9/22- Cases Membranous, Crescentic, Post-infectious and Membranoproliferative GN Flashcards
Into what 3 categories can renal diseases be divided?
Diseases affecting:
- Glomeruli
- Tubulo-interstitium
- Vessels
Clinical presentations of:
- Nephrotic syndrome
- Nephritic syndrome
- Acute renal failure
- Chronic renal failure
Nephrotic syndrome
- Proteinuria, edema, hypoalbuminemia, hypercholesterolemia, lipiduria
Nephritic syndrome
- Hematuria, mild proteinuria, hypertension
Acute renal failure
- Oliguria or anuria, elevated BUN and creatinine
Chronic renal failure
- Chronic elevation of BUN and Creatinine
Case)
- A 56 year-old woman without any significant past medical history presented with progressive edema for the past two months
- An annual check-up 10 months ago showed no protein excretion and normal serum creatinine (0.7mg/dl)
- Currently, the serum creatinine was 1.1 mg/dl.
- There was 4+ proteinuria by dip stick and the 24-hour urine collection revealed 5 grams of protein.
- Urine analysis showed 5 RBCs and no WBCs/HPF.
- All serologic studies including ANA, anti-DNA, and viral hepatitis panel were negative.
- A renal biopsy was performed.
What renal syndrome does this pt have?
Why is a renal biopsy indicated?
NEPHROTIC syndrome.
The two most important elements of this syndrome:
- Proteinuria > 3 g/day
- Peripheral edema
(Other elements include: hypeprlipidemia, lipiduria, hypoalbuminemia; plasma albumin under 3 g/dL)
There are a variety of renal lesions that can cause nephrotic syndrome and a specific diagnosis is needed for proper management of this patient.
Protein loss implies disease at what level?
Glomerulus
- Abnormal filtration and excretion of proteins
What provides the negative charge on the glomerular filtration membrane?
- Heparan sulfate -> GBM (-)
- Sialoproteins -> podocyte/endothelium (-)
What are possible causes of nephrotic syndrome?
Many; limited number account for a majority
Pediatrics:
- Minimal change disease (#1 in kids)
- Focal segmental glomerulosclerosis (idiopathic)
Adults:
- Membranous glomerulonephropathy
- Focal segmental glomerulosclerosis (idiopathic)
- Diabetic nephropathy
- Amyloidosis
What is seen here?
Membranous glomerulopathy (inset = normal)
- Diffuse thickening of the glomerular capillaries
- Glomerular capillary loops appear thickened, eosinophilic and “stiff”
- Some capillary loops may actually appear “fuzzy” and special stains may shows a “spiked” GBM or “hair on end” appearance
- Epi- or intramembranous deposits (red dots) may be seen on Trichrome staining
- It is not uncommon to have increased mesangial matrix and even segmental lesions
What does the IF staining for IgG show in Membranous GN?
Global, diffuse, and granular staining for IgG along the glomerular capillaries
What do you see in the EM of membranous GN?
- Multiple subepithelial or intramembranous immune deposits
- Thickened basement membrane
- Effacement of foot processes
(Don’t confuse with “humps”; latter are more like haystacks)
What will show up on silver stain in membranous GN?
EM with subepithelial electron dense deposits, separated by spikes of basement membrane material.
- Silver stains basement membrane but not deposits
- Results in “hair on end”, spiked look
What are the different types of Membranous GN?
Primary: idiopathic
Secondary:
- Solid tumors*
- Systemic lupus
- HepB
- Some drugs
*Up to about 5-10% of cases of membranous glomerulonephropathy (esp in elderly) are associated with neoplasms
Treatment: membranous GN?
- Investigate for 2ndary causes
- then start on steroid therapy?
Case 2)
- A 62 year-old woman without a significant past medical history presented with sore throat, malaise, arthralgia, and weight loss
- Physical examination was unremarkable.
Lab findings:
- Serum creatinine 3.6 mg/dl
- Urine analysis 3+ blood, 1+ protein + P-ANCA 1:600; + MPO-ANCA 20U/dl; negative C-ANCA, ANA, anti-DNA antibody, anti-GBM antibody, hepatitis serology, rheumatoid factor; normal serum C3 and C4.
- A renal biopsy was performed.
What renal syndrome does this patient have?
Why was a renal biopsy performed in this patient?
