Nephritic Syndrome I and II

Question 1

Azotemia

Answer 1

•Elevation of blood urea nitrogen and creatinine in the blood due to reduced glomerular filtration rate

Question 2

5 Components of Acute Nephritic Syndrome

Answer 2

1. Hematuria
2. Proteinuria
3. Azotemia
4. Oluguria
5. Hy[pertension

Question 3

Hematuria

Answer 3

•Hematuria of glomerular origin

• Dysmorphic red blood cells and red blood cell casts (active urine sediment)

Question 4

Proteinuria

Answer 4

• Usually between 150mg and 3.5 gm. b
• Usually not nephrotic range, but can with overlap syndromes (MPGN, lupus nephritis).

Question 5

Azotemia

Answer 5

•Elevated blood urea nitrogen with BUN:Creatinine ratio >15

Question 6

Oliguria

Answer 6

•<400 ml urine per day

Question 7

Hypertension

Answer 7

•Due to sodium retention, decreased filtration.

Question 8

Membranoproliferative Glomerulonephritis (MPGN) - Etiology

Answer 8

•Less common cause of nephrotic syndrome (~ 10%), often with both nephrotic and nephritic features

1. Idiopathic/autoimmune (uncommon)
2. Infections – Hepatitis C, chronic bacterial infections (subacute bacterial endocarditis, ventriculoatrial shunt infection)
3. Neoplasia – Multiple myeloma, chronic lymphocytic leukemia

Question 9

Membranoproliferative Glomerulonephritis (MPGN) - Pathogenesis

Answer 9

•Immune complex mediated disease

1. Antigen either unknown or viral/bacterial
2. Deposition of pre-formed circulating antigen-antibody complex or formation of immune complex in situ (planted antigen in kidney with secondary antibody recognition)
3. Immune complex formation - Potent activator of complement (classical pathway)
   - C3, C4, and total complement will be low in serum

Question 10

Membranoproliferative Glomerulonephritis (MPGN) - Diagnosis

Answer 10

1. Low C3, low total complement CH50 and low C4
2. Renal biopsy is definitive.

Question 11

Membranoproliferative Glomerulonephritis (MPGN) - Renal Biopsy Findings

Answer 11

1. Light Microscopy
   a. Glomeruli are diffusely and globally hypercellular with a lobulated appearance.
   b. Duplication of the GBM (“tram track” appearance), best seen on PAS and Jones silver stains.
2. Immunofluorescence
   a. Immune deposits within mesangium and along inner (subendothelial) aspect of GBM. i. IgG and/or IgM and C3 most common.
3. Electron Microscopy
   a. Electron dense immune-type deposits within mesangium and subendothelial aspect of GBM.
   b. Duplication of the GBM (new basement membrane formation).
   c. Interposition of cells (mesangial, endothelial, and/or leukocytes) between the original and the newly formed GBM.
   d. Variable podocyte foot process effacement, often extensive.

Question 12

Membranoproliferative Glomerulonephritis (MPGN) - Clinical Course

Answer 12

1. Idiopathic/autoimmune – Prolonged course with slow rate of disease progression (~30% progress to ESRD within 10-15 years).
2. Infectious, neoplasia associated MPGN
   a. Depends on treatment of underlying disease.

Question 13

Membranoproliferative Glomerulonephritis (MPGN) - Treatment

Answer 13

•Nonspecific therapy outlined Section VII of Nephrotic Syndrome lecture.

1. Idiopathic/autoimmune:
   a. Steroids (no good randomized clinical trial) – Patients often not responsive.
   b. Limited data for other immune therapies (cyclophosphamide and mycophenolate mofetil (Cellcept)).
2. Infectious, neoplasia associated MPGN:
   a. Treat the underlying condition.

