Transcript Nephrotic_Syndrome_American_Program_2007

Nephrotic Syndrome
Farid Nakhoul M.D.
Deputy Director
Dept. of Nephrology
Rambam Medical Ctr.
Faculty of Medicine Haifa
Tel: 04-8542590 Fax: 048542946
Email:[email protected]
Structure of the Glomerulus(1)
• One of the central function of the kidney is
to excrete low molecular weight watersoluble plasma waste products into the
urine. Whereas macromolecules the size
of albumin and larger are retained. The
filtration of plasma occurs in specialized
filtration units called Glomeruli.
Structure of the Glomerulus(2)
The glomerular filtration barrier consists of
the three layers of the capillary wall:
1. The innermost fenestrated vascular endothelium.
2. The GBM: the GBM is regarded as a primary size and
charge-selective molecular sieve of the glomerulus .
The GBM contains type IV collagen, laminin, nidogen,
and proteoglycans as its main components.
3. Podocyte cell layer facing the urinary space.
Proteinuria
Is the halmark of
glomerular disease !!
Clinical Evaluation of Glomerular
disease
1. History
2. Physical Examination
3. Laboratory Studies
4. Imaging: Ultrasound
5. Renal Biopsy ( Open, Closed,
Laparoscopic).
Proteinuria
• Asymptomatic Non-nephrotic Proteinuria
(<3.5 gr Protein/day).
- Glomerular
- Non-glomerular
• Nephrotic Syndrome: Pathognomonic of
glomerular disease
Non-Nephrotic Proteinuria
• Defined as a urine protein excretion of
less than 3.5 gr/d, and is absolutely
characteristic of glomerular disease,
but may occure in many nonglomerular parenchymal disease.
Clinical Classification
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Isolated Hematuria
Proteinuria / Nephrotic Syndrome
Acute Nephritic Syndrome
Rapidly Progressive Glomerulonephritis
Chronic Glomerulonephritis
Clinical Features of
Glomerular Diseases
Proteinuria
Hematuria
Edema
Hypertension
Renal Dysfunction
Evaluation of Proteinuria – General
Practice
History, Physical
Examination,
urinalysis
Repeat visit for qualitative proteinuria test
Positive
Negative
Measure U&E, Albumin,
Quantify urine protein excretion
Transient Proteinuria;
Reassure Patient
Quantifying protein excretion
• Should perform quantitative measure in
persistent proteinuria
24 hour urine collection
– Readily quantified
– Wide understanding
– Cumbersome
Protein-to-creatinine ratio (PCR)
– Simple
– Validated
Nephrotic Syndrome
Definition
• Urinary protein level exceeding 3.5 gr per
1.73m2 of body-surface area/day.
• Hypoalbuminemia.
• Sodium retention (Edema-State).
• Hyperlipoproteinemia.
• Hypercoagulopathy
Prognosis
• Depends upon degree of proteinuria
• 20 year follow up:
– Hypertension in 50%
– Renal Insufficiency in 40%
Diagnostic Approach
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24 urine collection
Serum electrolytes, BUN, creatinine, lipid profile,
serum albumin
Serological work up - depends upon the clinical
presentation - common serological tests done are
ANA; Anti-ds DNA
Complement levels (C3, C4)
Hepatitis B and C serologies
SPEP; UPEP, ANCA, anti GBM Abs
Renal Ultrasound
Renal Biopsy - Indications
Nephrotic Syndrome
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Primary
Membranous Glomerulopathy
Focal Segmental Glomerulosclerosis
Minimal Change Disease
Membranoproliferative GN
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Secondary
Diabetic glomerulosclerosis
Paraproteinemia /Amyloidosis
Lupus Nephritis
Nephrotic Syndrome
Thromboembolic Complications
• Major hazard of the nephrotic syndrome
• RVT( membranous GN) in 20-30% of adult
patients, 10% are symptomatic: flank pain,
gross hematuria
• Pulmonary emboli(Silent)
• DVT(frequent)
• Arterial thrombosis is less common
• Prophylaxis : Albumin< 2 gr, Uprotein>10
gr/d. decreased level of antithrombin III,
Increased fibrinogen, Hypovolemia
Nephrotic Syndrome
Infections
• Decreased levels of immunoglobulin
IgG
• Decreased the alternative complement
factor B
• Pneumococcal peritonitis
• Recurrent Cellulitis
General Management
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Edema - salt restriction, diuretics
Hyperlipidemia - lipid lowering agents
ACE/ARB – decrease Pgc and decrease proteinuria
– Renal protective
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Hypercoagulable - ASA
Specific treatment based on biopsy
Minimal Change Disease
MCD
Introduction and Definition
Minimal Change Disease
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Pathogenesis - unknown, most likely
autoimmune
Treatment
– 85% respond to steroids
– If resistant to steroid may require
cyclophosphamide
Minimal Change Nephropathy
(MCD)
• Minimal change disease (MCD) :is
defined by the absence of histologic
glomerular abnormality, other than
evidence of epithelial cell foot process
fusion (EM).
