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Overview of Glomerulonephritidies

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Overview of Glomerulonephritidies Madeleine V. Pahl, M.D. University of California, Irvine – PowerPoint PPT presentation

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Title: Overview of Glomerulonephritidies


1
Overview of Glomerulonephritidies
  • Madeleine V. Pahl, M.D.
  • University of California, Irvine

2
Objectives
  • To define common primary and secondary glomerular
    disorders
  • To discuss involved pathophysiology
  • To review their clinical presentation
  • To review clinical course and therapy

3
Definition (R. J. Glassock)
  • A primary GN is a disease where the sole organ
    involved is the kidney (the glomeruli)
  • Clinical manifestations due to the consequences
    or pathophysiologic derangements that resulted in
    glomerular damage
  • In contrast secondary GNs have manifestations due
    to systemic disease and glomerular injury

4
Presentation Clinical Syndromes
  • Asymptomatic hematuria (gross or microscopic)
    and/or proteinuria (lt 3g/day)
  • Acute glomerulonephritis (AGN)
  • Rapidly progressive glomerulonephritis (RPGN)
  • Chronic glomerulonephritis (CGN)
  • Nephrotic Syndrome (NS)

5
Clinical Syndromes AGN
  • Abrupt onset of variable degrees of hematuria,
    proteinuria, reduced GFR, sodium and fluid
    retention, HTN and oliguria
  • Tendency to spontaneous recovery
  • Association with proliferative GN, ie. bacterial
    infection

6
Clinical Syndromes RPGN
  • More insidious onset, not abrupt
  • Dominated by progressive loss of GFR and
    oliguria
  • Little tendency for spontaneous recovery
  • Classification and terminology of this group of
    disorders (Type I, II, II)

7
Clinical Syndromes CGN
  • Clinical expression of a wide variety of
    glomerular diseases
  • Vague, all inclusive term refers to progressive
    reduction in GFR
  • Varying degrees of hematuria, proteinuria, HTN
  • Course may be protracted but usually relentless

Composite plot of reciprocal serum creatinine
versus time in six patients with chronic kidney
disease.
8
Clinical Syndromes NS
  • Heavy proteinuria (gt 3-3.5g/day )
  • Reduced serum albumin
  • Edema
  • HTN
  • Hyperlipidemia
  • Lipiduria

9
Pathology
  • Minimal change
  • Focal and segmental glomerulosclerosis
  • Proliferative GN
  • Pure mesangial proliferative
  • Endocapillary proliferative
  • Extra-capillary proliferative (crescenteric)
  • Membrano-proliferative
  • Membranous GN
  • Fibrillary/ Immunotactoid GN, Collageno-fibrotic
    GN, Lipoprotein GN (deposits of Apo E Nephron 83
    193, 1999)

10
Normal Glomerular Histology
From tutorial J. Charles Jennette, M.D.
11
Common Primary Glomerulonephritidies
  • Minimal Change Disease
  • Focal Segmental Glomerulosclerosis (FSGS)
  • IgA Nephropathy (Bergèrs Disease)
  • Membranoproliferative GN (Types I, II, III)
  • Membranous GN

12
Case 1
  • 20 yo Caucasian male develops frothy urine and
    notes ankle edema. He takes no medication or
    drugs.
  • On exam he has a BP 180/98 and pitting lower
    extremity edema.
  • He has a Cr 2mg/dl and 12g/day urinary protein
    excretion.
  • HIV, HBSAg, and Hepatitis C negative.

13
FSGS
  • Incidence among all biopsied patients rising, up
    to 25 of all adults
  • Most common pattern among African Americans, some
    secondary forms more common in whites (obesity
    and hereditary)
  • Children usually present with NS, adults with
    asymptomatic proteinuria

14
UpToDate
15
FSGS
UpToDate
16
FSGS Histopathologic Variants
  • Glomerular tip lesion
  • epithelial cell proliferation and sclerosis in
    segment adjacent to origin of proximal tubule,
  • common in whites with heavier proteinuria,
    preserved GFR, good response to treatment and
    outcome
  • Collapsing/malignant variant
  • global collapse of capillary loops with visceral
    epithelial cell proliferation (similar to HIV),
  • common in AA with massive proteinuria, worse
    prognosis
  • Obesity
  • fewer glomeruli with FSGS but remaining with
    glomerulomegaly.
  • Increasing in prevalence, likely white, less
    likely NS, progression slower

