Nephrotic Syndrome
Introduction.
Nephrotic syndrome is the clinical manifestation of glomerular
diseases associated with heavy (nephrotic-range) proteinuria.
Nephrotic range proteinuria is defined as proteinuria >3.5 g/24 hr
or a urine protein : creatinine ratio >2.
The triad of clinical findings associated with nephrotic
syndrome arising from the large urinary losses of protein are
hypoalbuminemia (≤2.5 g/dL),
edema, and
hyperlipidemia (cholesterol >200 mg/dL).
Nephrotic syndrome affects 1-3 per 100,000 children <16yr of
age.
Without treatment: high risk of death (most commonly from
infections).
80% of children with nephrotic syndrome respond to corticosteroid
therapy.
mechanism of action of steroids has been determined.
ETIOLOGY
Most children with nephrotic syndrome have primary or idiopathic
nephrotic syndrome.
Glomerular lesions associated with idiopathic nephrotic syndrome
include
minimal change disease (the most common),
focal segmental glomerulosclerosis,
membranoproliferative glomerulonephritis,
C3 glomerulopathy,
membranous nephropathy
Nephrotic syndrome may also be secondary to systemic diseases
such as
Systemic lupus erythematosus,
Henoch-Schönlein purpura,
Malignancy (lymphoma and leukemia), and
Infections (Endocarditis, Hepatitides B, C, HIV-1, Infectious mononucleosis,
Malaria, Syphilis (congenital and secondary), Toxoplasmosis,
Schistosomiasis, Filariasis
GENETIC DISORDERS ASSOCIATED WITH PROTEINURIA OR
NEPHROTIC SYNDROME
Nephrotic Syndrome (Typical)
Finnish-type congenital nephrotic syndrome (absence of nephrin)
Focal segmental glomerulosclerosis (mutations in nephrin, podocin,
MYO1E, α-actinin 4, TRPC6)
Diffuse mesangial sclerosis (mutations in laminin β2 chain)
Denys-Drash syndrome (mutations in WT1 transcription factor)
Congenital nephrotic syndrome with lung and skin involvement (integrin α-
3 mutation)
Mitochondrial disorders
PATHOGENESIS
I. Role of the Podocyte
The podocyte is a highly differentiated epithelial cell located on the
outside of the glomerular capillary loop.
The podocyte functions as structural support of the capillary loop, is a
major component of the glomerular filtration barrier to proteins, and
is involved in synthesis and repair of the glomerular
basement membrane.
increased permeability of the glomerular capillary wall, which
leads to massive proteinuria and hypoalbuminemia.
Foot processes are extensions of the podocyte that terminate on the glomerular
basement membrane.
The foot processes of a podocyte interdigitate with those from adjacent podocytes
and are connected by a slit called the slit diaphragm.
The slit diaphragm is one of the major impediments to protein permeability across
the glomerular capillary wall.
Slit diaphragms are not simple passive filters—they consist of numerous proteins
that contribute to complex signaling pathways and play an important role in
podocyte function.
Important component proteins of the slit diaphragm include nephrin, podocin,
CD2AP, and α-actinin 4.
Podocyte injury or genetic mutations of genes producing podocyte proteins may
cause nephrotic-range proteinuria.
In idiopathic, hereditary, and secondary forms of nephrotic syndrome,
there are immune and nonimmune insults to the podocyte that lead
to
foot process effacement of the podocyte,
a decrease in number of functional podocytes, and
altered slit diaphragm integrity.
The end result is increased protein “leakiness” across the glomerular
capillary wall into the urinary space.
II. Role of the Immune System
Minimal change nephrotic syndrome (MCNS) may occur after viral
infections and allergen challenges.
MCNS has also been found to occur in children with Hodgkin lymphoma
and T-cell lymphoma.
That immunosuppressive treatment with drugs such as corticosteroids and
cyclosporine provides indirect additional evidence that the immune system
contributes to the overall pathogenesis of the nephrotic syndrome.
CLINICAL CONSEQUENCES OF
NEPHROTIC SYNDROME
Edema
Edema is the most common presenting symptom of children
with nephrotic syndrome.
Despite its almost universal presence, there is uncertainty as
to the exact mechanism of edema formation.
There are 2 opposing theories,
The underfill hypothesis and
The overfill hypothesis,
The underfill hypothesis: nephrotic-range proteinuria leads to a fall in the
plasma protein level with a corresponding decrease in intravascular oncotic
pressure
leakage of plasma water into the interstitium >> reduced
intravascular volume >> increased secretion of vasopressin and
atrial natriuretic factor and aldosterone >> result in increased
sodium and water retention by the tubules.
