GLOMERULAR DISEASES
Antonio V. Cayco, MD
Section of Nephrology
OBJECTIVES
Introduction
Approach to Glomerular Diseases
• Syndrome Diagnosis
• Clinical Diagnosis
• Histologic Diagnosis
• Clinicopathologic Correlation
General Principles of Management
CAUSES OF ESRD
IN THE PHILIPPINES:
Renal Registry Data, PSN, 2003
Cause/Etiology
(%) ESRD Cases
Diabetes mellitus
33
Glomerulonephritis
25
Hypertension
19
Afferent arteriole
Parietal EC
Capillary
loop
Endothelium
Macula densa
Mesangium
JG cells
Urinary
space
Efferent
arteriole
Visceral EC
Mesangium
Normal
Glomerulus
Normal glomerulus
PATHOLOGY
Definition of Terms
• Glomerulopathy vs. Glomerulonephritis
• Primary vs. Secondary
• Diffuse vs. Focal
• Global vs. Segmental
• Fibrosis vs. Sclerosis
• Membranous vs. Proliferative
• Endocapillary vs. Extracapillary
Fibrosis – increase in
the deposition of
collagen fibers
Sclerosis – increase in
the amount of homogenous nonfibrillar
extracellular material
Sclerosis
Segmental – lesion
involves < 50% of
the glomerulus
Sclerosis
Global – lesion
involves > 50%
of the glomerulus
Sclerosis
Diffuse Global Glomerulosclerosis
Focal – lesion seen in less
than 50% of glomeruli
Diffuse – lesion seen in
more than 50% of glomeruli
Mesangial
cells
Normal glomerulus
Proliferation – increase
in the glomerular cell
number
Mesangial
cells
Mesangial proliferativeGN
Endocapillary
proliferation
Extracapillary
proliferation
Normal glomerulus
Membranous – expansion
and thickening of the
glomerular basement
membrane (GBM) by
immune deposits
Primary Mechanisms of Glomerular Injury
Mechanism of
Injury
Renal Insults/ Defects
Glomerular Disease
Immunologic
Immunoglobulin
Immune-complex
GN
Cell-mediated injury
Pauci-immune GN
Cytokine
Primary FSGS
Complement activation
MPGN Type II
Hyperglycemia
DM Nephropathy
Fabry’s disease/ sialidosis
FSGS
Metabolic
Hemodynamic Systemic hypertension
Intraglomerular hypertension
HTN
Nephrosclerosis
Secondary FSGS
Primary Mechanisms of Glomerular Injury
Mechanism Renal Insults/ Defects
of Injury
Glomerular Disease
Toxic
E. coli-derived verotoxin
Thrombotic
microangiopathy
Therapeutic drugs (NSAIDs)
Minimal change disease
Recreational Drugs (Heroin)
FSGS
Deposition
Amyloid fibrils
Amyloid nephropathy
Infectious
HIV
HIV Nephropathy
Subacute Endocarditis
Immune complex GN
Inherited
Genetic defect for 5 chain of Alport’s Syndrome
type IV collagen
Abnormally thin basement
membrane
Thin basement
membrane disease
Immunologic Glomerular Injury
Humoral Antibody-Mediated Injury
• Autoantibodies against intrinsic antigens
(example: Goodpasture’s syndrome)
• Autoantibodies against extrinsic “trapped
antigens (example: Postinfectious GN)
• Trapping of circulating immune complexes
(example: Cryoglobulinemic GN)
Cellular Mediated Injury
GN
Loss of nephrons
Glomerular hyperfiltration
Glomerular HTN
Non-selective
prtoteinuria
Glomerular
sclerosis
Tubulointerstitial
inflammation
Ischemia
Tubulointerstitial atrophy/fibrosis
Two Final Common Pathways in Glomerular Injury
OBJECTIVES
Introduction
Approach to Glomerular Diseases
