Week 3: Clinical Aspects of proteinuria

Question 1

Describe normal handling of protein by the kidneys.

Answer 1

• Only the smallest plasma proteins are allowed to pass through glomerular basement membrane
• Of the protein excreted in the urine, 50% is plasma proteins (very little albumin, mostly immunoglobulins). Remaining 50% is non-plasma protein. (Tamm-Horsfall glycoprotein-major constituent of casts matrix).

Question 2

What is microalbuminuria?

Answer 2

• urinary albumin excretion between 30 and 300mg/24 hours or per g of creatinine
• Significance: prognostic indicator for future renal as well as CV disease. May have prognostic implications in patients with essential HTN

Question 3

What is transglomerular movement of proteins affected by?

Answer 3

1. Properties of protein
   - size
   - shape: linear, flexible, and round molecules cross GBM more easily than globular and rigid molecules
   - charge: + > neutral > -
   - deformability
2. Properties of capillary wall
   - RBF, GFR, FF
   - Anionic charge of GBM
   - integrity of GBM

Question 4

Describe the mechanisms of proteinuria.

Answer 4

1. Glomerular Proteinuria:
   - increased filtration of macromolecules (e.g. albumin) across glomerular capillary wall
   - increased glomerular permeability can be from loss of negative charges along the basement membrane or by alteration of normal structure of GBM
2. Tubular Proteinuria
   - smaller proteins are filtered and mostly reabsorbed by PT
   - diseases affecting tubular functions may result in decreased reabsorption and proteinuria
   - e.g. Fanconi, analgesic nephropathy
   - characterized by increased excretion of low molecular weight proteins
3. Overflow proteinuria
   - due to excessive production, filtration across GBM, and excretion of proteins of low molecular weight and size
   - e.g. multiple myeloma: monoclonal light chains of immunoglobulin
   - e.g. hemoglobinuria, myoglobinuria

Question 5

Describe isolated proteinuria.

Answer 5

• discovered on routine examination of an asymptomatic individual, absence of hematuria
• should be evaluated for constant or orthostatic proteinuria
• orthostatic occurs only during the day but not during rest. Usually disappears over time and has no significant histological abnormalities
• constant proteinuria have larger proportion of patients with significant histological alterations and less benign clinical course
• transient proteinuria: appears in connection with an acute illness, e.g. fever, CHF, and resolves with resolution of primary disease

Question 6

Define nephrotic syndrome.

Answer 6

-syndrome caused by renal diseases that increase permeability  
A collection of signs that include
1. Proteinuria >3.5gms/24hrs
2. Hypoalbuminemia
3. edema
Can have the following, but not necessary for diagnosis
4. Hyperlipidemia
5. disturbances of calcium metabolism
6. hypercoagulability
7. Thyroid dysfunction

Question 7

Describe hypoalbuminemia in nephrotic syndrome.

Answer 7

• when disease is characterized by loss of negative charges in the GBM, the primary protein lost is albumin (selective proteinuria)
• when disease is due to alternations in structure, other larger proteins can be loss (non-selective proteinuria)
• the urinary albumin loss stimulates hepatic synthesis of albumin, but compensation is not enough

Question 8

What causes the edema in nephrotic syndrome?

Answer 8

There are two hypotheses

1. Underfilling: the hypoalbuminemia causes decrease in effecting circulating volume, activating RAAS and causing water and Na retention
   - however, 2/3 of patients have normal plasma volume and normal aldosterone levels
2. Overfilling hypothesis
   - proteinuria and albuminuria causes increased Na+ reabsorption and decreased renal excretion of Na (EDEMA)–>arterial under filling since fluid is in ISF–> ADH release and RAAS increases

Question 9

What causes hyperlipidemia in nephrotic syndrome?

Answer 9

Complex mechanisms

• hypoalbuminemia (diminished plasma oncotic pressure) causes increased production of a variety of proteins and lipids
  1. proteinuria causes decreased catabolism of VLDL, chylomicrons
  2. Lipoprotein lipase (LPL) is reduced because lost in urine
  3. Increased HGM-CoA reductase activity
  4. LDL receptor deficiency

Question 10

Describe abnormalities of calcium and Vit D in nephrotic syndrome.

Answer 10

• 25-OH-Vit D is bound to alpha globulin in blood
• this globulin and Vit D is lost in urine of patients with nephrotic syndrome
• Lack of Vit D–>reduced intestinal absorption of Ca, skeletal resistance to PTH
• bones: osteomalacia-defective mineralization of osteoid, or enhanced bone resorption (hyperparathyroidism)

Question 11

Describe hypercoagulability in nephrotic syndrome.

Answer 11

• Alternations in levels of components in coagulation system
• Decreased: Factor XII, VII, IX, ATIII, plasminogen, activated protein C
• increased: Factor XIII, VIII, V, fibrinogen, fibronectin, platelets

Question 12

List the etiologies of nephrotic syndrome.

Answer 12

Secondary causes-most common
-diabetic nephropathy, amyloidosis, multisystem diseases (SLE), neoplasia, drugs, infections (parvo, HIV, syphilis, hep B)
Idiopathic form
-Minimal change disease
-membranous glomerulonephritis
-focal and segmental glomerulosclerosis
-membranoproliferative glomerulonephrits
-IgA nephropathy