Treating these patients with albumin alone may not be sufficient to induce a
diuresis without the concomitant use of diuretics.
Also, reducing the renin–aldosterone axis with mineralocorticoid receptor
antagonists does not result in a marked increase in sodium excretion.
The overfill hypothesis postulates that nephrotic syndrome is
associated with primary sodium retention, with subsequent volume
expansion and leakage of excess fluid into the interstitium.
The clinical weaknesses of this hypothesis are evidenced by the
numerous nephrotic patients who present with an obvious clinical
picture of intravascular volume depletion: low blood pressure,
tachycardia, and elevated hemoconcentration.
Furthermore, amiloride, an epithelial sodium channel blocker, used
alone is not sufficient to induce adequate diuresis.
The goal of therapy should be a gradual reduction of edema with
judicious use of diuretics, sodium restriction, and cautious use of
intravenous albumin infusions, if indicated.
Hyperlipidemia
increase in cholesterol,
triglycerides,
low-density lipoprotein, and
very-low-density lipoproteins.
Hyperlipidemia is thought to be the result of increased synthesis as
well as decreased catabolism of lipids.
Although commonplace in adults, the use of lipid-
lowering agents in children is uncommon.
Increased Susceptibility to Infections
Increased susceptibility to infections such as
cellulitis,
spontaneous bacterial peritonitis, and
bacteremia.
Mainly results from urinary losses of immunoglobulin (Ig) G.
Urinary loss of complement factors (predominantly C3 and C5), as well as
alternative pathway factors B and D, lead to impaired opsonization of
microorganisms.
Children with nephrotic syndrome are at significantly increased risk for infection
with encapsulated bacteria and, in particular, pneumococcal disease.
Spontaneous bacterial peritonitis presents with fever, abdominal
pain, and peritoneal signs.
Pneumococcus, Gram-negative bacteria
Children with nephrotic syndrome and fever or other signs of infection
must be evaluated aggressively, with appropriate cultures drawn, and
should be treated promptly and empirically with antibiotics.
Hypercoagulability
results from multiple factors:
vascular stasis from hemo concentration and intravascular volume depletion,
increased platelet number and aggregability, and
changes in coagulation factor levels. (increase in hepatic production of
fibrinogen, urinary losses of antithrombotic factors such as antithrombin III
and protein S.
Deep venous thrombosis:
the cerebral venous sinus,
renal vein, and pulmonary veins.
The clinical risk is low in children (2-5%) compared to adults,
Idiopathic Nephrotic Syndrome
Approximately 90% of children with nephrotic syndrome have
idiopathic nephrotic syndrome.
Idiopathic nephrotic syndrome is associated with primary
glomerular disease without an identifiable causative disease
or drug.
Idiopathic nephrotic syndrome includes multiple histologic types:
minimal change disease,
mesangial proliferation,
focal segmental glomerulosclerosis,
membranous nephropathy,
membranoproliferative glomerulonephritis.
PATHOLOGY
Minimal change nephrotic syndrome (MCNS)
(approximately 85% of total cases of nephrotic syndrome in children),
the glomeruli appear normal or show a minimal increase in mesangial
cells and matrix.
on immunofluorescence microscopy: negative,
electron microscopy: effacement of the epithelial cell foot processes.
More than 95% of children with minimal change disease respond to
corticosteroid therapy.
Mesangial proliferation
light microscopy: diffuse increase in mesangial cells and matrix
Immunofluorescence microscopy: might reveal trace to 1+ mesangial IgM
and/or IgA staining.
Electron microscopy: increased numbers of mesangial cells and matrix as
well as effacement of the epithelial cell foot processes.
Approximately 50% of patients with this histologic lesion respond
to corticosteroid therapy.
Focal segmental glomerulosclerosis (FSGS),
glomeruli show lesions that are both focal (present only in a proportion of
glomeruli) and segmental (localized to ≥1 intraglomerular tufts).
light microscopy: mesangial cell proliferation and segmental scarring
Immunofluorescence microscopy: positive for IgM and C3 staining in the
areas of segmental sclerosis.
Electron microscopy: segmental scarring of the glomerular tuft with
obliteration of the glomerular capillary lumen.
Similar lesions may be seen secondary to HIV infection, vesicoureteral
reflux, and intravenous use of heroin and other drugs of abuse.
