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 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/m 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 ) ; Relapse Remission Frequent relapses Steroid dependence Steroid resistance hypoalbuminaemia (<2.5g/dl) Urinary protein excretion > 40mg/mg/m2/h ; 3+ by dipstick for 3 consecutive days Urinary protein excretion < 4 mg/m2/h ; nil or trace by dipstick on spot sample for 3 consecutive days Two or more relapses in 6 months of initial response ; 4 or more relapses in any 12 month period Occurrence of 2 consecutive relapses during steroid therapy or within 2 weeks of its cessation Failure to achieve remission after 4 weeks of daily therapy with oral prednisolone at a dose of 2mg/kg/day
1

Definition

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 7080% 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 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 steroidresponsive patients, it is unlikely that the ISKDC observations can be replicated.2 Pathogenesis One of the kidneys 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 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; occurrence of occluding junctions with displacement of slit diaphragms; and detachment of the

podocyte from the GBM.810,12,20 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 as lower extremity edema that is worse at the end of the day. Moreover, excess fluid may collect
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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 bodys 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-lowdensity 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 conditions predispose patients to an increased risk of spontaneous thrombosis and embolism. In
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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 the GFB can be caused by damage of many macromolecules, including degradation of heparin
6

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 those with severe proteinuria and hypoalbuminemia. Low PCOP and primary sodium retention
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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 Negative or trace in a proteinuria concentrated urine performed in the specimen office

Falsepositive test can occur if urine is very alkaline (pH <.8.0) or very concentrated (specific gravity:

24-h urine for protein and creatinine excretion

Spot urine for protein/ creatinine ratio preferably on first

<.1.025) Quantitation of ,100 mg/m2/24 h in a More accurate than proteinuria (as documented 24-h spot urine well as creatinine analysis. Inconvenient collection for clearances) patient. Limited use in pediatric practice Semiquantitative ,.2 mg protein/mg Simplest method to assessment of creatinine in quantitate Proteinuria children .2 y old proteinuria. Less
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morning urine specimen Microalbuminuria Assess risk of progressive glomerulopathy in patients with diabetes mellitus

,.5 mg protein/mg creatinine in those 624 mo old ,30 mg urine albumin/g creatinine on first morning urine

accurate than measuring

24-h

proteinuria Therapy should be intensified in diabetics with microalbuminuria

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 the casenotes and on HISS. If prednisolone causes gastric irritation, start ranitidine 2mg/kg bid for the duration of steroid treatment.11
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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, hypovolemia condition must be excluded. After using diuretic in 1-2 weeks, blood sodium and potassium must be checked.12

