GLOMERULOPATHY

Nephrotic Syndrome in Adult

Haerani Rasyid

Division of Nephrology & Hypertension

Department of Internal Medicine, Hasanuddin University
2021
 Definition
• Glumerulopathies is a group of diverse conditions –
including, but not limited to, glomerulonephritis –
having in common the fact that the disease process
begins in the glomerulus or that the glomerulus is the
most importantly diseased part of the nephron.
• Glomerular disease associated with abnormalities of
the complement system include thrombotic
microangiopathy and glomerulonephrities.
• Glomerulopathies are the most common causes of
end-stage renal disease.
 Glomerulonephritis
• Definition :
– A group of diseases characterised by
inflammatory changes in glomerular capillaries
and accompanying signs and symptoms
haematuria, proteinuria, and some cases
associated with fluid retention, hypertension,
oedema & reduced GFR
• UK: Estimated incidences range from 17/million to
60/million.

• The most commonly diagnosed types of

glomerulonephritis in adults
– IgA nephropathy,
– focal and segmental glomerulosclerosis,
– vasculitis
 Pathogenic mechanisms are
responsible for the development of
glomerular injury
• Immunologic mechanisms
• Metabolic abnormalities
• Hereditary abnormalities
 Classification

Glomerulonephritis can be
classified on the basis of :
I. Etiologic cause
II. Histopathologic findings on examination
of kidney biopsy
III. Clinical presentation
 Etiologic Causes
• Primary (idiopathic) : the glomerular disease is not
part of systemic disease and the cause is unknown
• Secondary : glomerular disease is part of a systemic
disease
– Infection which may be bacterial (e.g. post-streptococcal),
viral (e.g. HBV, HCV, CMV), parasitic (e.g. Schistosoma
mansoni, malaria).
– Collagen disease (e.g. SLE, polyarteritis nodosa,
rheumatoid arthritis).
– Drug (e.g. Penicillamine, Paradione, Aspirin, Heroin).
– Metabolic disease (e.g. Diabetes mellitus, amyloidosis).
– Malignancy (e.g. lymphoma).
– Heredofamilial (e.g. Alport syndrome)
Histopathologic classification of
glomerulonephritis
1. Minimal change (Nil-change) disease
2. Focal and segmental glomerulosclerosis
3. Membranous glomerulonephritis
4. Proliferative glomerulonephritis
a. Mesangial proliferative glomerulonephritis
b. Mesangiocapillary (or
membranoproliferative) glomerulonephritis
c. Crescentic glomerulonephritis
d. IgA nephropathy
 Clinical Presentation of Glomerulonephritis

Asymptomatic
proteinuria

Chronic Asymptomatic
glomerulonephritis hematuria

Clinical Manifestation of
Glomerular Disease

Rapidly progressive Nephrotic

glomerulonephritis syndrome

Nephritic
syndrome
 1. 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/24h.

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
 2. Asymptomatic microscopic
hematuria
• Hematuria evaluation begin with determine
if bleeding from upper urinary tract or lower
urinary tract.
• Asymptomatic microscopic hematuria, which
is defined as the presence of three or more
red blood cells per high-power field visible in a
properly collected urine specimen without
evidence of infection
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.
 3. Nephrotic Syndrome

◆ Is not a disease but a group of signs and symptoms seen in

patients with heavy proteinuria
◆ Presents with Anasarca (generalized edema)
◆ Masif proteinuria usually > 3.5g / 24hrs (>0.05g / kg / 24hrs in
children)
◆ Hipoalbuminemia < 3,5 g/day
◆ Hipercholesterolemia
◆ Lipiduria

L. Aida, M. B. Marbun. Dalam : Setiati S, Alwi et al editors. Buku ajar ilmu penyakit dalam. Jakarta : Interna Publishing; 2014. 2081-2087
Nephrotic syndrome
• Heavy proteinuria (>3.5 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.
Pathophysiology

V. Elie et al. Physiopathology of idiopathic nephrotic syndrome:

lessons from glucocorticoids and epigenetic perspectives. Pediatr Nephrol. 2011
Pathophysiology

Cho MH et al. Pathophysiology of minimal change nephrotic syndrome and focal segmental glomerulosclerosis.
Nephrology 2007; 12, S11–S14
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
Clinical Manifestation
Nephrotic Syndrome

