Nephrotic Syndrome

GOOD MORNING
Welcome Applicants!
Friday, October 31, 2014
(Happy Halloween!)
PREP QUESTION
A 14-year-old girl has had 3 days of new, unremitting headache associated with
vomiting and awakening from sleep and 1 day of double vision. Physical
examination reveals normal visual acuity in each eye, normal pupillary responses in
each eye, subjective diplopia when looking to the left, and incomplete abduction of
the left eye. Fundoscopic examination reveals bilateral papilledema. Noncontrast
head CT scan yields normal results. Of the following, the MOST likely diagonsis is:
A.
B.
C.
D.
E.
Brain tumor in the posterior fossa
Communicating hydrocephalus
Complicated migraine
Optic neuritis
Pseudotumor cerebri
DIFFERENTIAL DIAGNOSIS
 Allergies
 Venous obstruction
 Protein deficiency
 Sickle cell related swelling
•
•
•
•
Dietary (ie Kwashikor)
Protein-losing enteropathy
Liver failure
Nephrotic Syndrome
 Angioedema
 Congestive heart failure
 Glomerulonephritis
 Renal failure
 Medications (CCB’s)
 Lymphatic disturbance
 Capillary leak syndromes
• Sepsis
• Burns
 Henoch-Schonlein Purpura
Know the differential diagnosis of nephrotic syndrome with and without hematuria.
NEPHROTIC SYNDROME
What’s the Triad?
1. Hypoalbuminemia
2. Edema
3. Hyperlipidemia
EPIDEMIOLOGY
 Incidence: 2.7/100,000 children per year
 Prevalence: 16/100,000 children per year
 2:1 males to females (in childhood)
 Peak age of onset: 2-3 years of age (75% of patients are <10 years old)
 Familial component
 African American and Hispanic children at increased risk of developing
nephrotic syndrome and having a more severe form with a poorer prognosis
SIGNS AND SYMPTOMS
edema
 The most common presenting sign: _______.
 1/3 with microscopic hematuria
 Other common complaints: headache, dysphnea, anorexia,
irritability, fatigue, abdominal discomfort, diarrhea.
Know the presenting signs and symptoms of minimal-change nephrotic syndrome.
NEPHROTIC SYNDROME
 Primary Causes
• Minimal change Nephrotic Syndrome
• Focal Segmental Glomerulosclerosis
• Membranous Nephropathy
 Secondary Causes
• Infections: Hepatitis B and C, HIV, Malaria, Toxoplasmosis, Syphillis,
PIGN
• Drugs: Gold, NSAID’s, Pamidronate, Interferon, Heroin, Lithium
• Malignancies: Leukemia, Lymphoma
• Miscellaneous: SLE, MPGN, Ig A nephropathy, DM, Sickle cell disease
GLOMERULUS
ANATOMY
 Integrity of glomerular filtration
barrier is compromised
• Fenestrated endothelium
• Glomerular basement membrane
• Visceral glomerular epithelium
(podocytes and slit diaphragms)
PRIMARY (IDIOPATHIC)
NEPHROTIC SYNDROME
 Minimal change nephrotic syndrome (MCNS)
 Focal segmental glomeruloscerlosis (FSGS)
 Membranous nephropathy (MN)
MINIMAL CHANGE
DISEASE
FOCAL SEGEMENTAL
GLOMERULOSCERLOSIS
MEMBRANOUS
NEPHROPATHY
OTHER ETIOLOGIES (10%)
 Mesangioproliferative glomerulonephritis
 Lupus nephritis
 Immunoglobulin A nephropathy
 Membranoproliferative glomerulonephritis due to Hepatitis C
 HIV nephropathy
DIFFERENTIAL DIAGNOSIS
 Allergies
 Venous obstruction
 Protein deficiency
 Sickle cell related swelling
•
•
•
•
Dietary (ie Kwashikor)
Protein-losing enteropathy
Liver failure
Nephrotic Syndrome
 Angioedema
 Congestive heart failure
 Glomerulonephritis
 Renal failure
 Medications (CCB’s)
 Lymphatic disturbance
 Capillary leak syndromes
• Sepsis
• Burns
 Henoch-Schonlein Purpura
Know that nephrotic syndrome in association with Henoch-Schonlein purpura is a poor
prognostic sign
PREP QUESTION 1
A 14-year-old boy presents to the emergency department with a 2-week history of bilateral leg
edema and a 3-day history of abdominal swelling. His vital signs are: temperature 98.4 F, BP
125/67, HR 84 beats/min, RR 20 breaths/min. Physical examination shows moderate ascites
and 2+ leg edema. His urinalysis reveals negative blood and 4+ protein. Serum complement
concentrations are ordered and found to be normal. Of the following, the MOST likely cause of
his edema and proteinuria is
A.
