CASE REPORT Non-Infection Unit NEPHROTIC SYNDROME Presentator : Edwin B. Saragih Sejahtera Surbakti Supervisor : dr. Yazid Dimyati, Sp.A Date of presentation : 12 th April 2010 I. INTRODUCTION Definition NS is a common chronic disorder, characterized by alterations of permselectivity at the glomerular capillary wall, resulting in its inability to restrict the urinary loss of protein. Nephrotic range proteinuria is defined as proteinuria exceeding 1000 mg/m² per day or spot (random) urinary protein- tocreatinine ratio exceeding 2 mg/ml. The proteinuria in childhood nephrotic syndrome is relatively selective, constituted primarily by albumin. 1 The diagnosis of nephrotic syndrome requires the presence of edema, severe proteinuria (> 40 mg/m2/h, or a protein:creatinine ratio > 2.0), hypoalbuminemia (< 2.5 g/dl), and hyperlipidemia. 2 Table I. Common definition to define the course of nephrotic syndrome. 3 Nephrotic Oedema ; nephrotic range proteinuria (> 1
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CASE REPORT
Non-Infection Unit
NEPHROTIC SYNDROME
Presentator : Edwin B. Saragih
Sejahtera Surbakti
Supervisor : dr. Yazid Dimyati, Sp.A
Date of presentation : 12th April 2010
I. INTRODUCTION
Definition
NS is a common chronic disorder, characterized by alterations of permselectivity at the
glomerular capillary wall, resulting in its inability to restrict the urinary loss of protein.
Nephrotic range proteinuria is defined as proteinuria exceeding 1000 mg/m² per day or spot
(random) urinary protein-tocreatinine ratio exceeding 2 mg/ml. The proteinuria in childhood
nephrotic syndrome is relatively selective, constituted primarily by albumin.1 The diagnosis of
nephrotic syndrome requires the presence of edema, severe proteinuria (> 40 mg/m2/h, or a
protein:creatinine ratio > 2.0), hypoalbuminemia (< 2.5 g/dl), and hyperlipidemia.2
Table I. Common definition to define the course of nephrotic syndrome.3
Nephrotic syndrome Oedema ; nephrotic range proteinuria (> 40mg/m2/h on timed
sample, spot albumin to creatine ration > 2mg/mg ) ;
hypoalbuminaemia (<2.5g/dl)
Relapse Urinary protein excretion > 40mg/mg/m2/h ; ≥3+ by dipstick
for 3 consecutive days
Remission Urinary protein excretion < 4 mg/m2/h ; nil or trace by dipstick
on spot sample for 3 consecutive days
Frequent relapses Two or more relapses in 6 months of initial response ; 4 or
more relapses in any 12 month period
Steroid dependence Occurrence of 2 consecutive relapses during steroid therapy or
within 2 weeks of its cessation
1
Steroid resistance Failure to achieve remission after 4 weeks of daily therapy
with oral prednisolone at a dose of 2mg/kg/day
Epidemiology
The annual incidence of nephrotic syndrome has been estimated to range from 2 to 7 new
cases per 100 000 children, and the prevalence is about 16 cases per 100 000 children, or 1 in
6000 children.2 In Jakarta Indonesia, Wila Wirya reported 6 new cases per 100.000 children
younger than 14 years old, making it a relatively common major disease in pediatrics.4 In
younger children, boys are about twice as likely to develop nephrotic syndrome as girls, but this
imbalance disappears by adolescence such that the incidence in adolescents and adults is equal
among males and females. The histologic lesion associated with nephrotic syndrome also differs
between genders. In a large multicenter study of childhood nephrotic syndrome carried out by
the International Study of Kidney Disease in Children (ISKDC), females represented 39.9% of
children with minimal change nephrotic syndrome (MCNS) and 30.6% of those with focal
segmental glomerulosclerosis (FSGS). In marked contrast, females represented 64.1% of those
