NEPHROTIC

SYNDROME
By: Yeni Ayu Prihastuti
Moderator: DR. dr. Hani susianti, Sp.PK (K)
INTRODUCTION
Glomerular Disease
 Disorders that affect the structure and function of the
glomerular apparatus
 Classification:
- Nephrotic syndrome
- Nephritic syndrome
- Asymptomatic renal disease
 INTRODUCTION
Spectrum of Glomerular Disease
 NEPHROTIC SYNDROME
Definition
 Part of glomerular diseases that are characterized
by:
- Massive proteinuria
- Hypoalbuminemia
- Edema
- Hyperlipidemia
- Lipiduria
NEPHROTIC SYNDROME
Pathophysiology
NEPHROTIC SYNDROME
Pathophysiology
NEPHROTIC SYNDROME
Etiology
Nephrotic Syndrome

Primary Secondary
• Membranous • Diabetic
nephropathy nephropathy
• Focal segmental • Systemic Lupus
glomerulosclerosis Erythematosus
(FSGN) • Renal amyloidosis
• Minimal change • Fabry’s disease
disease
• Membranoproliferative
glomerulonephritis
MEMBRANOUS NEPHROPATHY
• The glomerular capillary basement membrane
appears thickened
• There is an absence of glomerular inflammation
• Idiopathic membranous nephropathy is
suggested as an autoimmune disease.
Diagnosed by ruling out secondary causes
• Secondary cause include: infections, neoplasias,
autoimmune, drugs and others (renal transplant,
diabetes mellitus, etc)
 MEMBRANOUS NEPHROPATHY
• Clinical finding:
- Rare in children
- Common in adults; increasing frequency after age
40 years
- Males > females in all adults groups
- Whites > Asians > African-Americans > Hispanics
- Normal or mildly elevated BP at presentation
- “Benign” urinary sediment
- Nonselective proteinuria
- Tendency to thromboembolic disease
FSGN (Focal segmental
glomerulosclerosis)
• Characterized by segmental glomerular scars
that involve some but not all glomeruli
• Possible mechanisms:
- T cell-mediated circulating permeability factor
- TGF-mediated cellular proliferation and matrix
synthesis
- Podocyte abnormalities associated with genetic
mutations
• Manifest as proteinuria, progressive renal failure
(75% cases), early-onset hypertension
MINIMAL CHANGE DISEASE
• 70 – 90% in children

• May occur as primary renal disease or associated

with tumors (Hodgkin disease), allergies, or use
of NSAIDs

• May be due to a circulating cytokine, perhaps

related to T cell response that alters capillary
charge and podocyte integrity
MINIMAL CHANGE DISEASE
• Clinical finding:
- Abrupt onset of edema
- Hypertension
- Decreased renal function, abnormal urine
principally contains albumin
- Nephrotic syndrome, accompanied by
hematuria, atopy or allergic symptoms
DIABETIC NEPHROPATHY
• Morphologic changes appears within 1-2 years
after the onset of clinical diabetes

• Loss of heparan sulfate moieties that form the

negatively charged filtration barrier  GBM
alteration  increased filtration of serum proteins
in the urine (albumin)

• Indicated by the presence of microalbuminuria

(30 – 300 mg/24 hours)
RENAL AMYLOIDOSIS
• Primary: fibrillar deposits of immunoglobulin light
chains (amyloid L – AL)

• Secondary: fibrillar deposits of serum amyloid A

(AA) protein fragments

• Extracellular deposition of the fibrous protein

amyloid in kidney causes heavy proteinuria
FABRY’S DISEASE
• An X-linked inborn error of globotriaosylceramide
metabolism secondary to deficiency of lysosomal
agalactosidase A activity  excessive
intracellular storage of globotriaosylceramide

• Present as mild to moderate proteinuria, oval fat

bodies, and birefringent glycolipiglobules under
polarized light

• Progression to renal failures occurs by the 4th

decade
CLINICAL FINDINGS
• Edema
- In areas of high intravascular hydrostatic
pressure
 feet and ankles
- In areas in which tissue hydrostatic pressure is
lowest
 periorbital and scrotal
- Edema anasarca
 severe and generalized edema
LABORATORY FINDINGS
• Urine
- Urine dipstick = Protein 3+ to 4+
- 24-hours urine = Protein > 3.5 g/1.73 m2
- Sediment = Oval fat bodies

