NEPHROTIC SYNDROME ( NS)
Asist. prof. Magdalena Stârcea
IVth Pediatric Clinic
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DEFINITION: pathogenic entity clinically manifested
by edema and proteinuria biological> 50mg/kg/day in
urine over 24 hours, hypoalbuminemia below 30g / l,
dyslipidemia and hypercholesterolemia. After the last
diagnostic guide KDIGO (Kidney Disease The:
Improving Global Outcomes), nephrotic syndrome is
clinical entity associated pathogenic edema, compared
urinary protein / urinary creatinine ≥ 2000 mg / g,
proteinuria ≥ 300 mg / dL, or 3 + on dipstick urine and
hypoalbuminemia ≤ 2.5 mg / L.
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EPIDEMIOLOGY: 90% of cases of idiopathic
nephrotic syndrome is primitive
It affects children aged 2-10 years.
It affects mainly males (but not exclusively!).
Is 15 times more common in children than in adults.
The incidence is 2-7 cases per 100 000 children under 16
years.
Incidence of nephrotic syndrome corticorezistent seems
to be in black race and hispanic population greater than
in the general population.
The Asian population is 6 times more affected than the
European (as The Kidney Disease: Improving Global
Outcomes - KDIGO). Congenital nephrotic syndrome
have an increased incidence (1 / 10000-1 / in 5000
births) in the Finnish population.
CLASSIFICATION:
I. Primitive nephrotic syndrome
Minimal (MCNS) ( 79 % cases) - is the most common form
of NS in children, and its prevalence is inversely proportional to the
age at onset. MCNS have the highest rate of responsiveness to
standard therapy and the best long-term prognosis
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Chronic glomerulonephritis : segmental glomerulosclerosis and
focal ( GSFS ) , membranous, glomerulonephritis ,
membranoproliferative glomerulonephritis (deposit IgM, IgG ,
IgA , complement)
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Primitive congenital nephrotic syndrome ( Finnish type,
Denys - Drash , Frasier , Schimke ) or secondary infections/
intoxications maternal-fetal or maternal, systemic disease (SLE,
amyloidosis )
II. Secondary nephrotic syndrome :
- Systemic diseases : SLE, Henoch- Schonlein purpura , sickle cell
disease, hepatitis B / C , syphilis , malaria, chickenpox, AIDS ,
diabetes, amyloidosis , infections ventriculo - peritoneal shunt ,
endocarditis subacute thyroiditis Hashimoto
- Metabolic diseases : Diabetes
- Malignancies : lymphoma , neuroblastoma, carcinoma (rare)
- Hereditary diseases : Alport
- Drugs: gold salts , D -penicillamine , mercury , NSAIDs
(diclofenac, etc) , ACE ( catopril , etc).
- Others: Snake venom , injecting drugs (heroin ) poisoning with
volatile aromatic hydrocarbons , vaccines
ETIOLOGY: unclear, involving both genetic and immunological
factors, and may not be shown exactly their role.
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Genetic factors: have been identified gene belonging to HLADR7, and HLA-DQW2 in children with nephrotic syndrome.
Podocinei mutations, a membrane protein encoded by the gene
NPHS2 have been identified in cases of nephrotic syndrome with
autosomal recessive corticorezistent, and sporadic cases.
Nephrotic syndrome with GSFS was reported in patients with
mitochondrial disease, Galloway-Mowat syndrome (nephrotic
syndrome, microcephaly, hiatus hernia) and Schimke syndrome
(nephrotic syndrome, primary immunodeficiency T cell line,
dysplasia spondiloepifizară).
- Immunological factors - demonstrate the increased expression
of IL-2 receptor in patients with relapse of nephrotic syndrome
and its receptor expression in the absence of remission.
PATHOPHYSIOLOGY: the essential change is the
increase in glomerular basement membrane permeability,
which causes loss of protein in the urine (albumin,
immunoglobulins, clotting factors, proteins transport of
iodine, iron, vitamin D, etc.).
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Proteinuria arise in connection with the change of the
glomerular basement membrane discharges, the
reduction of sialic acid, heparan-sulfate neutralization of
the membrane structure. Proteinuria is variable during
the day, averaged over 40mg/m2/h.
