20 Non-Proliferative Glomerular Disease Flashcards Preview

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Flashcards in 20 Non-Proliferative Glomerular Disease Deck (22)
1

Glomerulonephritis / glomerulopathy

  • Glomerulonephritis / glomerulopathy
  • Principal clinical features of glomerular disease

  • Glomerulonephritis / glomerulopathy
    • Kidney disease that primarily affects the glomerulus
    • Leading cause of end stage renal disease (ESRD)
      • ESRD = renal disease that requires dialysis or transplant
  • Principal clinical features of glomerular disease
    • Proteinuria
      • Often present in glomerulonephritis
      • Heavy proteinuria (>3 g/d) is pathognomonic of glomerular disease and characteristic of nephrotic syndrome
      • Milder proteinuria (1-2 g/d) suggests glomerular disease but may be seen w/ chronic tubular disease
    • Hematuria
      • Reflects damage to glomerular capillary wall
      • May also be seen in conditions that don't affect the glomerulus.
    • Edema
      • Frequently seen w/ heavy proteinuria
    • HTN
      • Often present in glomerulonephritis
      • Due, in part, to salt & water retention
    • Renal dysfunction
      • Indicated by an elevated BUN and creatinine
      • May or may not be present

2

Clinical classification of glomerular syndromes

  • 5 categories of glomerular syndromes
  • Classification is based on clinical presentation
    • H&P
    • Urinalysis
    • Kidney injury
    • Variability
    • Glomerulopathy
    • Glomerulonephritis

  • 5 categories of glomerular syndromes
    • Asymptomatic (Isolated) hematuria
    • Proteinuria and Nephrotic Syndrome
    • Nephritic Syndrome
    • Rapidly Progressive GlomeruloNephritis (RPGN)
    • Chronic Glomerulonephritis
  • Classification is based on clinical presentation
    • H&P
      • Esp edema & HTN
    • Urinalysis
      • Nephritic (lots of red cells) vs. nephrotic (lots of protein) urine
    • Presence of & rate of development of kidney injury
    • For a particular pathologic entity, the presentation may vary
      • Ex. a pt w/ IgA nephropathy usually presents with hematuria (asymptomatic urinary abnormalities) but may occasionally present with nephrotic syndrome.
    • Glomerulopathy
      • Glomerular disease w/o an inflammatory component
    • Glomerulonephritis
      • Glomerular disease w/ an inflammatory component

3

Clinical classification of glomerular syndromes:
Asymptomatic hematuria

  • Hematuria
  • Isolated hematuria
  • Asymptomatic hematuria is not associated w/...
  • Prevalence of asymptomatic hematuria in general population
  • Origin of hematuria
  • Non-glomerular hematuria
  • Persistent hematuria w/o RBC casts or proteinuria requires...

  • Hematuria
    • > 3 RBC per high power field seen by microscopic examination of centrifuged urine sediment
  • Isolated hematuria
    • Not associated w/ any clinical manifestation of nephrotic or nephritic syndrome
  • Asymptomatic hematuria is not associated w/...
    • HTN, decreased GFR, or edema
    • These abnormalities may be found incidentally and may be persistent or recurrent
    • Recurrent gross hematuria may be superimposed on microscopic hematuria
  • Prevalence of asymptomatic hematuria in general population
    • 5-10%
  • Origin of hematuria
    • Hematuria is NOT always of glomerular origin
    • Most hematuria is not of glomerular origin (e.g., stones or UTI)
  • Non-glomerular hematuria
    • Considered if hematuria occurs in isolation
    • Can originate in the renal pelvis, ureter, bladder, prostate or urethra
    • After exercise: "runner's hematuria"
  • Persistent hematuria w/o RBC casts or proteinuria requires...
    • A urologic evaluation (cystoscopy & renal imaging studies like ultrasound or CT scan)

4

Clinical classification of glomerular syndromes:
Asymptomatic hematuria

  • Isolated hematuria
  • Causes of asymptomatic hematuria in children
  • Microscopic examination of the urine can help differentiate...
  • RBCs from a glomerular source
  • DDx for asymptomatic recurrent Glomerular hematuria
  • Renal biopsy