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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 therapy is indicated, the expected reduction in proteinuria and blood pressure with ACE-I or ARB agents make them first-line agents.13 Complications
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a. Infection Prophylaxis of S pneumoni 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 include: renal vein thrombosis, reduced renal perfusion, acute tubular necrosis, interstitial edema within the renal parenchymal bed, and alterations in glomerular permeability. A recent report of 11 children with biopsy-proven MCNS with oliguric ARF found that alterations in glomerular permeability played a greater role than that of reduced renal perfusion in these patients.2 Marked oliguria may occur in children. Oliguric renal failure may be the presenting symptom. Renal failure may be secondary to bilateral renal vein thrombosis, which is recognized by sonography or to interstitial nephritis which has been reported, especially with furosemide. Skin rash and eosinophilia are suggestive of this diagnosis.14 Acute renal failure is usually reversible, often with high dose furosemide induced diuresis, especially with intravenous infusion of albumin. In some cases, where glomerular structure is normal on initial histology, renal failure may last for as long as a year and sometimes be irreversible.14 c. Thromboembolism Thromboembolism is a potentially life-threatening complication of nephrotic syndrome. The incidence of thromboembolism in children has been reported to range from 1.8 to 5%, with
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the incidence being twice as high among children with SRNS as compared with SSNS. It is possible that this complication is underestimated in children due to subclinical manifestations. In one study of 26 children with SSNS who were systematically evaluated by ventilationperfusion scans to look for pulmonary emboli, findings consistent with pulmonary embolism were reported in 28% of children.2 The majority of episodes of thrombosis in children are venous in origin, although arterial thrombosis has been reported in 1945% of cases. The most common sites for thrombosis are the deep leg veins, inferior vena cava, and ileofemoral veins, although a variety of other veins and arteries have been reported to be affected. In addition, central venous catheters, which are sometimes used in the management of patients with refractory nephrotic syndrome with poor vascular access, can further increase the risk of thrombosis.2 Pain and swelling of an extremity is suggestive of a deep venous thrombosis, and upper extremity swelling accompanied by neck and facial swelling in the setting of a central venous catheter should raise clinical suspicions for a central venous thrombosis. Similarly, development of acute renal failure or gross hematuria should prompt a renal Doppler ultrasonographic evaluation for possible renal vein or inferior vena cava thrombosis. Finally, development of respiratory distress or cardiovascular symptoms should prompt evaluation by chest X-ray and consideration of a ventilationperfusion or chest CT scan to exclude possible pulmonary embolus.2 d. Respiratory distress In some patients, initiation of an albumin infusion in the setting of anasarca can lead to the development of acute respiratory distress. Most often this is a result of rapid return of interstitial fluid to the intravascular space, resulting in development of pulmonary edema. Highrisk patients include those with severe edema, those receiving albumin without adequate diuretics, and those with compromised renal function. However, other causes for respiratory distress, such as pleural effusion and pulmonary thromboembolism, should also be considered in any child with nephrotic syndrome who develops tachypnea or hypoxia. In the clinical setting of pleural effusion with respiratory compromise, hospitalization for monitoring and diuresis (often with albumin) is usually necessary. As noted above, in the setting of systematic screening of