Only 20% of patients with FSGS respond to prednisone.
MINIMAL CHANGE NEPHROTIC
SYNDROME
Clinical Manifestations
The idiopathic nephrotic syndrome is more common in boys than in
girls (2:1) and most commonly appears between the ages of 2 and 6
yr.
MCNS is present in 85-90% of patients <6 yr of age.
MCNS: in adolescents only 20-30% ( common cause being FSGS
at this age)
usually follows minor infections and, reactions to insect bites,
beestings, or poison ivy.
Edema periorbital and on lower extremity, progressively becomes
generalized
Anorexia, irritability, abdominal pain, and diarrhea are common.
Important features of minimal change idiopathic nephrotic
syndrome are the absence of hypertension and gross
hematuria (the so-called nephritic features).
The differential diagnosis
protein-losing enteropathy,
hepatic failure,
heart failure,
acute or chronic glomerulonephritis, and
protein malnutrition.
A diagnosis other than MCNS should be considered in
children <1 yr of age,
with a positive family history of nephrotic syndrome,
presence of extrarenal findings (e.g., arthritis, rash, anemia),
hypertension
acute or chronic renal insufficiency, and
gross hematuria.
Diagnosis
The diagnosis of nephrotic syndrome is confirmed by
urinalysis with first morning urine protein : creatinine ratio and
serum electrolytes,
blood urea nitrogen,
creatinine,
albumin,
and cholesterol levels;
Evaluation to rule out secondary forms of nephrotic syndrome (children
≥10 yr): complement C3 level, antinuclear antibody, anti-double-stranded
DNA and hepatitides B and C, and HIV in high-risk populations; and kidney
biopsy (for children ≥10 yr, who are less likely to have MCNS).
The urinalysis reveals 3+ or 4+ proteinuria, and
microscopic hematuria is present in 20% of children.
A spot urine protein : creatinine ratio should be >2.0.
The serum creatinine value is usually normal,
The serum albumin level is <2.5 g/dL, and serum cholesterol and
triglyceride levels are elevated.
Serum complement levels are normal.
A renal biopsy is not routinely performed if the patient fits the
standard clinical picture of MCNS.
Treatment
first episode of nephrotic syndrome and mild to moderate edema may be
managed as outpatients.
uncomplicated nephrotic syndrome between 1 and 8 yr of age are likely to
have steroid-responsive MCNS :
steroid therapy
Tuberculosis must be ruled out prior to starting immunosuppressive
therapy with corticosteroids
Use of Corticosteroids to Treat Minimal Change
Nephrotic Syndrome(KDIGO 2012)
Treatment of Initial Episode of Nephrotic Syndrome
MCNS: prednisone or prednisolone : single daily dose of 60 mg/m2/day or 2
mg/kg/day to a maximum of 60 mg daily for 4-6 wk followed by
alternate-day prednisone 40 mg/m2 qod or 1.5 mg/kg qod) for 8 wk - 5 mo,
with tapering of the dose.
Watch out side effecs (cushingoid appearance, hypertension, cataracts, and/ or
growth failure).
Approximately 80-90% of children respond to steroid therapy.
Response is defined as the attainment of remission within the initial 4 wk of
corticosteroid therapy.
Remission consists of a
urine protein : creatinine ratio of <0.2 or
<1+ protein on urine dipstick for 3 consecutive days.
The vast majority of children who respond to prednisone therapy do
so within the first 5 wk of treatment.
Managing the Clinical Sequelae of Nephrotic Syndrome
Edema.
severe symptomatic edema (large pleural effusions, ascites, or severe
genital edema) : hospitalization needed
sodium restriction (<1500 mg daily),
water/fluid restriction: if hyponatremic.
elevate swollen scrotum
Diuresis with loop diuretics (furosemide), orally or intravenously,
Aggressive diuresis can lead to intravascular volume depletion and an
increased risk for acute renal failure and intravascular thrombosis.
Severe generalized edema with evidence of intravascular volume depletion (e.g.,
hemoconcentration, hypotension, tachycardia), IV administration of 25%
albumin (0.5-1.0 g albumin/kg) as a slow infusion followed by furosemide (1-2
mg/kg/ dose IV)
Needs close monitoring of
volume status,
blood pressure,
serum electrolyte balance,
renal function.
Complication : Symptomatic volume overload,
hypertension,
heart failure,
pulmonary edema,
Dyslipidemia.
low-fat diet: Dietary fat <30% of calories (saturated fat intake <10%
calories).