  • Isolated hematuria
    • May occur after strenuous physical exertion (long distance running, football)
  • Causes of asymptomatic hematuria in children
    • Hypercalciuria and hyperuricosuria
  • Microscopic examination of the urine can help differentiate...
    • Glomerular vs. non-glomerular hematuria
  • RBCs from a glomerular source
    • Dysmorphic
    • Red cells undergo osmotic & chemical trauma as they pass through the nephron --> structural changes --> loss of biconcave configuration
      • "Mickey Mouse Cells"
    • Cells have multiple membrane blebs
    • RBC casts strongly supports the diagnosis of glomerulonephritis
  • DDx for asymptomatic recurrent Glomerular hematuria
    • Thin basement membrane disease (1% of the population, familial, benign)
    • IgA nephropathy
    • Hereditary Nephritis (Alport Syndrome)
  • Renal biopsy
    • Not usually needed to evaluate asymptomatic hematuria b/c biopsy results rarely affects the treatment
    • Warrented to identify the underlying pathology if pts start to develop siginficant proteinuria or a decline in GFR
  • These patients should be monitored for...
    • Other signs of glomerular disease
    • Renal dysfunction

5

Clinical classification of glomerular syndromes:
Hereditary nephritis (Alport syndrome):
Clinical

  • General
  • Gender
  • Presentation
  • Many pts present w/...
  • Frequency

  • General
    • Disorder of glomerular BM synthesis
    • Not a primary glomerulonephritis (inflammatory condition)
  • Gender
    • Found in both sexes
    • Affects men more severely than women
    • Women
      • Almost always heterozygous for the mutation in Alport Syndrome
      • Often have intermittent microscopic hematuria
      • May not develop any other manifestation
  • Presentation
    • Presents in early childhood w/ microscopic & then occasional macroscopic hematuria, w/ varying degrees of proteinuria
    • Later it progresses to severe proteinuria, HTN, & renal failure in men in their 20s and 30s
  • Many pts present w/...
    • High frequency sound nerve deafness
    • Cataracts
    • Colobomas of the eyes
    • Bone lesions
  • Frequency
    • Rare
    • Affects ~1 / 50,000 newborns

6

Clinical classification of glomerular syndromes:
Hereditary nephritis (Alport syndrome):
Pathology & pathogenesis

  • Pathology
    • LM
    • IF
    • EM
  • Pathogenesis
    • Inheritance pattern
    • Mutation

  • Pathology
    • LM
      • Focal & segmental or global glomerulosclerosis
      • Interstitial fibrosis & foam cells in advanced disease
    • IF
      • Absence of GBM staining w/ antibody to α5 type IV collagen
    • EM
      • Glomerular BMs are thickened & alternatively thinned
      • Splitting and fraying w/ small particles trapped b/n the lamellae
  • Pathogenesis
    • X-linked in ~80% of subjects
      • Also can be AD & AR
    • Mutation of the gene for α5 type IV collagen (COL4A5) --> defective assembly of the GBM

7

Proteinuria

  • Definition
  • Normal values depend on age
  • Normally, urinary proteins consist predominantly of...
  • Results from either...
  • Urinalysis to determine cause of proteinuria
    • Tubular injury
      • Specific gravity
      • Protein
      • Hematuria
      • Cellular casts
    • Glomerular disease
      • Specific gravity
      • Protein
      • Hematuria
      • Cellular casts