B.
C.
D.
E.
Immunoglobulin A nephropathy
Lupus nephritis
Membranous nephropathy
Membranoproliferative glomerulonephritis
Post-infectious acute glomerulonephritis
NEPHROTIC SYNDROME LABORATORY STUDIES
 Proteinuria
 Low plasma protein concentration (often albumin less than 2.5 g/dL)
 High levels of cholesterol, triglycerides, and lipoproteins
 Hyponatremia
 Low plasma calcium (normal ionized calcium)
 +/- Microscopic hematuria
Understand the etiology of
hyponatremia in nephrotic
syndrome.
 C3… Normal  MCNS
Low  post-infectious glomerulonephritis; HSP
Recognize the laboratory findings in children with minimal change nephrotic syndrome
Recognize that the prognostic significance of a decreased serum C3 concentration in a patient
with nephrotic syndrome is an indication of a diagnosis other than minimal change disease.
PREP QUESTION 2
A 4-year-old boy is seen in the emergency department because of recurrent facial swelling. The
mother reports that the boy has been evaluated by her pediatrician on several occasions with a similar
complaint. Each time, the boy was treated with 3 to 5- day courses of an antihistamine or oral
steroid. The mother maintains full adherence with these treatment recommendations. Physical
examination shows a healthy-appearing boy who has normal growth parameters. He is afebrile with a
RR 18 breaths/min, HR of 84 beats/min, and a BP 90/60 mm Hg. The only finding of significance
is facial puffiness and periorbital edema. Of the following, the MOST appropriate next step is to
A. Obtain C1 esterase concentration
B. Obtain a specimen for urinalysis
C. Prescribe a 5-day course of diphenhydramine and prednisone
D. Reassure the mother and discharge the patient home
E. Refer the patient for an allergy evaluation
EVALUATION
1st  confirm diagnosis!
 Thorough history and
physical examination!
 Is there…
• Severe proteinuria?
• Hypoalbuminemia?
• Edema?
2nd  rule out secondary causes
 Does the patient have…
• Normal blood pressure?
• Normal renal function?
• Hematuria? Microscopic or
Gross?
 Labs
•
•
•
•
•
•
•
•
Complement C3 and C4 values
Anti-nuclear antibody
Anti-double-stranded DNA
Hepatitis B surface antigen
Hepatitis C antibody
HIV antibody
CBC with differential
PPD
URINE DIPSTICK
Protein:
 1+ = 30 mg/dL
 2+ = 100 mg/dL
 3+ = 300 mg/dL
Then quantitative measurement:
Uprotein/creatinine:
<0.5
 6 months-2 years of age: ____.
<0.2
 >2 years of age: _____.
>3 = nephrotic syndrome
 ____
12 or 24-hour urine collection:
 Nephrotic range:
 4+ = 1,000 mg/dL
50 mg/kg/day or 40 mg/m2/hr
 False positives (alkaline urine, concentration dependent, or
contamination)
PREP QUESTION 3
A mother brings in her 4-year-old son because his eyelids are swollen. On physical examination, the boy
has normal growth parameters, normal blood pressure, bilateral periorbital edema, and pitting pretibial
edema. Laboratory findings include normal electrolyte concentrations, BUN 14 mg/dL, creatinine of
0.3 mg/dL, albumin 1.9 g/dL, and normal C3 and C4 complement values. Urinalysis reveals a specific
gravity of 1.030, pH of 6.5, 4+ protein, and 1+ blood, and microscopy demonstrates 5-10 RBC/hpf.
ANA test results are negative, and serologic tests are negative for hepatitis B surface antigen, negative
for hepatitis C, and nonreactive for HIV. A ppd is nonreactive after 48 hours. Of the following, the
MOST appropriate treatment for this patient is:
A. Diphendyramine
B. Furosemide
C. Low-sodium diet
D. Prednisone
E. Protein-rich diet
TREATMENT
Plan the initial treatment for a child with an initial episode of nephrotic syndrome.