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Hypoalbuminemia is secondary to renal losses,
increased catabolism, decrease synthesis and digestive
losses (through mucosal edema).
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Edema, the main clinical signs of nephrotic syndrome is
caused by colloid osmotic pressure drop which causes
extravasation in the interstitial water with intravascular
space contraction and renal hypoperfusion. Secondary
stimulation of the renin-angiotensin-aldosterone system,
retention of Na and water (under the action of ADH).
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Secondary
to
hypoalbuminemia
apears
hypercholesterolemia and hypertriglyceridemia by
increasing hepatic synthesis.
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An important complication NS thrombosis. Two
mechanisms are involved in the etiology of thrombosis:
decreased antithrombotic factors (urinary loss of
antitrombină III, protein S and C) and increased
prothrombotic factors (thrombocytosis, increased platelet
adhesiveness and increase serum levels of factors V,
VIII, von Willebrand factor, fibrinogen, etc).
PATHOGENY:
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On light microscopy, glomeruli may be normal with normal
capillary walls and normal cellularity. Swelling and vacuolation
of epithelial cells and a slight increase in mesangial matrix are
often observed. A mild mesangial hypercellularity may be noted as
well as tubular lesions and interstitial fibrosis.
Imunofluorescence are negative in MCNS.
Ultrastructural changes are always present, involving podocytes
and mesangial stalks. Podocyte foot process fusion is generalized
and constant; its extent is closely related to the degree of
proteinuria. The glomerular basement membranes are normal with
no parietal deposits. The endothelial cells are often swollen.
Mesangial alterations include mesangial cell hyperactivity,
increased mesangial matrix, and occasionally granular, deposits
located along the internal side of the basement membrane. These
ultrastructural alterations are nonspecific and are probably related
to massive proteinuria.
Minimal change disease - glomeruli appear normal by light
microscopy with no tubulointerstitial lesions
EM -FUSION OF THE EPITHELIAL CELL PODOCYTES.
NEPHROTIC SYNDROME DIAGNOSIS:
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HISTORY:
- Family history: nephrotic syndrome or other familial
nephropathy
-Personal history: viral, bacterial, parasitic, recent vaccinations
CLINICAL EXAMINATION
Measurements: weight, height, temperature, TA, ingestion, diuresis
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1. Debut: insidious, with pallor, loss of appetite, swelling
(eyelid, labia, scrotum), oliguria and digestive disorders,
tachycardia, abdominal pain, sometimes fever.
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2. Period status:
- Edema dominate the clinical picture from localized edema to
generalized edema, accompanied by ascites, pleural effusion.
- Urine output falls below 1ml/kg/hour (oliguria). Renal function
is generally preserved.
- AP is usually normal. It is possible to have moderate increases in
blood pressure in the early days of NS.
- Moderate hepatomegaly, liver - soft consistency.
- May be associated diarrhea, vomiting and abdominal pain due to
swelling parietal association tract, which may be from low
intensity to violent mimicking the acute abdomen surgery.
- Respiratory disorders occur in case of pleurisy massive
association infections asecensionarea diaphragm with massive
ascites.
- Rarely fever and clinical picture of sepsis with peritoneal starting
point / respiratory / urinary
- Specific rash systemic disease manifested by secondary SN
- Behavior changes, anxiety
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Complications
:
1. Thrombosis : occurring in 10 % cases of NS congenital up to 25
% of primitive NS.
 The risk of thrombosis increases with age, being higher in
adolescents than in children.
 It is also higher in children with NS in SLE or other systemic
disease secondary .
 This complication occurs on average in the first three months of
disease onset .
 The most common are venous thrombosis in the veins within the
renal vein, inferior cava vein and pulmonary vein thrombosis.
 Cerebral venous thrombosis is rare, as arterial thrombosis (axillary
artery , mesenteric, subclavian , coronary rarely ).
2. Primitive peritonitis : occurs in 2-6% of children, most
commonly caused by Streptococcus pneumoniae , Staphylococcus
aureus, Escherichia coli.
3. Infections (cellulitis, viral infections, meningitis, oto-rhino-laryngeal
infection, etc) - with an increased incidence of both onset and during
immunosuppressive therapy (cortisone or other immunosuppressive
drugs). They attributed the low level of IgG, urinary losses of factor
B (involved in opsonization of encapsulated bacteria by activating
the alternate complement pathway), modified T cell function and
induced immunosuppression therapy.
