Approach to

Glomerular Syndrome

Bancha satirapoj, MD
Division of Nephrology
Department of Medicine

Phramongkutklao Hospital

Picture glomerulus

GLOMERULAR STRUCTURE

Clinical Syndrome of Glomerular Diseases

Asymptomatic urinary
abnormalities

Isolated proteinuria (usually <2.0 g/day) or hematuria (with

or without proteinuria)

Acute
glomerulonephritis
(AGN)

An abrupt onset of glomerular hematuria (RBC cast and/or

dysmorphic RBCs) together with two or more of the
following proteinuria, azotemia, edema, oliguria, and recent
onset hypertension

Nephrotic syndrome
(NS)

A syndrome of massive proteinuria (>3.5 g/day), with

variable edema, hypoalbuminuria, hyperlipidemia, and
lipiduria

Rapidly progressive
glomerulonephritis
(RPGN)

Any glomerular disease characterized by extensive

crescents (usually >50%), as the primary histologic finding
and a rapid loss of renal function (usually a 50% decline in
GFR within 3 months)

Chronic
glomerulonephritis

Slowing developing renal failure accompanied by

proteinuria, hematuria, and hypertension

Asymptomatic
Isolated proteinuria 150 mg to 3 g/day
Hematuria > 2 red blood cells (RBC)/high-power field in spun urine
(RBC usually dysmorphic)
Nephrotic syndrome

Nephritic syndrome

Proteinuria
Adult >3.5 g/day
Child > 40 mg/h per m2
Edema
Hypoalbuminemia <3.5 g/dl
Hypercholesterolemia
Lipiduria

An abrupt onset of glomerular hematuria

(RBC cast or dysmorphic RBCs)
Proteinuria <3 g/day
Azotemia
Edema
Oliguria
Recent onset hypertension

Rapidly progressive glomerulonephritis

Chronic glomerulonephritis

Glomerular disease characterized by

extensive crescents (usually >50%)
RBC cast
A rapid loss of renal function (usually a 50%
decline in GFR within 3 months)

Slowing developing renal insufficiency

Proteinuria > 3 g/day
Hematuria
Hypertension
Shrunken smooth kidneys

Feehally, J and R.J. Johnson. Comprehesive clinical nephrology. 2007, 193-208.

Hematuria: Differential Diagnosis

Inflammation/infection
Stones
Malignancy
Trauma
Cyst
BPH
Excessive exercise
Sickle cell disease
Glomerular disease

Glomerular vs Extra-glomerular
hematuria
Urine is red, smoky brown or
coca-cola

Red or pink urine

Clots absent

Clots may be present

Proteinuria >500 mg/day

<500 mg/day proteinuria

Dysmorphic RBCs

Normal RBC

RBC casts are present

RBC casts may be present

Glomerular Hematuria
Dysmorphic RBC (Acanthocytes)

RBC cast

Asymptomatic:
Glomerular Hematuria

Most common causes of isolated

hematuria

IgA Nephropathy (Bergers disease)

Hereditary causes (Alport Syndrome)
Thin basement membrane disease (Benign
Familial Hematuria)

Early onset or recovery phase of AGN or RPGN

IgA nephropathy

Most common glomerular disease in worldwide (Asian)

In Thai ; cause of primary GN 32.9%
Systemic disease: Henoch-Schonlein purpura
Develops renal failure in 20-40% of patients within 5-25
yrs after diagnosis
Glomerular disease

Primary glomerular disease

IgAN
MN
FSGS
IgMN
PSGN
MPGN
Total

Age group
18-40 yr
N (%)

41-60 yr
N (%)

>60 yr
N (%)

22 (43.1%)
7 (13.7%)
8 (15.7%)
6 (11.7%)
7(13.7%)
1(1.9%)
51 (100%)

7 (33.3%)
6 (28.5%)
4 (19.0%)
2 (9.5%)
1 (4.7%)
1 (4.7%)
21 (100%)

12 (75.0%)
1(6.2%)
2 (12.5%)
1(6.2%)
16 (100%)

Total
N (%)

29 (32.9%)
25 (28.4%)
13 (14.7%)
10 (11.4%)
8 (9.1%)
3 (3.4%)
88 (100%)

Satirapoj B, et al. Royal Thai Army Medical Journal. 2010; 63 (2): 53-64.

