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‫العلمي‬ ‫والبحث‬ ‫العالي‬ ‫التعليم‬ ‫وزارة‬
‫جامعة‬‫النهرين‬
‫كلي‬‫ـ‬‫ة‬‫الطب‬
(A study in pediatric department)

2. ‫بحث‬‫به‬ ‫تقدم‬
‫الطالب‬
‫محمد‬ ‫هشام‬ ‫اسامه‬
‫وه‬‫و‬‫شهادة‬ ‫نيل‬ ‫متطلبات‬ ‫من‬ ‫جزء‬‫البكلوريوس‬‫فيال‬‫طب‬‫ال‬‫عام‬
‫بأشراف‬
‫االستاذ‬
‫الدكتور‬‫ة‬‫حسين‬ ‫شذى‬‫علي‬
‫ا‬‫أل‬‫هداء‬
‫اىل‬...
‫البشري‬ ‫النذير‬‫وشفيعها‬ ‫املنري‬ ‫الامة‬ ‫ورساج‬ ‫الاعىل‬ ‫الفردوس‬ ‫صاحب‬
‫ا‬‫ر‬‫خف‬ ) ‫وسمل‬ ‫عليه‬ ‫هللا‬ ‫صىل‬ ( ‫محمد‬‫ا‬‫ز‬‫ا‬‫زت‬‫واع‬
‫اىل‬...
... ‫الغوايل‬ ‫نيس‬‫و‬ ... ‫الليايل‬ ‫سهر‬ ‫من‬‫مبايل‬ ‫غري‬ ‫مهي‬ ‫ومحل‬ ... ‫املوايل‬ ‫ندي‬‫س‬ ‫وظل‬
‫الغايل‬ ‫وادلي‬ ...

3. ‫اىل‬...
‫هم‬ ‫الفؤاد‬ ‫ومحلت‬ ... ‫ا‬‫ر‬‫سه‬ ‫اجلفون‬ ‫اثقلت‬ ‫من‬‫ا‬‫رب‬‫ص‬ ‫الاايم‬ ‫وجاهدت‬ ...‫ف‬ ‫البال‬ ‫وشغلت‬ ...‫ا‬‫ر‬‫ك‬‫الاايدي‬ ‫ورفعت‬ ...
‫دعاءا‬...
‫الغالية‬ ‫يزة‬‫ز‬‫الع‬ ‫ايم‬ ... ‫الاحباب‬ ‫واحب‬ ‫الغوايل‬ ‫اغىل‬
‫اىل‬...
. ‫احملبة‬ ‫ورود‬‫اء‬‫رض‬‫وال‬ ‫اء‬‫رس‬‫ل‬‫ا‬ ‫يف‬ ‫افقوين‬‫ر‬ ‫من‬ ‫اىل‬ ... ‫الوفاء‬ ‫وينابيع‬ ..
‫اخويت‬ ... ‫الاحصاب‬ ‫اصدق‬ ‫اىل‬
‫اىل‬...
‫حفر‬ ‫من‬‫سطور‬‫ا‬‫كث‬‫ري‬‫اخ‬ ‫يف‬ ‫رمر‬ ‫ة‬‫يا‬..... ‫ل‬‫قليل‬ ‫الا‬ ‫املطاف‬ ‫هنايه‬ ‫يف‬ ‫لنا‬ ‫يبقى‬ ‫وال‬‫هب‬ ‫جتمعنا‬ ‫والصور‬ ‫اذلكرايت‬ ‫من‬،‫م‬‫اكنوا‬
‫جانيب‬ ‫اىل‬‫يوما‬ ‫ليس‬‫و‬ ‫دوما‬
‫اء‬‫ز‬‫الاع‬ ‫اصدقايئ‬
‫الباحث‬
‫وتقدير‬ ‫شكر‬
‫أشرف‬ ‫على‬ ‫والسالم‬ ‫والصالة‬ ، ‫الشاكرين‬ ‫شكر‬ ‫هلل‬ ‫والشكر‬ ، ‫الحامدين‬ ‫حمد‬ ‫هلل‬ ‫الحمد‬
‫أجمعين‬ ‫وأصحابه‬ ‫آله‬‫وعلى‬ ‫األمين‬ ‫محمد‬ ‫املرسلين‬
‫الكبير‬ ‫ام‬‫ر‬‫واألحت‬ ‫والعرفان‬ ‫بالشكر‬ ‫أتقدم‬ ‫عايته‬‫ر‬‫و‬ ‫هللا‬ ‫من‬ ‫ـل‬‫ض‬‫بف‬ ‫البحث‬ ‫أنجاز‬ ‫وبعد‬ ...‫بعد‬ ‫أما‬
‫إلى‬‫األستاذ‬‫حسين‬ ‫شذى‬ ‫ه‬‫ر‬‫الدكتو‬‫علي‬‫لها‬ ‫كان‬ ‫،والذي‬ ‫اسة‬‫ر‬‫الد‬ ‫هذه‬ ‫على‬ ‫اف‬‫ر‬‫باألش‬ ‫لتفضلها‬
‫خير‬ ‫وأهله‬ ‫العلم‬ ‫عن‬ ‫هللا‬ ‫اها‬‫ز‬‫فج‬ ، ‫البحث‬ ‫موضوع‬ ‫اح‬‫ر‬‫أقت‬ ‫منذ‬ ‫والرعاية‬ ‫التوجيه‬ ‫في‬ ‫الفضل‬
‫ماهو‬ ‫على‬ ‫ليظهر‬ ‫البحث‬ ‫متابعة‬ ‫في‬ ‫جهد‬ ‫من‬ ‫بذلته‬ ‫ملا‬‫و‬ ‫شاد‬‫ر‬‫واأل‬ ‫التوجيه‬ ‫من‬ ‫أبدته‬ ‫ملا‬ ‫اء‬‫ز‬‫الج‬