17
FSGS-Pathophysiology
  • Podocyte injury (JASN 2012 23381-99)
  • Unknown increased glomerular permeability factor
    Suggested by studies demonstrating in-vitro
    glomerular permeabiliy (NEJM 334878, 1996)
  • Certain forms of the soluble urokinase
    plasminogen activating receptor (suPAR) (Nat Med.
    201117(8)952)
  • Expression of a specific microRNA called miR-193a
    produced FSGS in mice (Nat Med. 2013
    Apr19(4)481-7)
  • Controversial role of Parvovirus B-19 (KI
    592126, 2001)
  • Evidence for hyperfiltration Glomerulomegaly and
    obesity, sleep apnea, or remnant kidney
  • Genetic Defect role of MYH9 or APOL1 in African
    Americans (Nat Genetics. 2008 Oct40(10)1185-92
    Science. 2010 Aug 13329(5993)841-5)

18
FSGS Clinical Course
  • Tendency for progressive renal failure, ESRD in
    5-20 yrs
  • Factors associated with progression
  • magnitude of proteinuria, higher serum Cr,
  • AA ethnicity, response to corticosteroids,
  • degree of sclerosis, TI damage, collapsing
    variety
  • Recurrence in allograft in up to 30. Treatment
    with plasmapheresis (Clin Nephrol 56271, 2001)
    and Rituximab (Transplantation. 2009 Aug
    1588(3)417-20)

19
FSGS Treatment
  • Prednisone 0.5-2.0 mg/kg/day. Total duration of 6
    month before declaring pt steroid resistant, then
    alternate day. Complete and partial response rate
    50-60 ( JASN 91333, 1998)
  • Cytotoxic therapy (cyclophosphamide,
    chlorambucil, MMF) may be useful but not proven
    (KI 55(S70) S26, 1999).
  • CsA at 5 mg/kg/day may be effective, relapses
    common, long term use may be required (KI
    55(S70) S26, 1999).
  • Synthetic ACTH (Am J Kidney Dis. 200647(2)233)
  • Rituximab (Intern Med. 201251(7)759-62)
  • Plamapheresis, in recurrent disease in transplant
    patients (Semin Nephrol. 200020(3)309)

20
Common Secondary Glomerulonephritidies
  • Infection
  • Malignancy
  • Drugs and toxins
  • Metabolic
  • Rheumatologic Disorders
  • Vasculitidies
  • Hereditary/Familial

21
GLOMERULAR DISEASES ASSOCIATED WITH INFECTIOUS
AGENTS, TUMORS OR DRUGS
Infection Glomerular disease
Bacteria of all types MCGN, diffuse proliferative GN
E coli and Shigella species HUS
Malaria Membranous GN, MCGN
Syphilis Membranous GN
Leprosy, schistosomiasis, TB Amyloidosis
Hepatitis B virus FSGS, MCGN, Membranous
Hepatitis C virus FSGS, MCGN, Membranous
HIV FSGS (collapsing variant), IgA nephropathy, immune complex GN, HUS
Parvovirus FSGS
22
Tumor Glomerular Disease
Lymphoma and leukemia Minimal change disease, Membranous, MCGN
Myeloma Amyloidosis, light chain nephropathy
Carcinoma (lung, gastrointestinal, uterine, prostate, etc) Membranous, MCGN, HUS
Drug Glomerular Disease
Heroin FSGS, MCGN
NSAIDs Minimal change disease, Membranous
Penicillamine, captopril Membranous
Tacrolimus, cyclosporine HUS
Bisphosphonates FSGS
23
Case 2
  • 28 yo woman with known SLE for 1 year and history
    of arthralgias develops proteinuria and hematuria
  • BP 138/86, faint malar rash, mild pitting edema
  • Cr 0.7
  • 24 hr 2.5 g of protein
  • DS-DNA positive high titer and low C3