4. Acute renal failure - occurs rarely (0.8 - 1% of onset of NS), being
due to a glomerulonephritis rapidly progressive, renal vein
thrombosis, acute interstitial nephritis (induced by antibiotic therapy
or NSAIDs , diuretics), tubular necrosis acute (induced sepsis or
severe hypovolemia) .
METABOLIC BALANCE – aims diagnosis of NS,
determining disease severity and type of NS ( primitive
pure / impure , secondary)
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CBC: moderate anemia (inflammatory and deficiency, plus the
loss of iron transport proteins), thrombocytosis, leukocytosis (in
association with infections)
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Inflammatory syndrome: ESR, PCR, fibrinogen
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Total protein, electrophoresis and immunelectrophoresis:
dramatic decrease of total proteins and serum albumin below 25g
/l, decreased IgG and IgA levels, increased IgM level .
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Lipid profile: cholesterol, triglycerides, total lipids
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Renal urea, creatinine, GFR (by Schwartz formula)
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Urinary dipstick - highlights nephrotic proteinuria , hematuria
association
Urine culture in case of fever, urinary symptoms , leucocyturia ,
nitrite per strip
24 Hour Urine: level of proteinuria
Report urinary protein / urinary creatinine over 2000mg / g
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Immunoassays for excluding secondary NS: HBsAg, HCV Ac,
HIV, RBW.
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In case of association of hematuria - Addis test , report urinary
calcium / urinary creatinine for hipercaciuria, erythrocyte
morphology - excluding impure NS, hypercalciuria , CGN
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If existe signs of systemic disease with impure aspect of NS:
ANA, lupus cells, RF, dsDNA, pANCA, cANCA, complement
(C3 , C4)
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Abdominal ultrasound: highlights ascites, hepatomegaly, any
processes manifested by NS secondary of tumor (lymphoma. Look
for the permeability of the renal vein and caval system (using
Doppler) .
Chest X-ray and PPD (10 units) in case of suspicion of TB
Echocardiography - in case of persistent hypertension ,
arrhythmia, congestive heart failure or signs of cardiac tamponade
(massive pericarditis)
The suspicion of thromboembolic complications: D-dimer,
antithrombin III, protein S, protein C, fibrinogen
Pulmonary perfusion scintigraphy reveals pulmonary
thromboembolism.
Cultures - blood cultures, urine culture, secretory otitis,
hypopharyngeal aspirate
DEXA, endocrinology and orthopedic exam after prolonged
cortisone therapy for secondary osteoporosis assessment
Renal biopsy has the following indications:
Before initiation of therapy:
1. major indications:
- Debut under the 6 months
- Initial macroscopic hematuria without infection
- important HTA + persistent microscopic hematuria
and low complement
2. relative indications:
- Onset between 6-12 months
- HTA + persistent hematuria
- Unassigned renal hypovolemia
After therapy:
- corticorezistant NS
- Frequent relapses
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DIFFERENTIAL DIAGNOSIS
1. Extrarenal diseases associated with edema:
- Angioedema
- Protein-calorie malnutrition
- Chronic liver disease
- Endocrine
- Heart failure
2.
Chronic glomerulonephritis manifested by NS:
- Segmental glomerulosclerosis and focal, macroscopic hematuria
+ / - hypertension and glycosuria (need renal biopsy)
- Congenital NS: age <6 months (need renal biopsy)
- Rapidly progressive glomerulonephritis: hematuria,
hipocomplementemie (need renal biopsy)
3.
Secondary SN
- IgA nephritis, hepatitis, malaria, lymphoma, AIDS, amyloidosis,
syphilis
- NS associated medications: antiinflammatory, D penicillamine,
salts of Au, heroin
- NS associated toxins, allergens
TREATMENT
Objectives:
- Complete remission
- Relapse prevention
- Treatment of acute complications or those related to
long-term medication
- Patient's quality of life
Management of edematous patient:
- Bed rest - need in case of important generalized edema
- Diet – no salt, normoproteic, normocaloric, hypolipidaemic,
hypoglucidic diet, imposed by dyslipidaemia associated with
cortisone therapy. Oliguria is required fluid restriction (intake =
400 ml + diuresis)
- Diuretic therapy: only recommended short courses at patient in
preserved diuresis (in case of hypovolemia may precipitate acute
interstitial nephritis or acute tubular necrosis) . Generally used
loop diuretics (furosemide) 1-2mg/kg/dosis, after infusion of
albumin /plasma. Spironolactone can be associated to the
potassium - sparing effect.