  • Definition
    • Urinary protein excretion 2 std dev above the mean
  • Normal values depend on age
    • Premature neonates < 140 mg/m2/d
    • Full term neonates < 70 mg/m2/d
    • Children < 10 y < 150 mg/d
    • Children 10-18 y < 300 mg/d
    • Adults < 150 mg/d
  • Normally, urinary proteins consist predominantly of...
    • Albumin
    • Ig
    • Tamm-Horsfall mucoprotein
      • Usually
      • Secreted from the renal tubules.
  • Results from either...
    • Increased glomerular BM permeability --> albuminuria as occurs with glomerulonephritis
    • Decreased tubular reabsorption of filtered protein (such as B2 macroglobulin, lysozyme as seen in tubular disorders)
  • Urinalysis to determine cause of proteinuria
    • Tubular injury
      • Specific gravity: isothenuric (~1.010)
      • Protein: < 1+ on dipstick
      • Hematuria: usually absent
      • Cellular casts: tubular cell casts or none
    • Glomerular disease
      • Specific gravity: high (concentrated)
      • Protein: > 3+ on dipstick
      • Hematuria: often present
      • Cellular casts: variable (granular, RBC, or none)

8

Proteinuria

  • Timed (24 hour) urine collection
  • Isolated non-nephrotic proteinuria
  • Orthostatic proteinuria
  • Patients with isolated proteinuria of < 2 gm/day

  • Timed (24 hour) urine collection
    • Done to quantitate the amount of protein if the urine dipstick is > 1+ for protein in 2 or more spot urine samples
      • Cr excretion in the collection should also be measured to determine the adequacy of the collection
    • Estimated by measuring the urinary protein : Cr ratio & multiplying this by the expected Cr excretion (based on age, sex, weight) for 24 hours
    • Urinary protein electrophoresis differentiates tubular from glomerular proteinuria
  • Isolated non-nephrotic proteinuria
    • Proteinuria > 150 mg/day but < 3 gm/day
    • Unaccompanied by abnormalities in the urine sediment, HTN, or reduced renal function
  • Orthostatic proteinuria
    • Proteinuria (< 1 gm) that occurs when the patient is upright but disappears when the patient is supine
      • Prevalence of 2-5% in adolescents
      • Rare > 30yo
      • Benign prognosis
    • Persistent proteinuria
      • Worse prognosis
      • Variable etiologies
  • Patients with isolated proteinuria of < 2 gm/day
    • Don't need a renal biopsy

9

Nephrotic syndrome

  • Definition
  • Nephrotic range proteinuria
  • Albumin
  • Nephrotic range proteinuria
  • Clinical features

  • Definition
    • Group of conditions characterized by heavy proteinuria (>3 g/24 hr), hypoalbuminemia, hyperlipidemia, edema and lipdiuria.
  • Nephrotic range proteinuria
    • Present when protein excretion > 3 gm/day in adults or > 40 mg/h in children
    • Urine dipstick is 3-4+ for protein
  • Albumin
    • Most of the protein excreted
    • Loss of albumin in the urine --> hypoalbuminemia, edema, hyperlipidemia & lipiduria (the nephrotic syndrome)
  • Nephrotic range proteinuria
    • Proteinuria > 3 – 3.5 g/d w/o the other features
    • Similar DDx as the nephrotic syndrome
  • Clinical features
    • Edema
      • In dependent areas such as ankles & legs
      • In areas of low tissue resistance such as around the eyes [periorbital], the abdomen [ascites] and external genitalia)
      • Occurs due to low plasma oncotic pressure & salt / water retention
    • Hyperlipidemia
      • Cholesterol & triglyceride levels are increased due to increased hepatic production of beta lipoproteins
      • Decreased levels of lipoprotein lipase & diminished conversion of triglycerides into free fatty acids
    • Fatty casts and oval fat bodies
      • Frequently seen in the urine of pts with the nephrotic syndrome
      • Proliferative forms of GN that cause nephrotic syndrome will also have RBCs and RBC casts
      • Pts w/ non-proliferative forms of GN --> nephrotic syndrome will not have these findings in their urine
    • Hypercoagulable states
      • Due to increased hepatic synthesis of coagulation factors & increased urinary losses of antithrombin III, protein C and protein S,
      • Due to hemoconcentration caused by decreased plasma oncotic pressure)
      • Pts are at increased risk for renal vein thrombosis, DVT of lower extremities, & pulmonary emboli
    • Increased risk for infection (children)
      • Esp peritonitis, pneumonia, sepsis
      • Due to urinary losses of gamma globulins