4. ‫فكانت‬ ، ‫األن‬ ‫عليه‬‫وأمدها‬ ‫هللا‬ ‫حفظها‬ ‫العلم‬ ‫طريق‬ ‫إلى‬ ‫بيدي‬ ‫باألخذ‬
ً
‫وحريصة‬
ً
‫فاضلة‬
ً
‫أستاذة‬
.‫والتوفيق‬ ‫والنجاح‬ ‫بالصحة‬
‫نخطو‬ ‫ونحن‬ ‫لنا‬ ‫والبد‬‫ا‬‫قضيناها‬ ‫أعوام‬ ‫إلى‬ ‫نعود‬ ‫وقفة‬ ‫من‬ ‫الجامعية‬ ‫الحياة‬ ‫في‬ ‫األخيرة‬ ‫خطواتنا‬
‫جه‬ ‫بذلك‬ ‫باذلين‬ ‫الكثير‬ ‫لنا‬ ‫قدموا‬ ‫الذين‬ ‫ام‬‫ر‬‫الك‬ ‫أساتذتنا‬ ‫مع‬ ‫الجامعة‬ ‫حاب‬‫ر‬ ‫في‬‫بناء‬ ‫في‬ ‫كبيرة‬ ‫ودا‬
‫جديد‬ ‫من‬ ‫األمة‬ ‫لتبعث‬ ‫الغد‬ ‫جيل‬...
‫واملحب‬ ‫والتقدير‬ ‫واالمتنان‬ ‫الشكر‬ ‫آيات‬ ‫أسمى‬ ‫تقدم‬ ‫ي‬ ‫نمض‬ ‫أن‬ ‫وقبل‬‫أقدس‬ ‫حملوا‬ ‫الذين‬ ‫إلى‬ ‫ة‬
‫الحياة‬‫في‬ ‫سالة‬‫ر‬...‫إلى‬‫واملعرفة‬ ‫العلم‬ ‫طريق‬ ‫لنا‬‫مهدوا‬ ‫الذين‬...‫األفاضل‬ ‫أساتذتنا‬‫جميع‬‫إلى‬..
‫الرحمي‬ ‫الرمحن‬ ‫هللا‬ ‫سم‬‫ب‬

5. ((ۚ‫ع‬َ‫ف‬ْ‫ر‬َ‫ن‬‫ات‬َ‫ج‬َ‫ر‬َ‫د‬ْ‫ن‬َ‫م‬‫اء‬ َ‫ش‬َ‫ن‬
َۚ‫ق‬ْ‫و‬َ‫ف‬َ‫و‬ِّ‫ل‬‫ك‬
‫ي‬ِّ‫ذ‬ْ‫مل‬ِّ‫ع‬‫م‬‫مي‬ِّ‫ل‬َ‫ع‬﴿٧٦﴾))
‫العظمي‬ ‫هللا‬ ‫صدق‬
‫(ا‬ ‫يوسف‬ ‫سورة‬‫ل‬‫يه‬76)
Abstract:
Background:
Children with nephrotic syndrome may have one or more relapse. These are diagnosed if
there is +++ or ++++ proteinuria for 3 or more days. Urine should be checked initially
twice weekly, then weekly after the first episode, and the families instructed to get in
contact should a relapse of proteinuria occur, or if there is ++ for more than 1 week.
The objective of this study was to identify predictors of relapse and determine the
predictive score for relapse. Ninety-nine children with nephrotic syndrome visiting the
pediatric nephrology outpatient clinic in Al- Kadhmia teaching hospital from2010 to 2013
were studied. This study was retrospective study. According to age , 5% of patients were
N.S. less than 1 year , 17.5 % of patientswere N.S. between 1-5 years & 77.5 % of
patientswere N.S. equal or above 5 years.Regarding gender, 62.5 % patients were
males while 37.5 %were females. Regarding relapses, 55 % of the patients had
frequent relapse while 45 % of the patients had infrequent relapse. 65 % of the

6. patients were steroid sensitive, 35 % of the patients steroid resistant.In this study the
majority of patients were “equal or more than 5 years, male, living in rural area, with
onset between 1-5 years, steroid responsive, frequent relapse, having a follow up
between 1-2 years& having MCD on renal biobsy”
Aim of study:
1- Study demographic characteristics in patients with N.S. regarding age, gender &
residency
2- Study the characteristics of N.S. in those children regarding onset of the disease ,
frequency of relapses & type of N.S. according to steroid sensitivity
3- Study the duration of follow up in patients with N.S.
4- Study renal biopsy findings in patients with N.S.
5- Study the atypical features in patients with N.S.
Introduction:
Nephrotic Syndrome (NS) is a common childhood illness characterized by massive
proteinuria, hyperlipidemia, hypoalbuminemia& edema. NS is a disease of relapse and it is
a major problem to manage the cases with frequent relapse. So it is very important to find
out such children who are prone to develop frequent relapse
The observations that nephrotic syndrome, some was responsive to corticosteroids others
not and that its clinical course could be characterized by remission and relapse led to
several further observations that remain highly relevant to both the treatment and prognosis
of nephrotic syndrome today.
DEFINITIONS(1)