Minimal Change Disease
MCD
Pathology
Minimal Change Disease
Nephrotic Syndrome
Minimal Change Disease
• Is the major cause of the nephrotic
syndrome in children(85-90%) and 10%
in adults
• Malignancies account for 10% of cases
of idiopathic nephrotic syndrome in
adults
• LM: Normal glomeruli
• EM: Fusion of the epithelial cell foot
Processes ( KNB).
Minimal Change Disease
MCD
Etiology and Pathogenesis
Minimal Change Disease
• Idiopathic
• Secondary: Malignancy
Drugs
Infections
Minimal Change Disease
MCD
Clinical manifestations
Minimal Change Nephropathy
MCD
• Patients with Minimal change disease
present with edema that develops over a
short period of time, with fluid retention
exceeding 3% of the body weight.
• Up to two-thirds of presentation and relapses
follow an infection, most commonly upper
respiratory tract infection.
Minimal Change Nephropathy
• Clinical Feature: Heavy proteinuria, low
serum albumin, edema formation and
elevated serum cholesterol.
• Normal urinary sediment
• Normal C3, C4
• Negative ANA and Cryoglobulins
• MCD patients are at risk of venous
thromboembolism.
• Hypovolemia and ARF, especially patients
with diuretic therapy.
Minimal Change Disease
Natural History
Minimal Change Disease
• There is a tendency for patients with MCD to
run a relapsing-remitting course and this is
more frequent in children.
• Long-term remission can be expected in 75%
of initial responders who do not relapse
within 6 months.
• MCD does not progress to Renal Failure
Membranous GN
Definition
Membranous Nephropathy(MN)
• Membranous Nephropathy is a glomerular
disease in which immune deposits of IgG
and complement components develop
predominantly or exclusively on the
subepithelial surface of the glomerular
capillary wall.
• Deposition is associated with a marked increase
in glomerular permeability to protein, which
manifest clinically as nephrotic syndrome.
• The pathogenesis of human MN is not known.
Membranous Nephropathy
ETIOLOGY
Membranous Nephropathy
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Most common cause of idiopathic
nephrotic syndrome in Caucasian
adults.
Heavy proteinuria is common.
Hypertension and azotemia develops
as disease progresses.
Increased incidence of renal vein
thrombosis.
Membranous nephropathy
• 2nd most common cause
of nephrotic syndrome in
adults (~30%)
• Usually idiopathic
• Associated with
– Autoimmune
diseases
– Hepatitis B
– Carcinoma
– Drugs (eg
penicillamine,
captopril, NSAID)
• Outcome very variable
– 1/3 spontaneous remission
– 1/3 partial remission or very
slow progression
– 1/3 progressive renal
impairment
• Higher incidence of
thromboembolism
• Therapy very difficult
Membranous Nephropathy
• Idiopathic
• Secondary GN:
• Immunological:
-SLE, MCTD
-Sjogren Syndrome
• Rheumatoid Arthritis
• Neoplasms:
-Ca of lung
-Ca of breast, Kidney
• Non-Hodgin Lymphoma
Membranous
Nephropathy
• Infectious:
-Hepatitis B
-Malaria
-Schistosomiasis
• Medications:
-NSAIDs, Gold, Penicillamine
-Capoten
Pathology
• The pathologic feature of MN evolve from the
initial formation of subepithelial immune
complexes of IgG and complement.
• Initial stage on EM ranging from minimal change
with only small deposits( stage 1) through the
evolution to thickened basement membrane with
resolution of deposits (stage IV).
