Overview of
Glomerulonephritidies
Madeleine V. Pahl, M.D.
University of California, Irvine
Objectives
• To define common primary and secondary
glomerular disorders
• To discuss involved pathophysiology
• To review their clinical presentation
• To review clinical course and therapy
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
Presentation: Clinical
Syndromes
• Asymptomatic: hematuria (gross or microscopic)
and/or proteinuria (< 3g/day)
• Acute glomerulonephritis (AGN)
• Rapidly progressive glomerulonephritis (RPGN)
• Chronic glomerulonephritis (CGN)
• Nephrotic Syndrome (NS)
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
Clinical Syndromes: RPGN
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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)
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.
Clinical Syndromes: NS
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Heavy proteinuria (> 3-3.5g/day )
Reduced serum albumin
Edema
HTN
Hyperlipidemia
Lipiduria
Pathology
• Minimal change
• Focal and segmental glomerulosclerosis
• Proliferative GN
o
o
o
o
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)
Normal Glomerular Histology
From tutorial: J. Charles Jennette, M.D.
Common Primary
Glomerulonephritidies
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Minimal Change Disease
Focal Segmental Glomerulosclerosis (FSGS)
IgA Nephropathy (Bergèr’s Disease)
Membranoproliferative GN (Types I, II, III)
Membranous GN
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.
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
UpToDate®
FSGS
UpToDate®
FSGS: Histopathologic Variants
• Glomerular “tip” lesion:
o epithelial cell proliferation and sclerosis in segment
adjacent to origin of proximal tubule,
o common in whites with heavier proteinuria, preserved GFR,
good response to treatment and outcome
• “Collapsing/malignant” variant:
o global collapse of capillary loops with visceral epithelial
cell proliferation (similar to HIV),
o common in AA with massive proteinuria, worse prognosis
• Obesity:
o fewer glomeruli with FSGS but remaining with
glomerulomegaly.
o Increasing in prevalence, likely white, less likely NS,
progression slower
FSGS-Pathophysiology
• Podocyte injury (JASN 2012; 23:381-99)
• Unknown: increased glomerular permeability factor
Suggested by studies demonstrating in-vitro
glomerular permeabiliy (NEJM 334:878, 1996)
o Certain forms of the soluble urokinase
plasminogen activating receptor (suPAR) (Nat Med.
2011;17(8):952)
o Expression of a specific microRNA called miR193a produced FSGS in mice (Nat Med. 2013 Apr;19(4):481-7)
• Controversial role of Parvovirus B-19 (KI 59:2126, 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 Oct;40(10):1185-92; Science. 2010 Aug 13;329(5993):841-5)
FSGS: Clinical Course
• Tendency for progressive renal failure, ESRD
in 5-20 yrs
• Factors associated with progression:
o magnitude of proteinuria, higher serum Cr,
o AA ethnicity, response to corticosteroids,
o degree of sclerosis, TI damage, “collapsing”
variety
• Recurrence in allograft in up to 30%.
Treatment with plasmapheresis (Clin Nephrol 56:271,
2001) and Rituximab (Transplantation. 2009 Aug 15;88(3):41720)
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 9:1333, 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. 2006;47(2):233)
• Rituximab (Intern Med. 2012;51(7):759-62)
• Plamapheresis, in recurrent disease in
transplant patients (Semin Nephrol. 2000;20(3):309)
Common Secondary
Glomerulonephritidies
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Infection
Malignancy
Drugs and toxins
Metabolic
Rheumatologic Disorders
Vasculitidies
Hereditary/Familial
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
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
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
Classification of Lupus Nephritis
ISN Classification
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KI 2004;65(2):521
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
Comparison to WHO
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 V—14.5% vs 4.6%
• Present with hematuria and proteinuria /nephrotic
syndrome, frequent HTN and reduced GFR.
• Serology: reduced C3, positive anti-DNA
• Histology: > 50 % glomeruli with endocapillary GN.
• Subclasses:
o Diffuse segmental or global proliferative nephritis, active vs chronic and/or
sclerosing
o Active disease: necrotizing changes, crescents and marked IgG and C3
deposition with thickening of GN capillary wall like MPGN.
Histology: Class IV
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)
Lupus Nephritis:
“Induction” therapy choices
Probability of developing ESRD
(prepared by R. Glassock, 2007)
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Oral cyclophosphamide
2.0mg/kg/d for 3-6 months,
with daily or alternate-day
oral prednisone (±or 3 IV MP
pulses)
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IV Cyclophosphamide 5001000mg/m2 monthly for 3-6
months (mini-dose or maxidose)
with daily or alternate-day oral
prednisone (± monthly IV MP
pulses)
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Oral Mycophenolate mofetil
2-3gms/d, with oral daily oral
alternate-day prednisone (±
IV MP pulses)
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Oral Tacrolimus (±MMF)
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 May;20(5):1103-12)
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)
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; 365:1886-95)
• 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; 69:2083-89)
• 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).