7. 1. NEPHROTIC SYNDROME:
Oedema, serum albumin < 25 g/l, proteinuria > 40 mg/m2 /hour or urine protein creatinine
ratio > 200 mg/mmol.
2. REMISSION:
Urinary protein excretion < 4 mg/m2/hour or urine dipstix nil/trace for 3 consecutive days.
3. RELAPSE:
Urinary protein excretion > 40 mg/m2/hour or urine dipstix ++ or more for 3 consecutive
days.
4. FREQUENT RELAPSES:
Two or more relapses within 6 months of initial response or four or more relapses within
any 12 month period.
5. STEROID DEPENDENCE:
Two consecutive relapses occurring during the period of steroid taper or within 14 days of
its cessation.
6. STEROID RESISTANCE:
Failure to achieve remission in spite of 4 weeks of standard prednisolone therapy
EPIDEMIOLOGY
The annual incidence of nephrotic syndrome in most countries in the Western Hemisphere
is estimated to range from 2 to 7 new cases per 100,000 children(2,3,4) and the prevalence is
about 16 cases per 100,000 children(4). There is a male preponderance among young
children, at a ratio of 2:1 to females, although this gender disparity disappears by
adolescence, making the incidence in adolescents and adults equal among males and
females (5, 6, and 7). The incidence of nephrotic syndrome has been fairly stable over the last
30 years, but there are suggestions that the histopathologic patterns may be changing. For
example, reports from different parts of the world indicate an increasing occurrence of focal
segmental glomerulosclerosis (FSGS) not only after adjusting for variations in renal biopsy
practices but also based on then generous assumption that all patients who did not have a
renal biopsy had minimal change nephrotic syndrome (MCNS)(5, 6, and 7). The incidence and

8. the histologic pattern of nephrotic syndrome are also affected by geographic location and
ethnic origin.
In this same study the authors found that although only 11% of Hispanic and 18% of
Caucasian patients with nephrotic syndrome had FSGS, 47% of African American children
had this less favorable diagnosis(6). Age also correlates with both the frequency of
presentation and the biopsy fi ndings associated with nephrotic syndrome.
The most common age for presentation is 2 years, and 70% to 80% of cases occur in
children younger than 6(2, 3). To some extent age also predicts the histologic lesion
associated with nephrotic syndrome. Children diagnosed before age 6 represented 79.6% of
those with MCNS compared with 50% of those with FSGS and only 2.6% of those with
membranoproliferative glomerulonephritis (MPGN)(8). When these data were analyzed on
the basis of renal histology, the median ages at presentation were found to be 3 years for
MCNS, 6 years for FSGS, and 10 years for MPGN(8). Thus excluding the fi rst year of life,
these data combined suggest that the likelihood of having MCNS decreases with increasing
age, whereas the likelihood of having the less favorable diagnosis of FSGS or MPGN
increases (8, 9).
The histologic lesion associated with nephrotic syndrome has important ramifications for
the likelihood of response to steroid treatment. Although almost 80% of children diagnosed
with nephrotic syndrome in a multicenter International Study of Kidney Diseases in
Children (ISKDC) study entered remission following an initial 8-week course using
prednisone, when these children were analyzed based on histology, steroid responsiveness
was found in 93% of those with MCNS compared with only 30% of those with FSGS and
7% of those with MPGN(8, 10). In addition to histology, response to steroids also varies with
geographic location and ethnicity. Whereas 80% of children in western countries will be
steroid responsive, studies from South Africa, Nigeria, and more recently Ghana show that
only 9% to 50% of children with nephrotic syndrome are steroid responsive(11,12,13).Failure
to respond to steroid treatment has important ramifications for the risk of developing
progressive renal failure later in life. In a multicenter evaluation of 75 children with FSGS,
it was found that within 5 years after diagnosis, 21% had developed ESRD, 23% had
developed CKD, and 37% had developed persistent proteinuria, whereas only 11%
remained in remission (14). Thus once a child is given the diagnosis of FSGS, the risk for
development of CKD or ESRD within 5 years is almost 50%.
ETIOLOGY
Nephrotic syndrome in childhood is largely primary or idiopathic, although a small
proportion of cases are secondary to infectious agents and other glomerular and systemic
diseases. The etiology of nephrotic syndrome is also age dependent. Most cases appearing
in the first 3 months of life are referred to as congenital nephrotic syndrome (CNS) and are
due to genetic diseases. Although there has been no systematic study of the etiology of
nephrotic syndrome presenting in the rest of the first year of life (3 to 12 months), there are
data suggesting that up to 40% of cases during this time may also be due to genetic causes

9. (15). Beyond the first year of life and in the first decade, most cases are due to primary or
idiopathic nephrotic syndrome, whereas the proportion of secondary nephrotic syndrome
cases increases beyond the first 10 years of life (figure 1).
Figure “1”: Etiology of Nephrotic syndrome(16)

10. Pathophysiology of the Nephrotic Syndrome

11. In addition to excessive loss of protein in the urine, the hallmarks of the nephrotic
syndrome include depression of certain serum proteins, edema formation, and a rise in
serum lipids. Loss of protein in the urine is the basic defect, and the fall in serum protein,
production of edema fluid and hyperlipidemia stem from it (Fig. 2). Hypoalbuminemia in
the nephrotic syndrome is owing to the combination of increased urinary loss and increased
catabolism of albumin, chiefly in the kidney (17). The liver reacts to the low serum albumin
levels by increasing albumin synthesis, but in the nephrotic syndrome, the response is
inadequate (17). The hypoalbuminemia then leads to both hyperlipidemia and edema
formation.
Figure “2”: Pathophysiology of edema(16)
Hyperlipidemia in the nephrotic syndrome stems from several different mechanisms. A
higher level of low-density lipoprotein (LDL) cholesterol is the principal alteration in the
lipid profile, with increases chiefly in very low density lipoproteins (VLDL) and
apolipoproteins B, C-II, and C-III (18,19,20,21). The increase in apolipoprotein B is probably
related to both hypoalbuminemia and changes in colloid oncotic pressure. The increase in
LDL and VLDL is not related to increased synthesis. Rather, it is owing to decreased
catabolism secondary to decreased binding of lipoprotein lipase to endothelial cells (19,22), to
reduced clearance of VLDL, and to a decrease in the VLDL receptor. In addition, lecithin
cholesterol acyl-transferase is lost in the urine so that there is limited uptake of surplus
cholesterol (21). High-density lipoprotein (HDL) cholesterol shows little change so that the

