Nephrotic syndrome – McMaster Pathophysiology Review

Definition

N Engl J Med. 1998 Apr 23;338(17):1202-11.

Kidney disease causing proteinuria (3 or more grams of protein/24 hours), hypoalbuminemia, and edema.

Etiology and pathogenesis

Semin Nephrol. 2009 Jul;29(4):389-98.
Lancet. 2003 Aug 23;362(9384):629-39.
Crit Rev Clin Lab Sci. 2008;45(2):139-220.
J Am Soc Nephrol. 2012 Mar;23(3):381-99.

The glomerular capillary walls are composed of three structures: the endothelial cells, the glomerular basement membrane (GBM) and the epithelial cells (podocytes; connected to each other via network of slit diaphragms). Passage of plasma proteins into the tubules is normally restricted due to the size (mediated by the pores in the BM) and charge (mediated by the polyanionic glycosaminoglycan) of this barrier. The former prevents the leakage of proteins greater than 150kD and the latter proteins 70kD-150kD.

Primary causes

Three distinct variants of nephrotic syndrome exist based on the histologic findings: minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and membranous nephropathy (MN)

Minimal change disease (MCD)

Pathogenesis remains unclear, but involvement of T-lymphocytes has been hypothesized. Dysfunctional T-cells are thought to produce increasing levels of glomerular permeability factor which directly affects the capillary walls, resulting in the foot process fusion.
Histologically, the glomeruli appear normal with the absence of complement or immunoglobulin deposits on immunofluorescence staining. Characteristic lesions, based on electron microscopy are the diffuse effacement of the epithelial foot processes.

Focal segmental glomerulosclerosis (FSGS)

In most forms of FSGS, injury to the foot process on the podocytes appears to be the primary cause. Pathogenesis is multifactorial; mechanisms include a T cell-mediated circulating permeability factor, transforming growth factor (TGF)-β-mediated cellular proliferation, matrix synthesis, and genetic podocyte abnormalities.
Light microscopy reveals mesangial cell proliferation and segmental scarring. Positive IgM and C3 complement protein staining on immunofluorescence and scarring of the glomerular tuft and obliteration of glomerular capillary lumen on electron microscopy are found.

Membranous nephropathy (MN)

Pathogenesis is currently unclear but experimental models suggest the GBM immune deposits develop in situ. These immune deposits are composed of circulating IgG antibodies directed against endogenous antigens expressed on or near the podocyte foot processes. Commonly targeted antigens include phospholipase A2 receptor and neutral endopetidase (both expressed on podocytes).
Light microscopy reveals thickening of the GBM along the capillary loops. IgG and C3 complement protein deposits can be found via immunofluorescence and electron dense subepithelial deposits can be found on electron microscopy.

Secondary causes

Secondary causes of nephrotic syndrome include:

Systemic lupus erythematosis (SLE)

Immune complex deposition within the GBM has been thought to be the primary cause of renal damage.

Malignancy (lymphoma and leukemia, solid tumours)

Solid tumours – immune complexes composed of tumour antigens and tumour-specific antibodies presumably damage the kidneys.
Lymphoma – proposed that the lymphoma produces a lymphokine that increases permeability of the glomerular capillary wall.

Infections (hepatitis B and C, HIV, malaria)

HIV – lesion is FSGS; renal epithelial cells express replicating HIV virus but host immune responses also play a role in pathogenesis.
Malaria – glomerulonephritis caused by immune complexes containing malarial antigens that are implanted in the glomeruli.

Diabetic nephropathy

Most common cause of NS in adults. 40% of patients with types 1 or 2 diabetes develop nephropathy.
Characteristic changes in the glomerulus (see CKD chapter for details):
- Altered basement membrane composition with loss of heparan sulfate that forms the negatively charged filtration barrier.
- Mesangial matrix expansion due to accumulation of the extracellular matrix (ECM).
- Vascular changes with hyaline and hypertensive arteriosclerosis.

Clinical and laboratory manifestations

Am Fam Physician. 2009 Nov 15;80(10):1129-34.
Lancet. 2003 Aug 23;362(9384):629-39.
N Engl J Med. 1998 Apr 23;338(17):1202-11.

Signs and symptoms/lab findings	Mechanisms
Foamy urine (proteinuria and hypoproteinemia)	Normal glomeruli prevent protein section due the small capillary size and the negative charge. Due to the damage to the glomeruli, proteins filter through causing large amounts of proteins to be secreted through the kidney. High levels are found in the urine and low in the blood.
Organ edema (ascites, pulmonary effusion, facial swelling and lower extremities) and anasarca	Loss of albumin through the glomeruli leads to a significant drop in oncotic pressure at the venular end of the vascular beds, causing fluid accumulation in the tissues. Interstitial edema is exacerbated by sodium and water retention. The nephrons work to retain sodium due to the “underfilled” blood vessels, and water absorption takes place with sodium.
Hyperlipidemia	Protein loss through the nephrons stimulates the liver to synthesize and produce more protein. It is hypothesized that this rise in sinusoidal activity leads to a rise in lipid production also causing hyperlipidemia. Furthermore, it is thought that the damage to the nephrons causes a loss of lipoprotein lipase, protein responsible for lipoprotein metabolism.
Fatigue, weakness (anemia)	Loss of transferrin through the nephrons.
Deep vein thrombosis	Thought to be secondary to the loss of anti-thrombin (AT), an anticoagulant protein that inhibits the pro-coagulant proteins such as thrombin, activated factors X and XI.

Treatment

Treating the primary cause (when known) is appropriate.

Steroids: Since the pathogenesis of primary NS appears to be immune mediated, prednisone appears to be helpful for idiopathic/primary disease. Mechanism seems to be mediated via immunosuppression.
Proteinuria: Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs): Work to control proteinuria by a number of mechanisms. ACEI and ARBs mediate their effects by lowering blood pressure and therefore the glomerular pressure. Furthermore, they are thought to have a direct action on podocytes reducing the loss of protein.
Edema: Dietary sodium restriction (<2g/day) is recommended along with the use of diuretics (mainly furosemide and spironolactone). Volume overload is reversed slowly to avoid acute hypovolemia.
Hyperlipidemia: Lipid lowering agents (statins) form the main stay of treatment.
Hypercoaguability: Currently not treated prophylactically. If DVT develops, treatment with heparin and warfarin is initiated.