Nephrotic Syndrome

proteinuria (>3g/day), edema, hypoalbuminemia, hyperlipidemia, and lipiduria (can be localized kidney process or as part of a systemic disease)
vs. nephritic syndrome: hematuria, oliguria, hypertension, and renal insufficiency (almost always immune mediated) --> often the two disorders overlap……..
Normally, charge and size-selective barriers on the glomerular basement membrane albumin and other large proteins from being filtered out (<20kD)
Small amounts of proteinuria can be from excreted protein (Tamm-Horsfall proteins are formed on the epithelial surface of a portion of the loop of Henle/ascending tubule)
Protein can be measured in random samples, timed overnight samples, or 24 hr collections
24 hr collections are notoriously challenging because of the likelihood of inaccurate collections (but, this can be corrected by measuring creatinine in the sample and correcting by knowing the expected 24 hr urine creatinine excretion)
Dipsticks are fairly sensitive for proteinuria (but lower limit is 10-20mg/dL); can have false positives at very high urine pH or with hematuria
Most quantitative or semiquantitative measurements of urine protein rely on concentration (mg/dL) (dipstick, spot protein) vary based on dieresis, hydration etc.
- To avoid this variability with urine concentration, we now mostly use protein:creatinine or albumin:creatinine ratio (which highly correlate with 24 hr collections)— protein mg/creatinine mg (so if you have 3.0 mg protein/mg creatinine, that can be estimated to be 3 g/day)
Several studies have found the prot/creat ratio to be more reliable, more predictive of disease severity/progression. Still has some limitations as the protein and creat content in the urine can vary throughout the day (recommend 2-3 samples over a 6 month period)
- Microalbuminuria= 30-300mg/g (0.03-0.30mg/mg)

Complications from Protein Loss:

Edema (low plasma oncotic pressure), hypercoaguability (loss of protein C, S, antithrombin III and impaired fibrinolysis, increase plt aggregation), low complement, hyperlipidemia (increased hepatic synthesis of lipoprotein), increased susceptibility to infections (loss of IgG).

Etiologies: Primary /Idiopathic vs. Secondary causes (DM, HIV, etc.)

Minimal change disease (idiopathic) --> see below
Focal segmental glomerulosclerosis (can be primary/idiopathic or secondary--drugs, viruses, malignancy; more common in African Americans. Focal scarring in the glomeruli)
Membranous nephropathy: primary vs. secondary--associated with malignancies, infections, autoimmune disease, drugs; high rates of VTE, more common in Caucasians. Immune complex deposition. Most common cause of primary nephritic syndrome in adults
Membranoproliferative glomerulonephritis: usually associated with autoimmune diseases, but can occur with Hep C, endocarditis, cancer. Always hypocomplementemic, often associated hematuria. Tram-tracking on EM
Diabetic nephropathy (most common secondary cause)
Plasma cell dyscrasias (amyloid, light chain deposition)
C1q nephropathy (rare, occurs mostly in African American males btwn age 15-30, stains + for C1q deposits)

Treatment of Nephrotic syndrome:

For secondary causes, treatment is aimed at the underlying disorder (Hep C, HIV, DM, malignancy etc.). Primary causes can be immune-mediated, and often respond to immunosuppression.

Mainstays of therapy are:

BP control, with goal BP 125/75, with ACE-I or ARB
Lipid lowering agents (statins)
Vit D and/or epo for anemia

Pearl:
-Effective diuretic dose in nephrotic syndrome is often twice what is needed in HF or cirrhosis, in part because loop diuretics are largely protein bound. If there is renal impairment you need to increase the dose further. We talked about seeing the patient back frequently, watching out for side effects and compliance to meds, and checking BMPs.

Complications of renal biopsy: rates from one large study
100% transient microscopic hematuria
3-18% transient macroscopic hematuria
50% decrease in hgn 1g/dl
1-2% bleeding severe enough to cause hypotension
6% bleeding severe enough to result in transfusion
0.1-0.4% surgery required, 0.3% nephrectomy required

Ultrasound guidance has not changed the mortality rate which is 0.1%!

Minimal change disease:

EM: effacement or flattening of the glomerular basement membrane cells
No abnormalities on immunoflourescence
Proteinuria can develop rapidly, can be severe (can exceed 9 g)
Loss of albumin in the urine is mostly due to loss of charge selectivity of the BM
Can have a relapsing, remitting course
Causes up to 80% of nephrotic synd in children, 10% of primary nephritic syndrome in adults
Pathogenesis is unclear, but appears to be a disorder of abnormal T-cell regulation
In adults, can be associated with drugs (particularly NSAIDs) or lymphoproliferative disorders
HTN and ESRD rare in children, but more common in older adults with underlying artherosclerosis
Treatment of the proteinuria resolves the AKI
Treatment: prednisone over 8+ weeks

Essential mixed cryoglobulinemia:

Causes symptoms through the deposition of ag-ab complexes in small and medium sized arteries. The cryoglobulin contains polyclonal IgG and monoclonal IgM RF against IgG. It is most commonly secondary to HCV, infact 95% have either anti-HCV AB, HCV RNA in plasma and cryoprecipitate, or polyclonal IgG anti-HCV AB within the cryoprecipitate. They can present with palpable purpura, nonspecific systemic symptoms, LAN, HSM, peripheral neuropathy and low complement. About 20% have renal disease at presentation, but eventually 35-60% will develop renal disease. The renal disease is classically MPGN with intraluminal thrombi of precipitated cryo.

(Katharine Cheung MD, 7/2/10)

(Victoria Kelly MD, 8/20/10, 10/12/10)