nephrotic syndrome

Question 1

Three cell populations in the glomerulus and their functions

Answer 1

The glomerular endothelial cell lines the inner side of the GBM (fenestrations), glomerular mesagnial cell (centrall located cell that secretes basement membrane like matrix, can contract like smooth muscle, and has macrophage like properties such as secreting cytokines, growth factors, proteases and oxidants), and epithelial cells (aka podocytes with foot processes separated by slit-like diaphragms)

Question 2

glomerulus charge barrier

Answer 2

the basement membrane is highly negatively charged (due to the presence of heparan sulfates) and the endothelium and podocyte are also coated in negatively charged proteins (consisting primarily of sialoproteins). This prevents most negatively charged molecules from being filtered (such as proteins)

Question 3

glomerulus size barrier

Answer 3

the critical site is the slit pore diaphragm that extends between the podocyte foot processes. The primary protein in the slit diaphragm is termed nephrin. Nephrin molecules interlock and prevent proteins from being filtered

Question 4

congenital nephrotic syndrome is due to a mutation in _________

Answer 4

nephrin

Question 5

Normal protein excretion

Answer 5

500mg of albumin escapes into Bowmans capsule, but most is reabsorbed in proximal tubule so only 20mg/day is excreted. Tamm-Horsfall protein from thick ascending limb and IgA are also normally excreted

Question 6

Abnormal protein excretion

Answer 6

Albumin >30mg/day is abnormal. 30-300mg/day albumin is not detectable by UA (microalbuminuria) and is suggestive of early glomerular damage. Albumin >300mg/day is identified in UA (300-2mg/day is glomerular or tubular disease, >3mg/day is defect in glomerular permeability and can result in decreased serum albumin)

Question 7

Define nephrotic syndrome

Answer 7

excessive leak of protein through the glomerular capillary wall into the urinary space

Question 8

Define nephritic syndrome

Answer 8

active inflammation within the glomerulus leads to damage to the glomerulus with subsequent loss of filtration and a reduction in the GFR

Question 9

Clinical definition of nephrotic syndrome

Answer 9

• Proteinuria (>3.5 gm/day or >40 mg/hr/M2 in children) • Hypoalbuminemia (<3.0 gms/dl) • Edema • Hyperlipidemia (elevated serum cholesterol) • Lipiduria (fat globules in the urine

Question 10

Clinical definition of nephritic syndrome

Answer 10

Decreased renal function, hypertension, RBC and RBC casts, edema, proteinuria

Question 11

What causes proteinuria in nephrotic syndrome?

Answer 11

Disruption of the slit diaphragm. This may result from a specific defect of the diaphragm (such as a mutation of nephrin) or if the podocyte is injured

Question 12

What causes hypoalbuminemia in nephrotic syndrome?

Answer 12

results from the proteinuria and increased catabolism of reabsorbed protein in the renal tubules. Protein synthesis by the liver is increased but can not compensate completely for the urinary losses.

Question 13

What causes edema in nephrotic syndrome?

Answer 13

1) Decreased serum albumin decreases plasma oncotic pressure, resulting in filtration of fluid into the interstitial space. This decreases intravascular volume with stimulation of renin-angjotensin-aldosterone and vasopressin leading to additional salt and water retention. 2) primary renal defect in sodium excretion, resulting in volume expansion, and fluid movement into the interstitium due to both the low oncotic pressure and high hydrostatic pressure

Question 14

What causes hyperlipidemia in nephrotic syndrome?

Answer 14

Decreased plasma oncotic pressure stimulates lipoprotein synthesis in liver (VLDL and LDL) and decreases peripheral removal of VLDL.

Question 15

What causes lipiduria in nephrotic syndrome?

Answer 15

Increased capillary wall permeability and hyperlipidemia leads to lipids in the urine that appear like Maltese crosses under polarized light

Question 16

What other conditions are common in nephrotic syndrome?

Answer 16

Increased risk for infections (urinary loss of IgG and complement), increased risk for thrombosis (increase in synthesis of coagulation factors by the liver, urinary loss of anti-thrombin III, increased platelet aggregability, and impairment of the fibrinolytic system), poor growth and osteomalacia (loss of Vitamin D) and protein malnutrition

Question 17

Classifications of glomerular disease

Answer 17

nephrotic syndrome, nephritic syndrome, asymptomatic proteinuria, or asymptomatic hematuria

Question 18

Causes of nephrotic syndrome

Answer 18

Renal only: Hereditary Nephrotic Syndromes, Minimal Change Disease, Focal Glomerular Sclerosis, Membranous Nephropathy, Membranoproliferative GN (MPGN). Systemic: Diabetes, amyloid, light chain deposition disease, lupus membranous type
Renal only: Hereditary Nephrotic Syndromes, Minimal Change Disease, Focal Glomerular Sclerosis, Membranous Nephropathy, Membranoproliferative GN (MPGN). Systemic: Diabetes, amyloid, light chain deposition disease, lupus membranous type