Question 14

C3 Glomerulopathies

Answer 14

• rare causes of nephrotic and nephritic syndromes
• Dense Deposit Disease
• rare, affects 2-3 people per million
• both nephrotic and nephritic syndromes

•C3 Glomerulonephritis

-newly recognized entity, incidence unknown

Question 15

C3 Glomerulopathies - Etiology

Answer 15

1. Disorders of complement regulation – Alternative pathway
2. Dense Deposit Disease - Clinical associations:
   a. “Drusen” in Bruch’s membrane of the retina (macular deposits)
   b. Acquired partial lipodystrophy

Question 16

C3 Glomerulopathies - Pathogenesis

Answer 16

1. Excessive activation of alternative complement pathway
   a. Circulating autoantibody – C3 nephritic factor (~ 70-80% of patients with DDD, 40-50% of patients with C3 glomerulonephritis)
   b. Deficient/mutated regulatory proteins - Factor H, Factor I
   c. Leads to persistent degradation of C3 protein and activation of alternative complement pathway
   i. C3 only will be low in serum

Question 17

C3 Glomerulopathies - Diagnosis

Answer 17

1. Low C3, low total complement CH50, normal C4
2. Assays for C3 nephritic factor, Factor H/Factor I activity/mutational analysis
   a. Send out tests (only performed at specialized centers).
3. Biopsy is definitive.

Question 18

C3 Glomerulopathies - Renal Biopsy Findings

Answer 18

1. Light Microscopy
   a. Dense Deposit Disease
   i. Glomeruli are usually diffusely and globally hypercellular with a lobulated appearance.
   ii. May have influx of inflammatory cells, especially PMN’s
   iii. Rare GBM duplication (vs. MPGN)
   b. C3 glomerulonephritis
   i. Variable patterns (ranging from mild mesangial proliferation to diffuse and global hypercellularity)
2. Immunofluorescence
   a. Irregular staining of mesangium and GBM with C3 only.
3. Electron Microscopy
   a. Dense Deposit Disease
   i. Linear deposition of electron dense material in a “ribbon-like” pattern directly into the GBM.
   a. Composed of complement activation products, membrane attack complex.
   ii. No significant GBM duplication.
   b. C3 glomerulonephritis
   i. Variable – May have mesangial, subendothelial and subepithelial amorphous deposits.
   ii. May have GBM duplication.

Question 19

C3 Glomerulopathies - Clinical Course

Answer 19

1. Dense Deposit Disease
   a. Poor prognosis with ~ 50% progression to ESRD after 10 years following diagnosis.
   b. High rate of recurrence after transplantation.
2. C3 Glomerulonephritis - Unknown.
   a. May have better prognosis vs DDD

Question 20

C3 Glomerulopathies - Treatment

Answer 20

•- Nonspecific therapy outlined Section VII of Nephrotic Syndrome lecture.

1. Plasma exchange (plasmapheresis) with albumin in patients with C3 nephritic factor.
2. Plasma infusion (without exchange) in patients with factor H deficiency.
3. Eculizumab – Monoclonal antibody to C5 complement protein
   a. Inhibits terminal events in complement activation
   i. Prevents formation of membrane attack complex
   b. Very expensive

Question 21

IgA Nephropathy - Epidemiology

Answer 21

1. Most common cause of glomerulonephritis world-wide.
2. Peak incidence in 2nd and 3rd decade of life.
3. Highest incidence in Asian and Caucasian populations.

Question 22

IgA Nephropathy - Etiology

Answer 22

1. Mucosal infections triggered by environmental antigens drive the generation of pathogenic IgA immune complexes.
   a. Antigens – Viral (may follow upper respiratory or GI viral illness), bacterial, food.
2. Genetic predisposition
   a. Polygenic (many genes involved)
   b. Commonly affects multiple family members.

Question 23

IgA Nephropathy - Pathogenesis

Answer 23

1. Thought to represent a disorder of mucosal IgA synthesis
   a. Normal conditions – IgA forms and immune complex with mucosal pathogen/antigen.
   i. Galactose residue on IgA allows the immune complex to be cleared from the circulation by the spleen
   b. IgA nephropathy - Increased synthesis of “abnormal IgA”
   i. Abnormally glycosylated IgA produced in affected patients
   ii. IgA immune complexes do not clear from the circulation.
   iii. IgG antibodies are produced against the abnormally glycosylated hinge region forming a large macromolecular complex.
   c. Macromolecular complexes deposit preferentially in the mesangium and activate complement.