Understand the appropriate initial management of a nephrotic patient.
Recognize the indications for alkalating agents in corticosteroid-responsive nephrotic syndrome
MANAGEMENT
 The
2012
Disease:
Improving
Globalthe
Outcomes
Steroid-dependent
disease:
Prednisone
remains
preferred:Conference:
therapy
2009 Kidney
Children's
Nephrotic
Syndrome
Consensus
2 x 4-6and
+/-therapy:
levamisole,
cyclophosphamide,
mycophenolate
mofetil,
calcineurin
•• 
Initial
Prednisone
2 2mg/kg/day
or x606mg/m
weeks,
then
Initial
therapy:
Prednisone
mg/kg/day
weeks,
then
alternate-day
2
inhibitors
(ie,
cyclosporine
or
tacrolimus)
alternate-day prednisone 1.5 mg/kg or 40 mg/m x 2-5 months
prednisonedisease:
1.5 mg/kg
x 6 weeks
2
 Steroid-resistant
Therapy
is based
upon the
histologicorfindings
found
• First relapse/Infrequent
relapse:
Prednisone
2 mg/kg/day
60 mg/m
First
relapse/Infrequent
Prednisone
2 mg/kg/day
until
on •renal
biopsy.
Treatment
mayrelapse:
include:
ACE-I
or yARB’s
and supportive
care
until
the
urine
protein tests
are
negative
or trace
for
3 consecutive
days,the
2 x 4 weeks.
urine
protein
tests
are
negative
trace
for403mg/m
consecutive
days, then
then
prednisone
1.5or
mg/kg
or
focused
onalternate-day
managing
the
complications
of nephrotic
syndrome.
prednisone
1.5 therapy
mg/kg x2 4mg/kg
weeks.per day or 60 mg/m2
• alternate-day
Frequent relapses:
Prednisone
the urine
protein
tests are negative
forper
3 consecutive
days,
• until
Frequent
relapses:
Prednisone
therapyor2 trace
mg/kg
day until the
urine
then lowest necessary alternate-day prednisone x at least 3 months
protein tests are negative or trace for 3 consecutive days, then
• +/- oral cyclophosphamide, cyclosporine, tacrolimus, chlorambucil, levamisole,
alternate-day
prednisone
1.5 mg/kg x 4 weeks, which is then tapered
and mycophenolate
mofetil
over
months
by 0.5 mg/kg every other day.
• 2
+/Rituximab
• +/- oral cyclophosphamide, cyclosporine, and mycophenolate mofetil
MANAGEMENT
 Ancillary support:
•
•
•
•
Diuretics
Blood pressure control
Salt-poor albumin infusions
Anti-angiotensin
• ACE inhibitors
• Angiotensin receptor blockers
• +/- Statins
• Low-sodium, low-fat diet
• Vaccinations
MANAGEMENT
 Indications for renal biopsy at time of diagnosis include:
•
•
•
•
•
Macroscopic or persistent hematuria
Severe hypertension
Persistent renal insufficiency
Low serum C3 complement values
Age >10 years old
 Indications for renal biopsy subsequent to treatment:
• Persistent proteinuria despite 4 weeks of daily prednisone
PREP QUESTION 4
A 4-year-old boy presents with peri-orbital edema. He is receiving no medications, and his family
history is negative for renal disease. On physical examination, he is afebrile; his HR is 88 beats/min, RR
18 breaths/min, BP 106/62 mm Hg. He has periorbital edema and pitting pretibial edema. Laboratory
evaluation shows normal electrolyte values, BUN of 14 mg/dL, creatinine of 0.3 mg/dL, and albumin
of 1.6 g/dL. Urinalysis demonstrates a specific gravity of 1.020; pH of 6.5, 3+ protein, and negative
blood, leukocyte esterase, and nitrite. Microscopy results are normal. Additionally, complement
component (C3 and C4) values are normal, and results of serologic testing for ANA, hepatitis B and C,
and HIV are negative. Of the following, you are MOST likely to advise the parents that
A. A renal biopsy is warranted to determine the optimal treatment
B. Disease relapse can be expected in fewer than 25% of those achieving remission
C. Patients who relapse have a similar prognosis as those who do not respond to steroids
D. Remission is expected in more than 75% of patients who receive corticosteroid treatment
E. Tacrolimus is the preferred treatment for patients who do not respond to corticosteroids