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asymptomatic children with nephrotic syndrome using ventilation perfusion scans, 28% of children had findings consistent with pulmonary embolism.2 e. Anemia Chronic nephrotic syndrome can also lead to the development of anemia. This is thought to be due primarily to the loss of both erythropoietin and transferrin into the urine. These losses, in combination with a reduced serum half-life for erythropoietin, and increased transferrin catabolism, can result in the development of an erythropoietin-responsive anemia or iron deficiency in patients who remain chronically nephrotic. Although treatable with erythropoietin, induction of remission of the nephrotic syndrome is the most effective approach to correct the anemia.2 Prognosis Likelihood of achieving remission It is generally accepted that the initial response to corticosteroids (i.e. induction of complete remission) is the single best indicator of the long-term prognosis for a child presenting with nephrotic syndrome, as children who fail to respond to an 8 week course of oral corticosteroids have a guarded prognosis. Steroid response has been reported to correlate with renal biopsy findings if done at disease outset prior to the institution of treatment. In these early studies, while overall steroid responsiveness was seen in 78% of newly-diagnosed children treated with corticosteroids, the likelihood of achieving remission varied greatly by histologic diagnosis. Steroid responsiveness was 93% for MCNS, 30% for FSGS, 56% for mesangial proliferative glomerulonephritis, 7% for MPGN, and 0% for membranous nephropathy. In addition, the likelihood of steroid responsiveness was decreased in older children, possibly related to the increasing incidence of the steroid-resistant glomerulopathies in later childhood. This was supported by the findings that the median ages for clinical presentation with MCNS, FSGS, and MPGN were 3 years, 6 years and 10 years old, respectively.2 Relapse rate Relapses of nephrotic syndrome occur commonly in SSNS. Only 30% patients with SSNS will never experience a relapse, although the overall tendency to relapse decreases with
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time. A large study of MCNS found that there was a gradual tendency toward an increase in the number of non-relapsing patients over time, reaching 80% eight years after onset of disease. Moreover, 75% of those patients who remained relapse-free for the initial six months after treatment either continued in remission during their entire course or relapsed only rarely. Such findings suggest that while the majority of children (60%) with nephrotic syndrome experience one or more relapses, most patients experience a gradual decrease in the frequency of relapses over time.2 ESRD and transplant recurrence risk Non-responsiveness to corticosteroids clearly identifies those patients at high risk for progressive kidney disease. In one large study of 389 children with nephrotic syndrome, 21% of children with biopsy-proven MCNS who were unresponsive to the initial 8-week course of steroids subsequently progressed to ESRD. Among children with nephrotic syndrome due to FSGS who progress to ESRD, renal transplantation can also pose serious challenges. Nephrotic syndrome recurs in the allograft in approximately 30% of such cases, and results in graft loss in approximately one-half of those patients affected. Because FSGS is the most common glomerulopathy associated with ESRD in children, this matter has received much attention in the pediatric transplantation literature. Disease recurrence can be a devastating complication, and efforts are ongoing to attempt to characterize patients at risk for disease recurrence. Clinical and biopsy features of children at high risk for recurrence of FSGS are: those who reached ESRD within 34 years following diagnosis, those with histologic features of mesangial proliferation, and those with previous history of recurrence. Treatment strategies for recurrent nephrotic syndrome post-transplant have included plasma exchange, cyclophosphamide, and intravenous cyclosporine but none of these have proven to be uniformly effective.2 Mortality risk Since the introduction of antibiotics and corticosteroids several decades ago, and the further refinement of immunosuppressive agents in recent years, the mortality rate for nephrotic syndrome has been reduced to < 5% from 67% seen in the preantibiotic era. In a large ISKDC series reported in 1984, the mortality rate was only 1.9%.339 Importantly, 9 of the 10 deaths in this study occurred in children who either had SRNS or in those who relapsed within the first 8
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weeks of steroid therapy, and six of these children died of infections, emphasizing the continued importance of this complication of nephrotic syndrome. Thus, despite dramatic improvements in the mortality risk for children with nephrotic syndrome over the last 50 years, it should be remembered that children who prove to be steroid-resistant remain at increased risk for potentially life-threatening complications of either nephrotic syndrome or its treatment.2 II.CASE G, male,8 years old, 26,5 kg, 124 cm. was admitted to the non-infection unit of H.Adam Malik Hospital on 18th March 2010 at18.45 pm. Main complaint was full body oedema. This condition had occurred for 1 month. Oedema begin at abdomen, then to face and extremities. Full body oedema subsides in 1 week after drug administration, but abdomen still enlarge. History of meat-washed color urine was positive since 1 month . History of sandy urine was negative. History of bloody urine was negative. Urinary pain was positive since 1 month. History of trauma was positive at right side abdomen and happened at 1 month ago. No fever, no cough, no vomiting, no diarrhea, no dyspnea. Family history of suffering renal problems was negative History of immunization was unclear. History of recurrent fever was negative. History of birth, spontaneous labor aided by midwife, spontaneous cry, birth weight : 3500gr. His past medical history that this patient was referred from Pirngadi Hospital by a pediatrician with diagnosed as Nephrotic Syndrome and had been taken care for 3 weeks. History of medication use, prednisone 4-4-3 and lasix 2x20 mg Physical Examination Generalized Status Sens : compos mentis. Temperature : 36,7 C. anemia (-), dyspnea (-), edema (+), cyanosis (-), icterus (-). Localized Status Head Neck Thorax : Eye: light reflex +/+, pupil isocor right = left, pale inferior conjungtiva palpebra -/ear / nose/ mouth = within normal limits : lymph node enlargement (-), stiff neck (-) : fusiformed symmetrical, retraction (-) HR = 92 bpm, regular, murmur (-)
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RR = 26 rpm, regular, rales (-). Decreased breath sound on the lower region of right and left lung Abdomen : distention, collateral vein (+), ascites (+), shifting dullness (+) Hepar/ spleen = difficult to be measured Sleeping abdomen circumference: 80cm, Sitting abdomen circumference: 83 cm Extremity : pulse 92 bpm, regular, Pressure/ Volume = adequate, acral warm blood pressure = 100/70 mmHg, oedema (-) Differential Diagnosis Nephrotic Syndrome + Bilateral Effussion Pleura Acute Glomerulonephritis + Bilateral Effussion Pleura Working Diagnosis. Nephrotic syndrome + Bilateral Effussion Pleura Management Spironolacton 2x25mg Prednisone 4-4-3 tab Captopril 2x12,5 mg tab Amoxicillin 3x250 mg tab Diet normal meal 1630 kkal with 53 gr of protein Investigation plan. Daily urinary dipstick Fluid balance per 6 hours Renal Function Test Liver Function Test Electrolyte Lipid Profile Urinalysis C3
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Culture Urine and Sensitivity Test Urine Esbach Laboratory results on February 27th 2010 Full Blood Count WBC : 16,2.103 cell/mm3 RBC : 4,35.106 /mm3 Hb Ht : 13,1 mg/dl : 41, 8 %