Dietary cholesterol intake should be <300 mg/day.
Infections.
cellulitis, peritonitis, and bacteremia.
Appropriate investigation
Pneumococcus and Gram-negative bacteria.
A 3rd-generation cephalosporin is a common choice of IV antibiotic.
Thromboembolism.
imaging studies
Studies to delineate a specific underlying hypercoagulable state are
recommended.
Anticoagulation therapy
heparin, low-molecular-weight heparin, and warfarin are therapeutic
options.
Obesity and Growth.
Glucocorticoids related overweight and obesity
Growth may be affected in children who require long-term corticosteroid
therapy.
Relapse of Nephrotic Syndrome
Relapse of nephrotic syndrome is defined as a
urine protein : creatinine ratio of >2 or
≥3+ protein on urine dipstick testing for 3 consecutive days.
Relapses are common,
Treatment is similar to the initial episode, except that daily
prednisone courses are shortened.
Daily high-dose prednisone is given until the child has
achieved remission, and the regimen is then switched to alternate-
day therapy.
The duration of alternate day therapy varies depending on the
frequency of relapses of the individual child.
Infrequent relapsers: One relapse within 6 months of initial
response, or one to three relapses in any 12-month period
Frequent relapsers: Frequent relapse Two or more relapses within 6
months of initial response, or four or more relapses in any 12-month
period
Steroid dependent: Two consecutive relapses during corticosteroid
therapy, or within 14 days of ceasing therapy.
Steroid Resistance.
Steroid resistance is defined as the failure to achieve remission
after 8 wk of corticosteroid therapy.
diagnostic kidney biopsy,
evaluation of kidney function, and
quantitation of urine protein excretion (in addition to urine dipstick
testing).
Steroid-resistant nephrotic syndrome is usually caused by FSGS
(80%), MCNS, or membranoproliferative glomerulonephritis.
Steroid-resistant nephrotic syndrome: 50% risk for end-stage
kidney disease within 5 yr of diagnosis
Persistent nephrotic syndrome is associated with
poor patient reported quality of life,
hypertension, serious infections,
thromboembolic events.
Children reaching end-stage kidney disease have a greatly reduced
life expectancy compared to their peers.
Alternative Therapies to Corticosteroids in the Treatment of Nephrotic
Syndrome.
Steroid-dependent patients,
frequent relapsers, and
steroid-resistant patients
severe corticosteroid toxicity (cushingoid appearance, hypertension,
cataracts, and/ or growth failure).
Cyclophosphamide (2 mg/kg) is given as a single oral dose for a total
duration of 8-12 wk.
The cumulative threshold dose above which oligospermia or azoospermia
occurs in boys is >250 mg/kg.
Side effects of the drug (neutropenia, disseminated varicella, hemorrhagic
cystitis, alopecia, sterility, increased risk of future malignancy)
Calcineurin inhibitors (cyclosporine or tacrolimus) are
recommended as initial therapy for children with steroid-
resistant nephrotic syndrome.
side effects: hypertension, nephrotoxicity, hirsutism, and gingival
hyperplasia.
Mycophenolate: (steroid-dependent or frequently relapsing
nephrotic syndrome)
Levamisole: reduce the risk of relapse
High chance of relapse when the medication is discontinued.
Angiotensin-converting enzyme inhibitors and angiotensin II receptor
blockers
Immunizations in Children with Nephrotic Syndrome.
pneumococcal vaccination
influenza vaccination annually to the child and their household contacts;
defer vaccination with live vaccines until the prednisone dose is below
either 1 mg/kg daily or 2 mg/kg on alternate days.
Live virus vaccines are contraindicated in children receiving
corticosteroidsparing agents such as cyclophosphamide or cyclosporine.
(varicella-zoster immune globulin)
Prognosis
repeated relapses during childhood,
Rapid response to steroids and no relapses during the first 6 mo after
diagnosis: are likely to follow an infrequently relapsing course.
Steroid -responsive nephrotic syndrome is
unlikely to develop chronic kidney disease,
the disease is rarely hereditary,
the child (in the absence of prolonged cyclophosphamide therapy) will
remain fertile.
Participation in all age-appropriate childhood activities
unrestricted diet when in remission
Steroid-resistant nephrotic syndrome (most often caused by FSGS):
poorer prognosis.
dialysis or kidney transplantation mostly will be required
Recurrent nephrotic syndrome develops in 30-50% of transplant
recipients with FSGS.