Question 24

IgA Nephropathy - Diagnosis

Answer 24

1. Renal biopsy is definitive.
2. No serum complement abnormalities.

Question 25

IgA Nephropathy - Renal Biopsy Findings

Answer 25

1. Light Microscopy
   a. Most common: Diffuse increase in mesangial matrix and cellularity (mesangial proliferative pattern).
   b. Changes may be segmental in early cases.
2. Immunofluorescence
   a. Mesangial deposits of IgA and C3
3. Electron Microscopy
   a. Electron dense immune-type deposits mainly within the mesangium.
   b. Increased mesangial matrix and cellularity

Question 26

IgA Nephropathy - Clinical Presentation

Answer 26

1. ~40% present with gross hematuria following upper respiratory infection “synpharyngitic hematuria”.
2. ~30% present with microscopic hematuria and mild proteinuria (incidentally detected on urinalysis).
3. 5-10% present with acute nephritic syndrome, occasionally with rapidly progressive glomerulonephritis (RPGN).
4. May have associated abnormalities of skin, GI tract
   a. Skin lesion – Dermatitis herpetiformis.
   b. GI – Celiac sprue, cirrhosis.

Question 27

IgA Nephropathy - Prognosis/Treatment

Answer 27

1. Prognosis is variable – Wide spectrum of disease.
   a. Slow progression to chronic renal failure in 15-40%.
2. Treatment
   a. No treatment if normal renal function and low proteinuria (<500 mg)
   b. ACE inhibition or Angiotensin Receptor Blocker (ARB) if proteinuria >1gm.
   i. Fish oil – Adjunct therapy, studies are equivocal as to efficacy.
   c. Prednisone – For patients with proteinuria (>1 gm/day) or progressive disease.

Question 28

Post - Infectious Glomerulonephritis - Epidemiology

Answer 28

1. Most common cause of acute nephritic syndrome. a. More common in developed countries.
2. Peak incidence in children aged 5-12 yrs and in adults >60 yrs.

Question 29

Post - Infectious Glomerulonephritis - Etiology

Answer 29

1. Develops in response to infection
   a. Presents as acute nephritis 1-6 weeks following infectious illness.
   b. Most commonly follows streptococcus pharyngitis or impetigo (skin infection), but may also occur secondary to staphylococcal endocarditis, pneumococcal pneumonia and meningococcus, viruses (hepatitis B & C, HIV, mumps, EBV) and parasitic infections (malaria, toxoplasmosis).

Question 30

Post - Infectious Glomerulonephritis - Pathogenesis

Answer 30

1. Immune complex disease induced by specific nephritogenic strains of bacteria
   a. Best characterized in Group A beta-hemolytic streptococcus
   b. Elevated titers of antibodies to streptococcal antigens are found in most patients with post-streptococcal GN.
   i. AS0 = Antistreptolysin antibody
2. Two hypotheses:
   a. Circulating immune complexes comprised of streptococcal antigen and recognizing antibody are deposited within glomeruli, causing activation of complement and resulting injury.
   b. The infection causes alterations of intrinsic proteins within the GBM, which then become antigenic; antibodies bind to this altered antigen and then activate complement.
3. Immune complex deposition/formation activates complement (Alternative pathway).

Question 31

Post - Infectious Glomerulonephritis - Clinical Presentation

Answer 31

1. Variable
   a. Can range from asymptomatic with microscopic hematuria to full-blown acute nephritic syndrome

Question 32

Post - Infectious Glomerulonephritis - Diagnosis

Answer 32

1. Active urine sediment
   a. Dysmorphic RBC’s, red cell casts, WBC’s and WBC casts (due to inflammation)
2. Alternative complement pathway activation a. Low C3, CH50 b. C4 is normal
3. Elevated antibody titers to extracellular streptococcal products (if recent infection).
   a. Streptozyme test – Measures 5 different anti-strep antibodies, including ASO.
4. Often clinical history and la

Question 33

Post - Infectious Glomerulonephritis - Renal Biopsy Findings

Answer 33

1. Light Microscopy a. Glomeruli are enlarged and are globally and diffusely hypercellular.
   a. Influx of large numbers of inflammatory cells (especially neutrophils).
   b. Proliferation of intrinsic cells of the glomerulus (mesangial cells, endothelial cells).
2. Immunofluorescence
   a. Large granular deposits of IgG and/or C3 in mesangium and along the glomerular capillary walls, irregularly distributed (“starry sky pattern”).
3. Electron Microscopy
   a. Discrete electron dense immune deposits on subepithelial side of GBM.
   i. The deposits are very large and have a “hump-like” appearance.

