Nephrotic Syndrome II Flashcards
What are some KEY findings in the following categories that help you to know you're dealing with someone with MINIMAL CHANGE DISEASE? • Hx • Physical Exam • Blood Tests • Urinalysis
Hx:
• Recent onset Facial and Lower Extremeity Edema
Physical Exam:
• PITTING EDEMA (3+)
Blood Tests:
• LOW serum albumin
• Normal BUN and Creatinine
• Negative Antibody Tests
Urinalysis:
• 4+ Proteinuria
• Urine Protein Creatinine ratio = 18 (very high)
Minimal Change Disease, describe the following:
• Age Distribution
• Blood Pressure
Bimodal Age Distribution
• Very Young and Very Old ppl. get it
***MOST COMMON cause of nephrotic syndrome in children
Blood Pressure:
• Normotensive
What are the Primary and Secondary causes of Minimal Change Disease?
Primary:
• Ideopathic
Secondary:
• Malignancy: Hodkin’s Lymphoma
• Drugs: NSAIDs, interferon alpha
Why would you not get a biopsy with minimal change disease?
If a child has nephrotic syndrome you can almost just bank on it being this
How is Minimal Change Disease Treated?
• two general tactics.
Supportive Measures:
• ACE I’s/ARB
• Treat Hyperlipidemia
Disease Modifiers:
• Oral Glucocorticoid
Why would you give people with Minimal Change Disease an ACE I or ARB despite the fact that they do not have HTN?
Lowering the Blood Pressure even in the absence of HTN is useful because it decreases proteinuria
What is the Disease Modifying drug used in Minimal Change Disease?
• Response between two age groups that typically are Dx with MCD?
• chance of recurrence?
Children:
• More than 90% have an Excellent Response to Steroids
Adults:
•Respond much more slowly to steroids
Recurrence Rate is HIGH in minimal change disease
What should you start thinking if you have a kid with minimal change disease that doesn’t respond to steroids?
• Consider FOCAL SEGEMENTAL GLOMERULOSCLEROSIS
Kids are expected to respond well to steroids if they have Minimal change disease (should respond within a few weeks)
T or F: Focal Segmental Glomerulosclerosis is more associated with childhood disease
False, FSGS is more associated with Adulthood Disease
Focal Segmental Glomerulosclerosis, key features in: • Hx • Physical Examination • Blood Tests • Urine Analysis
Hx:
• Lower Extremity Edema
Physical Exam:
• HYPERTENSIVE
• Pitting edema
Blood Tests:
• HIGH creatinine
• HIGH albumin
Urine Analysis
• 4+ proteinuria
• HIGH urine protein creatinine ratio
What is THE MOST IMPORTANT THING TO KNOW about Focal Segmental Glomerulosclerosis?
• 50% of pts. with FSGS will progress to end-stage kidney disease within 10 years of Dx.
FSGS (focal segmental glomerulosclerosis)
• Proteinuria?
• HTN?
• Renal Function?
Proteinuria:
• NOT selective in contrast to MCD (MCD proteinuria is albumin only)
HTN:
• Often Seen with FSGS
Renal Function:
• Compromised (aka you will have a high serum creatinine
What is suPAR?
• what is is?
suPAR = antibody that binds INTEGRIN so that PODOCYTE can’t binds to the GBM
What are the primary and secondary causes of Focal Segmental Glomerulosclerosis?
• 4 secondary causes
Primary:
• Idiopathic
Secondary: Mutations in genes of the Glomerular Basement Membrane • Alpha-actin-4 • Podocin • TRCP6 • APOLIPOPROTEIN L1 gene
Infection
• HIV
• Parvo Virus
Drugs:
• Pamidronate
• Heroin
• Lithium
Loss of part of the kidney (causing more strain on the remaining glomeruli)
T or F: mutations in Podocin and Nephrin are mild and typically do not become apparent until much later in life.
FALSE, mutations in Podocin and Nephrin usually are apparent at birth
Most other mutations cause FSGS in an adult
What is the only protein involved in Barrier formation of podocytes that will not cause a recurrence of FSGS in transplantation?
Alpha-Actin 4, most other mutations will recur
What protein is responsible for the increased risk of FSGS and renal failure in individuals of African Descent?
• what chromosome is it found on?
• what is the point of this gene mutation?
Apolipoprotein L1 gene
- Chromosome 22
- APOL1 mutation prevents resistance by SRA protein of Tryponosoma T brucie rhodesience (sleeping sickness)
What is the pattern of glomerular involvement in Focal Segemental Glomerulosclerosis?
• Key Features to look for on H and E?