12. LDL/HDL is increased. Triglycerides are thought to increase by augmented synthesis (23) or
decreased catabolism (22). Lipoprotein a [Lp(a)] is increased by synthesis alone. The
increased synthesis of fibrinogen, transferrin, albumin, and apoA-1 is regulated
transcriptionally (19).
Edema formation is the symptom of the nephrotic syndrome that usually brings the patient
to clinical attention. Two possible mechanisms of action may contribute to the production
of edema. The classic mechanism, now known as the underfill hypothesis, may manifest in
patients with low plasma volume and is usually seen in children with MCD (24, 25). In this
instance, hypovolemia is the primary stimulus driving the kidney to retain sodium and
water and eventually resulting in edema formation as the result of the Starling forces (Fig.
3).
Figure “3”: hypothesis of nephrotic syndrome
However, most patients with the nephrotic syndrome are either normovolemic or
hypervolemic. Thus, the overfill hypothesis was constructed. According to this theory,
sodium retention by the kidney is primary. Sodium retention leads to increased blood
volume and results in increased blood pressure. These changes then lead to alterations in
the Starling forces, which result in edema. Several factors result in sodium retention. The
fall in colloid osmotic pressure results in decreased Kf, causing decreased sodium filtration.
Distal tubular injury causes resistance to atrial natriuretic peptide, resulting in decreased
natriuresis(26). Chronic tubulointerstitial disease is associated with decreased GFR and
sodium retention (24). Recent studies have shown that albumin directly stimulates the
sodium hydrogen exchanger 3 (NHE3) in the proximal tubule with increased sodium
retention. Rostoker et al (27) showed abnormal capillary permeability in patients with
nephrotic syndrome that resolved with steroid therapy. They proposed that a cytokine or

13. other vascular permeability factor might be responsible. In any case, such increased
vascular permeability could lead to edema.
History and Physical Examination
The clinical diagnosis of idiopathic nephrotic syndrome is often very simple. In a child with
periorbital or generalized edema, the primary care physician can quickly make this
diagnosis by documenting significant proteinuria with more than 2albumin on urine
dipstick or a spot urine protein/ creatinine ratio greater than 2 mg/mg and serum albumin of
less than 2.5 g/dl. In addition, a careful history should exclude possible complications and
identify children with atypical presentations that might reflect other serious systemic
illnesses. It should include an evaluation of any abdominal distension, which is usually due
to ascites and sometimes edema of the anterior abdominal wall. Although severe distension
may be accompanied by abdominal discomfort, persistent abdominal pain may be due to
primary bacterial peritonitis (a potentially life-threatening complication), gut edema, or
relative gut ischemia due to hypoperfusion secondary to intravascular volume depletion.
Other causes of an acute abdomen should also be considered. A history of coughing or
breathing difficulties or both may indicate pleural effusion. Pulmonary edema, though
rarely found in idiopathic nephrotic children, should lead to consideration of secondary
causes of nephrotic syndrome that might cause significant intravascular fluid retention.
Although a history of gross hematuria is unusual in nephrotic syndrome, microscopic
hematuria may be seen in up to 23% of patients with MCNS and in a higher percentage of
patients with other histologic variants(8). Severe intravascular volume depletion may cause
acute renal failure, and some children may present with oliguria or anuria. In such cases
prompt intravascular volume repletion is important to correct prerenal acute renal failure
and to prevent development of acute tubular necrosis. A history of possible systemic
symptoms including fevers, weight loss, night sweats, polyuria, polydipsia, hair loss, oral
ulcers, rashes, abdominal pain, and joint pain or swelling should also be elicited, because
they may be manifestations of systemic diseases such as systemic lupus erythematosus,
Henoch-Schönleinpurpura, or diabetes mellitus, which can all cause nephrotic syndrome. A
medication history should also be taken in that medications such as NSAIDs, gold, and
penicillamine can also cause nephrotic syndrome. The history should exclude other causes
of generalized edema, such as chronic liver failure, heart failure, and malnutrition in areas
of the world where clinical malnutrition is prevalent. Regarding physical examination,
blood pressure should be carefully determined in nephrotic children; it can be either low
(due to intravascular volume depletion) or elevated (due to neurohumoral responses to
hypovolemia, intrinsic renal causes, or occasionally renal vein thrombosis). Hypertension
has been reported in up to 21% of children 6 years and under with biopsy-confirmed
MCNS, and may be present in up to 50% of children with other histologic types(8). A
careful examination of the abdomen should also be performed to exclude abdominal
tenderness or guarding that may be signs of bacterial peritonitis. In addition, extremities
should be examined to exclude warmth, tenderness, or pain that may suggest venous