Weight gain
Edema :
Hipoalbumin peripheral and
emia periorbital

Increase total
Nephrotic
cholesterol and LDL, Syndrome
Normotension
decrease HDL
Urinalysis :
+3
Hypercoagula proteinuria,
bility variable
24 h urine degree
collection : 3-
5 mg/kg/day
hematuria
proteinuria
 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
❑ Underlying disease or to identify idiopathic disease that is more
likely to respond to corticosteroids to make a diagnosis
❑ To inform prognosis
– Grade
– Severity
❑ To assess response to treatment
– Progression
– Regression
– Drug toxicity • Minimal change disease
• Focal segmental glomerulosclerosis
• Membranous nephropathy
• Membranoproliferative glomerulonephritis
• Other glomerulonephritis
 IV. Imaging Studies

Ultrasound scan
looks at the shape and size of kidneys and other parts of the urinary system. A small
handheld device is moved around your child’s skin and uses sound waves to create
an image on a screen.

Chest x-ray
for children with breathing problems, this test checks for any fluid (liquid) around
the lungs. Your child sits or lies still for a few seconds while a machine takes x-ray
images.
 Treatment
• The goal of treatment BASED ON ETIOLOGY.
• Idiopathic SN→ corticosteroids or drugs that
suppress the immune.
• Recommended to eat small meals but often.
• Sodium intake to 3 g per day, and may need
to restrict fluid intake (to less than
approximately 1.5 L per day)
• Reduce phosphorus intake and increase
calcium intake
• ACE inhibitors → anti proteinuria.
 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).
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
Intravenous methylprednisolone
pulse treatment
 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
 Treatment

Diuretics
✓ There is no evidence to guide drug selection or dosage
✓ Target weight loss of 1 to 2 lb (0.5 to 1 kg) per day >> acute renal failure or electrolyte
disorders
✓ Loop diuretics, such as furosemide (Lasix) or bumetanide, are most commonly used
➢ Large doses (e.g., 80 to 120 mg of furosemide) are often required
➢ Typically must be given intravenously because of the poor absorption of oral drugs
caused by intestinal edema
✓ Low serum albumin levels also limit diuretic effectiveness and necessitate higher
doses
✓ Thiazide diuretics, potassium-sparing diuretics, or metolazone (Zaroxolyn) may be
useful as adjunctive or synergistic diuretics
 Treatment
• Anticoagulants
➢ There are currently no recommendations for prophylactic anticoagulation to
prevent thromboembolic events
➢ should be considered for prophylactic anticoagulation while they have active
nephrotic syndrome
• Lipid-lowering drugs
➢ Some evidence suggests an increased risk of atherogenesis or myocardial
infarction in persons with nephrotic syndrome, possibly related to increased
lipid levels
➢ the role of treatment for increased lipids is unknown and, at present, the
decision to start lipid-lowering therapy in persons with nephrotic syndrome
should be made on the same basis as in other patients.
4. Acute nephritic syndrome
(acute glomerulonephritis)
– rapid onset of edema (less in severity than in
nephrotic syndrome), oliguria and hypertension.
– Urine analysis may show red cell casts,
proteinuria (less in amount than in nephrotic
syndrome), haematuria and leukocyturia
– increased serum creatinine, normal serum
albumin and cholesterol
– prognosis is usually good and recovery occurs
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

 5. Rapidly progressive
glomerulonephritis
– rapid (within days to weeks) loss of kidney function
with development of manifestations of uremia and
the patient needs dialysis treatment. If not treated
early and aggressively, the renal damage may be
irreversible
– Urine analysis may show findings which are similar to
acute nephritic syndrome
– rapidly increasing serum creatinine while serum
albumin remains within normal
6. Chronic nephritic syndrome
(Chronic glomerulonephritis)
– progressive uraemia and the patient usually
presents with manifestations of chronic renal
failure
– Urine analysis may show broad casts, loss of
ability to concentrate urine (urine specific gravity
is equal to plasma)
– proteinuria (mild) and microscopic haematuria
– high serum creatinine and phosphate, low
calcium, anaemia and metabolic acidosis
 Chronic glomerulonephritis
• Often, glomerulonephritis seems to result from
one of the same conditions that cause acute
glomerulonephritis, such as IgA nephropathy or
membranoproliferative glomerulonephritis.
• Sometimes, acute glomerulonephritis does not
resolve and instead becomes chronic.
• Occasionally, chronic glomerulonephritis is
caused by hereditary nephritis, an inherited
genetic disorder.
• In many people, the cause of chronic
glomerulonephritis cannot be identified
Figure 1. The diagnosis of GN is made easier by thinking about the
clustering of symptoms and signs that form recognisable patterns
Investigating glomerular disease
syndromes
 Dipstick Blood
analysis Protein
Urine
Protein-creatinine ratio
Albumin-creatinine ratio
Biochemical Creatinine clearances
Protein excretion (24hr)
Blood
Electrolytes