PLT : 541.103cell/mm3 Thorax and Abdomen Photo Results on March 2nd 2010 Consolidation on right ang left lung were seen Heart border was not clear Air distribution on intestine was common Intra abdominal organ was not clear Conclusion: right and left effusion, abdomen was common USG results on March 2nd 2010 Hepar and Lien were normal Right kidney 87cm, left kidney 84 cm, kidney was echo Cortex and medulla were common, not specific to nephritic Ascites was seen Conclusion: ascites Laboratory results on March 3rd 2010 Urinalysis Colour Turbidity Protein Reduction : yellow : turbid : ++ :18

Sedimen Erythrocyte Leukocyte Renal epithel Blaas epitel Vag/Urethra Ep Cristal Ca oxalate T. phosphate Cysteine Uric Cylindric Urobilin Bilirubin pH SG :::6 : 1,020 ::::: 1-2 leucocyte / wide field view :: 2-4 ::: 0-2

Urobilinogen : +

Laboratory results on March 6th 2010 Serum protein electrophoresis Albumin : 11,0 Alpha 1 : 1,6 Alpha 2 : 53,0 Beta : 12,1 Gamma : 22,3 Laboratory results on March 9th 2010 Full Blood Count WBC : 8,5.103 cell/mm3 RBC Hb Ht : 3,75.106 /mm3 : 11,7 mg/dl : 36,6 %
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PLT

: 355.103cell/mm3

Laboratory results on March 18th 2010 Full Blood Count WBC : 17,9.103 cell/mm3 Hb Ht PLT Ureum Liver Function SGOT : 52 U/L SGPT : 54 U/L Electrolyte Sodium Chloride Dipstick urine Leu Nit Uro Pro pH :70 : +1 : 0,2 : +3 :6 Blood : SG Bil Glu : 1,020 :+ :Keton : : 136 mEq/L : 94 mEq/L Potassium : 3,1 mEq/L : 14,9 mg/dl : 45,7 % : 510.103cell/mm3 : 70 mg/dl

Renal Function Creatinin : 0,4 mg/dl

Counsult Thorax Photo to Radiology Results can be interpretated as lung oedema Follow up March 19th 2010 S : distention of abdomen (+) O : Sens : compos mentis. Temperature : 37,1 C. BW: 26kg
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Head Neck Thorax

: light reflex +/+, pupil isocor right = left, pale inferior conjungtiva palpebra -/ear / nose/ mouth = within normal limits : lymph node enlargement (-), stiff neck (-) : fusiformed symmetrical, retraction (-) HR = 98 bpm, regular, murmur (-) RR = 22 rpm, regular, rales (-). Decreased breathing sound on the lower region of right and left lung

Abdomen : distention, collateral vein (+), ascites (+), shifting dullness (+) Hepar/ spleen = difficult to be measured Sleeping abdomen circumference: 78 cm, Sitting abdomen circumference: 79 cm Extremity : pulse 98 bpm, regular, Pressure/ Volume = adequate, acral warm, blood pressure = 110/70 mmHg, oedema (-) A: DD/- Nephrotic Syndrome + Bilateral Effussion Pleura - Acute Glomerulonephritis + Bilateral Effussion Pleura P: - Prednisone 4-4-3 - Lasix 2x20 mg Dipstick urine Leu Nit Uro Pro pH ::: 0,2 : +2 :6 Blood : SG Bil Glu : 1,020 :+ :Keton : -

Follow up March 20th 2010 S : distention of abdomen (+) O : Sens : compos mentis. Temperature : 36,9 C. BW: 25 kg Head Neck : light reflex +/+, pupil isocor right = left, pale inferior conjungtiva palpebra -/ear / nose/ mouth = within normal range : lymph node enlargement (-), stiff neck (-)
21