Clinical presentation

Recurrent macroscopic hematuria provoke by mucosal

infection (synpharyngitis) is characteristic (40-50%)
Microscopic hematuria with or without proteinuria
(30-40%)
Nephrotic syndrome (5%)
Hypertension and chronic kidney disease
RPGN (<10%)
Recurrent glomerulonephritis after transplantation

Diagnosis

Diagnosis of IgA nephropathy: only by kidney biopsy

Immunohistology is the clue of diagnosis show
mesangial IgA deposit predominate
Test of serum and urine are not useful

Antihypertensive therapy

Long-term ACE-I or ARB treatment: proteinuria >1 g/d,

with up-titration of the drug depending on blood pressure
(1B)
ACE-I or ARB be titrated upwards to achieve proteinuria
<1 g/d
(2C)
BP<130/80mmHg with proteinuria <1 g/d, and
<125/75mmHg with proteinuria >1 g/d
(Not Graded)

KDIGO. Kidney International Supplements (2012) 2, 143153

Corticosteroids

Persistent proteinuria >1 g/d, despite 36 months of

optimized supportive care, and GFR >50 ml/min per
1.73m2

Receive a 6-month course of corticosteroid therapy

(2C)

KDIGO. Kidney International Supplements (2012) 2, 143153

Alport Syndrome

85% is X-linked (mutation of

alpha 5 chain of collagen type
IV on Xq22)
15% is autosomal (mutation of
alpha 3 or alpha 4 chains of
collagen type IV)
Asymptomatic persistent
microscopic hematuria
Male: ESRD usually16-35 yr

Basket weave GBM

Splitting of the lamina densa

Gubler MC. Nat Clin Pract Nephrol. 2008 Jan;4(1):24-37.

Thin BM Disease
300-400 nM

150-225 nM

Benign familial hematuria

Autosomal dominant
Persistent or intermittent
asymptomatic microscopic
hematuria
Urinary protein excretion,
blood pressure, and renal
function are normal
Excellent long-term
prognosis

Tryggvason, K. J Am Soc Nephrol 2006; 17:813.

Isolated Hematuria:
Common Glomerular Causes
IgA nephropathy

Alport Syndrome

Thin BM

Prevalence

Most common

Rare

5-9%

Associated

Rash, URI

Hearing loss, cataract

Family History

Negative

X-link trait

AD

Yes

Yes

No

Abnormal IgA
regulation

Absent a 5 type IV
collagen

Defect a 4 type IV
collagen

Progress to ESRD
Pathogenesis

Glomerular Disease

Primary Glomerular Disease

Glomeruli are predominant tissue involved.
Idiopathic

Secondary Glomerular Disease

Glomerular injury is a feature of a systemic
disease involving multiple organs or systems.

Primary glomerular disease

Minimal change disease (MCD)

Focal segmental glomerulosclerosis (FSGS)
Membranous nephropathy (MN)
Mesangial proliferative glomerulonephritis

IgM deposition (IgM nephropathy)

IgA deposition (IgA nephropathy)

Membranoproliferative glomerulonephritis (MPGN)

Crescentic (extracapillary) glomerulonephritis/ necrotizing
glomerulonephritis

Picture glomerulus

Membranous nephropathy (MN)

Mesangial proliferative GN
Membranoproliferative GN
(MPGN)

Minimal change disease (MCD)

IgM deposition (IgM nephropathy)

IgA deposition (IgA nephropathy)

Focal segmental
glomerulosclerosis
(FSGS)
GLOMERULAR
STRUCTURE

Secondary glomerular disease

Glomerulonephritis of systemic disease

Lupus nephritis
Glomerular lesions in systemic infection
Acute post-streptococcal glomerulonephritis (PSGN)
HBV or HCV infection
Glomerular lesions in vascular disease
TTP/HUS
Vasculitis
Glomerular disease in metabolic disease
Diabetic nephropathy
Amyloidosis
Hereditary nephropathy
Miscellaneous glomerular disease
Drug induced glomerulonephritis
Malignancy

