GLOMERULOPATHIES

Hasyim kasim
Divisi nephrology and Hypertensi FKUH
2016
DEFINITION
Glomerulopathy is conditions in which there is injury in the
glomerulus.

Glomerular diseases can be categorized into

- Primary : primarily involve the kidney
- Secondary : kidney involvement is part of a systemic disorder

Glomerular disease can be assumed to be present if the patient

manifests glomerular hematuria, glomerular proteinuria, or both.

Floege J, Feehally J. Introduction to Glomerular Disease: Clinical Presentations in Comprehensive clinical nephrology 5th ed. 2015. Elsevier
Saunders. Philadelphia. p.184-197.
INTRODUCTION

• Early diagnosis is important for intervention that could have

impact on disease progression.

• Glomerulopathy have wide variability of clinical

presentation.

• The clinical distinction provides a reasonable starting point to

form an initial differential diagnosis, en route to serologic and
pathologic determination of the underlying glomerular disease.
PATHOGENESIS OF GLOMERULAR DISEASE

• Glomerulopathy
• Deposition and immunoglobulin entrapment.
• Complement activation at glomerulus without IgG
involvement.
• Complement system activation via classic
pathway, alternative pathway, and mannose lectin
binding pathway.

Floege J, Feehally J. Introduction to Glomerular Disease: Clinical Presentations in Comprehensive clinical nephrology 5th ed. 2015. Elsevier
Saunders. Philadelphia. p.184-197.
Common Pathways in Glomerular Injury
GN

Loss of nephrons

Glomerular hyperfiltration

Glomerular HTN

Non-selective
prtoteinuria

Glomerular Tubulointerstitial
sclerosis inflammation
Ischemia
Tubulointerstitial atrophy/fibrosis
GLOMERULOPATHY CLASSIFICATION

Primary glomerulopathy

Disorders that affect glomerular structure, function, or

both in the absence of a multisystem disorder

Secondary glomerulopathy

Disorders that affect glomerular as part of systemic

disease
 Asymptomatic
proteinuria

Chronic Asymptomatic
glomerulonephritis hematuria

Clinical Manifestation of
Glomerular Disease
Rapidly
Nephrotic
progressive
syndrome
glomerulonephritis

Nephritic syndrome
ASYMPTOMATIC PROTEINURIA
Proteinuria can be as result from systemic overproduction,
tubular dysfunction, and glomerular dysfunction.

Important to determine whether proteinuria as manifestation

of glomerular disease or benign functional, transient,
postural, or intermittent proteinuria.

The hallmark of glomerular disease is the excretion of protein

in the urine.

Normal urine protein excretion : < 150 mg/24 h

(20-30 mg of albumin, 10-20 mg of LMW protein that undergo
glomerular filtration, and 40-60 mg of secreted proteins)
ASYMPTOMATIC PROTEINURIA

Non-nephrotic proteinuria : urine protein excretion of less than 3.5 g/24 h or a

urine protein-creatinine ratio of less than 3 g/g.

Non nephrotic proteinuria is non specific, and need further clinical evaluation
and test.

Patients with coincident asymptomatic hematuria and proteinuria have a

much greater risk of significant glomerular injury, hypertension, and
progressive renal dysfunction.

Biopsy indicated only at persistent microhematuria with cast, even if

proteinuria only 0,5-1g/24 h
MACROSCOPIC HEMATURIA
Hematuria evaluation begin with determine if bleeding from
upper urinary tract or lower urinary tract.
Erythrocyte morphology help to determination of hematuria
etiology.

Glomerular hematuria marked with dysmorphic erythrocte.

Proteinuria >2g/day, hemoglobinuria, RBC cast increase

possibility of glomerular hematuria.

Glomerular hematuria often found with albuminuria.

Macrohematuria from glomerulopathy found commonly at

children, young adults, rarely after 40s.
NEPHROTIC SYNDROME

Nephrotic syndrome
• Heavy proteinuria (>3.0 g/24 h), hypertension, hypercholesterolemia,
hypoalbuminemia, edema/anasarca, and microscopic hematuria.

Nephrotic-range proteinuria
• Large amounts of proteinuria are present without
clinical manifestations.

Severe nephrotic syndrome

• Proteinuria exceeding 10 g/day, serum albumin <2.5 g/dl,
and severe edema.
NEPHROTIC SYNDROME

Weight gain

Edema :
Hipoalbuminemia peripheral and
periorbital

Increase total
cholesterol and Nephrotic Hypertension
LDL, decrease Syndrome
HDL

Urinalysis : +3
Hypercoagulability proteinuria,
variable degree
hematuria
24 h urine
collection : 3-5
mg/kg/day
proteinuria
COMMON GLOMERULAR DISEASES PRESENTING AS
NEPHROTIC SYNDROME IN ADULTS
Differentiation between nephrotic and nephritic syndrome
Typical features Nephrotic Nephritic

Onset Insidious Abrupt

Edema ++++ ++

Blood pressure Normal Raised

Jugular venous Normal/low Raised

pressure
Proteinuria ++++ ++

Hematuria May/may not occur +++

Red-cell casts Absent Present

Serum albumin low Normal/slightly reduce

Clinical manifestation of nephrotic syndrome :

