Download - approach to glomerular syndrome
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Approach to
Glomerular Syndrome
Bancha satirapoj, MD
Division of Nephrology
Department of Medicine
Phramongkutklao Hospital
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Picture glomerulus
GLOMERULAR STRUCTURE
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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
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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.
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Hematuria: Differential Diagnosis
Inflammation/infection
Stones
Malignancy
Trauma
Cyst
BPH
Excessive exercise
Sickle cell disease
Glomerular disease
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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
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Glomerular Hematuria
Dysmorphic RBC (Acanthocytes)
RBC cast
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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
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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.
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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
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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
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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
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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)
KDIGO. Kidney International Supplements (2012) 2, 143–153
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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.
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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.
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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
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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.
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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
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Picture glomerulus
GLOMERULAR STRUCTURE Minimal change disease (MCD) Focal segmental glomerulosclerosis (FSGS)
Membranoproliferative GN
(MPGN)
Membranous nephropathy (MN)
Mesangial proliferative GN IgM deposition (IgM nephropathy)
IgA deposition (IgA nephropathy)
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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
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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
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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)
Hodgkin’s disease; MCD
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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)
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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
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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)
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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, Sjögren's syndrome
Systemic diseases:
Fanconi's syndrome, Crohn's disease, Sarcoidosis, Guillain-Barré syndrome
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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
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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
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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%)
Glomerular Disease and Age Group
Satirapoj B, et al. Royal Thai Army Medical Journal. 2010; 63 (2): 53-64.
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Glomerular Disease and Age Group
Glomerular disease Age group Total
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%)
Satirapoj B, et al. Royal Thai Army Medical Journal. 2010; 63 (2): 53-64.
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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
Feehally, J and R.J. Johnson. Comprehesive clinical nephrology. 2007, 193-208.
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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 + ++++
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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
Feehally, J and R.J. Johnson. Comprehesive clinical nephrology. 2007, 193-208.
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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
Feehally, J and R.J. Johnson. Comprehesive clinical nephrology. 2007, 193-208.
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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
Feehally, J and R.J. Johnson. Comprehesive clinical nephrology. 2007, 193-208.
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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.
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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.
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Glomerular Disease and Age Group
Brenner BM, The Kidney 8th ed.,W.B. Saunders Company, Philadelphia, 2008
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Kidney biopsy
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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
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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
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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, 143–153
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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, 143–153
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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
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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
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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.
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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.
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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, 143–153
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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)
KDIGO. Kidney International Supplements (2012) 2, 143–153
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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
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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
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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
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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
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The End