14. thrombosis. Finally, obtaining a detailed family history is also important, because some
causes of nephrotic syndrome are familial, as previously discussed.
Laboratory Evaluation
Diagnosis of nephrotic syndrome is confirmed by the triad of generalized edema,
proteinuria, albuminuria (2on dipstick or urine protein/creatinine ratio 2 mg/mg), and
hypoalbuminemia(serum albumin 2.5 g/dl), although hypercholesterolemia is also
commonly present. In addition to documenting proteinuria, urinalysis with microscopy
should be carried out to look for hematuria and possible red blood cell casts. In patients
with a typical presentation, serum studies should include an evaluation of complete blood
count, electrolytes, blood urea nitrogen (BUN), creatinine, and albumin levels. For patients
at an older age at presentation or with atypical presentation, additional serum studies to
exclude secondary causes of nephrotic syndrome should include C3 and C4 complement
levels; antinuclear antibody (ANA) and possibly anti-double-stranded DNA; HIV antibody;
hepatitis A, B, and C serologies; and consideration of other viral serologies such as HIV
antibodies. Because immunosuppressive therapy is the mainstay of treatment for most cases
of childhood nephrotic syndrome, many pediatric nephrologists recommend placing a PPD
(purified protein derivative) test to screen for occult tuberculosis before instituting
immunosuppression. This is particularly important in areas of the world where tuberculosis
is endemic and for recent immigrants from such regions. In addition, many nephrologists
obtain a varicella IgG titer before treatment to classify patients as varicella-naive or
varicella-immune, which can be of great aid when suspecting or confirming varicella
exposure in children who are immunocompromisedduring treatment. A varicella-naive
patient receiving immunosuppressive treatment for nephrotic syndrome who is exposed to
varicella should be treated with varicella zoster immunoglobulin (VZIG) within 96 hours of
exposure if possible(28). This passive immunization can sometimes be lifesaving due to the
potential severity of a primary varicella infection in an immunocompromised host. Renal
ultrasound does not usually have a role in the evaluation of childhood nephrotic syndrome.
However, in the setting of a nephrotic child who develops gross hematuria,
thrombocytopenia, or unexplained persistent hypertension, a renal ultrasound should be
considered to exclude possible development of renal vein thrombosis.
Renal Biopsy
More than 80% of children with idiopathic nephrotic syndrome will respond to steroid
therapy by entering complete remission. Based on this statistic, an initial trial of 4 to 8
weeks of high-dose daily steroid therapy is usually prescribed in children under 10 before
considering renal biopsy. In general, renal biopsy is indicated only in the setting of atypical
features such as (1) age at onset (less than 1 year or more than 10), (2) SDNS or SRNS, (3)
gross or persistent microscopic hematuria or presence of red cell casts, (4) abnormal
serologies, or (5) significant persistent renal failure. Due to the known nephrotoxicity
(interstitial fi brosis) of calcineurininhibitors such as cyclosporine and tacrolimus, renal
biopsy is also indicated before initiation of these second-line or third-line

15. immunosuppressive agents, as well as approximately every 2 years as long as use of these
medications continues.
Risk factors for relapses:
Infection is an important cause of relapse in MCNS, prevention & treatment of which could
reduce proteinuria without necessity of steroid(3). An Upper Respiratory Tract Infection
(URTI) or a febrile episode often precipitates a relapse; occasionally there is no obvious
cause1. Asymptomatic UTI might be an important and under diagnosed cause of relapse(5).
Role of Tuberculosis in inducing relapse remain controversial10. Young age and low level
of serum protein at onset are independent risk for relapse(4). Relapse within the first year is
a powerful independent predictor of subsequent relapse and relapse within first 6 months of
presentation is highly predictive of subsequent course(6).

16. COMPLICATIONS

17. MANAGEMENT(29)
MANAGEMENT OF THE OEDEMATOUS STATE.
Bed rest
This is not required and usually not practical unless the child has gross oedema.
B. Diet
A normal protein diet with adequate calories is recommended. Previous
recommendations of high protein diet had not been shown to improve serum albumin
concentration.
Salt intake should be reduced during the oedematous state.
Antibiotics.
Children with nephrotic syndrome are more prone to primary bacterial peritonitis.
Prophylactic oral penicillin at doses of 125 mg BD or 250 mg BD depending on the size
of the child is recommended during relapse particularly with gross oedema in view of
the lack of home albuminuria monitoring and long distance from the hospital.
Pneumococcal vaccine can be considered. However, it must be cautioned that the
vaccine does not cover all strains of pneumococci and some children with nephrotic
syndrome have been shown to be poor responders to this vaccine.
Hypovolaemia.
Children with nephrotic syndrome can present with hypovolemia, the manisfestations of
which include abdominal pain, cold peripheries, poor pulse volume, hypotension, and
haemoconcentration.
The treatment is to infuse salt poor albumin at 0.5 to 1.0 g/kg/dose over one to two
hours. If salt poor albumin is not available, other volume expanders like 5% albumin,
plasma protein derivatives or human plasma can be used.
Fluid restriction
This is not usually recommended except in chronic oedematous states.

18. Diuretics.
Diuretic therapy is not usually necessary in steroid responsive nephrotic syndrome but if
required should be used with caution as it can precipitate hypovolemia.
Salt poor albumin of 20 - 25% concentration can be used in symptomatic grossly
oedematous states together with intravenous frusemide at 1-2 mg/kg to produce a
diuresis. There is however, the danger of fluid overload with salt poor albumin infusion
and the child’s urine output and blood pressure should be closely monitored.
Hypercholesterolaemia
There is insufficient evidence for a recommendation to be made as yet.
MANAGEMENT OF THE COMPLICATIONS OF NEPHROTIC SYNDROME
A. Infections.
Children with nephrotic syndrome are prone to infections particularly cellulitis &
primary peritonitis.
Should a child with nephrotic syndrome develop primary peritonitis, the antibiotics
recommended is parenteral penicillin and a third generation cephalosporin as it has been
found that about half of primary peritonitis is due to Streptococcal pneumoniae and the
other half to gram negative bacilli.
The parents and children should be advised and cautioned about contact with chickenpox
and measles, and if exposed should be treated like any immunocompromised child. If
varicella-zoster immunoglobulin (VZIG) is available, it should be given within 72 hours
after exposure to chickenpox. If VZIG is not available, some units recommend giving a
single dose of intravenous immunoglobulin.
B. Immunisation.
While the child is on corticosteroid treatment and within 6 weeks after its cessation, only
killed vaccines may be safely be administered to the child. Live vaccines can be
administered 6 weeks after cessation of corticosteroid therapy
C. Acute renal failure
This is a rare complication in children with steroid responsive nephrotic syndrome. The
actual cause is not known although hypovolemia has been implicated. Intrarenal factors
have also been postulated to play a role.