with membranoproliferative glomerulonephritis (MPGN).2
Familial occurrence of idiopathic nephrotic syndrome is also a well-recognized
phenomenon and the disorder has been reported in identical twins. In a report of 1877 children
with idiopathic nephrotic syndrome in Europe, 3.3% of children were found to have affected
family members, most often siblings. The disorder tended to occur in the siblings at the same
ages, and with similar biopsy findings and clinical outcomes. At least one locus for SSNS has
been mapped to chromosome 1q25, which is near, but distinct from, the NPHS2 gene locus
encoding the podocyte protein podocin.2
The peak age of presentation of nephrotic syndrome is 2 years, and 70–80% of cases of
nephrotic syndrome occur in children less than 6 years of age. Age of onset may also be
predictive of the underlying histologic lesion causing nephrotic syndrome. MCNS is seen in 80%
of children diagnosed with nephrotic syndrome before 6 years of age. In comparison, only 50%
of those with FSGS, and 2.6% of those with MPGN present before 6 years.12 In the same study,
the median age at presentation of MCNS was 3 years, compared with 6 years for FSGS, and 10
years for MPGN. These findings suggest that the likelihood of having MCNS decreases with
2
increasing age at onset, whereas the likelihood for having the less-favorable diagnoses of FSGS
or MPGN increases.2
Failure to respond to steroid treatment (SRNS) has an important ramification for the risk
of developing progressive renal failure later in life. Within 5 years of diagnosis, 21% of children
with FSGS developed ESRD and another 23% developed CKD. Thus, in a child diagnosed as
having FSGS, the risk of developing CKD or ESRD within 5 years is almost 50%.2
Although the overall prevalence of nephrotic syndrome has remained relatively stable
over the last 20 years, a dramatic increase in the incidence of FSGS and decrease in the incidence
of MCNS has been reported. The reported increased incidence of FSGS needs, however, to be
interpreted cautiously, since renal biopsies are generally obtained only in a preselected group of
children with atypical presentations, or those exhibiting steroid resistance. It is possible that an
increased incidence of FSGS merely represents the fact that a larger percentage of children with
SRNS undergo renal biopsies in the present era. This is in marked contrast to an early ISKDC
study where all children underwent a renal biopsy at the time of presentation, prior to the
institution of treatment. Because renal biopsies are no longer routinely performed in steroid-
responsive patients, it is unlikely that the ISKDC observations can be replicated.2
Pathogenesis
One of the kidney’s most important functions is filtration of the blood by glomeruli,
allowing excretion of fluid and waste products, while retaining all blood cells and the majority of
blood proteins within the bloodstream. Each glomerulus is composed of numerous capillaries
which have evolved to permit ultrafiltration of the fluid that eventually forms urine. The
capillary walls are composed of an inner endothelial cell cytoplasm, with pores known as
‘fenestrations’, the glomerular basement membrane (GBM), and outer glomerular epithelial cells
(podocytes) whose distal ‘foot’ processes are attached to the GBM. Under normal conditions,
molecules greater than 42 Å in diameter, or more than 200 kDa, are unable to cross the filtration
barrier.2
The role played by podocytes in glomerular function in renal disease and pathogenesis is
evolving. Several morphologic changes have been reported in podocytes in nephrotic syndrome.