Approach

Signs/symptoms of possible secondary causes

Demographic: Age, Race
Family history
Clinical signs/symptoms
Initial Lab: Urine sediments, Azotemia (BUN/cr)
Lab investigation: Complement, ANA
Response to treatment

History/Physical Examination (1)

Photosensitivity, arthritis, alopecia : Lupus nephritis

History of diabetes: DN
Family history of CKD and hearing loss: Alport
syndrome
Malignancy (CA lung, breast, colon, prostate);
Membranous nephropathy (MN)
Hodgkins disease; MCD

History/Physical Examination (2)

HBV or HCV infection: HBV/HCV associated

glomerulonephritis or MPGN

Previous pharyngitis/skin infection; PSGN

Drugs

NSAIDs, interferon, lithium, penicillin, probenecid,

anticonvulsant agents: MCD

NSAIDs, captopril, gold, penicillamine, mercury, silver,

probenecid: MN
Heroin, pamidronate: Focal segmental glomerulosclerosis
(FSGS)

Minimal change disease (MCD)

Drugs

Infection

Nonsteroidal anti-inflammatory drugs

Mononucleosis

Ampicillin/penicillin

Human immunodeficiency virus

Trimethadione

Immunizations

Toxins

Tumors

Mercury

Hodgkins lymphoma

Lead

Other lymphoproliferative disorders

Bee sting

Carcinoma

Focal Segmental Glomerulosclerosis (FSGS)

Reduced nephron numbers

Glomerulomegaly

Unilateral renal agenesis

Morbid obesity

Oligomeganephronia

Sickle cell disease

Reflux-interstitial nephritis

Cyanotic congenital heart disease

Post-focal cortical necrosis

Hypoxic pulmonary disease

HIV disease

Drugs (pamidronate, interferon)

IV drug abuse

Genetic abnormalities (podocin,

alpha-actinin-4,TRPC6)

Membranous nephropathy (MN)

Primary/idiopathic membranous glomerulonephritis
Secondary membranous glomerulonephritis
Infection:
Hepatitis B and C, syphilis, malaria, schistosomiasis, leprosy
Cancer:
Breast, colon, lung, stomach, kidney, esophagus
Drugs:
Gold, mercury, penicillamine, NSAIDS, probenecid
Autoimmune diseases:
SLE, RA, dermatitis herpetiformis, myasthenia gravis, Sjgren's syndrome
Systemic diseases:
Fanconi's syndrome, Crohn's disease, Sarcoidosis, Guillain-Barr syndrome

Membranoproliferative glomerulonephritis (MPGN)

Type I Disease (Most Common)
Idiopathic
Subacute bacterial endocarditis
Systemic lupus erythematosus
Hepatitis C cryoglobulinemia
Mixed cryoglobulinemia
Hepatitis B
Cancer: Lung, breast, and ovary (germinal)
Type II Disease (Dense Deposit Disease)
Idiopathic
C3 nephritic factor-associated
Partial lipodystrophy
Type III Disease
Idiopathic

Approach

Signs/symptoms of possible secondary causes

Demographic: Age, Race

Family history
Clinical signs/symptoms
Initial Lab: Urine sediments, Azotemia (BUN/cr)
Lab investigation: Complement, ANA
Response to treatment

Glomerular Disease and Age Group

Glomerular disease

Age group

Total
N (%)

18-40 yr
N (%)

41-60 yr
N (%)

>60 yr
N (%)

IgAN
MN

22 (43.1%)
7 (13.7%)

7 (33.3%)
6 (28.5%)

12 (75.0%)

29 (32.9%)
25 (28.4%)

FSGS
IgMN

8 (15.7%)
6 (11.7%)

4 (19.0%)
2 (9.5%)

1(6.2%)
2 (12.5%)

13 (14.7%)
10 (11.4%)

PSGN
MPGN
Total

7(13.7%)
1(1.9%)
51 (100%)

1 (4.7%)
1 (4.7%)
21 (100%)

1(6.2%)
16 (100%)

8 (9.1%)
3 (3.4%)
88 (100%)

Primary glomerular disease

Satirapoj B, et al. Royal Thai Army Medical Journal. 2010; 63 (2): 53-64.