10

Nephrotic syndrome

  • DDx of nephrotic syndrome
  • Common primary renal diseases leading to nephrotic syndrome
  • Conditions leading to secondary kidney disease with nephrotic syndrome
  • Management of proteinuria

  • DDx of nephrotic syndrome
    • Primary (idiopathic) glomerular disease
      • More common in children (w/ minimal change constituting the majority of cases)
    • Secondary - due to one of several other diseases or toxic agents
      • More common in adults
  • Common primary renal diseases leading to nephrotic syndrome
    • Minimal change disease (akacalled nil disease)
    • Focal segmental glomerulosclerosis (FSGS)
    • Membranous nephropathy
    • Membranoproliferative glomerulonephritis (MPGN)
      • Can cause both nephrotic & nephritic syndrome
  • Conditions leading to secondary kidney disease with nephrotic syndrome
    • Diabetic Nephropathy
    • Lupus nephritis
    • Dysproteinemias & Amyloidosis
    • Some of the secondary causes of nephrotic syndrome have the same clinical and histological features as the primary renal diseases
  • Management of proteinuria
    • Salt restriction
    • ACE-Is and/or ARBs
    • Judicious use of diuretics to control edema
    • Lipid lowering agents
    • Treatment based upon specific pathology

11

Nephrotic syndrome evaluation

  • H&P
  • Urinalysis
    • Nephritic urine
    • Nephrotic urine
    • Chronic GN
  • Nephritic sediment
  • Nephrotic sediment
  • Hematuria & RBC casts
  • Lab investigation of suspected GN
  • Other serological tests that may or may not be useful depending on the clinical setting
  • Renal biopsy
  • Percutaneous renal biopsy may be done safely if...

  • H&P
    • May suggest systemic disease
    • Important findings: HTN, rash, & edema
  • Urinalysis
    • Nephritic urine
      • Red cells (hematuria)
      • Variable proteinuria
      • RBC casts
    • Nephrotic urine
      • Heavy protienuria
      • Free fat droplets
      • Oval fat bodies
      • Fatty casts (maltese cross)
    • Chronic GN
      • Proteinuria
      • Variable hematuria
      • Broad waxy casts
      • Granular casts
  • Nephritic sediment
    • RBCs, RBC casts, granular casts, & proteinuria
    • Suggests a proliferative GN or vasculitis (i.e. inflammatory process)
  • Nephrotic sediment
    • Oval fat bodies, fatty casts, & 3-4+ proteinuria
    • Indicates non-proliferative GN
  • Hematuria & RBC casts
    • May occur in nephrotic GN
    • Appear in greater #s in nephritic forms of GN
  • Lab investigation of suspected GN
    • Electrolytes, glucose, BUN and Cr, lipid profile, albumin
    • Serologic evaluation should include C3 and C4
      • Complements are decreased in post infectious GN, sub acute bacterial endocarditis, membranoproliferative GN, cryoglobulinemia, SLE, & cholesterol emboli
  • Other serological tests that may or may not be useful depending on the clinical setting
    • ANA, anti-DNA
    • Streptozyme titers
    • Serum and urine electrophoresis along with immunofixation
    • ANCA (anti neutrophil cytoplasmic antibody)
    • Liver function tests, hepatitis B and C serology
    • Cryoglobulins
    • Anti-glomerular BM antibodies
  • Renal biopsy
    • May be required for a definitive diagnosis
    • Glomerular diseases: most common reason for renal biopsy
    • Glomerulopathies (esp in adults) usually require pathologic diagnosis since a GN can have multiple clinical presentations
  • Percutaneous renal biopsy may be done safely if...
    • 2 functioning are kidneys
    • BP is controlled
    • Urine is sterile
    • Coagulation parameters (including the bleeding time – a measure of platelet function) are normal 
    • Pt can coorperate

12

Pathology of specific non-proliferative GN:
Minimal change disease (lipoid nephrosis, nil disease)

