leads to hypoalbuminemia;
Hypoalbuminemia changes the osmotic forces that regulate body fluids and leads to salt and water retention and edema; note that the edema can be particularly apparent around the eyes and lower extremities.
Immunoglobulins and anticoagulants can also leak into the urine, which causes increased infections and thrombotic complications.

TREATMENT

Treatment depends on the causes and complications of the nephrotic syndrome: We often use corticosteroids, angiotensin inhibitors, diuretics, and statins to reduce protein loss and counteract complications.

Patients with end stage renal disease need dialysis and kidney transplants.

ETIOLOGIES

Minimal change disease is the most common cause of nephrotic syndrome in children.

The pathophysiology of minimal change disease is uncertain, but researchers think T-cell dysfunction and/or autoantibodies to the slit diaphragm are involved.
Most cases are idiopathic, but minimal change disease can also be caused by drugs (NSAIDs, antimicrobials), infection, allergy, neoplasm.
As the name suggests, the glomeruli look normal under light microscope (changes are minimal), but, with electron microscope, we can see podocyte diffuse effacement.

Focal segmental glomerulosclerosis (FSGS) is characterized by podocyte detachment and death, which "denudes" the glomerular basement membrane and leads to scarring.

FSGS is a pattern of histopathological changes, not a specific disease. There are 5 variants (collapsing, glomerular tip lesion, cellular, perihilar, not otherwise specified).
Early in the disease process, sclerosis is limited to segments of some glomeruli; however, as it progresses, sclerosis becomes diffuse and global.
FSGS may be idiopathic, genetic, or secondary to atheroembolic disease, sickle cell disease, HIV infection, obesity, drug use, or other renal diseases that lead to nephron loss.
Be aware that FSGS is a top cause of nephrotic syndrome in Black men (due to genetic influences), and that prognosis is poor – FSGS often leads to renal failure within 10 years.

Membranous nephropathy is characterized by immune complex deposition between the podocytes and basement membrane. The immune complexes activate the complement system and other immune responses.

As a result, podocyte effacement with thickening of the basement membrane and capillaries occurs.
Primary membranous nephropathy is often due to antibodies against phospholipase A2 receptors (others include antibodies to neural epidermal growth-like factor 1 and thrombospondin).
Secondary causes include infection, autoimmune disease, drugs, and other factors.

Renal amyloidosis is characterized by amyloid deposits; in biopsy specimens, look for Congo red positivity, with apple-green birefringence under polarized light.

Treatment and prognosis depend on the amyloid type (see notes) but, generally, renal amyloidosis progresses to renal insufficiency.
Renal amyloidosis is most often associated with AL (immunoglobulin light chain) and AA (serum amyloid A) amyloidosis, ALECT2 (leukocyte derived chemotaxin 2), dialysis-related amyloidosis (which also affects the joints).
Amyloidosis can affect multiple parts of the nephron, nephrotic syndrome occurs when the glomerulus is damaged.

Diabetic glomerulonephropathy is the most common cause of chronic kidney injury and end stage renal disease in U.S. adults.

Metabolic and hemodynamic changes in diabetes lead to sclerosis and fibrosis.
Hyperglycemia leads to mesangial cell proliferation and sclerosis, with thickening of the capillary walls and glomerular basement membrane. Be aware that we may also see hyalinosis in the afferent and efferent arterioles.

Nephrotic Syndrome & Key Pathologies

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