Question 19

Causes of nephritis

Answer 19

renal only: Post Infectious (post strep), IgA Nephropathy
Rapidly Progressive GN (RPGN) such as Anti-GBM Nephritis or Idiopathic RPGN. Systemic disease: vasculitis, lupus, Henoch-Schonlein Purpura, Cryoglobulinemia, Wegener’s Granulomatosisrenal only: Post Infectious (post strep), IgA Nephropathy
Rapidly Progressive GN (RPGN) such as Anti-GBM Nephritis or Idiopathic RPGN. Systemic disease: vasculitis, lupus, Henoch-Schonlein Purpura, Cryoglobulinemia, Wegener’s Granulomatosis

Question 20

Minimal change disease definition, epidemiology, pathology

Answer 20

Common cause of nephrotic syndrome with normal appearing glomeruli. Mainly affects young children (2:1 M:F) or 50-60yrs. Light microscopy is normal and electron microscopy shows foot process fusion (seen in all nephrotic syndromes)

Question 21

Minimal change disease cause, presentation, treatment and prognosis

Answer 21

Caused by a T cell derived circulating permeability factor that acts on the glomerulus to damage podocyte and permeability barrier. Presents with edema, severe hypoalbuminemia and associations with Hodgkins disease, NSAID use or allergic disease. Treatment with steroids and long term prognosis is good

Question 22

FOCAL SEGMENTAL GLOMERULOSCLEROSIS (FSGS) definition, epidemiology, pathology

Answer 22

Type of nephrotic syndrome common in young adults and african americans, characterized by segmental scarring in some glomeruli and diffuse defect involving the entire capillary wall. Can develop from minimal change disease. EM shows diffuse foot process fusion and light microscopy shows scarring

Question 23

Focal segmental glomerulosclerosis (FSGS) cause, associations, presentation, treatment and prognosis

Answer 23

Cuased by circulating factor (such as suPAR). May be idiopathic or associated with minimal change disease, heroin use, HIV, and rarely sickle cell, parvo virus and obesity. Presents with idiopathic nephrotic syndrome but may be hypertensive or have microhematuria. Treated with steroids (less responsive),cyclosporine. Renal failure is common

Question 24

Membranous nephropathy definition, epidemiology and pathology

Answer 24

immune mediated glomerular disease associated with immune complex deposits in the subepithelial space (between the podocyte and GBM). GBM appears thickened by light microscopy. Most common in older adults. Silver stains show spikes in BM representing extensions of new BM btw immune complex deposits. Immunofluorescence shos granular deposits of Ig and C3/C5b-9 in GBM.

Question 25

Membranous nephropathy causes, associations, presentation, treatment, prognosis

Answer 25

Autoimmune- Abs against phospholipase A2 receptor on podocytes. Idiopathic or associated with chronic infection, drugs, lupus or cancer. Presents as nephrotic syndrome with edema, HTN and renal failure develop over time. Treated with steroids and cytotoxic drugs. 50% end stage renal failure

Question 26

Membranoproliferative Glomerulonephritis definitions and epidemiology

Answer 26

MPGN refers to a histologic pattern in which there is both proliferation (usually mesangial and in a lobular pattern) as well as thickening of the GBM. Type I associated with immune complex deposits, type 2 associated with complement activation in capillary wall. affects children and adolescents

Question 27

Membranoproliferative Glomerulonephritis pathology, pathogenesis,

Answer 27

type I light microscopy shows thickend basement membrane, mesagnial cell proliferation, lobulated glomerulus, C3 deposits on capillary walls/ mesangium and IgG deposits. Type II only has C3 deposits, no IgG. Type I is due to passive trapping of circulating immune complexes in the subendothelial and mesangial areas, followed by complement activation and leukocyte recruitment. Type II is due to circulating nephritic factor that activates the alternative pathway of complement.

Question 28

Membranoproliferative Glomerulonephritis presentation, treatment and prognosis

Answer 28

Most present with nephrotic syndrome, some with acute nephritis. Early HTN. Associated with Hep C, cryoglobulins and RF. Prognosis is poor (many develop end stage renal disease). Treated with steroids, anti-platelet drugs

Question 29

Diabetic nephropathy

Answer 29

Presents with nephrotic proteinuria, microhemature is common, nodular glomerulosclerosis with thickening of BM is renal biopsy. Treated with glucose control, BP control and ACEI

Question 30

SLE and nephrotic syndrome

Answer 30

Membranous histological pattern in which renal function is normal or slightly depressed and proteinuria/nephrotic syndrome occur. Treated with prednisone and mycophenolate

Question 31

Amyloidosis and plasma cell dyscrasias

Answer 31

Usually in older people. Workup includes free plasma light chains, and serum and urine protein electrorphoresis to look for monoclonal light chains. Renal biopsy shows amyloid deposits (in amyloidosis) or nodular glomerulosclerosis (in light chain disease).

Question 32

General management of nephrotic syndrome

Answer 32

low salt diet, diuretics, BP control, cholesterol lowering meds, ACEI to decrease proteinuria, Vit D replacement, low protein diet