19. D. Thrombosis
This complication if suspected should be thoroughly investigated and treated to prevent
fatal complications.
Treatment consists of anticoagulation with the various anticoagulants available. The
duration of anticoagulation required is still controversial.
E. Acute Adrenal Crisis
This may be seen in children who have been on long term corticosteroid therapy
(equivalent to 18 mg/m2 of cortisone daily) when they undergo situations of stress.
Adequate cover with corticosteroids during these periods of stress is recommended to be
given in 3 divided doses.
CORTICOSTEROIDS IN NEPHROTIC SYNDROME
At Initial diagnosis
A paediatrician should be consulted before initiation of therapy in a child with newly
diagnosed nephrotic syndrome
Corticosteroids was found to be effective in inducing remission of nephrotic syndrome
from the 1940’s, and has since then been used as first line therapy in the treatment of
idiopathic nephrotic syndrome although no controlled trial was ever conducted about its
efficacy
Controversy lies in the dosage and duration of corticosteroids used at initial diagnosis of the
nephrotic syndrome. Various regimes of corticosteroids have been used. The two regimes
discussed were the modified ISKDC regime; and the so called longer initial steroid
induction regime proposed and studied by Ueda et al(30) and Ksiazek and Wysznska(31), who
showed a 2 year relapse free rate of 50% for the long initial prednisolone dose versus
27.3% for the modified ISKDC regime.

20. Modified ISKDC regime
Prednisolone dosage at:
 60 mg/m2/day (maximum 80 mg/day) for 4 weeks
 40 mg/m2/48 hours for 4 weeks only.
Long initial prednisolone regime:
Prednisolone dosage at:
 60 mg/m2/day (maximum 80 mg/day) for 4 weeks
 40 mg/m2/48 hours for 4 weeks.
 Reduced by 25% monthly over the next 4 months
The choice of using either regime was left to the individual attending paediatrician.
A child with nephrotic syndrome who fails to respond to an initial four week treatment with
corticosteroids should be referred to a paediatric nephrologist for a renal biopsy.
Relapse
The majority of children with idiopathic nephrotic syndrome will relapse (32, 33). A relapse is
defined by urine albumin excretion of > 40 mg/m2/hour or urine dipstix of 2+ or more for 3
consecutive days.
Treatment of relapse
Prednisolone at 60 mg/m2/day (maximum 80 mg) is to be given until remission defined as
urine dipstix is trace or nil for 3 consecutive days after which the prednisolone dose is
reduced to 40 mg/m2/48 hours for 4 weeks.
It has not been shown that giving more corticosteroids for treatment of relapses results in
longer period of remission.
Breakthrough proteinuria may occur with intercurrent infection and usually does not require
corticosteroid therapy if the child has no oedemaand remains well.

21. Frequent relapses and steroid dependence
An initial responder who has 2 or more relapses within 6 months of initial response or 4 or
more relapses in any 12 month period is said to have frequent relapses.
Re-induction of any relapse with corticosteroids is as described in the section 3.4.2 on
relapse i.e. Prednisolone at 60 mg/m2/day (maximum 80 mg) until urine dipstix is nil/trace
for 3 consecutive days, after which the prednisolone dose is reduced to 40 mg/m2/48 hours
for 4 weeks .The prednisolone is now tapered instead of discontinued at the end of the re-
induction regime. The rate of tapering depends on the patient and the paediatrician in
charge. The prednisolone is then kept on as low an alternate day dose as possible for 6
months. This low dose alternate day prednisolone should preferabley not exceed 0.5
mg/kg/dose.
Should a child relapse while on low dose alternate day prednisolone, the child should be re-
induced as for a relapse; the prednisolone is again tapered to low dose alternate day
prednisolone. Cyclophosphamide should be considered if the nephrotic syndrome is steroid
dependent and the child shows signs of steroid toxicity
CYCLOPHOSPHAMIDE
A renal biopsy is not needed prior to cyclophosphamide therapy.
Cyclophosphamide therapy is indicated for the treatment of steroid dependent nephrotic
syndrome with signs of steroid toxicity like stunting of growth, cataracts, striae, severe
cushingoid features and osteoporosis and should be started when the child is in remission
following induction with corticosteroids.
Various trials have shown the superiority of cyclophosphamide with prednisolone versus
prednisolone alone in maintaining prolonged remission. (33, 34) Various dose and duration of
oral cyclophosphamide have been used. The report by APN (35) demonstrated a 2 year
remission rate of 67% for cyclophosphamide at 2 mg/kg/day for 12 weeks against 22% for
8 weeks given for children with steroid dependent nephrotic syndrome. Ueda et al (36) in a
later paper comparing the 8 week versus 12 week duration of cyclophosphamide however,
showed no difference. Concern was expressed about the side effects of cyclophosphamide
particularly on the gonads.
A total cumulative dose of cyclophosphamide of 168 mg/kg was adopted for the treatment
of steroid dependent nephroticsyndrome i.e. 2 mg/kg/day for 12 weeks or 3 mg/kg/day for 8

22. weeks. While the child is on cyclophosphamide, prednisolone therapy which can be further
reduced and discontinued once the child completes the cyclophosphamide therapy and
remains in remission. Regular fortnightly review with full blood counts and urinalysis
should be carried out while the child is on oral cyclophosphamide.
RELAPSES POSTCYCLOPHOSPHAMIDE
Relapses after a course of cyclophosphamide is treated as for relapses after the initial
diagnosis of nephrotic syndrome if the child does not exhibit any further signs of steroid
toxicity.
Should the relapse occur soon after a course of cyclophosphamide when the child is still
steroid toxic, or the child again becomes steroid toxic after multiple relapses, then a
paediatric nephrology opinion should be sought.
Options available here are not many but fortunately this group of patients make up only
about 10 – 20% of children with nephrotic syndrome. The available options available
include:
 A second course of cyclophosphamide
 Cyclosporine can also be used on a very selective basis by paediatric nephrologists and
has been shown to maintain remission in 80% of these patients.
 Levamisole
URINE ALBUMIN MONITORING
It is advocated that monitoring of urine albumin excretion be done regularly either at home
with urinary dipstix or at the nearest health centre.