• Syndrome Diagnosis
• Clinical Diagnosis
• Histologic Diagnosis
• Clinicopathologic Correlation
General Principles of Management
Approach to Glomerular Diseases
•
•
•
•
Syndrome Diagnosis
Clinical Diagnosis
Histologic Diagnosis
Clinicopathologic Correlation
Syndrome Diagnosis
History
Physical Examination
Ancillary Laboratory Tests
• Chemistry
• Serology
• Urinalysis
Syndromes in
Glomerular Diseases
Syndrome
Clues to
Diagnosis
Common
Findings
Rapidly
Progressive
Renal Failure
(RPRF)
Anuria
Oliguria
Decline in GFR
over weeks
Hematuria, RBC
casts, Azotemia,
Oliguria, Edema,
HTN
HTN, Hematuria,
Proteinuria,
Pyuria
Nephritic
Syndrome
Proteinuria,
Syndromes in
Glomerular Diseases
Syndrome
Clues to Diagnosis
Common
Findings
Nephrotic
Syndrome
Proteinuria > 3.5 gms
Hypoalbuminemia
Hyperlipidemia
Lipiduria
Casts
Edema
Asymptomatic Isolated hematuria
urinary
Isolated proteinuria
abnormality
(AUA)
Approach to Glomerular Diseases
•
•
•
•
Syndrome Diagnosis
Clinical Diagnosis
Histologic Diagnosis
Clinicopathologic Correlation
C-ANCA: Cytoplasmic Antineutrophil
Cytoplasmic Antibodies
C-ANCA
•Antibodies against
Proteinase 3
•Associated with
Wegener’s ggranulomatosis
P-ANCA: Perinuclear Antineutrophil
Cytoplasmic Antibody
P-ANCA
•Antibodies against
myeloperoxidase
•Associated with a
variety of vasculitides
•Non-specific for
Wegener’s granulomatosis
Clinical Diagnosis
Disease
Renal
Syndrome
Clinical Features
Diabetic
nephropathy
Nephrotic
CRF
Chronic course, (+) DM
retinopathy, nl-sized kidneys,
bland urine sediment
Goodpasture’s
syndrome
Nephritic
RPRF
antiGBM-aby (+), cANCA (-),
nl C3
Wegener’s
Nephritic
granulomatosis RPRF
antiGBM-aby (-), cANCA (+),
nl C3
Clinical Diagnosis
Disease
Renal
Clinical Features
Syndrome
Lupus nephritis
Nephritis
RPRF
antiGBM-aby (-), cANCA (-),
low C3, ANA (+), (+) ACR
criteria for the diagnosis of
SLE
Poststreptococcal Nephritis
GN
antiGBM-aby (-), cANCA (-),
low C3, ASO (+), prior
Streptococcal infection
Approach to Glomerular Diseases
•
•
•
•
Syndrome Diagnosis
Clinical Diagnosis
Histologic Diagnosis
Clinicopathologic Correlation
Indications for a Kidney Biopsy
• Unexplained ARF
• Unexplained RPRF
• Adult nephrotic syndrome w/out systemic
disease
• Proteinuria < 2 g/d w/ deterioration of renal
function
• Proteinuria > 2 g/d
• DM w/ acute onset of proteinuria and renal failure
• DM with proteinuria but w/out retinopathy
• Selected cases of Lupus nephritis
Crescent
Membrane thickening
Mesangial expansion
Cellular proliferation
MPGN
Deposits
Splitting
MPGN
Normal glomerulus
Fusion of
foot processes
Minimal Change Disease
Sclerosis
FSGS
Foot process fusion
FSGS
Membranous Nephropathy
Deposits
Membranous GN
Mesangial
proliferation
Mesangial IgA Deposits
IgA Nephritis
Approach to Glomerular Diseases
•
•
•
•
Syndrome Diagnosis
Clinical Diagnosis
Histologic Diagnosis
Clinicopathologic Correlation
Clinicopathologic Correlation
Syndrome
Diagnosis
Histologic
Diagnosis
Etiologic
Diagnosis
Nephritic
Diffuse
Immune complex GN (>70%)*
Proliferative GN Pauci-immune GN (<30%)**