Question 34

Post - Infectious Glomerulonephritis - Prognosis/Treatment

Answer 34

1. Relatively good prognosis, most patients recover.
   a. Children – >95% recover without complications.
   b. Adults – More insidious; may have slow progression to chronic glomerulonephritis.
2. Treatment – Supportive care
   a. Treat underlying infection.
   b. Manage hypertension, edema and proteinuria (if significant).

Question 35

Lupus Nephritis - Epidemiology

Answer 35

1. Occurs in 50% of patients with SLE; frequent cause of morbidity and mortality
2. Increased incidence in females and African Americans.

Question 36

Lupus Nephritis - Etiology

Answer 36

1. Genetic
   a. Increased concordance rate in monozygotic twins.
   b. Polygenic (multiple genes involved).
2. Environmental
   a. Higher prevalence in lower socioeconomic settings.
   b. Viral antigens
3. Immune
   a. Loss of tolerance, polyclonal B-cell activation.

Question 37

Lupus Nephritis - Pathogenesis

Answer 37

1. Autoimmune disease: Antibodies are produced against self-antigens.
   a. Antibody target: Nucleosomes (nephritic antigen).
   b. Cells undergoing apoptosis/necrosis fail to clear from the circulation, exposing immune system to intracellular contents.
2. Antibodies directed at nucleosomes form immune complexes that deposit in the kidney
   a. Mechanisms:
   i. Anti-nucleosome antibody cross-reacts with intrinsic renal antigen and binds directly. i
   i. Anti-nucleosome antibody binds to soluble nucleosomes/ antigenic proteins in circulation, then immune complexes are passively deposited in the kidney.
   iii. Nucleosome antigen is deposited first (i.e. “planted”, usually due to charge interactions) and then the antibody binds to the antigen.

Question 38

Lupus Nephritis - Diagnosis

Answer 38

1. Positive serologies: ANA (anti-nuclear antibody), anti-dsDNA, antiSmith
2. Low serum complement – Classical pathway activation.
   a. Low C3, low C4, low CH50.
3. Active urine sediment.
4. Membranous lupus nephritis may have normal serum complements, minimal serologic abnormalities, and bland urine sediment.
5. Renal biopsy is definitive.

Question 39

Lupus Nephritis - Renal Biopsy Findings

Answer 39

1. Light Microscopy
   a. Highly variable: Six distinct classes of lupus nephritis have been recognized (Classes I-IV)
   b. Focal proliferative pattern (Class III): Less than 50% of the glomeruli in the sample show active lupus lesions
   i. Active lesions may include: Increased cellularity due to influx of inflammatory cells, proliferation of intrinsic glomerular cells (mesangial cells, endothelial cells), visible immune complexes by light microscopy (“wire loops” – thick capillary loops due to large subendothelial deposits), crescents, necrosis
   c. Diffuse proliferative pattern (Class IV): Most (>50%) glomeruli contain active lupus lesions
   i. Most severe renal lesion of SLE
   d. Membranous pattern (Class V): Similar histology to primary (idiopathic) membranous nephropathy (thick loops with “spikes”)
2. Immunofluorescence
   a. “Full house” immune complex deposition
   i. IgA, IgM, IgG, C3, C1q all present within mesangium and capillary loops
3. Electron Microscopy
   a. Varies, according to class of lupus
   b. Often, large electron dense immune deposits are present in all compartments (within mesangium, and subendothelial and subepithelial glomerular capillary wall)
   c. Membranous lupus nephritis will have multiple small, subepithelial deposits, similar to idiopathic membranous nephropathy

Question 40

Lupus Nephritis - Clinical Presentation

Answer 40

1. Variable clinical presentations, depending on pattern of injury.
   a. Overlap of nephrotic and nephritic syndromes common.
   b. Relapsing and remitting disease symptoms.