23. Diagram “1”: Summery of treatment in children with nephrotic syndrome (16)
PROGNOSIS
The single most important prognostic factor for maintenance of long-term normal renal
function in nephrotic syndrome is the patient’s initial response to corticosteroids. Although
children who enter complete remission during an 8-week initial course of oral
corticosteroids have an excellent prognosis, the prognosis for those who fail to enter
remission is more guarded. Overall, close to 80% of newly diagnosed children treated with
corticosteroids will achieve complete remission(10).Steroid responsiveness varies by renal
histologic type, with93% of children with MCNS being steroid responsive comparedwith

24. 56% with mesangial proliferative glomerulonephritis(IgM nephropathy in some centers),
30% with FSGS,7% with MPGN, and 0% with membranous nephropathy.5In addition, the
frequency of steroid responsiveness generallydecreases with increasing age at
presentation.Among children with SSNS, relapse is common. It isestimated that 70% of
children with nephrotic syndrome willexperience one or more relapses. However, the
frequency ofrelapses decreases over time. A large study of children withMCNS reported a
gradual increase in the number of nonrelapsingpatients over time, such that 8 years after
diseaseonset 80% of children were relapse-free(35). In addition, 75%of those children with
no relapses in the first 6 months aftertreatment either had rare relapses or continued in
remissionfor their entire clinical course. Risk factors for frequentrelapses or a steroid-
dependent course have not been carefullystudied, but the literature suggests that an age of
lessthan 5 years at onset and a prolonged time to initial remissionare possible risk factors(36,
37). More recently Tsai et al. reporteda higher incidence of the DD (homozygous deletion)
genotypefor the angiotensin converting enzyme (ACE) gene inSDNS and SRNS children
compared with SSNS children,suggesting a potential role for ACE in regulating
clinicalresponse to steroids(38).Initial steroid resistance clearly identifies a subset ofpatients
at high risk for progressive kidney disease. It is estimatedthat 40% to 50% of children with
SRNS will progressto CKD or ESRD within 5 years of diagnosis, despite
aggressiveimmunosuppression. Among children with nephroticsyndrome due to FSGS who
progress to ESRD, renal transplantationcan also pose serious challenges. Nephrotic
syndromerecurs in the allograft in up to 30% of children with FSGS and leads to graft loss
in about 50% of such patients(39).Among children with FSGS due to NPHS2 mutations,
therisk for recurrence has been controversial(40).The introduction of antibiotics and steroids
in treatingnephrotic syndrome has led to a significant reduction in mortality,from 60% to
70% to less than 5%. In an ISKDC seriesof 521 children with nephrotic syndrome, 10
deaths werereported, resulting in a mortality rate of 1.9%(41). Of note, 9of these 10 children
had either early relapses or SRNS and6 (60%) died from infections, confirming infection as
animportant cause of mortality in nephrotic syndrome.Nephrotic syndrome is one of the
most common forms ofrenal disease seen in children. Although the introduction
ofantibiotics and refinement of immunosuppressive medicationshave greatly decreased
mortality and improved thequality of life for children with this disease, neither
themechanism(s) of action nor the target cell for these therapiesis known. In spite of this,
the prognosis for long-term maintenanceof normal renal function is excellent unless
completeremission cannot be achieved. Hopefully our growing understandingof the
pathobiology of nephrotic syndrome will leadto development of more effective therapies in
the future.

25. Patients & methods:
Data were collected from patients recording files
 Study design: reterospective
 Period of study : from 1of march 2013 – 1 of May 2013
 Place: Al- Kadhimiateaching hospital in pediatric nephrology clinic
 Number of patients: 40
 Parameters : Age, Gender, Residency, duration of follow up , characteristics of
nephrotic syndrome , biopsy, atypical feature
 Categorization: The patient categorized as follows:
o Group 1: remission
o Group 2: relapse.The children with relapse were further grouped according
to clinical course as
o Group 3: steroid responders:
 infrequent relapses (IFR) with ≤2 relapses in 6 months or ≤3 relapses
in a year
 frequent relapses (FRNS) with ≥2 relapses in 6 months or ≥3 relapses
in a year
o Group 4: steroid nonresponders (SNR) comprising those who have not
attained remission with 4 weeks of daily steroid therapy at 2 mg/kg/day.
 Inclusion criteria
A. Children with nephrotic syndrome, aged 1–12 years, following up at our
hospital for at least 1 years
B. Children in remission todetermine the occurrence of relapse or not
C. Children in relapse to see if they were respond to steroid or not
 Exclusion criteria:
o Children who not completethier follow up for at least 1 year in our hospital