- Hypovolemia associating severe hypotension and tachycardia
can be improved by albumin infusion 1g/kg (5ml/kg of 20%
solution), infused slowly direct iv way, diluted with glucose 5%
with BP control. A low serum albumin level is not an indication
for albumin infusion!
- Immunization: the live attenuated vaccines are contraindicated
during cortisone therapy and at least 6 months thereafter .
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1.
Specific therapy
Primitive NS: oral prednisone 5 mg/tb
- One month coticoterapie attack: daily 60mg/m2/day (or
2mg/kg/day),
- A month discontinuous, the same dose
- 2 months - gradual dose reduction with 10mg/week up to 0.25 mg /
kg and stop the therapy after 4 months.
After ISKDC (International Study of Kidney Disease in Children )
Classic mode : Prednisone
• 60 mg/m2/day (maximum 60 mg / day) 4 weeks
• 40 mg/m2/la 2 days , 4 weeks
Prednisone therapy should receive adjuvant, needed to counter
adverse effects :
- Gastric protector (protector or nhibitor mucosa proton pump )
- Calcium and vitamin D for osteoporosis
- KCl
- Antiplatelet agents - in situations of significant thrombocytosis
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Depending on the initial response to therapy evolutionary
describes several forms:
- Initial Responder: remission after 4 weeks of therapy
- Rare relapse: relapse within 6 months of first remisune
- Frequent relapses: two or more relapses within 6 months of first
remisune
- Steroid dependent after attack therapy - 4 week: relapse at the
end of the attack or the onset of therapy staple
- Initial steroid - resistant lack of response in the first 4 weeks after
the onset
- Secondary steroid - resistant: initial responder does not respond
to therapy later, after first relapse
- Nonresponder lack any response to therapy
- Remission: Urinary protein removal under 4mg/m2/hour, or trace
for 3 consecutive days
Steroid-dependent nephrotic syndrome therapy
1. Oral therapy with cyclophosphamide at a dose of 2-3 mg / kg / day
from 8 - 12 weeks can induce remission steroid-dependent nephrotic
syndrome
Precautions:
- Reduce the dose to 50 % when neutrophils are between 1500 1000/mmc
- Suspended therapy if neutrophils fall below 1000/mmc therapy
and/or if occurs significant cytotoxicity (neutropenia, hemorrhagic
cystitis, gonadal toxicity, rare secondary malignancies)
2. In steroid-dependent nephrotic syndrome can be used as
second-line therapy:
- Pulsterapie with MTP – 30mg/Kgbw/dailly
- Cyclosporine A 3-5 mg / kg / day , in two divided doses, 3 years
- Tacrolimus 0.05 - 0.1 mg / kg / day in 2 divided doses
- Mycophenolate mofetil 24-36 mg / kg / day or 1,200 mg/m2 / day
divided in 2 doses up to 3 years
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Follow-up therapy with cyclosporine dosing is done by initial serum 2 weeks after
initiation of therapy , the optimal level of 50-100 nmol / l initially. During therapy is
contraCy - grapefruit use and administration of macrolide antibiotics.
Steroid-resistant nephrotic syndrome therapy
Renal biopsy is necessary for classification. Subsequent regimens
should be individualized according to histology. Patients receive
supportive therapy associated immunosuppression.
Steroid-resistant nephrotic syndrome involves risk of complications
such as the progression to end-stage chronic kidney disease. The goal
of therapy is to achieve remission and preservation of renal function.
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Three broad categories of treatments are available for Steroidresistant nephrotic syndrome:
- immunosuppressive therapy include pulsterapie with MTP ,
calcineurin inhibitors , mycophenolate mofetil , alkylating agents
- immunostimulatory therapy include levamisole - dose 2.5 mg /
kg, up 150mg/zi. Effectiveness of therapy is determined by the
maximum of 4 weeks. If 's success continues up to 3 years. Side
effects include gastrointestinal upset, rash and severe neutropenia
- supportive therapy includes treatment with inhibitors of
angiotensin converting enzyme, angiotensin receptor (ARBs) and
vitamin E.