Urea, creatinine

Biochemical
Glucose Exclude DM

Exclude
Immunoglobulins
dysproteinemias
 Blood
Culture
Microbiology Serology Exclude infection
ASOT (streptococcal)

Anti glomerular basement

Goodpasture‘s
membrane Ab (AGBM)
Anti neutrophil cytoplasmic
Vasculitis
antibody (ANCA)
Immunology
Anti nuclear antibody
Lupus
Anti dsDNA
Cryoglobulins Cryoglobulinemia
Pathomechanism of
Glomerulonephritis
 Mesangial Cell & matrix
Parietal epithelium Fenestrated
endothelium

Urinary space

Visceral
epithelium

Endothelium

Basement membrane
Foot processes
 Pathogenesis of Glomerular Diseases

• Deposition of circulating Ag-Ab complexes

in the glomerulus

• Antibody (Ab) reacting in situ within

glomerulus
CIRCULATING IMMUNE COMPLEX NEPHRITIS

• Glomerulus is a innocent by-stander

• Ag is not of glomerular origin, it can be :
endogenous, eg: SLE
exogenous, eg: GN post streptococcus, post viral
hepatitis B, malaria parasitic (Plasmodium
falciparum), Treponema pallidum, HIV
• Complex Ag-Ab trapped in glomeruli
• Often activate complement system
• Under immunoflorescence microscope: granular
deposit pattern
 IMMUNE COMPLEX NEPHRITIS IN SITU
• Ab react directly with fixed or planted Ag in the glomeruli
• Anti-Glomerular Basement Membrane Disease (Anti-GBM
disease)
– Ab. react directly to GBM=Masugi nephritis (rabbit)
– Immunofluorescence microscope: linear pattern
– Sometimes anti-GBM Ab cross-react with alveoli
basement membrane (lung), resulting simultaneous
lung and kidney lesion (Goodpasture syndrome)
• Heymann Nephritis (rat model) resembles human
membranous GN
A. Circulating immune complex deposition

B. Anti-GBM disease
 A. Circulating immune complex deposition

B. Anti-GBM disease

Granular pattern

Linear pattern
 A. Granular pattern, characteristic of
circulating and in situ immune
complex nephritis

B. Linear pattern, characteristic of

classic anti-glomerular
basement membrane disease
TREATMENTS OF GLOMERULONEPHRITIS
NEW TREATMENTS OF GLOMERULONEPHRITIS
POTENTIAL TARGETS
• T cells
• Macrophages
• Cytokines
• Adhesion molecules
• Chemokines
• Profibrotic growth factors
Management of Complications of Glomerular Disease

• Hypertension:
– Protect against the cardiovascular risks of hypertension and to
delay progressive loss of GFR
– RAS inhibitor to be first-choice therapy
• Proteinuria:
– Reduction in proteinuria is important, as it reflects control of
the primary disease, reduction of glomerular hypertension, and
also reduction of podocyte damage
– The antiproteinuric agents of choice are RAS blockers
• Hyperlipidemia:
– Statins (HMG CoA reductase inhibitors) are well tolerated and
effective in correcting the lipid profile
– Statin therapy protects a decline in GFR although this is not
established
KDIGO Clinical Practice Guideline for Glomerulonephritis, Kidney Int 2012
• Nephrotic edema:
– The mainstay of treatment is diuretics accompanied by
moderate dietary sodium restriction (1.5–2 g [60–
80mmol] sodium /24 hrs)
• Hypercoagulability:
– The risk of thrombotic events becomes progressively
more likely as serum albumin values fall below 2.5 g/dl
(25 g/l)
– Heparin, Warfarin
• Risk of infection

KDIGO Clinical Practice Guideline for Glomerulonephritis, Kidney Int 2012

 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
 Summary
• Glomerulonephritis is a group of diseases characterised by
inflammatory changes in glomerular capillaries and
accompanying signs and symptoms haematuria, proteinuria, and
some cases associated with fluid retention, hypertension, oedema
& reduced GFR

• Clinical Presentation of Glomerulonephritis are Asymptomatic

urinary abnormality, Nephrotic syndrome, Acute nephritic
syndrome, Rapidly progressive glomerulonephritis and Chronic
glomerulonephritis

• As many types of GN are mediated by immune mechanisms, most

attempts at treatment involve corticosteroids, antiinflammatory,
cytotoxic or immunosuppressive drugs