• Blood
- Decreased serum total protein (< 6 g/dL)
- Decreased serum albumin (< 3 g/dL)
- Hyperlipidemia
 LABORATORY FINDINGS
Renal
Nephrotic Syndrome Proteinuria Hematuria
Injury
Membranous ++++ + -
nephropathy
Focal segmental
+++/++++ + -
glomerulosclerosis
Minimal change ++++ - -
disease
Diabetic nephropathy ++/++++ -/+ -
Renal amyloidosis +++/++++ + +/++
Fabry’s disease + + -
COMPLICATIONS
• Thrombosis
- Urinary losses of antithrombin III, protein C & S,
factor IX, XI, & XII
- Increased tissue plasminogen activator and
platelet aggregability

• Vitamin D deficiency & Hypocalcemia

- 25-Hydroxyvitamin D, which is bound to vitamin
D-binding protein, is also lost in the urine
COMPLICATIONS
• Infection
- Urinary losses of immunoglobulins
- Defects of the complement cascade
- Use of immunosuprresive medications
 High susceptibility to infection

• Hypoalbuminemia
- Lost of albumin in the urine
- Increased albumin catabolism
COMPLICATIONS
• Malnutrition
- Prolonged and massive proteinuria
 negative nitrogen balance

• Anemia
- Urinary loss of erythropoietin and transferrin
 iron-resistant hypochromic microcytic anemia
REFERENCES
1. Fauci AS, Kasper DL, Longo DL, Braunwald E, Hauser SL,
Lameson JL, et al, editors. Harrison’s Principles of Internal
Medicine, 17th ed. New York: McGraw-Hill. 2008.
2. Lerma EV, Berns JS, Nissenson AR, editors. CURRENT Diagnosis
and Treatment: Nephrology & Hypertension, 1st ed. New York:
McGraw-Hill. 2009.
THANK YOU
Spectrum of glomerular diseases
 Theory
Nephrotic Syndrome
• Massive proteinuria
(>3.0g/24 h)
• Hypoalbuminemia
• Edema
• Hyperlipidemia
Complications: Ascites,
Anemia, Infection, Tubular
dysfunction, Renal
dysfunction,
Hypercoagulable state, Bone
disorder, CAD
Nephritic Syndrome
• 1–2 g/24 h of
proteinuria
• Hematuria with RBC
casts and/or
dysmorphic red blood
cells
• Pyuria
• Hypertension
• Fluid retention
• Increase serum
creatinine dt reduction
in glomerular filtration
 Nephrotic Syndrome 29

Typical features Atypical features

Age 1-10 years <1 year, > 10 years
Normotensive Hypertensive
Normal adrenal function Elevated creatinin
+/- microscopic
Glomerular Macroscopic
Renal non haematuria
Urological
haematuria glomerular
Proteinuria
ResponsiveSignificant
to steroid Significant
Unresponsive toAbsent or
steroid
treatment treatmentminimal
RBC form Dysmorphic Isomorphic Isomorphic
Renal biopsy: minimal Renal biopsy : FSGS or one
RBC change
cast +
nephrotic of- the other forms- of
Cause(s) syndrome
Most prominent: Tubulointerstitial, Tumors, calculi,
nephrotic syndrome
IgA nephropathy renovascular, or and infections
Started on steroid Needdisorders
metabolic renal biopsy before
without renal biopsy receiving steroid treatment
 Hematuria, Hemoglobinuria and
Myoglobinuria

Hematuri Hemoglobinur Myoglobinur

a ia ia
Color Red Red Brown
Supernatan Clear / Equally Equally
after less discolored discolored
centrifugatio colored
n
Dipstick (+) (+) (+)
Presence of (+) (-)/few (-)/few
RBC in
microscopic
examination
Glomerular Hematuria Renal (Nonglomerular) Hematuria
•With significant •Secondary to tubulointerstitial,
proteinuria, erythrocyte renovascular, or metabolic disorders
casts, and dysmorphic RBCs •With significant proteinuria, without
•Isolated hematuria in 20% dysmorphic RBCs nor erythrocyte casts
of patients •Further evaluation of glomerular and
•IgA nephropathy is the nonglomerular hematuria  renal
most common cause function test and 24-hour urinary protein
OR spot UPCR
Urologic Hematuria
•Causes include tumors, calculi, and infections
•Absence of proteinuria, dysmorphic RBCs, and erythrocyte casts.
Even significant hematuria will not elevate the protein
concentration to the 2+ to 3+ range on the dipstick test
•Up to 20 % of patients with gross hematuria have urinary tract
malignancy  indication for a full work-up with cystoscopy and
upper-tract imaging
Nephrotic Syndrome
Histologic Patterns and Features of Primary Nephrotic Synd
Histologic
pattern Key pathologic features
Focal Sclerosis and hyalinosis of
segmental segments of less than 50
glomeruloscler percent of all glomeruli on
osis electron microscopy
Membranous Thickening of the
nephropathy glomerular basement
membrane on electron
microscopy;
immunoglobulin G and C3
deposits with
immunofluorescent staining
Minimal Normal-appearing
change glomeruli on renal biopsy
disease microscopy; effacement of
foot processes on electron
microscopy
Key clinical features
May be associated with
hypertension, renal insufficiency,
and hematuria
Peak incidence at 30 to 50 years
of age; may have microscopic
hematuria; approximately 25
percent of patients have
underlying systemic disease,
such as systemic lupus
erythematosus, hepatitis B, or
malignancy, or drug-induced
nephrotic syndrome
Relatively mild or benign cases of
nephrotic syndrome; may occur
following upper respiratory
infection or immunization
 Common Secondary Causes of Nephrotic Syndrome
Cause Key features
Diabetes mellitus Glucosuria, hyperglycemia, polyuria
SLE Anemia, arthralgias, autoantibodies, photosensitivity,
pericardial or pleural effusion, rash
Hepatitis B or C Elevated transaminases; high-risk sexual activity, history of
transfusion, intravenous drug use, or other risk factors for
disease transmission
Nonsteroidal Causes minimal change disease
anti-inflammatory
drugs
Amyloidosis Cardiomyopathy, hepatomegaly, peripheral neuropathy
Multiple myeloma Abnormal urine protein electrophoresis, back pain, renal
insufficiency
HIV Pathologically similar to focal segmental
glomerulosclerosis; risk factors for HIV transmission,
possible reduced CD4 cell count
Preeclampsia Edema and proteinuria during pregnancy; elevated blood
pressure
Proteinuria