Glomerular Disease and Age Group

Glomerular disease

Secondary glomerular
disease
LN
DN
Amyloidosis
Systemic vasculitis
Total

Age group

18-40 yr
N (%)

41-60 yr
N (%)

>60 yr
N (%)

46 (97.9%)
1(2.1%)
47 (100%)

18 (69.2%)
7(26.9%)
1 (0.4)
26 (100%)

2 (40.0%)
2 (40.0%)
1 (20.0%)
4 (100%)

Total
N (%)

66 (84.6%)
10 (12.8%)
1(1.3%)
1(1.3%)
78 (100%)

Satirapoj B, et al. Royal Thai Army Medical Journal. 2010; 63 (2): 53-64.

Differentiation between NS and

nephritis syndrome
Typical feature

Nephrotic

Nephritic

Onset

Insidious

Abrupt

Edema

++++

++

Normal

Raised

Normal/Low

Raised

Proteinuria

++++

++

Hematuria

May/May not occur

+++

Absent

Present

Low

Normal /slight
reduced

Blood pressure

JVP

Red cell cast

Serum albumin

Feehally, J and R.J. Johnson. Comprehesive clinical nephrology. 2007, 193-208.

Manifestations by Glomerular disease

Disease

Nephrotic
feature

Nephritic
feature

Minimal change glomerulopathy

++++

Membranous glomerulopathy

++++

Focal segmental glomerulosclerosis

+++

++

Fibrillary glomerulonephritis

+++

++

Mesangioproliferative glomerulopathy

++

++

Membranoproliferative glomerulonephritis

++

+++

Acute diffuse proliferative glomerulonephritis

++++

Crescentic glomerulonephritis

++++

Brenner BM,The Kidney 8th ed.,W.B. Saunders Company, Philadelphia, 2008

Complement levels with Glomerular

disease
Pathway

Complement
changes

Glomerular disease

Classical pathway
activation

Low C3, C4, CH50 Lupus nephritis (esp. class IV)

+C4 nephritic factor Mixed essential cryoglobulinemia

Alternative pathway
activation

Low C3 and CH50, Post-streptococcal GN

GN associated with other infection
normal C4
+C3 nephritic factor -Endocarditis

Nonglomerular
disease

Membranoproliferative GN type I

Atheroembolic
renal disease

-Shunt nephritis
-Hepatitis B
Hemolytic uremic syndrome
Membranoproliferative GN type II

Reduced
complement
synthesis

Acquired
Hepatic disease
Hereditary
Lupus nephritis
Malnutrition
- C2 deficiency
Familial hemolytic-uremic syndrome
- Factor H deficiency Membranoproliferative GN

Feehally, J and R.J. Johnson. Comprehesive clinical nephrology. 2007, 193-208.

Nephritis syndrome
Diseases
Membranoproliferative
glomerulonephritis type I
Membranoproliferative
glomerulonephritis type II
Post-streptococcal glomerulonephritis
Post-infectious disease
-Endocarditis
-Abscess
-Shunt
IgA nephropathy

Lupus nephritis
Cryoglobulinemic
membranoproliferative
glomerulonephritis

Associations

Serologic Tests

C4 nephritic factor

Low C3 and C4

C3 nephritic factor

Low C3 and normal C4

Pharyngitis, impetigo

ASO titer, streptozyme antibody

Cardiac murmur
Treated hydrocephalus

Blood cultures, low C3

Blood cultures, normal C3 and
C4
Blood cultures, low C3
Increase serum IgA

Upper respiratory or
gastrointestinal infection
Other multi-systemic
features of lupus
Hepatitis C

ANA, anti-ds DNA antibody, low

C3 and C4
Anti-hepatitis C virus antibody,
rheumatoid factor,
cryoglobulinemia, low C3 and C4

Feehally, J and R.J. Johnson. Comprehesive clinical nephrology. 2007, 193-208.