  • Clinical
    • Frequency
    • Types
      • Primary
      • Secondary
    • Presentation
    • Clinical problems
  • Pathology
    • LM
    • IF
    • EM
  • Pathogenesis
  • Treatment

  • Clinical
    • Frequency
      • Most common cause of idiopathic nephrotic syndrome in children (85%)
      • Accounts for only about 10 -15% of nephrotic syndrome in adults.
      • Incidence 2-3 per 100,000 in children < 15yo
      • Boys > girlis
      • More common in Asians
    • Types
      • Generally idiopathic (primary)
      • Can occur secondary to the following conditions
        • Drugs: Non-steroidal anti-inflammatory drugs
        • Toxins: Mercury, lead
        • Infections: HIV, Mononucleosis
        • Tumors: Hodgkin disease, other lymphoproliferative disorders.
    • Presentation
      • Normotensive w/ normal renal function
      • Urine sediment
        • Bland w/o blood
        • Typical of a nephrotic sediment w/ oval fat bodies, fatty casts & 3 to 4+ proteinuria
      • No known serological abnormalities
      • Does not progress to ESRD
    • Clinical problems
      • Related to the effects of the nephrotic syndrome
      • Massive edema, increased risk of infections (esp spontaneous bacterial peritonitis & pneumonia)
  • Pathology
    • LM -  normal appearing glomeruli
    • IF - negative
    • EM - fusion of podocyte foot processes w/ cytoplasmic microcysts & podocyte microvillus transformation
  • Pathogenesis
    • Primary disorder of podocytes
    • May be linked to T-cell mediated immunity
  • Treatment
    • Steroids
    • Steroid dependent or steroid resistant cases are treated with oral cyclophosphamide

13

Pathology of specific non-proliferative GN:
Focal segmental glomerulosclerosis (FSGS)

  • Clinical
    • Frequency
    • Pts generally...
    • Types
      • Primary
      • Secondary
  • Pathogenesis
    • Proposed etiologies
    • Must be distinguished from...
    • Primary FSGS (familial)

  • Clinical
    • Frequency
      • Most common primary renal disease (esp in African-Americans) --> nephrotic syndrome
      • Occurs in ~20% of adults w/ nephrotic syndrome
    • Pts generally...
      • Have HTN
      • Have some hematuria
      • Progress to renal failure over 10 years (less if untreated)
    • Types
      • Idiopathic (primary)
        • High recurrence rate in transplanted kidneys
      • Can be associated (secondary) w/...
        • Drugs: Intravenous heroin drug use
        • Infections: HIV infection (with or without AIDS)
        • Others: Reflux nephropathy, morbid obesity, sickle cell disease
  • Pathogenesis
    • Proposed etiologies: hyperfiltration injury, altered T-cell function, & primary visceral epithelial cell injury
    • Must be distinguished from segmental glomerulosclerosis that occurs in the scarring phase of segmental proliferative necrotizing GN
    • Primary FSGS (familial)
      • Defects in constitutive podocyte proteins
      • Multiple disease causing genes that encode critical structural podocyte elements
      • Genetic variation in APOL1 gene in African-Americans
        • Major risk factor for development of FSGS, hypertensive nephrosclerosis
        • Correlates w/ rate of progression in diabetic & nondiabetic kidney disease
      • Disease associated ApoL1 variants
        • Lyse Trypanosoma brucei rhodesiense (causes sleeping sickness)
        • Confers a survival benefit in Africans

14

Pathology of specific non-proliferative GN:
Focal segmental glomerulosclerosis (FSGS)