Nephritic
Nephrotic
MembranoImmune complex GN*
Proliferative GN Thrombotic microangiopathy
RPRF
Crescentic GN
Isolated
hematuria
Mesangial
IgA nephropathy
Proliferative GN HSP
Immune complex GN (45%)*
Pauci-immune GN (45%)**
Anti-GBM disease (10%)
* SLE, Postinfectious GN, IE, Cryoglobulinemia
** Wegener’s granulomatosis, Microscopic PAN
Clinicopathologic Correlation
Syndrome Histologic
Diagnosis Diagnosis
Etiologic
Diagnosis
Nephrotic
Minimal Change
Disease (MCD)
Idiopathic, drugs, heroin,
HIV, lymphoma
Nephrotic
Focal Segmental
Glomerulosclerosis
(FSGS)
Idiopathic, HIV, heroin,
secondary forms from
reduced nephron number
Nephrotic
Membranous
Glomerulopathy
Idiopathic, infections, drugs,
autoimmune diseases,
paraneoplastic syndrome
Nephrotic
CRF
Nodular sclerosis
DM nephropathy
Chronic GN
Wire Loop
Cellular proliferation
Lupus nephritis
TRI
Lupus Nephritis
Postinfectious GN
Postinfectious GN
DM Nephropathy
Collapsing FSGS
Sclerosis
Tubuloreticular
Inclusion bodies
Amyloid
SAMPLE CASE
• 28 year old female referred for acute onset of
pedal edema X 1 week
• No other associated signs and symptoms
• Single; sexually active; silent past medical
history; not on any medications; no history of
IVDA
• ROS: denies other symptoms
• Well-nourished, not obese
• BP = 120/80, clear BS
• Grade III pedal edema
SAMPLE CASE
• Serum creatinine = 0.7 mg/dl (nl)
• Albumin = 2 g/L (low); Cholesterol = 300 mg/dl
(high); FBS = 100 mg/dl (nl)
• CXR: normal; UTS of kidneys: normal
• Urinalysis: +4 protein, 0-1 RBC/hpf, 0-1 WBC/hpf,
no casts
• 24-hour urine study: creatinine clearance of 98
cc/min and proteinuria of 4.5 g/day
Approach to Glomerular Diseases
•
•
•
•
Syndrome Diagnosis
Clinical Diagnosis
Histologic Diagnosis
Clinicopathologic Correlation
SAMPLE CASE
What is the renal syndrome present?
• Nephritic syndrome
• Nephrotic Syndrome
• Rapidly progressive renal failure
• Asymptomaric urinary abnormality
SAMPLE CASE
Answer: Nephrotic syndrome
• Edema
• Hypoalbuminemia
• Hyperlipidemia
• Proteinuria > 3.5 g/day
Approach to Glomerular Diseases
•
•
•
•
Syndrome Diagnosis
Clinical Diagnosis
Histologic Diagnosis
Clinicopathologic Correlation
SAMPLE CASE
Is it possible to make a clinical diagnosis?
• Yes or No ?
• If yes, what is your clinical diagnosis?
• If no, is a kidney biopsy indicated?
SAMPLE CASE
Answer: No
• No signs of systemic disease, ROS
negative for other symptoms
• PE normal except for edema
• Normal FBS
• Adult nephrotic syndrome – unlike
children, no room for empiric steroid
therapy
• Kidney biopsy indicated
Approach to Glomerular Diseases
•
•
•
•
Syndrome Diagnosis
Clinical Diagnosis
Histologic Diagnosis
Clinicopathologic Correlation
Sclerosis
Foot process fusion
SAMPLE CASE
Histologic Diagnosis:
• Focal segmental glomerulosclerosis
Approach to Glomerular Diseases
•
•
•
•
Syndrome Diagnosis
Clinical Diagnosis
Histologic Diagnosis
Clinicopathologic Correlation
SAMPLE CASE
• What are the possible causes of FSGS?
• What additional test/s is/are needed?
• Is this primary vs. secondary FSGS?