35
Proteinuria

36
Edema in
Nephrotic
Syndrome
 Hematuria

• Hematuria = the presence of > 3 RBCs/HPF in 2-3 urine

samples (American Urological Association)
• The dipstick test for blood detects the peroxidase activity of
erythrocytes. However, myoglobin and hemoglobin also will
catalyze this reaction, so a positive test result may indicate
hematuria, myoglobinuria, or hemoglobinuria
• Visualization of intact erythrocytes on microscopic examination
of the urinary sediment can distinguish hematuria from other
conditions. Microscopic examination also may detect RBC casts
or dysmorphic RBCs
• Hematuria is divided into glomerular, renal (i.e., nonglomerular),
and urologic etiologies
Glomerular Hematuria
• With significant proteinuria, erythrocyte casts, and dysmorphic
RBCs
• 20% of patients  hematuria alone
• IgA nephropathy is the most common cause

Renal (Nonglomerular) Hematuria

• Secondary to tubulointerstitial, renovascular, or metabolic
disorders
• With significant proteinuria, without dysmorphic RBCs nor
erythrocyte casts
• Further evaluation of glomerular and nonglomerular hematuria
should include determination of renal function and 24-hour
urinary protein or spot urinary protein-creatinine ratio
Causes of Hematuria
Glomerular causes
Familial causes
Fabry’s disease, Hereditary nephritis (Alport’s
syndrome), Nail-patella syndrome, Thin basement-
membrane disease
Primary glomerulonephritis
Focal segmental glomerulonephritis, Goodpasture’s
disease, Henoch-Schönlein purpura, IgA nephropathy
(Berger’s disease), Mesangioproliferative
glomerulonephritis, Postinfectious glomerulonephritis,
Rapidly progressive glomerulonephritis
Secondary glomerulonephritis
Hemolytic-uremic syndrome, Systemic lupus
nephritis, Thrombotic thrombocytopenic purpura,
Urologic causes
Benign prostatic hyperplasia, Cancer (kidney, ureteral,
bladder, prostate, and urethral), Cystitis/pyelonephritis,
Nephrolithiasis, Prostatitis,
Schistosoma haematobium infection, Tuberculosis

Other causes
Drugs (e.g., NSAIDs, heparin, warfarin [Coumadin],
cyclophosphamide [Cytoxan]), Trauma (e.g., contact sports,
running, Foley catheter)
CLASSIFICATION NEPHROTIC SYNDROME
• Idiopathic (primary) nephrotic syndrome (95%)
• Minimal change disease (80-90%)
• Focal segmental glomerulosclerosis (FSGS) (10-20%)
• Mesangioproliferative glomerulonephritis (MPGN)
• Secondary nephrotic syndrome (5%)
• Henoch Schonlein Purpura (HSP)
• Systemic Lupus Erithematousus (SLE)
• Amyloidosis
• Infection with HIV, Parvovirus B19, Hepatitis B and C
• Congenital nephrotic syndrome
• presenting in the first three months of life might be secondary
to intrauterine infections, e.g., congenital syphilis,
toxoplasmosis and cytomegalovirus disease
Guidelines Management of Nephrotic Syndrome. 2007
Indian J Med Res 122, July 2005, pp 13-28