Focal - only some glomeruli involved
Segmental - only some lobules within each glomerulus are involved
Key Features:
•Increased Mesangial Matrix
- Obliterated Capillary Lumina
- Deposition of hyaline masses and lipid droplets
What is the problem with diagnosing Focal Segmental Glomerulosclerosis off of a biopsy?
A person may have FSGS BUT you can miss it because of the FOCAL nature of the disease
What will you see on immunofluorescence and EM with FSGS?
• which is more important in diagnosis?
IF:
• IgM and C3 may stain positive and get trapped in the GBM but this is NOT PATHOGENIC and not that imp. in dx.
EM
• **SEVERE PODOCYTE FOOT PROCESS EFFACEMENT
• occlusion of capillaries and endocapillaries
• Hyaline Deposits
What two subtypes of FSGS involve heavy proteinuria?
• which has the worst prognosis?
• Which as the best prognosis?
Collapsing - (11% of pts) WORST RENAL SURVIVAL
Tip - (17% of pts.) more likely to obtain remission
Ironic b/c these are the only two types that involve proteinuria*
What does the Collapsing Type of FSGS look like on H and E?
• Crushed Glomerulus similar to Crescentric but in collapsing the cellular expansion extends between glomerular lobules
Compare and Contrast Immunofluorescence properties of Minimal Change Disease and FSGS.
BOTH:
• Stain Negative on IF
FSGS - may have some non-specific staining with IgM that deposits in the scar tissue
What are the treatment methods for FSGS?
• two aspects from which the disease is treated.
- Supportive Measures
• Control BP - ACE Is/ARB
• Treat Hyperlipidemia - Disease Modifiers
• Corticosteroids
• Calcineurin Inhibitors (Cyclosporin or Tacrolimus)
How do the treatment measures for FSGS differ from minimal change disease?
Calcineurin inhibitors like CYCLOSPORIN and TACROLIMUS are implemented in the treatment of FSGS but these chemo. drugs are NOT used in MCD (minimal change disease)
Note: the response to cyclosporin etc. is still not that great
Apply the following terms to Minimal Change Disease and Focal Segmental Glomerular Sclerosis:
• Good/Bad Px.
• (non)/Steroid Sensitive NS
Minimal Change Disease:
• Good Px.
• Steroid Sensitive
Focal Segemental Glomerular Sclerosis:
• Bad Px.
• Steroid Resistant
T or F: MCD may just be an early form of FSGS.
True, these disease are probably part of the same disease spectrum as seen in looking at children who progress to FSGS from MCD
What two type of Nephrotic Syndrome are associated with Subepithelial Immune complex deposits?
- Membranous Nephropathy
2. Post-infectious Glomerulonephrtitis
Membranous Nephropathy:
• Who is this mostly seen in?
• Prognosis?
Membranous Nephropathy Seen in:
• WHITE CAUCASION MALES between 40 and 60 y/o
Px:
• 30% of cases spontaneously resolve
• 40% progress to renal failure
What should you do if you have a pt. that is 60 or 70 and is found to have a membranous nephropathy?
Send them for common cancer screenings such as LUNG, COLON Cancer, and Melanoma
this is because cancer is often a secondary cause of Membranous Nephropathy
What are the categories of Primary and Secondary Membranous Nephropathies?
Primary: always idiopathic
Secondary: • Infection: Hep B, Syphilis, Malaria • Autoimmune: SLE • Drugs: Penicillamine, NSAIDs, Gold • Malignancy: Lung cancer, Colon cancer, Melanoma
*also associated with sickle cell
Compare the two theories of immune complex deposition in Membranous Nephropathy and the processes/disease that are thought to follow these patterns.
Filtered Antigen Theory:
• Circulating Ab. it deposited in the Subepithelial Space (after passing through the endothelium)
• POST-STREPTOCOCCAL GLOMERULONEPHRITIS is believed to work this way
AUTOIMMUNITY model:
• Auto antibody forms to a locally generated antigen
*Important concept: this is IN SITU formation of immune complexes AFTER they make it through the GBM, otherwise they are too large to pass through
What are frequently the Targets of autoanibodies generated in Membranous Nephropathy?
• are these associated with congenital or primary MN?
- M-type phospholipase A2 receptor
- -> PRIMARY MN - Neutral Endopeptidase
- -> Congenital MN
What two types of membranous nephropathy are associated with the autoimmunity model?
Targets of Autoimmunity:
• M-type Phospholipase A2 receptor (primary MN)
• Neutral Endopeptidase (congenital)
Describe the 5 steps in In-Situ Immune Complex formation in Membranous Nephropathy.