NEPHRITIC syndrome
- Decreased renal function
- Hematuria (RBCs in urine)
- Classically: grossly visible hematuria, mild-mod proteinuria and HTN
Why renal biopsy?
- Possibility of a glomerulonephritis
- The positive ANCA suggests that the glomerulonephritis may be related to ANCA.
- However, there is still reason to perform the kidney biopsy in this patient
- ANCA may be positive in many unrelated conditions including inflammatory bowel disease, some types of hepatitis, and other non-renal immune-mediated diseases
- In addition, there are well-illustrated cases in which there is a discrepancy between the clinical presentations and the renal lesions revealed by kidney biopsy
- Therefore, the kidney biopsy findings serve not only to confirm the diagnosis of crescentic glomerulonephritis but also to determine how severe and how active the renal lesions are.
- These features are important for treatment decisions.
What is the underlying pathophysiology of nephritic syndrome?
Disruption of capillary loops with spillage of protein and red cells
- Active urinary sediment Spilled proteins may incite crescent formation
What is the significance of the laboratory findings, especially the serologic tests?
- Serum creatinine 3.6 mg/dl
- Urine analysis 3+ blood, 1+ protein
+ P-ANCA 1:600; + MPO-ANCA 20U/dl; negative C-ANCA, ANA, anti-DNA antibody, anti-GBM antibody, hepatitis serology, rheumatoid factor; normal serum C3 and C4.
Help with DDx for crescentic glomerulonephritis
- Negative ANA, anti-DNA, and anti-GBM and other negative serological tests help to rule out lupus nephritis, anti-GBM antibody mediated disease and viral hepatitis-related glomerular lesions
- Positive ANCA supports possibility of ANCA-related glomerulonephritis
What is ANCA?
AntiNeutrophilic Cytoplasmic Antibodies
- Mainly in primary granules of neutrohpils, but also lysosymes of monocytes and endothelial cells
What are the 2 ANCA patterns?
Cytoplasmic (C-ANCA)
- Proteinase 3 (PR-3)
- Lysosomes of neutrophils and monocytes
- Rule in neutrophil maturation
- Digest tissues to facilitate neutrophil migration to inflammatory sites Perinuclear (P-ANCA)
- Myeloperoxidase (MPO)
- In lysosomes of neutrophil and monocytes
- Helps generate reactive oxygen mcls that are bactericidal
THINK: C3PO
How is ANCA detected?
Immunofluorescent (IF) technique
- Normal human alcohol fixed neutrophils as substrate
- Cytoplasmic pattern (C-ANCA)
- Perinuclear pattern (p-ANCA): artifactual due to redistribution of the MPO to perinuclear location during alcohol fixation
Enzyme linked immunosorbent assay (ELISA)
- C-ANCA PR3-ANCA
- P-ANCA MPO-ANCA
What does biopsy show?
Crescentic glomerulonephritis
- Circumferential cellular crescent (outlined) compressing the underlying glomerular caps
- Collapsed glomerular tufts with a crescent shaped mass of proliferating cells and leukocytes internal to Bowman capsule
- The crescents are formed by proliferation of parietal epithelial cells and by migration of monocytes and macrophages into Bowman’s space
- Neutrophils and lymphocytes may be present.
- The crescents eventually obliterate Bowman’s space and compress the glomerular tuft
- Fibrin strands are present between the cellular layers in the crescents.
What is seen here?
Crescentic glomerulonephritis
- A cellular crescent with focal rupture of Bowman’s capsule (arrow) with surrounding inflammation
- Intact Bowman’s capsule (arrow head).
What is seen here?
Crescentic glomerulonephritis
- Cellular crescent, associated with fragmentation of the glomerular capillaries (black strands)
What is expected on EM in crescentic glomerulonephritis?
Fragmentation of glomerular caps
What is seen here?
Crescentic glomerulonephritis
- A fibrous crescent (green), associated with sclerosis of the underlying glomerular capillaries
What are possible causes of crescentic glomerulonephritis?
- ANCA associated
- Pauci-immune
Pathogenesis of crescentic GN?
- Crescents forms when there is rupture of the glomerular capillary loops and fibrin is extruded into the urinary space
- The parietal epithelial cells (cells lining Bowman’s capsule) proliferate to form the crescent, along with inflammatory cells.
- Bowman’s capsule may rupture leading to interstitial inflammation, even granuloma formation.