Membranous Nephropathy
Membranous Nephropathy
Clinical manifestation
Membranous Nephropathy
• Is the most common cause of the idiopathic
nephrotic syndrome in adults(30-50%)
• Nephrotic Syndrome is the common
presentation
• Hypertension 30%
• In children: 50% spontaneous remission,
10% to ESRD
• Stage 1 >>>good prognosis
• Stage 4>>>>bad Prognosis
Membranous Nephropathy
Natural History and Prognosis
Membranous GN
• The prognosis of untreated MN is
somewhat worse in adults: 20% will have
progressed to ESRD at 5-10 years
followup.
. Bad outcome: male, age>50, HTN, Pcr
high at presentation.
• Recurrence after Renal Transplantation
Membranous Nephropathy
Treatment
Treatment
• Steroides
• Cyclosporine
• Imuran
• Cyclophosphamide
• Chlorambucil
Treatment of Membranous
Nephropathy
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Rule of 1/3
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1/3 – Spontaneous remission
1/3 – Partial remission / slow
deterioration
1/3 – Progress to ESRD
Steroids alone are not very effective
Methylprednisolone alternating with
chlorambucil, Methylprednisolone
alternating with cyclophosphamide.
Cyclosporin
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Focal Segmental
Glomerulosclerosis
Introduction and Definition
Focal Segmental
Glomerulosclerosis
Etiology and Pathogenesis
Focal Segmental
Glomerulosclerosis (FSGS)
• Primary (Idiopathic)
• Secondary:
-Sickle cell disease
-Heroin Nephropathy
-Morbid obesity
-HIV Nephropathy
-Aging Kidney
-Vesico-Ureteral Reflux
- Pamidronate
FSGS
• Most common idiopathic nephrotic
syndrome in adults (33%)
• Increasing incidence
• More common in blacks
• Treatment very difficult
Focal Segmental
Glomerulosclerosis
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Most common primary renal disease in
African-Americans
Etiology:
Idiopathic
Drugs – Intravenous heroin
Infections – HIV
Others – reflux nephropathy, obesity
Patient usually hypertensive. Usually
progresses to ESRD over 5-20 years.
FSGS
Pathology
Focal Segmental
Glomerulosclerosis (FSGS)
• FSGS is defined on histologic criteria by
segmental capillary obliteration with
increased mesangial matrix deposition,
intracapillary hyaline deposits, and focal
adhesions of the capillary tuft to Bowman’s
capsule.
• Primary FSGS occur in patient with nephrotic
syndrome in the absence of any of the
known causes of secondary FSGS.
FSGS
Mild
Normal
Collapsing
Moderate
Associations
Idiopathic
Morbid obesity
Heroin abuse
HIV infection
NSAID
(Minimal change disease)
FSGS
• In FSGS, evidence for a circulating
factor is more substantial, mainly
based on the high incidence of
recurrence following transplantation,
with heavy proteinuria developing
sometimes within hours.
• Plasma exchange can lead to remission
in tranplant recurrence of FSGS.
FSGS
Clinical Manifestations
FSGS
• Typically patients present with edema
that develops over a short period of
time.
• Very rapid onset of nephrotic syndrome
• Microscopic hematuria 14-30%
• Arterial Hypertension especially with
renal insufficiency.
• Increased incidence pf venous
thromboembolism.
Focal Segmental
Glomerulosclerosis
• Microscopic Hematuria
• Proteinuria >>20-30 gram/daily
• Both children and adults usually develops
ESRD 5-20 yrs from presentation.
• Idiopathic FSGS may recur in the
transplanted kidney with severe
proteinuria and Nephrotic Syndrome and
rapid course to ESRD.
Collapsing FSGS
• Collapsing FSGS is a histologic variant of
FSGS characterized by extensive focal or
global glomerular capillary tuft collapse,
podocyte hypertrophy and hyperplasia.
• Varying degree of tubulointerstitial injury.
• African Americans
• Severe nephrotic syndrome at presentation,
steroid resistance, and rapid developing
ESRD (median time of 13 month).
FSGS-Treatment
• 1mg/kg Prednisone daily for 6 month
• PO Cyclosporine
• Cytotoxic Treatment (Cytoxan, Imuran)
• Symptomatic treatment with ACEI
• CellCept (Mycophenolate Mofetil).