Thorax

: fusiformed symmetrical, retraction (-) HR = 90 bpm, regular, murmur (-) RR = 24 rpm, regular, rales (-). Decreased breathing sound on the lower region of right and left lung

Abdomen: distention, ascites (+), shifting dullness (+), collateral vein (+) Hepar/ spleen = difficult to be measured Sleeping abdomen circumference: 73 cm, Sitting abdomen circumference: 78 cm Extremity: pulse 98 bpm, regular, Pressure/ Volume = adequate, acral warm, blood pressure = 130/70 mmHg, oedema (-) A: DD/- Nephrotic Syndrome + Bilateral Effussion Pleura - Acute Glomerulonephritis + Bilateral Effussion Pleura P: - IVFD D5% + Meylon 25 mEq 6 gtt/i mikro - Inj. Ceftriaxone 750 mg diluted in D5% 20cc / 12 hours - Inj. Lasix 30mg / 8h / iv - Spironolactone 2 x 25 mg - Prednisone 4-4-3 - Captopril 2x12,5 mg - KSR 3 x 500mg - Diet normal meal low salt 1630 kkal with 26 gr protein - Nephrisol ad lib Dipstick urine Leu Nit Uro Pro pH :::::8 Blood : SG Bil Glu : 1,005 ::Keton : -

Counsult to Nephrology Division Advise: - IVFD D5% + Meylon 25 mEq 6 gtt/i mikro
22

- Inj. Ceftriaxone 750 mg diluted in D5% 20cc / 12 hours - Inj. Lasix 30mg / 8h / iv - Spironolactone 2 x 25 mg - Prednisone 4-4-3 - Captopril 2x12,5 mg - KSR 3 x 500mg - Diet normal meal low salt 1630 kkal with 26 gr protein - Nephrisol ad lib - Daily urinary dipstick - Fluid balance per 6 hours - Abdomen and Urinary USG - Blood Culture and Sensitivity Test - Urine Culture and Sensitivity Test - Urine Esbach - ASTO, CRP, C3 Follow up March 21th 2010 S : distention of abdomen (+) O : Sens : compos mentis. Temperature : 36,8 C. BW: 25 kg Head Neck Thorax : light reflex +/+, pupil isocor right = left, pale inferior conjungtiva palpebra -/ear / nose/ mouth = within normal limits : lymph node enlargement (-), stiff neck (-) : fusiformed symmetrical, retraction (-) HR = 100 bpm, regular, murmur (-) RR = 32 rpm, regular, rales (-). Abdomen: distention, shifting dullness (+), ascites (+), collateral vein (+) Sleeping abdomen circumference: 66 cm, Sitting abdomen circumference: 75 cm Hepar/ spleen = difficult to be measured Extremity: pulse 100 bpm, regular, Pressure/ Volume = adequate, acral warm, blood pressure = 90/60 mmHg, oedema (-) A: Nephrotic Syndrome
23

P: - IVFD D5% + Meylon 25 mEq 6 gtt/i mikro - Inj. Ceftriaxone 750 mg diluted in D5% 20cc / 12 hours - Inj. Lasix 30mg / 8h / iv - Spironolactone 2 x 25 mg - Prednisone 4-4-3 - Captopril 2x12,5 mg - KSR 3 x 500mg - Diet normal meal low salt 1630 kkal with 26 gr protein - Nephrisol ad lib Dipstick urine Leu Nit Uro Pro pH :+ :+ :::7 Blood : SG Bil Glu : 1,005 ::Keton : -