Etiology of FSGS
Idiopathic (Majority)
Systemic Diseases or Drugs
• HIV
• Diabetes mellitus
• Fabry’s disease
• Sialidosis
• Charcot Marie-Tooth Disease
• Heroin
Etiology of FSGS
Congenital Oligonephropathies
Acquired nephron loss
• Surgical resection
• Reflux nephropathy
• Chronic GN/ renal disease
Other adaptive responses
• Sickle-cell nephropathy
• Obesity with sleep apnea
• Familial dysautonomia
SAMPLE CASE
• No signs of systemic diseases
• No history or sign (normal kidneys on UTS) of
nephron loss
• Not obese
• No history of IVDA/ heroin use
• Sexually active – need to rule out HIV
• HIV ELISA test ordered – negative
• Final diagnosis: Idiopathic Primary FSGS
OBJECTIVES
Introduction
Approach to Glomerular Diseases
• Syndrome Diagnosis
• Clinical Diagnosis
• Histologic Diagnosis
• Clinicopathologic Correlation
General Principles of Management
General Principles of Management
• Disease-specific therapy for primary and
secondary GN
• Therapy to retard the progression of
disease
• Therapy to address complications
Disease-specific
therapy
GN
Loss of nephrons
Glomerular hyperfiltration
Glomerular HTN
Non-selective
prtoteinuria
Glomerular
sclerosis
Tubulointerstitial
inflammation
Ischemia
Tubulointerstitial atrophy/fibrosis
Two Final Common Pathways in Glomerular Injury
Disease-Specific Therapy
for Primary (Idiopathic) GN
Syndrome
Disease
Therapy
Nephritic
MPGN
Aspirin plus dipyridamole
Nephrotic
MCD
Steroids
Nephrotic
FSGS
Steroids
Nephrotic
Membranous
Steroids plus chlorambucil
(Ponticelli protocol)
Disease-Specific Therapy
for Secondary GN
Syndrome
Disease
Therapy
Nephritic
Poststreptococcal GN
Penicillin; supportive
RPRF
Wegener’s
granulomatosis
Steroids plus PO
cyclophosphamide
RPRF
Goodpasture’s
syndrome
Plasmapharesis
Nephritic
Lupus nephritis IV
Steroids, IV
cyclophosphamide
Nephrotic
Hep B membranous GN Interferon
Nephrotic
MCD due to NSAIDs
Discontinue offending
drug
GN
Loss of nephrons
Glomerular hyperfiltration
Measures to
delay
progression
Glomerular HTN
Non-selective
prtoteinuria
Glomerular
sclerosis
Tubulointerstitial
inflammation
Ischemia
Tubulointerstitial atrophy/fibrosis
Two Final Common Pathways in Glomerular Injury
Renoprotective Strategies
(Hebert, 2000)
•
•
•
•
•
•
Control blood pressure (< 127/75). (1)
Use of ACE-I for BP. (1)
Control of blood glucose for diabetics.(1)
Limit protein intake to 0.8 g/kg IBW/day.(1)
Limit NaCl intake (2-3 g/day).(3)
Control lipids using statins (HMG-CoA reductase
inhibitor therapy). (2)
• Avoid cigarette smoking. (2)
• Avoid regular intake of NSAIDs.(3)
( ) Level of Recommendation
Renoprotective Strategies
(Hebert, 2000)
• Control plasma homocysteine level using folic
acid (2-15 mg/d). (3)
• Control hyperinsulinemia (exercise and weight
reduction). (3)
• Use of antioxidants (Vit C and Vit E). (3)
• Correct anemia (HgB 11-12). (2)
• Avoid hypokalemia. (3)
• Control hyperphosphatemia. (3)
• Low dose ASA. (3)
• Estrogen replacement for women. (3)
( ) Level of Recommendation
Treatment of Complications
• Diuretics to control edema.
• ACE-I/AII-RBs to control BP.
• Anticoagulants (warfarin) for hypercoagulable
states.
• Statins for hyperlipidemia
• Measures to prevent osteoporosis for patients on
steroids (Calcium, Vit D, biphosphonates).
• Co-trimoxazole to prevent Pneumocystic
pneumonia for patients on steroids
SUMMARY
Introduction
Approach to Glomerular Diseases
• Syndrome Diagnosis
• Clinical Diagnosis
• Histologic Diagnosis
• Clinicopathologic Correlation
General Principles of Management
HUS
Thrombi
DM Nephropathy
DM Nephropathy
Membranous GN (Silver stain)
Spikes
Immunofluoresence- Membranous GN
Mesangial
proliferation
Lupus Nephritis
Lupus Nephritis
Membrane
thickening
TRI
Membranous Lupus GN
Immunofluorescence- Postinfectious GN
RPGN
Immunofluoresence: Anti-GBM Disease