What is the standard treatment for the renal disease identified in the biopsy and how is the prognosis?
- The standard treatment for ANCA-related crescentic GN is cyclophosphamide
- Usually the patient responds well to therapy, especially in those with a kidney biopsy showing active and acute lesions
- Renal function may return to near normal.
- However, the disease may recur later and recurrences may be heralded by elevations of serum ANCA levels.
Case 3)
- A 6 year old child presented with a 5 day history of vomiting, diarrhea, and fever
- The patient’s mother noted that the child had cola colored urine along with markedly decreased urine output
- Swelling of the face, abdomen, and legs was noted physical examination.
Lab findings:
- Serum creatinine 6.7 mg/dl
- Normal serum C3 and C4 levels
- Urine analysis 3+ blood and 3+ protein
- Antistreptolysin O (ASO) titer was in process.
- A renal biopsy was performed.
What renal syndrome is this?
Gross hematuria and is edematous, suggesting overlapping nephritic and nephrotic syndrome
What would a positive ASO titer suggest?
Previous strep infection (possibly strep throat or skin infection)
- Titer elevations may suggest post-infectious GN
What is seen on this biopsy?
Post-infectious glomerulonephritis
- Glomeruli are cellular and small crescent is noted (arrow)
- Diffuse endocapillary proliferation with many neutrophils (“exudative glomerulonephritis”) with crescent formation
What is expected to be seen in EM of Post-infectious glomerulonephritis?
- Epimembranous “humps” by electron microscopy
What is expected to be seen in IF of Post-infectious glomerulonephritis?
- Coarse globular deposits are seen on C3 immunofluorescence staining and correspond to epimembranous “humps” by electron microscopy
What is seen here?
Post-infectious glomerulonephritis
- Contains many neutrophils (“exudative glomerulonephritis”)
What is seen here?
Post-infectious glomerulonephritis
- Trichrome staining shows large red collections (“humps” on the GBM(arrows and inset)
Case 3 cont’d)
- Child diagnosed with Post-infectious glomerulonephritis and treated with steroids
- The child responds well to steroids and is discharged home and seen in follow-up over the next year
- 15 months after the original hospitalization there is recurrent hematuria and edema. Another renal biopsy is performed
What does it show? What is this?
Dense deposit disease (DDD), formerly known as MPGN type II
- Hypercellular glomeruli; increased matrix but no crescents or neutrophils are seen
- The glomerular basement membranes appear thickened and eosinophilic on PAS stain with some reduplication on Jones staining
- Linear “sausage-like” intramembranous densities are seen on EM.
What is seen here?
Dense deposit disease (DDD), formerly known as MPGN type II
- On PAS the basement membranes appear thickened with some reduplication on Jones stain.
What is expected on EM with Dense deposit disease (DDD), formerly known as MPGN type II?
- On EM thick section the GBM appears ribbon like (black arrow)
- Ultrastructural examination shows increased density and darkening of the lamina densa of the GBM (yellow arrow).
What is seen here?
Dense ribbon like expansion of the GBM in dense deposit disease (DDD), also known as MPGN type II (see schematic ).
How does type II change the diagnosis?
- PIGN has a good prognosis (many are self-resolving) with only rare patients progressing to chronic renal failure.
- DDD quickly progresses to end stage disease (50% of patients in 10 years) and often recurs after transplant.
- DDD occurs due to abnormalities in the alternative complement pathway (C3 glomerulopathies). Humps may be seen and PIGN may precede development of DDD.
In nephrotic syndrome, what part of the glomerulus is damaged? Result?
- Increased permeability of GBM -> leak of protein (heavy proteinuria, hypoalbuminemia, hyperlipidemia, edema)
Could be due to:
- Charge issues (increased matrix of GBM with diabetes or electron dense deposits with membranous glomerulonephropathy)
- Podocyte changes (effaced foot processes like in minimal change disease or focal segmental glomerulonphritis)
- Diffuse!
Think: chain link fence intact but missing privacy screen (podocyte processes)
In nephritic syndrome, what part of the glomerulus is damaged? Result?
- Disruption of capillary loops with spillage of protein and red cells -> active urinary sediment
- Spilled proteins may incite crescent formation
- FOCAL PROCESS ALONG THE GBM!
Think: car driving through opening in totally intact chain link fence
- GBM underlying structure may be intact but it is disrupted in regions (the gate is open)