Follow up March 22th 2010 S : distention of abdomen (+) , heartburn (+), tenderness on right abdominal (+) O : Sens : compos mentis. Temperature : 36,80 C. BW: 21 kg Head Neck Thorax : light reflex +/+, pupil isocor right = left, pale inferior conjungtiva palpebra -/ear / nose/ mouth = within normal range : lymph node enlargement (-), stiff neck (-) : fusiformed symmetrical, retraction (-) HR = 118 bpm, regular, murmur (-) RR = 30 rpm, regular, rales (-). Abdomen : soepel, peristaltic (+), tenderness on hypochondrium dextra (+) Hepar = difficult to be measured, spleen: unpalpable Sleeping abdomen circumference: 59 cm, Sitting abdomen circumference: 65 cm Extremity : pulse 118 bpm, regular, Pressure/ Volume = adequate, acral warm,
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blood pressure = 100/60 mmHg, oedema (-) A: Nephrotic Syndrome P: - IVFD D5% NaCl 0,45% 20gtt/i micro - Inj. Ceftriaxone 750 mg diluted in D5% 20cc / 12 hours - Inj. Lasix 2 x 20mg - Spironolactone 2 x 12,5 mg - Prednisone 4-4-3 - Captopril 2x12,5 mg - KSR 3 x 500mg - Diet normal meal low salt 1630 kkal with 26 gr protein - Nephrisol ad lib Dipstick urine Leu Nit Uro Pro pH :+ :+ : 0,2 ::7 Blood : SG Bil Glu : 1,005 ::Keton : -

Chest X-Ray conclusion Sign of peritonitis was not found USG conclusions Abnormalities of renal and gallbladder were not confirmed Follow up March 23th 2010 S : distention of abdomen (+) , heartburn (+), tenderness on right abdominal (+) O : Sens : compos mentis. Temperature : 36,6 C. BW: 21 kg Head Neck : light reflex +/+, pupil isocor right = left, pale inferior conjungtiva palpebra -/ear / nose/ mouth = within normal range : lymph node enlargement (-), stiff neck (-)
25

Thorax

: fusiformed symmetrical, retraction (-) HR = 108 bpm, regular, murmur (-) RR = 30 rpm, regular, rales (-).

Abdomen : soepel, peristaltic (+) Hepar = difficult to be measured, tenderness on hypochondrium dextra (+) spleen: unpalpable Sleeping abdomen circumference: 57 cm, Sitting abdomen circumference: 61 cm Extremity : pulse 108 bpm, regular, Pressure/ Volume = adequate, acral warm, blood pressure = 100/60 mmHg, oedema (-) A: Nephrotic Syndrome P: - IVFD D5% NaCl 0,45% 20gtt/i micro - Inj. Ceftriaxone 750 mg diluted in D5% 20cc / 12 hours - Inj. Lasix 2 x 20mg - Spironolactone 2 x 12,5 mg - Prednisone 4-4-3 - Captopril 2x12,5 mg - KSR 3 x 500mg - Diet normal meal low salt 1630 kkal with 26 gr protein - Nephrisol ad lib Dipstick urine Leu Nit Uro Pro pH ::+ : 0,2 ::7 Blood : SG Bil Glu : 1,015 :+ :Keton : -

Laboratorium results March 23th 2010 Full Blood Count WBC : 25,1.103 cell/mm3 Hb : 13,3 mg/dl
26

Ht PLT Ureum

: 41,8 % : 425.103cell/mm3 : 70 mg/dl

Renal Function Creatinin : 0,4 mg/dl Uric Acid : 3,5 Glucose ad random : 91,8 mg/dl Electrolyte Sodium Chloride CRP + ASTO < 200 Follow up March 24th 2010 S : distention of abdomen (+) , heartburn (+), tenderness on right abdominal (+) O : Sens : compos mentis. Temperature : 36,8 C. BW: 21 kg Head Neck Thorax : light reflex +/+, pupil isocor right = left, pale inferior conjungtiva palpebra -/ear / nose/ mouth = within normal range : lymph node enlargement (-), stiff neck (-) : fusiformed symmetrical, retraction (-) HR = 118 bpm, regular, murmur (-) RR = 30 rpm, regular, rales (-). Abdomen : soepel, peristaltic (+) Hepar = difficult to be measured, tenderness on hypochondrium dextra (+) spleen: unpalpable Sleeping abdomen circumference: 56 cm, Sitting abdomen circumference: 59 cm Extremity : pulse 118 bpm, regular, Pressure/ Volume = adequate, acral warm, blood pressure = 100/60 mmHg, oedema (-) A: Nephrotic Syndrome P: - IVFD D5% NaCl 0,45% 20gtt/i micro
27