Question 41

Lupus Nephritis - Treatment

Answer 41

1. Depends on clinical presentation and class of lupus nephritis on biopsy.
2. Most Class III-V are treated aggressively
   a. Active lesions: Cyclophosphamide or Cellcept + prednisone
   b. Other immune therapies: Azathioprine (maintenance), Rituximab (anti-CD20 antibody) to target B-cells.

Question 42

Rapidly Progressive Glomerulonephritis (RPGN) - Definition

Answer 42

1. Clinical syndrome of severe acute nephritic syndrome.
   a. Active urine sediment.
   b. Progressive loss of function over period of days to weeks, with rapid progression to renal failure.
2. Can be caused by a variety of renal diseases.
3. Characterized morphologically by the presence of necrosis and crescent formation on biopsy.
   a. Non-specific response to severe injury to the glomerular capillary wall.

Question 43

Rapidly Progressive Glomerulonephritis (RPGN) - 3 Categories

Answer 43

1. Type I - Anti-GBM disease

•Patients present with acute nephritis and may also have hemoptysis due to pulmonary hemorrhage (i.e. Goodpasture’s syndrome).

2. Type II - Immune complex mediated (due to any immune complex mediated disease that causes acute nephritic syndrome).

•Most common: IgA, post-infectious GN, Lupus Nephritis.

3.Type III - Pauci-immune type (i.e. ANCA-associated GN).

•Small vessel vasculitis targeting glomerular capillaries.

Question 44

Rapidly Progressive Glomerulonephritis (RPGN) - Pathogenesis Anti-GBM

Answer 44

a. Due to formation of autoantibodies against Type IV collagen (can be detected in patient’s serum).
b. Goodpasture’s syndrome: Antibodies target GBM and basement membranes of the pulmonary alveoli.
c. Can occur in all ages – Younger patients (<30 yrs) more likely to present with full Goodpasture’s syndrome.

Question 45

Rapidly Progressive Glomerulonephritis (RPGN) - Pathogenesis - Pauci immune glomerulonephritis

Answer 45

a. Associated with antineutrophil cytoplasmic antibodies (ANCA).
b. Pathogenesis is incompletely understood – ANCA’s are likely pathogenic, but other factors also involved.
c. No or minimal immune deposits (i.e. “pauci-immune”).
d. May be associated with systemic disease or may be renallimited.
e. Two types of ANCA:
i. c-ANCA (cytoplasmic). Target antigen – proteinase 3. Associated with Granulomatosis with Polyangiitis (GPA) (formerly Wegner’s granulomatosis). May be renal limited (crescentic glomerulonephritis) or have associated sinusitis and pulmonary hemorrhage.
ii. p-ANCA (perinuclear). Target antigen - myeloperoxidase (MPO)). Associated with microscopic polyangiitis; may be renal limited or with pulmonary hemorrhage.

Question 46

Rapidly Progressive Glomerulonephritis (RPGN) - Pathogenesis - Immune Complex Mediated

Answer 46

•Due to formation/deposition of immune complexes and activation of complement

Question 47

Rapidly Progressive Glomerulonephritis (RPGN) - Diagnosis

Answer 47

1. Clinical presentation – Acute nephritis with active sediment and rapid loss of renal function.
2. Positive serologic tests:

• Anti-GBM antibodies (in Anti-GBM disease)
• pANCA, cANCA (in ANCA-associated disease)
• Up to 5% of pauci-immune GN can be ANCA negative.
  3. Biopsy is definitive.