Nephrotic Syndrome
Secondary To Systemic Disease
• Diabetes Mellitus—Type I, Type II
• Amyloidosis
Diabetes Mellitus
INTRODUCTION
Diabetic Nephropathy
Diabetic Nephropathy is a common
problem that is most likely to occur in
patients who have worse glycemic
control, Hypertension, glomerular
hyperfiltration, Blacks, Mexican, or
Pima Indian.
Diabetic Nephropathy
• Diabetic nephropathy is a leading cause of
end-stage renal disease (ESRD) in Western
societies
• Diabetic nephropathy is a clinical syndrome
characterized by persistent albuminuria(>300
mg/24hr or >200ug/min) on at least two
occasions separated by 3-6 months.
• Patients invariably develop hypertension,
progressive increase in proteinuria, and decline
in GFR.
Diabetic Nephropathy
Major Risk Factors For DN
1. Genetic Susceptibility
2. Arterial Hypertension
3. Increased glomerular filtration rate
4. Worse Glycemic Control
5. Blacks, Pima Indian
Microalbuminuria
. Increased protein excretion is the earlies
clinical finding of diabetic nephropathy.
• The normal rate of albumin excretion is less than
20 mg/day; persistent values between 30 and 300
mg/day( 20 to 200 ug/min) in a patient with
diabetes is called Microalbuminuria .
Microalbuminuria and
correlation with DN
• Great attention to control of both hyperglycemia
and hypertension (with ACEI) may also
contribute to the apparent improvement in the
course of the disease.
• Patient who progress are more likely to have
higher HbA1c values and higher blood pressure
than non progresses.
• The incidence of overt hypertension is
approximately 15 to 25 percent in all patients
with microalbuminuria and much higher as the
patient progress to overt nephropathy.
Epidemiology
• Type 1 diabetic nephropathy, occur in 30-40% of
patients with type 1 diabetes after 25-40 years
with diabetes
• In type 2 diabetes, the cumulative incidence of
nephropathy is similar to that seen in type 1 ,
25% at 20 years after diagnosis.
• Since type 2 diabetes is 10-15 times more
common than type 1, the prevalence of type 2
diabetic nephropathy is substantialy higher.
Renal Pathology
• The kidneys of patients with diabetes are, on
average larger than those of nondiabetic
control subjects(15%).
• Nodular glomerular intercapillary lesions,
described by Kimmelsteil and Wilson.
• Diffuse glomerular lesion is more frequent
than the nodular lesion, with an incidence of
over 90% for patients with type 1 DM of over
10 years duration and an incidence of 25-50%
in patients with type 2 DM.
Diabetic Nephropathy
Diabetic Nephropathy
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Most common cause of nephrotic syndrome
in adults.
Leading cause of ESRD in USA
30% of patients with Type I and 20% of
patients with Type II DM develop diabetic
nephropathy.
Initially microalbuminuria followed by heavy
proteinuria and decline in renal function.
Diagnosis usually made on clinical grounds
and biopsy not needed.
Diabetic Nephropathy
Clinical Manifestations and
Natural History
Treatment of Diabetic Nephropathy
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Blood glucose control
Control of hypertension
Use of ACE inhibitors/ARBs
Control of hyperlipidemia
Smoking cessation
Protein Restriction
Nephrotic Syndrome
Secondary To Systemic
Disease: Amyloidosis
-Primary Amyloidosis
-Secondary Amyloidosis
Amyloidosis
• The Amyloidosis are a group of
disorders in which soluble proteins
aggregate and deposit extracellulary in
tissues as insoluble fibrils, causing
progressive organ dysfunction. The
kidney is one of the most frequent sites
of amyloid deposition in AA, AL, and
several of the hereditary amyloidoses.
Amyloidosis
• Amyloidosis is defined by the ability of a
variety of proteins to form B-pleated
sheets. These fibrils can be identified on
biopsy specimens both by their
characteristic appearance on electron
microscopy and by their ability to bind
Congo Red(leading to green birefringence
under polarized light) and thioflavine-T
(producing an intense yellow-green
fluorescence).
Amyloidosis
• Amyloid A in secondary amyloidosis
• Immunoglobulin light chains in primary
amyloidosis
• B2-microglobulin in dialysis-patients
associated arthropathy
• Amyloid beta protein in Alzheimer’s
disease
Amyloidosis
• Renal involvement occurs in over 90% of
patients with either primary or secondary
amyloidosis.