Oedema
Hypertension
Dyslipidemia
Hypercoagulable state
Hypoproteinemia / proteinuria
Progressive renal failure
Trace metal deficiencies
Endocrine disturbances
Infectious / immunodeficiency states
 Classification of the disease states associated with the development of
nephrotic syndrome

I. Idiopathic nephrotic syndrome due to Primary Glomerular Disease

II.Nephrotic syndrome associated with spesific etiologic events or in which

glomerular disease arises as a complication of other disease

1. Medications
2. Allergens, venoms, immuization
3. Infection ( bacterial, viral, protozoal, helminthic )
4. Neoplasmic ( solid tumors, leukemia and lymphoma )
5. Multisystem disease
6. Heredofamilial and metabolic disease
7. Miscellaneous
 Formation of nephrotic edema
Underfill Overfill
Proteinuria Primary tubular defect
causing sodium retention
Hypoalbuminemia

Plasma colloid Normal/raised

Oncotic pressure  plasma volume

Starling forces
Vasopressin Aldosterone 
Reduced plasma volume normal

ANP 
Vasopressin  ANP normal/low RAS activated
Aldosterone 

Water retention

Sodium retention
Edema
 Management of oedema in nephrotic syndrome

Mild
Dietary NaCl restriction ( to 3-4 g NaCl per day )
Support stockings
Hydrochlorothiazide 12.5-50 mg/day ( if GFR > 50 ml/min )
Frusemide 40-80 mg/day ( if GFR < 70 ml/min )
Moderate
Continue NaCl restriction
( Frusemide 160-480 mg/day or bumetamide 1-2 mg/day or torsemide
40-160 mg/day )
Severe
Continue NaCl restriction
Oral or IV frusemide 160-480 mg/day ( or bumetanide or torsemide ) plus
metalozone 2.5-10 mg/day
Refractory
Continuous IV infussion or frusemide ( 20 mg/h ) or bumetanide ( 1 mg/h )
after a loading dose
or
Hyperosmotic salt-poor albumin ( 25-50 g ) mixed with 120 mg of
furosemide
or
Slow continuous veno-venous ultrafiltration using a highly permeable
membrane
 Plasma lipid concentrations in nephrotic syndrome

Increased
Very low density lipoproteins
Intermediate density lipoproteins
Low density lipoproteins
Apolipoprotein B
Apolipoprotein CIII
High density lipoproteins
Lipoprotein (a)
Total cholesterol
Triglycerides ( when serum albumin < 2 g/dl

Unchanged
Apolipoprotein AI
Apolipoprotein AII
Apolipoprotein CIII

Decreased
High density lipoprotein 2
 Therapy of dyslipidemia in nephrotic syndrome

• Only full successful when the underlying cause is remidied

and long term complete remission of proteinuria are
induced
• Reduced cholesterol and saturated fat intake
( relatively ineffective )
• Drugs : HMG co-enzyme A reductase inhibitors
( lovastatin, simvastatin, fluvastatin, atorvastatin )
Coagulation abnormalities in nephrotic syndrome

Increased ( prothrombotic )
Fibrinogen
Platelets ( and platelet adhesiveness )
Plasma viscosity ( cholesterol, lipid )
Lipoprotein (a)
Plasminogen activator inhibitor

Decreased ( antithrombotic )
Active protein C
Active protein S
Antithrombin III
Prothrombotic state are correlated with serum albumin levels

Serum albumin < 2-2.5 g/dl appears to be associated with an

increased risk of thromboembolism
Diagnostic approach in nephrotic syndrome

I. Clinical
II. Laboratory studies
III. Renal biopsy
I. Clincial

History
Preexisting disease
Previous infection
Drug ingestion
Arthritis, rash
Current pregnancy
Family history of renal disease

Physical examination
Severe obesity
Rash, arthritis
Diabetic retinopathy
Hypertension
Evidence of malignancy
Lipodystrophy
Lymphoadenopathy/hepatosplenomegaly
II. Laboratory Studies

Urinalysis

In all cases ( nondiagnstic )

Creatinine clearance
Serum protein electrophoresis
Serum tota;cholesterol, lipoprotein
Serum ionized calcium
Parathyroid hormone

In selected cases ( to establis the diagnosis )

Complement level
Antinuclear antibody assay
Cryoglobulins
Hepatitis and HIV serology
Serum and urine immunoelectrophoresis
III. Renal biopsy

