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 Visceral EC
arteriole
 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 homo-
genous 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

Mesangial
cells
Proliferation increase
in the glomerular cell
number

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 Renal Insults/ Defects Glomerular Disease

Injury
Immunologic Immunoglobulin Immune-complex
GN
Cell-mediated injury Pauci-immune GN

Cytokine Primary FSGS

Complement activation MPGN Type II

Metabolic Hyperglycemia DM Nephropathy

Fabrys disease/ sialidosis FSGS

Hemodynamic Systemic hypertension HTN

Nephrosclerosis
Intraglomerular hypertension Secondary FSGS
 Primary Mechanisms of Glomerular Injury

Mechanism Renal Insults/ Defects Glomerular Disease

of Injury
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 Alports Syndrome
type IV collagen
Abnormally thin basement Thin basement
membrane membrane disease
 Immunologic Glomerular Injury

Humoral Antibody-Mediated Injury

Autoantibodies against intrinsic antigens
(example: Goodpastures 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 Tubulointerstitial
sclerosis 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 Common
Diagnosis Findings

Rapidly Anuria HTN, Hematuria,

Progressive Oliguria Proteinuria,
Renal Failure Pyuria
Decline in GFR
(RPRF) over weeks
Nephritic Hematuria, RBC Proteinuria,
Syndrome casts, Azotemia,
Oliguria, Edema,
HTN
 Syndromes in
Glomerular Diseases
Syndrome Clues to Diagnosis Common
Findings
Nephrotic Proteinuria > 3.5 gms Casts
Syndrome Hypoalbuminemia Edema
Hyperlipidemia
Lipiduria

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
Wegeners ggranulomatosis
 P-ANCA: Perinuclear Antineutrophil
Cytoplasmic Antibody

P-ANCA
Antibodies against
myeloperoxidase
Associated with a
variety of vasculitides
Non-specific for
Wegeners granulomatosis
 Clinical Diagnosis
Disease Renal Clinical Features
Syndrome

Diabetic Nephrotic Chronic course, (+) DM

nephropathy CRF retinopathy, nl-sized kidneys,
bland urine sediment
Goodpastures Nephritic antiGBM-aby (+), cANCA (-),
syndrome RPRF nl C3

Wegeners Nephritic antiGBM-aby (-), cANCA (+),

granulomatosis RPRF nl C3
 Clinical Diagnosis
Disease Renal Clinical Features
Syndrome

Lupus nephritis Nephritis antiGBM-aby (-), cANCA (-),

RPRF low C3, ANA (+), (+) ACR
criteria for the diagnosis of
SLE

Poststreptococcal Nephritis antiGBM-aby (-), cANCA (-),

GN 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 Histologic Etiologic
Diagnosis Diagnosis Diagnosis
Nephritic Diffuse Immune complex GN (>70%)*
Proliferative GN Pauci-immune GN (<30%)**
Nephritic Membrano- Immune complex GN*
Nephrotic Proliferative GN Thrombotic microangiopathy
RPRF Crescentic GN Immune complex GN (45%)*
Pauci-immune GN (45%)**
Anti-GBM disease (10%)
Isolated Mesangial IgA nephropathy
hematuria Proliferative GN HSP
* SLE, Postinfectious GN, IE, Cryoglobulinemia
** Wegeners granulomatosis, Microscopic PAN
 Clinicopathologic Correlation
Syndrome Histologic Etiologic
Diagnosis Diagnosis Diagnosis
Nephrotic Minimal Change Idiopathic, drugs, heroin,
Disease (MCD) HIV, lymphoma

Nephrotic Focal Segmental Idiopathic, HIV, heroin,

Glomerulosclerosis secondary forms from
reduced nephron number
(FSGS)
Nephrotic Membranous Idiopathic, infections, drugs,
Glomerulopathy autoimmune diseases,
paraneoplastic syndrome
Nephrotic Nodular sclerosis DM nephropathy
CRF 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
Fabrys 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 GN
therapy
Loss of nephrons

Glomerular hyperfiltration

Glomerular HTN

Non-selective
prtoteinuria

Glomerular Tubulointerstitial
sclerosis 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 Wegeners Steroids plus PO

granulomatosis cyclophosphamide
RPRF Goodpastures Plasmapharesis
syndrome
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
Glomerular HTN
delay
progression
Non-selective
prtoteinuria

Glomerular Tubulointerstitial
sclerosis 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
 Membrane
Lupus Nephritis
thickening
 TRI

Membranous Lupus GN
Immunofluorescence- Postinfectious GN
RPGN
Immunofluoresence: Anti-GBM Disease