These changes include cell swelling; retraction and effacement of the podocyte foot processes,
resulting in the formation of a diffuse cytoplasmic sheet along the GBM; vacuole formation;
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occurrence of occluding junctions with displacement of slit diaphragms; and detachment of the
podocyte from the GBM.8–10,12,20 These structural alterations in podocytes, often associated
with detachment from the underlying GBM have been shown to result in proteinuria.2
Proteinuria occurs due to increased glomerular permeability of proteins resulting from the
loss of fixed negative charges and inability of the proximal tubules to reabsorb all of the filtered
proteins. Mean glomerular pore size or density may be altered due to lack of electrostatic
interaction between glomerular capillaries and polyionic plasma proteins, such as albumin. [25] In
addition, the type of proteinuria appears to correlate with response to therapy. Patients with
highly selective proteinuria respond better to corticosteroids and are more likely to have minimal
change disease than those with nonselective proteinuria. In highly selective proteinuria, only
intermediate-sized proteins (< 100 kD), such as albumin and transferrin, leak through the
glomerulus; in nonselective proteinuria, a large range of proteins leak through the glomerulus. [9]
In the modern era, use of protein selectivity to predict response to therapy has been replaced by
observation of the response to corticosteroids in favorable populations, and renal biopsy and
electron microscope results in patients in less favorable subgroups.3
Clinical Features
The idiopathic nephrotic syndrome is more common in males than in females (2:1) and
most commonly appears between the ages of 2 and 6 yr. It has been reported as early as 6 mo of
age and throughout adulthood. The initial episode and subsequent relapses may follow minor
infections and, occasionally, reactions to insect bites, bee stings, or poison ivy. Children usually
present with mild edema, which is initially noted around the eyes and in the lower extremities.
Nephrotic syndrome may initially be misdiagnosed as an allergic disorder because of the
periorbital swelling that decreases throughout the day. With time, the edema becomes
generalized, with the development of ascites, pleural effusions, and genital edema. Anorexia,
irritability, abdominal pain, and diarrhea are common; hypertension and gross hematuria are
uncommon.5
a. Edema
Edema is the most profound symptom of the nephrotic syndrome. It may present in a
mild localized form or in a generalized fashion and also may be mobile, presenting as puffiness
of the eyelids that is worsened with lying down, especially in the morning upon awakening, and
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as lower extremity edema that is worse at the end of the day. Moreover, excess fluid may collect
internally and present as pleural or pericardial effusions and ascites. Subungual edema may
manifest as parallel white lines in the fingernail beds. In cases of severe edema, the patient may
have generalized swelling, or anasarca, which is usually pitting and worse in dependent areas of
the body such as the genitalia and lower extremities. Because of the excess body fluid, patients
generally report unexplained weight gain and fatigue. Edema of the nephrotic syndrome may be
a manifestation of hypoalbuminemia with increased water and salt retention, or it may be due to
a primary defect within the collecting tubule of the nephron that leads to uncontrolled water and
salt retention. Regardless of the pathophysiology of edema, it is important to consider other
conditions that present with edema and/or hypoalbuminemia.(Mira)
b. Hypoalbuminemia
In nephrotic syndrome, the serum concentration of albumin often is significantly low as it
is one of the smaller proteins and therefore is easily lost in the urine. When albumin appears in
the urine, the patient may complain of urine frothiness. Albumin synthesis is upregulated by the
liver because of the urinary losses, but the body’s compensatory mechanisms to maintain
albumin homeostasis are insufficient as urinary losses exceed hepatic production. (Mira)
c. Hyperlipidemia
The other characteristic findings in the nephrotic syndrome may present clinically as
medical complications. The hyperlipidemia associated with the syndrome is primarily due to
abnormal lipoprotein homeostasis that results in an increase in synthesis and decrease in
catabolism. Patients usually have elevations of total plasma cholesterol, triglyceride, very-low-
density lipoprotein (VLDL), and low-density lipoprotein (LDL). Dyslipidemia increases the risk
of atherosclerosis and cardiovascular disease in patients with the nephrotic syndrome, and
patients may present with complications of these diseases.6
d. Hypercoagulability
The hypercoagulable state associated with the nephrotic syndrome is caused by an
increased urinary loss of antithrombin III, altered activity and levels of proteins C and S,
increased hepatic synthesis of fibrinogen, and increased platelet aggregation. Clearly, these
5
conditions predispose patients to an increased risk of spontaneous thrombosis and embolism. In
adults, most thromboses are venous, while in children arterial thromboses are more common.