- Free IgG binds to Clatherine coated parts of foot processes
- IgG induces MAC formation
- (a) Antigen-antibody compexes are shed to form subepithelial deposits (b) C5b-9 are sent to the urinary space
- Podocytes (gomerular epithelium) responds to C5b-9 by releasing oxidants and proteases in
- Damage to Podocytes allows for increased protein passage through slits and Effacement of podocytes
If you were to test someone with IDEOPATHIC MEMBRANOUS NEPHROPATHY for an autoantibody, which would you choose?
• where is the target expressed?
• type of antibody?
- PLA2R autoantibody is present in 70% of pts. with M type phospholipase A2
- Expressed in PODOCYTES in normal human glomeruli
- IgG4 = autoantibody type
Do you ever see PLA2R in patients with secondary membranous nephropathy?
• where is the damage done in membranous nephropathies?
PLA2R:
• NO - this is found in patients with PRIMARY IDEOPATHIC Membranous Nephropathy
• Damage in membranous Nephropathy = Subendothelial
What are 6 risk factors for loss of renal function in membranous Nephropathy?
- Male Gender
- Over 10g/day of proteinuria
- HTN
- Azotemia
- Tubulointerstitial Fibrosis
- Glomerulosclerosis
What are some key features to look for on LM, IF, and EM in membranous Nephropathy?
LM:
• SPIKES on silver STAIN
IF:
• Granular along GBM
EM:
• SPIKE and DOME appearance of Subepithelial Deposits along GBM
T or F: in membranous nephropathy the capillary loops are thickened and prominent and the cellularity is increased
FALSE, cellularity is NOT increased in the membranous nephropathy
What is the typically treatment for membranous nephropathy?
• what happens if this treatment fails?
• Why do we treat is this way?
Treat this way because 30% of cases Regress Spontaneously
IF proteinuria is LESS than 4gm/day:
• give ACEI or ARB to get BP below 125/75
IF proteinuria is GREATER than 4gm/day:
• give ACEI or ARB to get BP below 125/75
IF on ACEI or ARB and Proteinuria remains above 4 gm/day:
• USE CYTOTOXIC agents - Steroids or Calcineurin inhibitors
KEY features of Post-Infectious Glomerulonephritis? • Hx • Physical Exam. • Blood Tests • Urine Analysis
Hx:
• Dark Colored Urine
• Wt. Gain
• Decreased Urine output
Physical:
• HYPERTENSION
• pitting edema
Blood Tests:
•HIGH creatinine
• LOW albumin
Urine Analysis:
• 3+ proteinuria
• Urine Protein Creatinine ratio = 3.6 (high but not in nephrotic range)
How will a patient with Post-Infectious Glomerulonephritis typically present?
Pt. who has recently cleared an UPPER RESPIRATORY TRACT infection that presents with HYPERTENSION and COLA Colored URINE. They will show ASCITES, Peripheral Edema and signs of fluid retention
What key immunological studies to lood for in POST-INFECTIOUS GLOMERULONEPHRITIS?
• what do these indicate?
• How will you select the test based on the preceding infection?
LOW C3 and Normal C4 (normal C4 indicates that ALTERNATIVE complement cascade is activated)
THROAT INFECTION:
• anti-streptolysin O (ASO)
SKIN INFECTION:
• Anti-DNAse B titers
SEPSIS:
• positive blood culture
What is the typical appearance of Glomeruli in Post-streptococcal GN on H and E?
• what physiologic problem is caused by these changes?
- Glomeruli are Globally and diffusely enlarged and HYPERCELLULAR due to NEUTROPHILS, MACROPHAGES, MESANGIAL and ENDOTHELIAL proliferation
- INFLAMMATION causes obstruction of Capillary Lumen
What will you see on immunofluorescence of someone who has a Nehpritis following clearance of a recent infection?
• what causes this appearance?
this is POST-STREPTOCOCCAL GLOMERULONEPHRITIS
Appearance:
• Diffuse granular deposits in MESANGIUM and CAPILLARY walls
Stain will be positive for C3 and IgG Granular Appearance b/c this is a SUBENDOTHELIAL disease
What do you expect to see on EM for patients that have hematuria, Low C3 and normal C4 following a recent URI?
Post-streptococcal GN
• DOME-SHAPED SUBEPITHELIAL HUMPS
What treatment measures are taken for PIGN?
• Prognosis?
Post-Infectious GN
SUPPORTIVE measures taken (disease should clear itself)
• Control HTN (ACE/ARB)
• Dialysis
PROGNOSIS = good, disease should resolve over a few weeks
What lab values should you track after someone has been Dx with PIGN to ensure that they’re improving?
C3 Levels:
• these should normalize over the period of about 6 wks
Hematuria:
• should resolve withing 12 months
