Glomerular Diseases| Nephrotic syndrome Notes| Causes| Pathogenesis| Morphology

Glomerular Diseases

Glomerular

Glomerular diseases constitute some of the major problems in nephrology; indeed, chronic glomerulonephritis is one of the most common causes of chronic kidney disease in humans. Glomeruli may be injured by a variety of factors and in the course of several systemic diseases. Systemic immunologic diseases such as systemic lupus erythematosus (SLE), vascular disorders such as hypertension, metabolic diseases such as diabetes mellitus, and some hereditary conditions such as Fabry disease often affect the glomerulus. These are termed secondary glomerular diseases. Disorders in which the kidney is the only or predominant organ involved constitute the various types of primary glomerulonephritis. lists the most common forms of glomerulonephritis are given below:

1. Primary Glomerulopathies

• Acute proliferative glomerulonephritis
• Post infectious
• Other
• Rapidly progressive (crescentic) glomerulonephritis
• Membranous nephropathy
• Minimal-change disease
• Focal segmental glomerulosclerosis
• Membranoproliferative glomerulonephritis
• Dense deposit disease
• IgA nephropathy
• Chronic glomerulonephritis

2. Systemic Diseases with Glomerular Involvement

• Systemic lupus erythematosus
• Diabetes mellitus
• Amyloidosis
• Goodpasture syndrome
• Microscopic polyarteritis/polyangiitis
• Wegener granulomatosis
• Henoch-Schonlein purpura
• Bacterial endocarditis

3. Hereditary Disorders

• Alport syndrome
• Thin basement membrane disease
• Fabry disease

The clinical manifestations of glomerular disease are clustered into the five major glomerular syndromes summarized below;

Syndrome                                                                     Manifestations

• Nephritic syndrome---Hematuria, azotemia, variable proteinuria, oliguria, edema, and                                                          hypertension
• Rapidly progressive glomerulonephritis   ---   Acute nephritis, proteinuria, and acute renal failure
• Nephrotic syndrome --- >3.5 gm/day proteinuria, hypoalbuminemia, hyperlipidemia, lipiduria
• Chronic renal failure---  Azotemia → uremia progressing for months to years
• Isolated urinary abnormalities   --- Glomerular hematuria and/or sub-nephrotic proteinuria

Here, I will discuss on Nephritic syndrome and Nephrotic syndrome.

Nephrotic syndrome

Nephrotic syndrome is caused by a derangement in glomerular capillary walls resulting in increased permeability to plasma proteins. The manifestations of the syndrome include:

• Massive proteinuria, with the daily loss of 3.5 gm or more of protein (less in children)
• Hypoalbuminemia, with plasma albumin levels less than 3 gm/dL
• Generalized edema
• Hyperlipidemia and lipiduria

Causes of nephrotic syndrome:

primary Glomerular Disease 

• Membranous nephropathy
• lipoid nephrosis
• focal segmental glomerulosclerosis
• IgA nephropathy

Systemic Diseases

• Diabetes mellitus
• Amyloidosis
• Systemic lupus erythematosus
• Drugs (nonsteroidal anti-inflammatory, penicillamine, heroin)
• Infections (malaria, syphilis, hepatitis B and C, HIV)

Pathogenesis

• Increased permeability (structural / physiochemical alteration) allows protein to escape (Proteinuria)
• Resulting in depliets in serum albumin beyond the compensatory synthetic capacity of liver (Hypoalbuminemia)
• Decreased intravascular colloid osmotic pressure and increased Na and water retention:
• compensatory secretion of aldosterone by hypovolemia enhanced renin secretion,
• stimulation of sympathetic system and
• reduced secretion of natriuretic factors (atrial peptides) resulting Generalized Edema
• Due to increased blood level of blood cholesterol, triglycerides, VLDL, LDL, apoprotein, lipoprotein A and decrease HDL(increased synthesis of lipoprotein in liver, abnormal transport of circulating lipid particles and decreased lipid catabolism) Hyperlipidemia
• Follows by lipiduria because lipoproteins also leaks across glomerular capillary wall
• Lipid appears in urine as free fat or oval fat body (representing lipoprotein reabsorbed by the tubular epithelial cell and then shed along the injured tubular cell that have detached from BM ) Lipiduria.

Membranous Nephropathy

Membranous nephropathy is characterized by diffuse thickening of the glomerular capillary wall due to the accumulation of deposits containing Ig along the sub epithelial side of the basement membrane. It is most common between 30-50 years of age.

Morphology

• LM: diffuse thickening of the GBM
• With progression, the glomeruli can become sclerosed.
• EM:  subepithelial deposits on GBM and are separated from each other by small, spikelike protrusions of GBM matrix that form in reaction to the deposits ("spike and dome" pattern)
• Podocytes show effacement of foot processes.
• IF: typical granular deposits of Igs and complement along the GBM.

microscopic slide of Membranous Nephropathy
 

Clinical Course

• insidious development of the Nephrotic syndrome, without antecedent illness
• some patents may have lesser degrees of proteinuria
• Proteinuria is nonselective
• Does not usually respond to corticosteroid therapy.
• 40% suffer progressive disease terminating in renal failure after 2 to 20 years.
• 10% to 30% have partial or complete remission of proteinuria.

Lipoid Nephrosis

This is characterized by diffuse effacement of foot processes of visceral epithelial cells (podocytes), detectable only by electron microscopy, in glomeruli that appear virtually normal by light microscopy. It is the most frequent cause of nephrotic syndrome in children, but it is less common in adults.

 Morphology

• LM: glomeruli appear normal.
• Cells of the proximal convoluted tubules - heavily laden with protein droplets and lipids (lipoid nephrosis).
• EM:  uniform and diffuse effacement of the foot processes of the podocytes.
• When the changes in the podocytes reverse (corticosteroids), the proteinuria remits.

 Clinical Course

• no HTN, and renal function is preserved in most individuals.
• Prognosis - good.
•  > 90% - respond to a short course of corticosteroid therapy
• Proteinuria recurs in >2/3 of the initial responders,
• < 5% develop CRF after 25 years

 

Focal Segmental Glomerulosclerosis

It is characterized histologically by sclerosis affecting some but not all glomeruli and involving only segments of each affected glomerulus.

Types

• Primary (or idiopathic) FSGS - 20% to 30% of all cases of the nephrotic syndrome.
• Secondary
• HIV infection or heroin abuse
• other forms of GN (IgA nephropathy)
• mutations - podocin, actin or nephrin

Morphology

• IF:  nonspecific trapping of Ig, usually IgM, and complement in the areas of hyalinosis.
• EM: podocytes exhibit effacement of foot processes
• Affected segment shows basement membrane thickening with deposition of hyaline mass & lipid droplets.

Clinical Course

• little tendency for spontaneous remission
• responses to corticosteroid therapy are poor.
• Progression to renal failure occurs at varying rates,
• 50% of individuals suffer renal failure after 10 years.
• Renal allografts recipient develops proteinuria- sometimes within 24 hours of transplantation

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