Nephrotic syndrome
Diseases

Minimal change disease

Focal segmental glomerulosclerosis
Membranous nephropathy

Diabetic nephropathy
Amyloidosis

Associations

Serologic Tests

Allery, atopy, NSAIDs, Hodgkin

disease
African American,
HIV antibody
HIV infection, Heroin,
pamidronate
Drugs; gold, penicillamine,
NSAIDs
Hepatitis B surface antigen,
Infection; hepatitis B, C; malaria anti-hepatitis C virus antibody
Lupus nephritis
ANA, Anti-DNA antibody
Malignancy; breast, lung
gastrointestinal tract
Other diabetic
microangiopathy
Myeloma
Serum protein electrophoresis,
Rheumatoid arthritis,
urine immunoelectrophoresis
bronchiectasis, Crohns s
disease, familial Mediterranean
fever

Feehally, J and R.J. Johnson. Comprehesive clinical nephrology. 2007, 193-208.

Minimal change disease

Complete remission: 85-90 %

Prednisolone 1 mg /kg/day or 2 mg/kg/AD
Duration

> 8 wk (remission 60%)

age > 40 yr 16-20 wk (remission 76-81%)

Nolasco F, et al. Kidney Int, 1986. 29: 1215-23.

Response to corticosteroid treatment

at 16 week
Primary NS

Responder
N (%)
Complete
Partial
remission
remission

Time to response
(medianSD)

Unknown

28 (84.5)

3 (9.1)

8.02.8

MCN

6 (85.7)

8.03.1

IgMN

10 (83.3)

2 (16.7)

8.00.8

MN

4 (57.1)

2 (28.6)

26.019.7

FSGS

3 (75.0)

3.00.1

IgAN

6 (75.0)

2 (25.0)

19.01.2

Total

57 (79.2)

9 (12.5)

9.01.2

MPGN

Prasertpetmanee S, Satirapoj B. Royal Thai Army Medical Journal. 2010; 63 (1): 23-31.

Glomerular Disease and Age Group

Brenner BM,The Kidney 8th ed.,W.B. Saunders Company, Philadelphia, 2008

Kidney biopsy

Indication for Kidney biopsy

First presentation

Verify diagnosis
Assessment of activity & severity
Assessment of chronicity

Repeat attack

Distinguish active and chronic forms

Prognosis and treatment

Membranous nephropathy
Second common causes of the nephrotic
syndrome in nondiabetic adults
Mean age at disease onset is 35 yrs

80% nephrotic syndrome

25% non nephrotic-range proteinuria
15-55% hypertension
30-50% microscopic hematuria
Rarely gross hematutria
Slow progressive disease

Immunosuppressive agents in MN patients

Only in patients with nephrotic syndrome with

Persistent urinary protein >4 g/d AND remains at over 50% of

the baseline value, during anti-proteinuric therapy at least 6
months
(1B)
Presence of severe, disabling, or life-threatening symptoms
related to the nephrotic syndrome
(1C)
Serum Cr has risen by 30% within 6 to 12 months from the
time of diagnosis AND this change is not explained by
superimposed complications
(2C)

KDIGO. Kidney International Supplements (2012) 2, 143153

Regimens not recommended or suggested

for initial therapy of IMN

Corticosteroid monotherapy not be used for

initial therapy of IMN
(1B)
Monotherapy with MMF not be used for initial
therapy of IMN
(2C)

KDIGO. Kidney International Supplements (2012) 2, 143153

Case 4
A 48-yr-old woman is receiving therapy for metastatic breast cancer (bones, liver,
lung). Treatment consists of trastuzumab (Herceptin) and Adriamycin. Pamidronate
has also been administered for intermittent hypercalcemia. She abruptly developed
severe nephrotic syndrome (urine protein excretion 22 g/d), renal failure (serum
creatinine 3.6 mg/dl), and hypertension. A urinalysis shows 4+ protein, 2+ blood,
numberous dysmorphic RBC and no glucose.

A renal biopsy is MOST likely to show which ONE of the

following lesions?