24
Classification of Lupus Nephritis
  • ISN Classification KI 200465(2)521
  • Comparison to WHO
  • Minimal mesangial lupus nephritis (class I) 
  • Mesangial proliferative lupus nephritis (class
    II) 
  • Focal lupus nephritis (class III)
  • Diffuse lupus nephritis (class IV)  
  • Membranous lupus nephritis (class V) 
  • Sclerosing lupus nephritis (class VI)  a healing
    /scarring of prior injury advanced stage of
    chronic class III, IV, or V
  • Overlap of SLE and ANCA GNs  ANCA found in 20
    of SLE and some have superimposed ANCA GN, with
    prominent necrosis and crescent with minimal
    endocapillary proliferation or subendothelial
    deposits

25
Class IV
  • Most common and severe (historically 50
    developed ESRD in 5 yrs)
  • Class IV showed higher rate of ESRD compared to
    I, II, III or V14.5 vs 4.6
  • Present with hematuria and proteinuria /nephrotic
    syndrome, frequent HTN and reduced GFR.
  • Serology reduced C3, positive anti-DNA
  • Histology gt 50 glomeruli with endocapillary
    GN.
  • Subclasses
  • Diffuse segmental or global proliferative
    nephritis, active vs chronic and/or sclerosing
  • Active disease necrotizing changes, crescents
    and marked IgG and C3 deposition with thickening
    of GN capillary wall like MPGN.

26
Histology Class IV
27
Severe Lupus Nephritis Optimal Therapy
  • There is no universally agreed upon optimal
    therapy for severe proliferative lupus nephritis
  • Therapeutic approaches are divided into
    Induction therapy (first 6-12 months of
    treatment) and Maintenance therapy (beyond 6-12
    months
  • Generally, the earlier intensive Induction
    therapy is begun the better the response
  • Combined therapy (cytotoxic agents and steroids)
    are indicated in most cases
  • Complete and/or partial remissions are the goal
    of induction therapy, accompanied the minimum
    amount of untoward side-effects (particularly
    infection)

28
Lupus Nephritis Induction therapy choices
Probability of developing ESRD
  • Oral cyclophosphamide 2.0mg/kg/d for 3-6 months,
    with daily or alternate-day oral prednisone (or
    3 IV MP pulses)
  • IV Cyclophosphamide 500-1000mg/m2 monthly for
    3-6 months (mini-dose or maxi-dose)
  • with daily or alternate-day oral prednisone
    ( monthly IV MP pulses)
  • Oral Mycophenolate mofetil 2-3gms/d, with oral
    daily oral alternate-day prednisone ( IV MP
    pulses)
  • Oral Tacrolimus (MMF)

(prepared by R. Glassock, 2007)
29
ALMS Trial MMF v IV CP Induction Therapy
  • Largest prospective randomized trial in SLE, 88
    centers, 370 patients with Class III, IV, V
  • At the end of a 6 months induction no difference
    in remission rate for oral MMF compared to
    maxi-dose IV CP in patients with severe lupus
    nephritis (neither superior or inferior)- about a
    60 remission rate overall
  • During a 6 months course of induction the adverse
    event rates were similar for oral MMF and IV CP
    (leukopenia, alopecia, amenorhea, infection in
    CP anemia, diarrhea, infections in MMF)
  • (Appel G, et al JASN, 2009
    May20(5)1103-12)

30
Lupus Nephritis Maintenance Therapy
  • The primary goals of maintenance therapy in LN
    are
  • 1) to prevent or minimize relapses
  • (renal flares )
  • 2) to reduce the side-effects of the
  • therapy
  • 3) to improve quality of life
  • 4) to reduce the risk of ESRD and death
  • Evaluation of efficacy and safety of maintenance
    therapy requires long-term follow up (perhaps 5
    years minimum)

31
Clinical Trial in Maintenance Therapy
  • ALMS trial after 3 yrs regardless of induction
    therapy, MMF (16.4 flare) was superior to AZA
    (32.4 flare), irrespective of race,
    gender,region and more AE with AZA (NEJM 2011
    3651886-95)
  • MAINTAIN nephritis trial (EURO-lupus nephritis
    trial high vs low dose cyclophosphamide) at 48
    mo. no statistical difference between AZA (25
    flare) and MMF (19 flare). (Ann Rheum Dis 2010
    692083-89)
  • Recent review concludes that maintenance therapy
    with either MMF or AZA is overall well tolerated
    and leads to excellent results (Nephrol. Dial.
    Transplant. (2013) 28 (6) 1371-1376).

32
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