approach to glomerular syndrome

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)

Nephritic syndrome

• An abrupt onset of glomerular hematuria

(RBC cast or dysmorphic RBCs)

• Proteinuria <3 g/day

• Azotemia

• Edema

• Oliguria

• Recent onset hypertension

Nephrotic syndrome

• Proteinuria

• Adult >3.5 g/day

• Child > 40 mg/h per m2

• Edema

• Hypoalbuminemia <3.5 g/dl

• Hypercholesterolemia

• Lipiduria

Rapidly progressive 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)

Chronic glomerulonephritis

• 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 RBC’s

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 (Berger’s 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 Age group Total

N (%) 18-40 yr

N (%)

41-60 yr

N (%)

>60 yr

N (%)

Primary glomerular disease

IgAN 22 (43.1%) 7 (33.3%) - 29 (32.9%)

MN 7 (13.7%) 6 (28.5%) 12 (75.0%) 25 (28.4%)

FSGS 8 (15.7%) 4 (19.0%) 1(6.2%) 13 (14.7%)

IgMN 6 (11.7%) 2 (9.5%) 2 (12.5%) 10 (11.4%)

PSGN 7(13.7%) 1 (4.7%) - 8 (9.1%)

MPGN 1(1.9%) 1 (4.7%) 1(6.2%) 3 (3.4%)

Total 51 (100%) 21 (100%) 16 (100%) 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, 143–153

Corticosteroids

Persistent proteinuria >1 g/d, despite 3–6 months of

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

1.73m2

Receive a 6-month course of corticosteroid therapy

(2C)


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

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

300-400 nM 150-225 nM

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

Progress to ESRD Yes Yes No

Pathogenesis Abnormal IgA

regulation

Absent a 5 type IV collagen

Defect a 4 type IV collagen

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.


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

GLOMERULAR STRUCTURE Minimal change disease (MCD) Focal segmental glomerulosclerosis (FSGS)

Membranoproliferative GN

(MPGN)


Mesangial proliferative GN IgM deposition (IgM nephropathy)

IgA deposition (IgA nephropathy)

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);


Hodgkin’s 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 - Hodgkin’s 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)


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, Sjögren's syndrome

Systemic diseases:

Fanconi's syndrome, Crohn's disease, Sarcoidosis, Guillain-Barré 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


N (%) 18-40 yr

N (%)

41-60 yr

N (%)

>60 yr

N (%)


IgAN 22 (43.1%) 7 (33.3%) - 29 (32.9%)

MN 7 (13.7%) 6 (28.5%) 12 (75.0%) 25 (28.4%)

FSGS 8 (15.7%) 4 (19.0%) 1(6.2%) 13 (14.7%)

IgMN 6 (11.7%) 2 (9.5%) 2 (12.5%) 10 (11.4%)

PSGN 7(13.7%) 1 (4.7%) - 8 (9.1%)

MPGN 1(1.9%) 1 (4.7%) 1(6.2%) 3 (3.4%)

Total 51 (100%) 21 (100%) 16 (100%) 88 (100%)

Glomerular Disease and Age Group




N (%) 18-40 yr

N (%)

41-60 yr

N (%)

>60 yr

N (%)

Secondary glomerular

disease

LN 46 (97.9%) 18 (69.2%) 2 (40.0%) 66 (84.6%)

DN 1(2.1%) 7(26.9%) 2 (40.0%) 10 (12.8%)

Amyloidosis - - 1 (20.0%) 1(1.3%)

Systemic vasculitis - 1 (0.4) - 1(1.3%)

Total 47 (100%) 26 (100%) 4 (100%) 78 (100%)


Differentiation between NS and

nephritis syndrome Typical feature Nephrotic Nephritic

Onset Insidious Abrupt

Edema ++++ ++

Blood pressure Normal Raised

JVP Normal/Low Raised

Proteinuria ++++ ++

Hematuria May/May not occur +++

Red cell cast Absent Present

Serum albumin Low Normal /slight reduced


Manifestations by Glomerular disease

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

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 + ++++

Complement levels with Glomerular

disease

Pathway Complement

changes

Glomerular disease Non-

glomerular

disease Classical pathway

activation

Low C3, C4, CH50

+C4 nephritic factor

Lupus nephritis (esp. class IV)