  • Pathology
    • LM
    • IF
    • EM
  • Treatment

  • Pathology
    • LM
      • Focal glomerulosclerosis: involves some, but not all of the glomeruli
      • Segmental glomerulosclerosis: involves only a part of the glomerulus
      • Hyaline insudates (hyalinosis lesions)
      • Glomerular tip lesions of capillary tuft
      • Variable mesangial hypercellularity
      • Glomerular hypertrophy
    • IF
      • Focal segmental IgM and C3 in areas of sclerosis (nonspecific trapping of proteins)
    • EM
      • Effacement of foot processes
      • Cytoplasmic vacuolization
      • Focal visceral epithelial cell detachment from GBM
      • Sub epithelial membrane neogenesis
      • Sclerotic loop w/ foamy cell & collagen fibers but no immune deposits
  • Treatment
    • May or may not respond to steroids
    • Other options: cyclosporine, tacrolimus, & mycophenolate mofetil
    • Control of HTN & hyperlipidemia
    • ACE-Is 

15

Pathology of specific non-proliferative GN:
Membranous GN (MGN)

  • Clinical
    • Frequency
    • Characterized by...
    • Urine sediment
  • Types
    • Primary
    • Secondary
  • Pathology
    • LM
      • Stage 1
      • Stage 2
      • Stages 3 & 4
    • IF
    • EM

  • Clinical
    • Frequency
      • Most common cause of idiopathic nephrotic syndrome in Caucasian adults (30% of cases)
      • Uncommon in children
      • Peak incidence: 4th - 6th decade.
      • Male:female :: 2-3:1.
    • Characterized by...
      • Heavy proteinuria (usually full expression of nephrotic syndrome)
      • Hematuria occurs only in minority of pts
      • HTN & azotemia develop as disease progresses
      • Associated w/ increased incidence of renalv ein thrombosis due to loss of anti-thrombin III
    • Urine sediment
      • Nephrotic elements: fatty casts, lipid droplets, & oval fat bodies
  • Types
    • May be primary
    • Secondary may also occur w/...
      • Drugs: NSAID, Gold, Penicillamine
      • Infections: hepatitis B, syphilis, malaria
      • Tumors: carcinoma (particularly of the colon, lungs, breast),
      • Immunologic Disorders: SLE, Rheumatoid arthritis
  • Pathology
    • LM
      • Stage 1: normocellular glomerulus w/ normal to mildly thickened capillary wall
      • Recognized on silver stains (BMs)
        • Stage 2: epimembranous spikes that correspond to the new basement membrane material adjacent to the deposits (GBM thickening)
        • Stages 3 & 4: train tracks (split basement membranes)
    • IF
      • Diffuse granular deposits outline the membrane w/ IgG & C3
      • Sometimes IgA, IgM, & C4 ("full house" pattern in lupus MGN)
    • EM
      • Diffuse epimembranous (subepithelial deposits) electron dense deposits

16

Pathology of specific non-proliferative GN:
Membranous GN (MGN)

  • Stages
    • Stage 1
    • Stage 2
    • Stage 3
    • Stages 4 & 5
  • Pathogenesis
    • Primary
    • Secondary
    • Either
  • Rule of 1/3
  • Risk factors for progression
  • Treatment
    • First line
    • If first line fails
    • "New kid on the block"

  • Stages
    • Stage 1: deposits only
    • Stage 2: deposits with epimembranous spikes of membrane material between the deposits
    • Stage 3: spikes link up & deposits are then incorporated into the membrane
    • Stages 4 & 5: deposits are gradually rarefied ("absorbed") --> reduplicated membrane w/ irregular thickening
      • Also non-specific podocyte changes of nephrotic syndrome
  • Pathogenesis
    • Primary: etiologic agent = autoantibody to a glomerular antigen (m-type phospholipase A2 receptor)
    • Secondary: known antigen is first "planted" & then antibody to the planted antigen follows --> immune complex deposition
    • Either: subepithelial immune complex deposits activate complement --> GBM/epithelial cell injury via the C5-9 membrane attack complex
  • Rule of 1/3
    • 1/3 – progress to ESRD over 20 years
    • 1/3 – partial remission/ very slow deterioration
    • 1/3 – spontaneous remission without treatment
  • Risk factors for progression
    • Male gender
    • Severe proteinuria (>10g/24 hours)
    • HTN
    • Azotemia
    • Tubulointerstitial fibrosis
    • Glomerulosclerosis
  • Recommended therapy of membranous GN
    • First line: alternating months of corticosteroids w/ alkylating agents (chlorambucil or cyclophosphamide)
    • If first line fails: Calcineurin inhibitors (tacrolimus or cyclosporine)
    • “New kid on the block”: rituximab (anti-CD20 antibody)