A. Membranous nephropathy
B. Minimal change nephropathy
C. IgA nephropathy
D. Collapsing FSGS
E. Acute hypersensitivity interstitial nephritis

FSGS: Clinical feature

Degree of proteinuria varies from non-nephrotic (1 to 2
g/day) to massive proteinuria (>10 g/day)

Hilar variant

Tip variant

Collapsing variant

Nephrotic syndrome;
60-75 %
Hypertention;
45-65%
Microscropic hematuria;
30-50%
Renal insufficiency;
25-50%

Clinical feature

Primary or idiopathic FSGS, which typically

presents with the acute onset of overt nephrotic
syndrome.

Secondary FSGS

Slowly increasing proteinuria and renal insufficiency over

time
No peripheral edema
Normoalbuminemia
Non-nephrotic range proteinuria

Praga, M., et al., Am J Kidney Dis, 1999. 33(1): 52-8.

Different pathologic phenotypes

Collapsing variant
More severe renal involvement, including higher levels of
proteinuria (commonly over 10 g/day) and more severe
renal dysfunction

Detwiler, R.K., et al. Kidney Int, 1994. 45(5): p. 1416-24.

Initial treatment of FSGS

Immunosuppressive therapy should be considered only

in idiopathic FSGS associated with clinical features of
the nephrotic syndrome
(1C)
Prednisone 1 MKD OD or 2 MKD (maximum 120 mg)
AD: Remission 28-74%
(2C)
Minimum of 4 wks; continue high-dose corticosteroids
up to a maximum of 16 wks
(2D)

KDIGO. Kidney International Supplements (2012) 2, 143153

Initial treatment of FSGS

Corticosteroids be tapered slowly over a period of 6

months after achieving complete remission
(2D)
CNIs be considered as first-line therapy for patients
with relative contraindications or intolerance to highdose corticosteroids

Remission 50 60 % (steroid response)

Remission 15 20 % (steroid non response)

(2D)

KDIGO. Kidney International Supplements (2012) 2, 143153

Other causes of CKD should be

considered

Absence of diabetic retinopathy;

Low or rapidly decreasing GFR;
Rapidly increasing proteinuria or nephrotic syndrome;
Refractory hypertension;
Presence of active urinary sediment;
Signs or symptoms of other systemic disease; or
>30% reduction in GFR within 2-3 months after initiation of an
ACE inhibitor or ARB.

NKF KDOQI GUIDELINES for Diabetes and Chronic Kidney Disease 2007

Clinical and lab. Features in AL

amyloidosis 474 pts
Laboratory findings

Initial symptoms
Fatigue

62%

Weight

52%

Pain

5%

Purpura

15%

Gross bleeding

3%

Physical finding

Increase plasma cell( BM> 6%)

56%

Anemia (Hb< 10 g/dL)

11%

Serum creatinine> 1.3 mg/dL

45%

Elevated alkaline phosphatase

26%

Hypercalcemia(>11 mg/dL)

2%

Palpable liver

24%

Proteinuria( > 1 g/24 hr)

55%

Palpable spleen

5%

Urine light chain

73%

Lymphadenopathy

3%

chain

23%

Macroglossia

9%

chain

50%
Kyle, RA, Semin Hematol 1995; 32: 45.

Clinical and lab. Features in AL

amyloidosis 474 pts
Laboratory findings

Initial symptoms
Fatigue

62%

Weight

52%

Pain

5%

Purpura

15%

Gross bleeding

3%

Physical finding

Increase plasma cell( BM> 6%)

56%

Anemia (Hb< 10 g/dL)

11%

Serum creatinine> 1.3 mg/dL

45%

Elevated alkaline phosphatase

26%

Hypercalcemia(>11 mg/dL)

2%

Palpable liver

24%

Proteinuria( > 1 g/24 hr)

55%

Palpable spleen

5%

Urine light chain

73%

Lymphadenopathy

3%

chain

23%

Macroglossia

9%

chain

50%
Kyle, RA, Semin Hematol 1995; 32: 45.

Renal Amyloidosis

Light microscopy :

Amorphous hyaline material

Congo red (green birefringence under polarized light)

Immunofluorescence microscopy

Positive for monoclonal lambda or kappa light chains in the primary

form.

Electron microscopy : 8-10 nm in width and straight and

unbranching

The End