Renal vein thrombosis is present in approximately 30% of patients with the nephrotic syndrome,
and the rate is highest in patients with membranous glomerulopathy. The patient with acute renal
vein thrombosis can present with sudden onset of flank or abdominal pain, gross hematuria, and
an acute decline in renal function, but most patients are asymptomatic. In addition to renal vein
thrombosis, 20% to 30% of nephrotic patients develop pulmonary emboli. Strokes and
myocardial infarctions are also potential complications that can occur as a result of the
hypercoagulable state associated with the nephrotic syndrome.6
e. Immunocompromised State
The nephrotic syndrome is associated with increased urinary loss of immunoglobulins,
especially IgG, as well as defects in the complement cascade. Each of these defects weakens the
immune system and increases susceptibility to infections. The pneumococcal vaccine, commonly
given to patients with nephritic syndrome, may have limited efficacy due to a rapid decline of
antipneumococcal antibody levels.6
f. Anemia
Patients with nephrotic-range proteinuria have a tendency to lose different types of
proteins in the urine, including binding proteins. With transferrin loss due to proteinuria, patients
present with an iron-resistant microcytic hypochromic anemia. With progressive renal failure,
anemia may result from decreased renal synthesis of erythropoietin.6
Pathophysiology
The basic functional defect in NS is an increased permselectivity of the glomerular
filtration barrier (GFB) to molecules that ordinarily would not be filtered. Numerous factors
affect the filtration of molecules, such as properties of molecules themselves, the properties of
the filtration barrier, and hemodynamic factors. Properties of molecules themselves include the
size and the charge of the molecule. The GFB has a negative charge imparted to it by a heparin
sulfate proteoglycan that retards the transport of negatively charged molecules across the GFB
while facilitating the passage of positively charged molecules. The increase of permeability of
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the GFB can be caused by damage of many macromolecules, including degradation of heparin
sulfate. This damage is suggested to be caused at least in part, by free radicals . The extremely
short half life of free radicals seems that they cannot be measured directly and that oxidative
activity must be measured indirectly by the levels of antioxidant substances in the body.7
Yet, in the nephrotic syndrome, the pathogenesis of edema is still a matter of controversy,
as several studies have given results that are inconsistent with the postulate that
hypoalbuminemic patiens have a contracted (‘under filled’) intravascular space. Although the
interpretation of these investigations has been challenged, the fact remains that only some
patients, especially children with minimal-change nephrotic syndrome (MCNS), as evidenced by
decreased blood volume, stimulated rennin-angiotensin-aldosteron secretion, and head-out water
immersion. In contrast, most patients with nephritic syndrome have evidence for a renal defect in
sodium excretion and thus have evidence of an expanded (‘overfilled’) plasma volume. Indeed, a
reduction in urinary sodium excretion can be shown to occur in the incipient stage of adults with
relapsing MCNS and in experimental nephritic syndrome coincident with the proteinuria, but
prior to fall in plasma albumin and PCOP.8
The interstitial inflamation of the kidney has a key role in the pathogenesis of nephrotic
edema by inducing primary sodium retention. The generation of vasoconstrictive substances in
the interstitium, driven by the inflammatory cell infiltrate, may influence sodium handling at
both the glomerular and tubular level, resulting in both decreased sodium filtration and increased
net sodium reabsorption. It should be recognized that tubulointerstitial mononuclear cell
infiltration is not always associated with sodium retention. For example, natriuresis follows the
release of urinary obstruction, an effect that may be mediated by the effect of interleukin-1 (IL-1)
in a collecting duct. IL-1 is a well-known macrophage product; therefore, the net effect of the
inflammatory infiltrate in urinary sodium excretion would depend on the secretory phenotype of
the infiltrating cells.8
Clearly, there is also a key role for the reduction in PCOP in the pathogenesis of edema.