17

Pathology of specific non-proliferative GN:
Diabetic nephropathy

  • Clinical
    • Frequency
    • Presentation
    • Diagnosis
  • Other findings

  • Clinical
    • Frequency
      • Most common cause of nephrotic syndrome in adults (as opposed to minimal change disease in young children)
      • Leading cause of ESRD in US (~40% of new pts starting dialysis)
      • ~40% of pts w/ insulin dependent DM & 30% of non-insulin dependent diabetics (type II) will develop diabetic nephropathy
    • Presentation
      • Early (prior to proteinuria)
        • Increased GFR due to hyperfiltration
        • Urine has microalbuminuria (30 - 300 mg/d of proteinuria) --> heavy proteinuria, but minimal blood
      • Microalbuminuria can be reversed by excellent glucose control.
      • Nephrotic range proteinuria follows as nephropathy progresses
    • Diagnosis
      • Made on clinical grounds (biopsy not usually needed)
      • In a pt w/ atypical features, renal biopsy is needed for diagnosis (ex.s)
        • Ex. heavy proteinuria within first 5 years of diagnosis of Type I DM
        • Deterioration of GFR faster than anticipated (usual rate of loss of GFR is 1 ml/month in untreated pts)
        • Presence of other systemic disease that can affect kidneys
  • Other findings
    • Nodular glomerulosclerosis
      • Nodular accumulation of mesangial matrix (Kimmelsteil-Wilson lesions)
    • Diffuse glomerulosclerosis
      • Diffusely distributed increase in mesangial matrix

18

Pathology of specific non-proliferative GN:
Diabetic nephropathy

  • Pathology
    • LM
    • IF
    • EM
  • Pathogenesis
  • Treatment

  • Pathology
    • LM
      • Mesangial matrix expansion --> 2 morphologic patterns
      • Fibrin cap (hyalinosis lesion)
      • Capsular drop
      • Tubular BM thickening
      • Arteriolar hyaline sclerosis
      • Arterial intimal thickening
      • Striking PAS positivity
    • IF
      • Nonspecific linear staining w/ IgG and many proteins (esp albumin)
    • EM
      • Lamellar thickening of glomerular BM
      • Mesangial matrix hyperplasia
      • Lipid droplets
      • No immune complex deposits
  • Pathogenesis
    • Generalized renal growth occurs early in diabetes due to hormonal factors in the hyperglycemic environment
    • Increased GFR --> renal hyperfiltration
    • Abnormalities in glucose metabolism --> glycosylation of...
      • Serum proteins (advanced glycosylation end products)
      • BM proteins (glomerular, tubular)
      • Blood vessel walls
      • Glomerular mesangial matrix
  • Treatment
    • Control of blood glucose, BP, & hyperlipidemia
    • ACE-I
    • Smoking cessation
    • Protein restriction

19

Pathology of specific non-proliferative GN:
Dysproteinemia & amyloidosis:
Myeloma cast nephropathy

  • Clinical
  • Diagnosis
  • Pathology
    • LM
    • IF
  • Pathogenesis
  • Treatment

  • Clinical
    • Renal failure from multiple myeloma may develop acutely or as a chronic progressive disease
    • Disease of older adults
    • Chronic bone pain
    • Anemia
    • Pathologic fracture
    • Hypercalcemia
    • Proteinuria: consists of monoclonal Igs
  • Diagnosis
    • Confirmed by finding monoclonal Igs in serum and urine
    • Serum and Urine Protein Electrophoresis, SPEP and UPEP
  • Pathology
    • LM
      • Multiple intraluminal proteinaceous casts in the distal nephron.
      • Casts are usually acellular & homogenous w/ multiple fracture lines
      • Persistence of casts --> giant cell inflammation & tubular atrophy
    • IF
      • Confirms that casts contain light chains
  • Pathogenesis
    • Occurs in patients w/ significant production of an unbalanced light chain
    • Light chains (Bence Jones proteins) are freely filterable across the normal glomerulus
    • In high concs in the urine (ex. in pts w/ large light chain production who become volume depleted), the light chains many form insoluble casts in the tubules
  • Treatment
    • Emergent
    • Hydration, plasmapheresis, & chemotherapy to suppress plasma cells