Mixed essential cryoglobulinemia

Membranoproliferative GN type I

Alternative pathway

activation

Low C3 and CH50,

normal C4

+C3 nephritic factor

Post-streptococcal GN

GN associated with other infection

-Endocarditis

-Shunt nephritis

-Hepatitis B

Hemolytic uremic syndrome

Membranoproliferative GN type II

Atheroembolic

renal disease

Reduced

complement

synthesis

Acquired

Hereditary

- C2 deficiency

- Factor H deficiency

Lupus nephritis

Familial hemolytic-uremic syndrome

Membranoproliferative GN

Hepatic disease

Malnutrition


Nephritis syndrome Diseases

Associations Serologic Tests

Membranoproliferative

glomerulonephritis type I

C4 nephritic factor Low C3 and C4

Membranoproliferative

glomerulonephritis type II

C3 nephritic factor Low C3 and normal C4

Post-streptococcal glomerulonephritis Pharyngitis, impetigo ASO titer, streptozyme antibody

Post-infectious disease

-Endocarditis

-Abscess

-Shunt

Cardiac murmur

-

Treated hydrocephalus

Blood cultures, low C3

Blood cultures, normal C3 and

C4

Blood cultures, low C3

IgA nephropathy Upper respiratory or

gastrointestinal infection

Increase serum IgA

Lupus nephritis Other multi-systemic

features of lupus

ANA, anti-ds DNA antibody, low

C3 and C4

Cryoglobulinemic

membranoproliferative

glomerulonephritis

Hepatitis C Anti-hepatitis C virus antibody,

rheumatoid factor,

cryoglobulinemia, low C3 and C4


Nephrotic syndrome Diseases Associations

Serologic Tests

Minimal change disease Allery, atopy, NSAIDs, Hodgkin

disease

-

Focal segmental glomerulosclerosis African American,

HIV infection, Heroin,

pamidronate

HIV antibody

Membranous nephropathy Drugs; gold, penicillamine,

NSAIDs

Infection; hepatitis B, C; malaria

Lupus nephritis

Malignancy; breast, lung

gastrointestinal tract

-

Hepatitis B surface antigen,

anti-hepatitis C virus antibody

ANA, Anti-DNA antibody

Diabetic nephropathy Other diabetic

microangiopathy

-

Amyloidosis Myeloma

Rheumatoid arthritis,

bronchiectasis, Crohn’s s

disease, familial Mediterranean

fever

Serum protein electrophoresis,

urine immunoelectrophoresis


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%)

Minimal change disease

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

Response to corticosteroid treatment

at 16 week

Primary NS Responder N (%)

Time to response (median±SD)

Complete remission

Partial remission

Unknown 28 (84.5) 3 (9.1) 8.0±2.8

MCN 6 (85.7) 0 8.0±3.1

IgMN 10 (83.3) 2 (16.7) 8.0±0.8

MN 4 (57.1) 2 (28.6) 26.0±19.7

FSGS 3 (75.0) 0 3.0±0.1

MPGN 0 0 -

IgAN 6 (75.0) 2 (25.0) 19.0±1.2

Total 57 (79.2) 9 (12.5) 9.0±1.2

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


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)


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)


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)

Nephrotic syndrome;

60-75 %

Hypertention;

45-65%

Microscropic hematuria;

30-50%

Renal insufficiency;

25-50%

Hilar variant Tip variant Collapsing variant

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)


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 high-

dose corticosteroids

Remission 50 – 60 % (steroid response)

Remission 15 – 20 % (steroid non response) (2D)


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

Initial symptoms

Fatigue 62%

Weight 52%

Pain 5%

Purpura 15%

Gross bleeding 3%

Physical finding

Palpable liver 24%

Palpable spleen 5%

Lymphadenopathy 3%

Macroglossia 9%

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

Laboratory findings

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%

Proteinuria( > 1 g/24 hr) 55%

Urine light chain 73%

Ќ chain 23%

chain 50% ג

Clinical and lab. Features in AL amyloidosis 474 pts

Initial symptoms

Fatigue 62%

Weight 52%

Pain 5%

Purpura 15%

Gross bleeding 3%

Physical finding

Palpable liver 24%

Palpable spleen 5%

Lymphadenopathy 3%

Macroglossia 9%

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

Laboratory findings

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%

Proteinuria( > 1 g/24 hr) 55%

Urine light chain 73%

Ќ chain 23%

chain 50% ג

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

Renal Amyloidosis

The End

Documents

approach to glomerular syndrome