: 132 mEq/L : 99 mEq/L

Potassium : 2,9 mEq/L

- Inj. Ceftriaxone 750 mg diluted in D5% 20cc / 12 hours - Prednisone 4-4-3 - Captopril 2x12,5 mg - KSR 3 x 500mg - Omeprazole 1x10mg - Antasid - Diet normal meal low salt 1630 kkal with 26 gr protein - Nephrisol ad lib Dipstick urine Leu Nit Uro Pro pH ::+ : 0,2 ::6 Blood : SG Bil Glu : 1,010 ::Keton : -

Patient was discharged in March 24th 2010 and given : Amoxicillin oral 3 x 250 mg Prednisone 4-4-3 Captopril 2 x 12,5mg KSR 3 x 500 mg Omeprazole 1x10mg This patient was referred to the outpatient clinic to continue the treatment.

III. DISCUSSION Nephrotic syndrome (NS), also known as nephrosis, is defined by the presence of nephrotic-range proteinuria, edema, hyperlipidemia, and hypoalbuminemia. Based on those definition, the diagnose nephrotic syndrome can be made based on history of edema and laboratoies finding. These conditions were found in this patient. The patient came to Adam
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Malik Hospital with abdomen swelling which had been experienced in the last month. The laboratories finding in this patient were proteinuria (++), hyperlipidemia (Cholesterol total was 571 mg/dL), and hypoalbuminemia (1,42 g/dL). So, the patient was diagnosed as nephrotic syndrome. The other laboratories investigation which can do in nephrotic syndrome suspect are C3, C4, ANA (Anti Nuclear Antibody), and anti ds-DNA. But, in this patient, those investigations were not done because the investigations were expensive and whether they were not done, the diagnose nephrotic syndrome can made in this patient. Approximately 7080% of cases of nephrotic syndrome occur in children less than 6 years of age. In this patient, he was 8 years old. More than 80 % patients with nephrotic syndrome show minimal change disease (MCD) characterized by normal renal histology on light microscopy. Based on the condition, renal biopsy is not routine investigation in most cases of nephrotic syndrome. The indications of doing renal biopsy is: (1) the age of first attack was under 1 year old or above 16 years old; (2) there are gross hematuria, persistent microscopy hematuria, or low serum C3 complement; (3) persistent hypertention; (4) decreasing of renal function that are not related with hypovolemia condition; (5) suspected with secondary nephrotic syndrome; (6) resistent steroid nephrotic syndrome; (7) before starting cyclosporine therapy. In this patient, the above conditions were not found, so we were not doing renal biopsy in this patient. Patient was diagnosed with Nephrotic Syndrome. Since heavy proteinuria is a predictor of rapid progression of renal failure, therefore reduction of proteinuria is a therapeutic goal. To reduce heavy proteinuria in this patient, renal function improvement was the goal of treatment. Initial therapy as recommended by the ISKD is prednisone 60mg/m2/ day or 2mg/kgBW/day (maximum dose 80mg/day), given in divided dose to induce remission. Dosage of prednisone is calculated based on ideal body weight. Full dose of initial prednisone is given for 4 weeks, if remission occurs in the first 4 weeks, continued therapy of alternating dose (once every 2 days) of 40mg/m2/day (2/3 of the initial dose) or 1,5 mg/kgBW/day for the next 4 weeks. If after the first 4 weeks of full dose, patient does not show any remission, patient is classified as steroid resistant. In this patient, the initial prednisone therapy given was 55 mg/day (based on body surface area) for first 4 weeks, divided in 3 dose in a day. After using prednisone, remission was experience in this patient. Proteinuria was lost during 3 days of prednisone using.