20

Pathology of specific non-proliferative GN:
Dysproteinemia & amyloidosis:
Amyloidosis

  • Amyloid
  • 2 biochemical forms
  • Primary amyloidosis & plasma cell-dyscrasia-related amyloidosis
  • Secondary amyloidosis
  • Pathology
    • LM
    • EM

  • Amyloid
    • Proteinaceous material that accumulates b/n cells
    • If sufficiently abundant, produces atrophy & death of these cells via pressure & anoxic effects
  • 2 biochemical forms
    • Amyloid of ImmunogLobuLin origin (amyloid AL)
      • Light chains + fragments of LC's (Bence Jones proteins), majority of which are lambda chains
      • Hereditary
    • Amyloid associated w/ chronic inflAmmAtory states (amyloid AA)
  • Primary amyloidosis & plasma cell-dyscrasia-related amyloidosis
    • Diagnosis: amyloid deposition in a characteristic distribution (heart, GI tract, skin, nerves, tongue) in pts w/o bone lesions or excess marrow plasma cells
    • Some amyloid + benign monoclonal gammopathies --> overt myeloma
  • Secondary amyloidosis
    • Deposits most striking in liver, spleen, kidneys and adrenals
    • Associated w/ chronic conditions with varying inflammation & cell breakdown
      • TB, chronic osteomyelitis, rheumatoid arthritis, ulcerative colitis, Hodgkin's disease, etc.
  • Pathology
    • LM
      • Amyloid is an amorphous, hyaline, eosinophilic (weakly PAS positive) material
      • Amyloid stains metachromatically w/ dyes like crystal violet and red with Congo red (green birefringence of amyloid when polarized)
    • EM
      • Amyloid consists of small non-branching fibrils 7.5-10.0 nm wide of variable length & periodicity
      • In glomeruli, amyloid deposits first in the mesangium & later in the capillary walls

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Pathology of specific non-proliferative GN:
Dysproteinemia & amyloidosis:
Light chain deposition disease (kappa chain)

  • Amyloid produced in plasma cell dyscrasias
  • In some plasma cell dyscrasias
  • Kappa chain deposits
  • Course
  • Treatment

  • Amyloid produced in plasma cell dyscrasias
    • Composed of lambda light chains
  • In some plasma cell dyscrasias
    • A distinctive form of light chain deposition composed of kappa chains occurs
      • Designated as light chain deposition disease
    • May present w/ asymptomatic albuminuria w/ renal insufficiency or nephrotic syndrome.
  • Kappa chain deposits
    • K = killer (worse than lambda)
    • Similar to amyloid on H&E stain
    • Congo-red negative
    • PAS positive
    • Represented by a granular, electron dense material on EM
    • Involve glomeruli (mesangium and GBM) & tubular BMs
    • Spare vessels (in contrast to amyloid)
  • Course
    • Progressive renal failure 
  • Treatment
    • Same as myeloma
    • Melphalan & prednisone
      • May prevent deterioration in renal function in some patients with mild azotemia
      • Associated w/ high morbidity

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Key features of non-proliferative GN

  • Minimal change
  • FSGS
  • Membranous
  • Diabetes
  • Amyloidosis

  • Minimal change
    • Normal Looking glomeruli
    • Foot process fusion on EM
  • FSGS
    • Segmental sclerosis
  • Membranous
    • Silver stain – thick BM
    • Spikes, Train track
  • Diabetes
    • Nodular sclerosis
    • KW lesions
  • Amyloidosis
    • Congo red positive
    • Green birefringence
    • Fibrils - EM