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Protocol KDIGO recommends:
- Therapy with calcineurin inhibitors (CyA , tacrolimus) if get full
remisiunes
- Extension of the calcineurin inhibitor therapy to 12 months if it
was a partial remission after 6 months
- Second-line therapy may be administered with low-dose
prednisone (0.25 mg / kg / day)
- In the absence of remision after one year can asssociate
mycophenolate mofetil therapy or pulsterapie of MTP, or
combinations of both immunosuppressive
- Not recommended CTX therapy in steroid-resistant nephrotic
syndrome
- For relapse after complete remision resume therapy using
oral corticosteroids or scheme under which there was
previously used for remiosion.
- Immunosuppressive doses and precautions are similar to those
recommended for steroid-dependent nephrotic syndrome
Management of complications
Hypertension:
- Sodium restrictions
- Exercise
- Weight loss if is associated obesity
- First line therapy consists of inhibitopri angiotensin converting
enzyme and angiotensin receptor
Obesity:
- Monitoring of BMI, stimulating sport for weight control
- Decreasing doses of glucocorticoids / change medications
Dyslipidemia:
- Low- fat diet containing < 30 % of the daily calorie intake
(saturated <10 % )
- Lipid-lowering statin class if the LDL cholesterol remains >
160mg/dl
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Infections are an important cause of morbidity and mortality in
children with nephrotic syndrome. Streptococcus pneumoniae is
the main bacteria involved in the genesis of peritonitis in
patients with primitive NS. In this respect pneumococcal
vaccination is recommended for all children with NS.
Prophylaxis with varicella-zoster virus is also required in these
children. In patients with onset varicella Acyclovir therapy is
indicated. Immunization was repeated every 5 years. Live
vaccines attenuated contraindicated during treatment with
corticosteroids and at least 3 months after.
Thromboembolism
Up to 25 % of children with NS have thromboembolic
complications. The risk seems to be greater in patients with
Steroid-resistant nephrotic syndrome to those with
corticosensibil NS. Specific therapy includes heparin, low
molecular weight heparin and oral anticoagulants. During
anticoagulant therapy encourage movement and contraindicate
rest time
EVOLUTION for NS with minimal damage:
-1/3 patients had a single episode
-1/3 patients have occasional relapses
-1/3 patients become steroid dependent after attack
period therapy
PROGNOSIS
- NS with minimal damage: favorable prognosis
- NS with histological lesions - depends to the etiology,
morphology and therapeutic response
- Secondary SN:
* good prognosis: allergic and toxic drug NS
* poor prognosis systemic diseases
References:
 1. O. Brumariu, Florentina Cucer, Sindromul nefrotic, în Hematologie și
nefrologie pediatrică, elemente practice de diagnostic și tratament,
editura Junimea, Iași, 2008, cap. 5, pag. 226 – 228
 2. KDIGO Clinical Practice Guideline for Glomerulonephrites, Chapter
3: Steroid-sensitive nephrotic syndrome in children, Kidney
International Supplements (2012) 2, 163–171;
 3. KDIGO Clinical Practice Guideline for Glomerulonephrites, Chapter
4: Steroid-resistant nephrotic syndrome in children, Kidney
International Supplements (2012) 2, 172–176;
 4. Nelson textbook of pediatrics - 18 ed. Behrman RE, Kliegman RM,
Jenson HB: Nephrotic Syndrome, cap. 527, pag. 2190 – 2195,
Saunders Elsevier, 2007.
 5. Patrick H. Nachman, J. Charles Jennette, Ronald J. Falk, Primary
Glomerular Disease, cap. 31, pag. 1100 – 1165, în BRENNER &
RECTOR’S THE KIDNEY, ediția 9, , Saunders Elsevier, 2012.
 6. Rees L., Brogan P., Bockenhauer D., Webb N., Glomerular disease,
în Pediatric Nephrology, Oxford Specialist Handbooks in Pediatrics,
second edition, cap. 9, pag. 181 – 224.