PREP QUESTION 5
A 14-year-old girl presents with peri-orbital swelling for the past week this is worsening. She had upper
respiratory tract symptoms approximately 10 days ago. She denies itching at her eyes. Otherwise, she has
been well. On physical examination, she is afebrile with a pulse rate of 76 beats/min, a respiratory rate
of 16 breaths/,min, and blood pressure of 136/86 mm Hg. Her examination is remarkable for bilateral
periorbital edema with normal conjunctivae. She also has pitting edema from her pretibial region to the
level of her knees. You suspect that the patient may have nephrotic syndrome. The following are results
of her urinalysis: Specific gravity 1.025, pH 7, 3+ protein, 1+ blood. Of the following, the laboratory
finding that is MOST likely to indicate a poor renal prognosis for this girl is
A. Serum albumin of 1.4 g/dL
B. Serum complement component 3 (C3) of 40
C3 Normal
C. Serum creatinine of 0.7 mg/dL
135
D. Urine microscopy of 10-20 RBC/hpf
E. Urine protein to creatinine ratio of 14
Range 75-
COMPLICATIONS
 Acute Renal Failure
 Pulmonary edema
 Infection
Recognize the complications of nephrotic
syndrome (eg, peritonitis, thromboses)
Recognize peritonitis as a major complication of
minimal-change nephrotic syndrome
• Spontaneous bacterial peritonitis
 Hypercoaguability
• Thrombotic events
 Steroid effects
COURSE/PROGNOSIS
•
•
•
 The
best
prognostic
Know
the
factors
(i.e. indicator in
hypertension)
that
predictsyndrome
the
children who have
nephrotic
prognosis
nephrotic syndrome.
steroidofresponsiveness
is: ________________________.
Recognize that response to therapy
95%
children
who eventually
isone
of ofthe
best indicators
of the
prognosis
nephrotic
respond to in
steroids
do so syndrome
within the
Understand
that minimal-change
4 (four)
first _________
weeks of treatment.
nephrotic syndrome is a relapsing
60% respond to steroids initially
disease
 _____
but relapse.
STEROID -RESISTANT
NEPHROTIC SYNDROME
 ~10% of children with nephrotic syndrome
 Poor prognosis
 Alkylating agents often necessary
 Renal biopsy indicated
 Most often dx: Focal segmental glomerulosclerosis
OUR KIDDO….
CONGENITAL NEPHROTIC
SYNDROME
 Proteinuria present at birth (or up to 3 months of age)
 Often massive proteinuria during fetal life
•
 metabolic disturbances (lipid abnormalities, thyroid abnormalities, atherosclerotic changes)
 Edema and abdominal distention develop soon after birth
 Diagnosis: increased alpha fetoprotein in amniotic fluid + normal fetal ultrasound
 Histology: slight-to-moderate mesangial proliferation, effacement of foot processes, thin GBM
 Course: Eventually become sclerotic with disappearance of slit diaphragms
 Finnish type
•
•
Autosomal recessive disease
NPHS1/2 code for nephrin  mutated
Recognize the presentation and intrauterine diagnosis of congenital nephrotic
syndrome
CONGENITAL NEPHROTIC
SYNDROME
 Treatment:
• Good nutritional support
• Control edema (often requires unilateral or bilateral nephrectomy)
• Often require peritoneal dialysis
• Prevent complications (ie infections, thrombosis)
• Eventually require renal transplantation
Recognize the improved outcome of children with congenital nephrotic syndrome
through early intervention and renal transplantation
SUMMARY
 Most with nephrotic syndrome have MCNS and respond to steroid
therapy.
 Steroid-responsiveness is the best prognostic indicator.
 Renal biopsy can be deferred and prednisone started empirically if
high suspicion for MCNS.
 60% of children with MCNS will relapse.
 Most children with nephrotic syndrome and fail steroid therapy will
have FSGS with a poor prognosis
HAVE A GREAT DAY!!
Noon conference: “Personal Perspective on Evaluation of UTI”
Visiting professor, Dr. Douglas Canning