Thus, hypoalbuminemia effectively buffers the hemodynamic effects of acute increments in
blood volume as the fluid overload is sequestered into the tissues and is responsible for the fact
that while patients with acute glomerulonephritis show a steep relationship between weight gain
and the humoral response, indicating plasma expansion, the patients with nephrotic syndrome do
not. This could help explain why many nephrotic subjects do not show hypertension, especially
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those with severe proteinuria and hypoalbuminemia. Low PCOP and primary sodium retention
combine to overwhelm the mecanisms protecting from changes in interstitial volume and drive
the development of edema.8
Investigation
Investigations at Initial Presentation9
a) Full blood count, blood levels of albumin,Cholesterol.
b) Renal profile: urea & creatinine.
c) Blood level of antistreptolysin O and C3.
d) Urinalysis and Quantification for urinary protein excretion and culture and sensitivity
e) X-ray chest, Montaux test, Hepatitis B surface antigen.
Other investigations depends on the clinical features and the physician in charge.
The international study of kidney Disease in children (ISKDC) had found that at the initial
presentation of children with minimal change nephrotic syndrome.
a. 20.7% of children had systolic blood pressure above 98th percentile for age ,
b. 22.7% had microscopic haematuria,
c. 32.5% had transiently raised plasma creatinine concentration.
Methods Available to Test for Proteinuria10
Method Indications Normal Range Comments
Dipstick testing Routine screening for proteinuriaperformed in the
office
Negative or trace in aconcentrated urine specimen
False–positive test can occur ifurine is very alkaline (pH<.8.0) or very concentrated(specific gravity:
<.1.025)
24-h urine for proteinand creatinineexcretion
Quantitation of proteinuria (aswell as creatinine
clearances)
,100 mg/m2/24 h in adocumented 24-h
collection
More accurate than spot urineanalysis. Inconvenient forpatient. Limited use inpediatric practice
8
Spot urine for protein/creatinine ratio—preferably on firstmorning urinespecimen
Semiquantitative assessment ofProteinuria
,.2 mg protein/mg creatinine inchildren .2 y old,.5 mg protein/mg creatinine inthose 6–24 mo old
Simplest method to quantitateproteinuria. Less accurate thanmeasuring 24-h
proteinuria
Microalbuminuria Assess risk of progressiveglomerulopathy in patientswith diabetes mellitus
,30 mg urine albumin/gcreatinine on first morningurine
Therapy should be intensified indiabetics withmicroalbuminuria
Treatment of Initial Presentation of Nephrotic Syndrome
Since proteinuria is the main manifestation of nephritic syndrome and the cause of its
complications, several measures should be implemented to help reduce the proteinuria. The use
of angiotensin-converting enzyme inhibitors is the most important intervention, even in
normotensive patients. In addition, a low-protein diet has been shown to help reduce the
proteinuria, with a recommended daily protein intake of 0.7 g/kg/day. Patients should be
carefully monitored, however, to avoid malnutrition.6
a. Prednisolone
When the diagnosis of nephrotic syndrome has been made, prednisolone treatment can be
started in children with typical features. Children with atypical features should be referred to
paediatric nephrology for consideration of renal biopsy.
There is increasing evidence that longer initial courses of prednisolone are associated
with a lower incidence of relapse, and therefore a 12-week initial course is recommended. The
dose of prednisolone is based on surface area.11,12
• 60 mg/m2/day for 4 weeks (maximim 80 mg)
• 40 mg/m2/on alternate days for 4 weeks (maximum 60mg)
• Reduce dose by 5-10mg/m2 each week for another 4 weeks then stop
Prednisolone can be given as a single dose in the morning with food, or as divided doses
during the day. Patients should be issued with a steroid warning card, and they should be aware
of the side effects and risks of steroid treatment. Varicella status should be documented clearly in
9
the casenotes and on HISS. If prednisolone causes gastric irritation, start ranitidine 2mg/kg bid
for the duration of steroid treatment.11
b. Albumin
As discussed above the clinical indications for albumin are
• Clinical hypovolaemia
• Symptomatic oedema
A low serum albumin alone is not an indication for intravenous albumin.
