Pathophysiology
Summary
Nephrotic syndrome refers to a group of glomerular disorders marked by significant proteinuria (>3.5 grams/day). It occurs due to cytokine-mediated damage to the glomerular basement membrane, resulting in a loss of the negative membrane charge and podocyte damage, increasing the permeability across the GM and leading to protein in the urine. Clinically, nephrotic syndrome manifests with frothy urine, a hypercoagulable state due to loss of antithrombin III, and an increased risk of bacterial infections from hypogammaglobulinemia.
The most common cause of nephrotic syndrome is minimal change disease, which often affects children and presents with minimal histological alterations but significant albuminuria. It often follows upper respiratory infections or allergic reactions and responds well to glucocorticoids. Focal segmental glomerulosclerosis (FSGS) is a more severe form that frequently leads to end-stage renal disease and is triggered by various etiologies such as viral infections, heroin use, and certain systemic diseases like diabetes and vasculitis.
Diabetic nephropathy starts with GBM thickening (non-enzymatic glycosylation) and progresses to nodular glomerulosclerosis, characterized by Kimmelstiel-Wilson nodules. Membranous nephropathy involves autoantibodies against podocyte receptors, leading to 'spike and dome' subepithelial deposits on immunofluorescence, and can be secondary in conditions like SLE, HBV & HCV, and solid tumors. Amyloidosis in the kidney begins with amyloid deposits within the mesangium but eventually results in obliteration of glomerular capillaries over time. Amyloid is appears pink on Congo red stain and displays apple green birefringence in polarized light.
Lesson Outline
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FAQs
The glomerular basement membrane (GBM) is a thick, electron-dense structure composed of collagen, laminins, and glycoproteins. It carries a negative charge, which is crucial for its function as a filtration barrier. In nephrotic syndrome, injury to the GBM can result in the loss of this negative charge and less selective filtration, resulting proteinuria—a hallmark of nephrotic syndrome.
Nephrotic syndrome primarily results from diseases that affect the glomerular filtration barrier, particularly the podocytes. The damage to the filtration barrier increases glomerular permeability, including albumin. The loss of albumin in the urine results in hypoalbuminemia, which leads to reduced oncotic pressure. This causes fluid to shift into the interstitial space, resulting in generalized edema. Additionally, hypoalbuminemia triggers the liver to synthesize more proteins, including lipoproteins, leading to hyperlipidemia.
Podocytes are specialized epithelial cells with foot processes that contain filtration slits, making them a key component of the glomerular filtration barrier. In nephrotic syndrome, these foot processes undergo effacement, or flattening. This structural change compromises the integrity of the filtration barrier, contributing to the onset and progression of nephrotic syndrome.
Nephrotic syndrome leads to proteinuria, which includes the loss of immunoglobulins in the urine. This results in hypogammaglobulinemia and weakened immunity. Nephrotic syndrome therefore increases the risk of infections, particularly those caused by encapsulated bacteria.
Nephrotic syndrome can be triggered by various underlying conditions, including minimal change disease, focal segmental glomerulosclerosis (FSGS), diabetic nephropathy, and membranous nephropathy. Systemic diseases like amyloidosis can also cause nephrotic syndrome. While the mechanisms may differ, all these conditions result in increased permeability of the glomerular capillary wall, resulting in significant proteinuria.
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