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Fluid restriction is recommended while severe edema is still exists. 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, hypovolemia condition must be excluded. After using diuretic in 1-2 weeks, blood sodium and potassium must be checked. In this patient, furosemide and spironolactone were given. And based on laboratory finding which blood potassium level was low (3,1 mEq/L), KSR was given to this patient. Dietary management is based on RDA (Recommended Daily Allowances) for normal protein diet of 1,5-2 g/ day to maintain child normal growth without risking glomerolus function overload. In this patient, the protein diet should be given is 36 grams, but in fact, protein diet was given only 26 grams. The other dietary management in nephrotic syndrome is low sodium dietary (1-2 gr/day) while patient has edema. In this patient, low sodium dietary was given since he was admitted to the hospital. Patient with nephrotic syndrome are at increased risk of infection. This condition is associated with low immunoglobulin (Ig)G that is seem to be the result of impaired synthesis pointing to a primary disorder in lymphocyte regulation in Idiopathic Nephrotic Syndrome. Infection risk is mostly of cellulitis, primary peritonitis, pneumonia, and upper respiratory tract infection. The use of prophylactic antibiotic is somewhat more controversial. Although a recent review on this subject supported its use, others have noted that prophylactic antibiotic usage may result in development of resistant organism. Therefore, antibiotic prophylactic may be given on this patient, especially those who undergo steroid therapy.The 3rd generation of cephalosporin such as cefotaxim or ceftriaxone can be given for 10 to 14 days. This patient was given ceftriaxone injection 750mg/12 hours/ iv in 20 cc of D 5 % in 30 minutes. Hypertension can be find in SN patient related with steroid toxicity. The treatment of hypertension is started with ACE-Inhibitor, ARB (angiotensin receptor blocker), blocker, until the blood tension of patient is under 90th percentil. In this patient, Captopril 3 x 12,5 mg was given, because blood tension of patient was 130/70 mmHg. The prognose of this patient is good according to the sensitivity of steroid. IV. REFERENCES

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1. Bagga A, Mantan M. Nephrotic Syndrome in Children. Indian J Med. 2005; 122: 13-28 2. Valentini RP and Smoyer WE. Nephrotic Syndrome. Kheev KK, Schnaper HW, Mahkev SP. Clinical Pediatric Nephrology. UK: Informa Health Care 2007; 155-194. 3. Lane CJ. Nephrotic Syndrome. eMedicine Pediatrics. 2009. Available from: http://emedicine.medscape.com/article/982920-overview [Accessed March 20th 2010] 4. Noer MJ. Long Versus Standard Initial Steroid Therapy for Children with Idiopathic Nephrotic Syndrome. Folia Medica Indonesiana. 2005; 41: 205-211. 5. Bergstein JM. Sindrom Nefrotik. Behrman, Kliegman, Arvin. Ilmu Kesehatan Anak Nelson. Jakarta: EGC. 2000; 1828-1829 6. Keddis Mira T and Kamath BM. The Nephrotic Syndrome. Hospital Physician. 2007; 25-31 7. Ghodale SR, Suryakar AN, Ankesh RD, et all. Role of Reactive Oxigen Species in Pathogenesis of Nephrotic Syndrome. Indian Journal of Clinical Biochemistry. 2010; 25: 8285. 8. Iturbe BR, Acosta JH, Johnson RJ. Interstial Inflammation, Sodium Retention, and the Pathogenesis of Nephrotic Edema: An Unifying Hypothesis. Kidney International. 2002; 62: 1379-1384. 9. Uddin GM. Management of Steroid Sensitive Idiopathic Nephrotic Syndrome in Children. Journal of Bangladesh College of Physicians and Surgeons. 2007; 25: 38-42. 10. Mogg RJ, Portman RJ. Milliner Daun, et all. Evaluation and Management of Proteinuria and Nephrotic Syndrome in Children: Recommendations from a Pediatric Nephrology Panel Established at the National Kidney Foundation Conference on Proteinuria, Albuminuria Risk, Assesment, Detection and Elimination (PARADE) Pediatrics. 2000; 105: 1242-1249. 11. Beattie J. Guideline for the Management of Nephrotic Syndrome. Renal Unit Royal Hospital for Sick Children Yorkhill Division. 2007; 1-8. 12. Trikono PP, Tambunan T, Pudjiastuti F, et all. Konsensus Tatalaksana Sindrom Nefrotik Idiopatik pada Anak. Jakarta: Badan Penerbit IDAI. 2008: 1-22. 13. Gipson DS, Massengill SF, Yao L, et all. Management of Childhood Onset Nephrotic Syndrome. Pediatrics. 2009; 124: 747-757. 14. Niaudet P & Boyer O. Idiopathic Nephrotic Syndrome in Children: Clinical Aspects. Avner ED, Haman WE, Niaudet P, et all. Pediatric Nephrology. Berlin Heidelberg: Springer. 2009; 662-702.
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