• Minimal change disease

• Focal segmental glomerulosclerosis
• Membranous nephropathy
• Membranoproliferative glomerulonephritis
• Other glomerulonephritis
 Suggested approach for initial treatment
( Minimal change disease )
Children
• Prednisone 60 mg/m2/day until remission, then 40 mg/m2/48 h for 12
weeks, then reduce by 5-10 mg/m2/48 h every month.
• Remission was defined as no or trace proteinuria on dipstick test for
three consecutive days or urine protein:creatinine ratio of <0.2 mg/mg.
• Relapse was defined as proteinuria of ≥ 2+ on dipstick test for three
consecutive days or urine protein:creatinine ratio of ≥ 2.0 mg/mg.
• Partial response was defined as 2+ proteinuria on urine dipstick or urine
protein:creatinine ratio < 2.0 mg/mg after a maximum of 8 weeks of
high dose steroid treatment (2 mg/kg/day).
• Steroid resistance was defined as persistent proteinuria ≥2+ and urine
protein:creatinine ratio ≥ 2.0 mg/mg after a maximum of 8 weeks of
high dose steroid treatment (2 mg/kg/day).
INTRAVENOUS METHYLPREDNISOLONE PULSE
TREATMENT
Adults
• Prednisone 1mg/kg/day until remission or for 6 weeks, then 1.6
mg/kg/48 h for 1 month, then reduce by 0.2-0.4 mg/kg/48 h.

Elderly
• Prednisone 1 mg/kg/day until remission or for 4 weeks, then 0.8
mg/kg/day for 2 weeks, then 1.6 mg/kg/48 h for 2 weeks. Then
reduce by 0.4 mg/kg/48 h every 2 weeks. If no remission continue
with 1.2 mg/kg/48 h for another 4 weeks then reduce.

Contraindications to prednisone
• Cyclophosphamide 2 mg/kg/day or chlorambucil 0.15mg/kg/day for 8-
12 weeks
 Definitions used to describe responses and relapses in patients with minimal
Change nephropathy

Complete remission Proteinuria lower than 4 mg/m2/day in children or lower

than 0.2 g/day in adults for three consecutive days

Partial remission Proteinuria between 4 and 40 mg/m2/dayin children or

between 0.21 and 3.5 g/day in adults for three consecutive
days
Relapse of proteinuria Proteinuria excreeding 4 mg/m2/day in children or 0.2
g/day in adults for at least 1 week, in patients who were
in complete remission
Relapse of nephrotic Proteinuria exceeding 40 mg/m2/day in children or 3.5
syndrome g/day in adults for at least 1 week, in patients who were
in complete or partial remmision
Frequent relapses Patients with 2 or more episodes of the nephrotic
syndrome in 6 months or 3 or more episodes of the
nephrotic syndrome in 12 month
Steroid-dependent nephrotic Reappearance of the nephrotic syndrome within 2 weeks
syndrome after reduction or discontinuation of glucocorticoids

Steroid-resistant nephrotic Controversial

syndrome
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS

RPGN is a clinical description which determines by symptoms and signs of

glomerulonephritis (GN); edema, hypertension and gross hematuria, evidence of
severe decrease ARF, and crescentic lesion at microscopic renal biopsy specimen
involving whole glomerular structure.

It also characterized by rapid loss of renal function (GFR<50% within 3 months).

RPGN can be primary or secondary. Secondary forms occur in any form of severe
glomerulonephritis including membranoproliferative GN, IgA nephropathy, post
infectious GN, and SLE.
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS

Primary RPGN is an autoimmune disease which is

divided into three immunopathologic categories:

Type I RPGN: glomerulonephritis with antibodies

directed against the GBM (anti-GBM mediated GN)

Type II RPGN: immune-complex induced GN

Type III RPGN: Antineutrophil cytoplasmic antibody

associated glomerulonephritis (ANCA-associated
glomerulonephritis or pauci-immune GN)
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS

Different forms of RPGN share similar clinical features;

hematuria, proteinuria, edema, hypertension and
symptoms of ARF .

Patients with Anti –GBM antibody or pauci-immune

RPGN (ANCA -associated vasculitis) may have
pulmonary hemorrhage and hemoptysis.

In pauci-immune RPGN the initial symptoms are non-

specific; often fatigue, fever, night sweats and
arthralgias are first clinical manifestations.
RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS

If the disease left untreated typically progresses to end-stage

renal disease over a period of weeks to a few months.

Despite various immuno suppressive therapy protocols

mortality of ANCA positive RPGN patients is still high, with
mortality mostly caused by infection.
CHRONIC GLOMERULONEPHRITIS
Many forms of glomerulopathies, except minimal change glomerulopathy and thin
basement membrane nephropathy can progress into chronic glomerular sclerosis
with progressive renal function decline and end up as end stage renal failure.

In longstanding GN, the kidneys shrink, but remain smooth and symmetric .

Renal biopsy at this stage is more hazardous and less likely to provide diagnostic
material.

Light microscopy often shows nonspecific features of end-stage renal disease

(ESRD), consisting of focal or global glomerulosclerosis and dense
tubulointerstitial fibrosis, and it may not be possible to define
.
CHRONIC GLOMERULONEPHRITIS

Anti GBM and ANCA crescentic

glomerulonepritis
IgA nephropathy

FSGS
PROGNOSIS

• Renal failure in GN best correlates histologically with the

appearance of tubulointerstitial nephritis

• Persistent damage to glomerular capillaries spreads to the

tubulointerstitium in association with proteinuria

• Poor prognostic factor : hypertension, severe and persistent

proteinuria, renal function disturbance by the time of diagnosis,
glomerulosclerosis and interstitial fibrosis at renal biopsy
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