If there is evidence of hypovolaemia, give 1 g/kg 20% albumin (5ml/kg) over 4 - 6 hours. Give
2mg/kg of iv frusemide mid-infusion. If clinically shocked give 10ml/kg 4.5% albumin. Children
should be closely monitored during albumin infusions, and where possible they should be
administered during working hours.11
c. Penicillin Prophylaxis
Whilst nephrotic, children are at increased risk of infection, particularly with
encapsulated organisms such as pneumococcus. There is no evidence that antibiotic prophylaxis
is of benefit, and some centres do not use prophylaxis. Penicillin V can be given while there is
proteinuria and discontinued when the child goes into remission. Grossly oedematous children
are at risk of cellulitis and may benefit from antibiotic prophylaxis.
Dose: Under 5 yrs 125 mg bid
5yrs or above 250 mg bid11
d. Salt/Fluid Restriction
A low salt diet is used to try to prevent further fluid retention and oedema.11 Patients are
advised to limit their sodium chloride intake to 2 g/day.6 Fluid restriction may also be helpful.
These restrictions are lifted once the child goes into remission.11 For mild cases of edema, salt
restriction is coupled with a mild diuretic such as a thiazide.6 Loop diuretic like furosemide 1-3
mg/kgbw/day is given, if necessary, furosemide can be combined with spironolactone
(aldosteron antagonis, potassium thrifty diuretic) 2-4 mg/kgbw/day. Before giving diuretic,
10
hypovolemia condition must be excluded. After using diuretic in 1-2 weeks, blood sodium and
potassium must be checked.12
e. Dietary Management
Although some benefit from dietary protein restriction has been described in a small
series of children with chronic renal insufficiency, a recent controlled study has not demonstrated
a significant impact of protein restriction on the rate of progression of renal disease. However, it
seems reasonable to avoid an excess of dietary protein in children with proteinuric renal diseases,
because high dietary protein intake may actually worsen proteinuria, at least in some patients
with nephrotic syndrome (NS), and does not result in a higher serum albumin. Thus, it is
recommended that children with proteinuria receive the recommended daily allowance of protein
for age.10 The necessity of protein diet according to RDA is 1,5-2 g/kgbw/day.12
f. Vaccination
Pneumococcal vaccination is recommended for children with NS. Consider giving at the
time of diagnosis. Varicella vaccination is only available on a named patient basis.11
g. Hyperlypidemia
The hyperlipidemia associated with the nephrotic syndrome may be managed with
nonpharmacologic interventions such as the use of soy protein diet to lower the total cholesterol
and LDL levels. The use of fish oil has been shown to lower triglycerides and VLDL. Statins are
the mainstay of treatment as they have been proven to reduce LDL levels.6
hs. Hypertension Management
● control blood pressure to 90th percentile of normal
● recommend low-salt diet, exercise, and weight reduction if obesity is present; and
● ACE-Is and/or ARBs for chronic pharmacologic management.
Hypertension is present in 13% to 51% of children with nephrotic syndrome. Blood
pressure generally improves with remission of nephrotic syndrome. When antihypertensive
11
therapy is indicated, the expected reduction in proteinuria and blood pressure with ACE-I or
ARB agents make them first-line agents.13
Complications
a. Infection
Prophylaxis of S pneumoniæ with oral penicillin is often applied in patients during the
initial treatment with corticosteroids. Pneumococcal vaccine may be performed and is not
associated with an increased risk of relapse. In cases of peritonitis, antibiotics against both
S.pneumonia and gram-negative organisms are started after peritoneal liquid sampling. Varicella
is a serious disease in patients receiving immunosuppressive treatment or daily corticosteroids.
Varicella immunity status should be checked in these patients. In cases of exposure, early
preventive treatment by acyclovir must be instituted. Varicella vaccination is safe and effective if
the child is in remission even if he is on low-dose alternate day steroids.14
b. Acute renal failure
Acute renal failure (ARF) is another complication of nephrotic syndrome that occurs in a
small percentage of children.2 Renal function is usually within normal limits at presentation. A
reduction of the GFR, secondary to hypovolemia, infection or thrombosis is frequent. A reduced
GFR may be found in patients with normal effective plasma flow.14 Possible explanations for this