• Primary forms(> 90%) is a plasma cell
dyscrasia and may be associated with MM.
• Light Chain Deposition Disease (LCDD) is a
disorder of similar pathogenesis. The abnormal
protein do not form the B-pleated amyloid fibrils.
• Secondary amyloidosis is a consequence of
chronic inflammatory diseases such as :
Rheumatoid arthritis, FMF, Osteomyelitis,
Hypernephroma, PID.
Amyloidosis-Secondary
• Clinically evident renal involvement occurs only
in primary or secondary amyloidosis
• Secondary amyloidosis is associated with
increased hepatocyte production of the acute
phase reactant serum amyloidosis A (SAA);
this process may be stimulated by the release of
cytokines ( Interleukin-1) from activated
macrophages. Cleavage in circulating
monocyte/macrophages results in the
generation of smaller fragments, called AA
protein, that can then deposit in the tissue.
Primary Amyloidosis (AL)
• The fibrils in AL consist of segments of the
variable portions of monoclonal light
chains
• AL Amyloidosis is a plasma cell dyscrasia
in which the malignant characteristic of M.M
are usually absent and circulating light
chains are frequently demonstrated .
• Only a minority of patients who produce an
excessive amounts of light-chains (as M.M)
develop amyloidosis.
• Lambda light-chains are much more likely
to produce amyloidosis than Kappa light
chains.
Dysproteinemia
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Myeloma Cast Nephropathy
– Path shows multiple intraluminal
proteinaceous casts
– Pathogenesis
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Disorder of plasma cells with overproduction
the antibody light chain
– Treatment
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Hydration, plasmapheresis to remove the
abnormal protein and chemotherapy to
suppress plasma cells
Myeloma Cast Nephropathy
Light Chain Deposition Disease
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Amyloid protein produced in plasma
cell dyscrasias is preferentially lamda
light chains
Kappa chain can occur and termed
light chain deposition disease
Kappa chain deposits tend to deposit
in tubules and glomeruli, spare vessels
Kappa more aggressive than lambda
Diagnosis
• Documentation of tissue deposition of amyloid
fibrils.
• Kidney biopsy> 90% of patients
• Abdominal fat pad> 80-90%
• Rectal> 50-80%
• Gingival>60%
• Once the DX of primary amyloidosis is made,
the patient should be evaluated for M.M ! ! !
Pathology
• On light microscopy> >>Diffuse deposition of
amorphous hyaline material in the
mesangium and then capillary loops.
• Amyloid deposition in the glomeruli can result in
the formation of nodules.
• Congo Red induces green birefringence
when viewed under polarized light.
• Immunofluorescence for immunoglobulin and
complement is negative.
Key things to Remember
Amyloid is hyaline, eosinophils, Congo Red +
Green Birefringence when polarized
Small non-branching fibrils on EM
Amyloidosis
• More common in elderly
• Two main types of renal amyloid
– AL amyloid
– AA amyloid
Normal
Clinical Presentation
• Non-specific symptoms, Fatigue, Weight loss,
Anemia
• Proteinuria, edema>>>Nephrotic Syndrome
• Carpal tunnel syndrome
• Peripheral neuropathy
• Hepato-Splenomegaly, Macroglossia
• Renal insufficiency
• Tubular involvement : RTA, NDI, Hyperkalemia
Course and Treatment
• Prognosis depend on type of amyloidosis
• MM= bad Prognosis
• In primary Amyloidosis usually progress slowly
to CRF
• Prednisone an Melphalan is the major mode of
therapy for primary amyloidosis
• Colchicine in AL, AA amyloidosis
• In AA the progression depend upon the ability to
control the underlying disease.
Asymptomatic Non-Nephrotic
Proteinuria
• Overflow Proteinuria: Multiple Myeloma
-Light Chain
• Tubular Proteinuria: Tubulointerstitial dis.
< 2 gr/day
• Glomerular proteinuria
Treatment
• Steroid Treatment induces remission in
almost all patients with MCD.
• Adults usually biopsied before treatment
(KNB).
• Controll first volume overload (Diuretics).
Treatment
• Steroid responsive
• Steroid dependent
• Frequent relapsers