26. Results:40 children with nephrotic syndrome visiting the pediatric nephrologyclinic,
Al- kadhimia teaching hospital, were eligible for the study
o Regarding the distribution of patient with nephrotic syndrome according
to age “as in table 1” , 2 patients (5%) were N.S. less than 1 year , 7
patient (17.5 %) were N.S. between 1-5 years & 31 patient (77.5 %) were
N.S. equal or above 5 years.
o Regarding the Demographic data in patients with nephrotic syndrome:“as
in table 2”
 25 (62.5 %) patients were males while 15 were females (37.5 %)
 22 (55 %) of patients reside a rural area while 18 (45 %) of
patients reside an urban area
o Regarding the Characteristics of nephrotic syndrome: “as in table 3”
 2 (5 %) of the patients had onset of N.S. within 1 year ,23(57.5 %)
of the patients had onset of N.S. between 1- 5 years & 15 (37.5 %)
of the patients had onset of N.S. equal & above 5 years
 2 (5 %) of the patients had frequent relapse while 38 (95 %) of the
patients had infrequent relapse
 26 (65 %) of the patients were steroid sensitive , 14 (35 %) of the
patients steroid resistant
o Regarding the duration of follow up: “as in table 4”
 6 (15 %) of the patients were followed for 1 year ,17 (42.5 %) of
the patients were followed for 1- 2 years , 13 (32.5 %) of the
patients were followed for 2- 4 years & 4 (10 %) of the patients
were followed for equal & above 4 years
o Regarding renal biopsy characteristics in 17 patients with nephrotic
syndrome : “as in table 5”
 12 (70.6 %) of the patients had MCD , 2 (11.8 %) of the patients
had FSGN &3 (17.6 %) of the patients had MPGN

27. o Regarding atypical features in patients with nephrotic syndromein 40
patients: “as in table 6”
 10 (25 %) of the patients were hypertensive
 7 (17.5 %) of the patients had a hematuria at initial diagnosis
 8 (20 %) of the patients had a raised in blood urea
 0 (0 %) of the patients had a raised in serum creatinine
Tables:
Table number (1) ….. Distribution of patient with nephrotic syndrome according to
age group
age Number of patients (%)
< 1 2 5
1-5 7 17.5
≥5 31 77.5
Total 40 100 %
Table number (2) ….. Demographic data of patient with nephrotic syndrome
Number of patients (%)
Gender
♂ 25 62.5
♀ 15 37.5
Residency
rural 22 55
urban 18 45
Total / each 40 100 %
Table number (3) ….. Characteristics of nephrotic syndrome
Number of patients (%)
Onset of disease
< 1 2 5
1-5 23 57.5
≥5 15 37.5
relapses
frequent 2 5

28. infrequent 38 95
Types of NS
sensitive 26 65
Resistant 14 35
Total / each 40 100 %
Table number (4) ….. Duration of follow up
age Number of patients (%)
< 1 6 15
1-2 17 42.5
2-4 13 32.5
≥4 4 10
Total 40 100 %
Table number (5) ….. Renal biopsy characteristics in 17 patients with nephrotic
syndrome
biopsy Number of patients (%)
MCD 12 70.6
FSGN 2 11.8
MPGN 3 17.6
Total 17 100 %
Table number (6)…. Atypical features in patient with nephrotic syndromein 40
patients
feature Number of patients (%)
hypertension 10 25
hematuria 7 17.5
↑ blood urea 8 20
↑ serum creatinine 0 0

29. Discussion:
o In this study, the distribution of patient with nephrotic syndrome
according to age “as in table 1”, the majority (77.5 %)were N.S. equal or
above 5 years.
 This study similar to other study were the majority of patient
(67%) were between equal or above 5 years.(43)
o In this study, the Demographic data in patients with nephrotic
syndrome:“as in table 2”
 (62.5 %) patients were males while were (37.5 %)females
 (55 %) of patients reside a rural area while (45 %) of patients
reside an urban area
 Which is nearly similar to other study :
 (67.9 %) patients were males while were (32.1 %)
females(42)
 (60 %) of patients reside a rural area while (40 %) of
patients reside an urban area(43)
o In this study, the Characteristics of nephrotic syndrome: “as in table 3”
 (5 %) of the patients had onset of N.S. within 1 year ,(57.5 %) of
the patients had onset of N.S. between 1- 5 years & (37.5 %) of
the patients had onset of N.S. equal & above 5 years
 (55 %) of the patients had frequent relapse while (45 %) of the
patients had infrequent relapse
 (65 %) of the patients were steroid sensitive , (35 %) of the
patients steroid resistant
 Which is nearly similar to other study :(43)
 (3 %) of the patients had onset of N.S. within 1 year ,(67 %)
of the patients had onset of N.S. between 1- 5 years & (30%)
of the patients had onset of N.S. equal & above 5 years
 (50 %) of the patients had frequent relapse while (50 %) of
the patients had infrequent relapse

30.  (70 %) of the patients were steroid sensitive , (30 %) of the
patients steroid resistant
o In this study, the duration of follow up: “as in table 4”
 (15 %) of the patients were followed for 1 year ,(42.5 %) of the
patients were followed for 1- 2 years , (32.5 %) of the patients
were followed for 2- 4 years & (10 %) of the patients were
followed for equal & above 4 years
 Which is nearly similar to other study :(42)
 (12 %) of the patients were followed for 1 year ,(40 %) of
the patients were followed for 1- 2 years , (30 %) of the
patients were followed for 2- 4 years & (18 %) of the
patients were followed for equal & above 4 years
o In this study, renal biopsy characteristics in 17 patients with nephrotic
syndrome : “as in table 5”
 (70.6 %) of the patients had MCD , (11.8 %) of the patients had
FSGN & (17.6 %) of the patients had MPGN
 Which is differ to other study :(44)
 Minimal change disease (85%), mesangial proliferation
(5%), and focal segmental glomerulosclerosis (10%).
o In this study, atypical features in patients with nephrotic syndromein 40
patients: “as in table 6”
 (25 %) of the patients were hypertensive
 (17.5 %) of the patients had a hematuria at initial diagnosis
 (20 %) of the patients had a raised in blood urea
 Which is nearly similar to other study :(43)
 (22.5 %) of the patients were hypertensive
 (22.2 %) of the patients had a hematuria at initial diagnosis
 (30 %) of the patients had a raised in blood urea

31. Conclusions:
In this study the majority of patients were “equal or more than 5 years, male, living in
rural area, with onset between 1-5 years, steroid responsive, frequent relapse, having a
follow up between 1-2 years& having MCD on renal biobsy”