Question 48

Rapidly Progressive Glomerulonephritis (RPGN) - Renal Biopsy Findings

Answer 48

1. Light Microscopy
   a. Key features: Necrosis of glomerular capillaries and/or formation of crescents
   i. Necrosis = Rupture of the glomerular capillary loops with extrusion of fibrin and blood into the urinary space.
   ii. Crescent = Reactive proliferation of cells within the urinary space (podocytes, parietal epithelium) with influx of inflammatory cells.
   b. Anti-GBM disease and pauci-immune GN: Glomeruli unaffected by necrosis/crescents appear normal (no immune complexes, no hypercellularity).
   c. Immune complex mediated: Depends on underlying cause. Will appear similar to that already described but with additional features of necrosis and crescents.
2. Immunofluorescence
   a. Anti-GBM disease: Linear staining for IgG along glomerular basement membrane
   b. Pauci-immune types: Usually negative or minimal staining
   c. Immune complex mediated: Depends on underlying cause of GN.
3. Electron Microscopy
   a. Anti-GBM disease and pauci-immune types: Absent or scant immune deposits; may see rupture of GBM with fibrin tactoids and cells in urinary space
   b. Immune complex mediated: Electron dense immune deposits present; pattern depends on the underlying cause.

Question 49

Rapidly Progressive Glomerulonephritis (RPGN) - Prognosis/Treatment

Answer 49

1. Chance of recovery depends on rapid institution of therapy (renal emergency).
2. High-dose steroids - IV pulse methylprednisolone over 3 days, then oral prednisone.
3. Cyclophosphamide (oral or IV) x 3-6 months; azathioprine for maintenance.
4. Rituximab (monoclonal antibody to CD20) for induction and maintenance increasingly used for ANCA-associated vasculitis
5. Plasmapheresis
   a. Anti-GBM disease
   b. ANCA-associated GN that is dialysis dependent or associated with hemoptysis.

Question 50

Chronic Glomerulonephritis - Definition

Answer 50

•Not a distinct entity; end result of many primary forms of GN.

Question 51

Chronic Glomerulonephritis - Clinical Presentation

Answer 51

1. Renal failure, with elevated serum creatinine.
2. If advanced, may have symptoms of uremia.
3. May have varying degrees of proteinuria and/or hematuria, depending on underlying cause and presence of active disease.

Question 52

Chronic Glomerulonephritis - Renal Biopsy Findings

Answer 52

1. Light Microscopy
   a. Glomeruli: Many are globally sclerosed (obsolescent); others may have areas of segmental scarring or appear shrunken and ischemic.
   b. Tubules/interstitium: Interstitial fibrosis (best seen on trichrome stain) and small, shrunken, or dilated atrophic tubules.
   c. Vessels: Arteriosclerosis and arteriolosclerosis/hyalinosis.
2. Immunofluorescence/Electron Microscopy – Variable, depends on underlying cause and extent of chronicity.
3. Important point: Morphologic features of chronic GN are often not specific for underlying etiology. At end stage, it may be impossible to determine the primary cause of the renal injury because the characteristic light microscopic, immunofluorescence and electron microscopic features are no longer present.

Question 53

Chronic Glomerulonephritis - Treatment

Answer 53

1. Depends on severity of renal failure, symptoms, degree of fibrosis on biopsy.
   a. Steroids/immunosuppressive agents are not generally useful at advanced stage.
2. Anti-hypertensive agents to lower blood pressure.
   a. ACE inhibition or angiotensin-receptor blocker (ARB) to decrease glomerular capillary pressure.
3. Dialysis
4. Transplantation

Question 54

MPGN

Answer 54

Question 55

MPGN - New GBM

Answer 55

Question 56

DDD - Glomeruli

Answer 56

Question 57

DDD - Tubules

Answer 57

Question 58

IgA

Answer 58

Question 59

IgA Mesangial Deposits

Answer 59

Question 60

PIGN

Answer 60

Question 61

PIGN - “hump like” deposit

Answer 61

Question 62

Lupus Nephrtitis Full House IF

Answer 62

Question 63

Lupus Nephritis

Answer 63

Question 64

Lupus Nephritis

Answer 64

Question 65

RPGN

Answer 65

Question 66

RPGN

Answer 66

Question 67

RPGN

Answer 67

Question 68

RPGN

Answer 68

Question 69

RPGN

Answer 69

Question 70

Chronic Glomerulonephritis

Answer 70