Case Report

A 6 YEARS AND 5 MONTH BOY WITH CKD STAGE-1, STEROID-RESISTANT NEPHROTIC SYNDROME,
HYPERTENSION ON THERAPY, ACUTE DIARRHEA WITH MILD DEHYDRATION AND URINARY TRACT
INFECTIONS

Oleh :
Vickha Dian Hapsari

Pembimbing :
DR. Dr.Omega Mellyana SpA(K)

PPDS-1 BAGIAN ILMU KESEHATAN ANAK FK UNDIP

SMF ILMU KESEHATAN ANAK RSUP Dr. KARIADI
SEMARANG
2019

1
 CHAPTER 1
INTRODUCTION

Nephrotic syndrome (NS) is characterized by massive proteinuria (> 40 mg/m2/h), heavy

hypoalbuminemia ( < 2,5 g/dL), edema, and usually accompained by hypercholesterolemia > 200
mg/dL, based on the International Study of Kidney Disease in Children (ISKDC) criteria.1
Nephrotic syndrome is the most common kidney disease of children generally occurring in
school-aged children less than 14 years of age. Reports from the USA and UK showed that NS
affects 2-7/100,000 children per year; whereas a report from Indonesia showed that NS affects
6/100,000 children under 4 years of age per year. The ratio of boys to girls was reported
to be 2:1.2
The mainstay of treatment for NS is corticosteroids (steroids) with protocols largely
based on seminal studies from the International Study of Kidney Disease in Children.3 Steroid
responsiveness and frequency of relapses provide the best guide to therapy in idiopathic NS. The
majority of children respond well to steroids within 4 weeks (steroid-sensitive NS [SSNS]);
however, most will relapse, with approximately half becoming frequent relapsers or steroid
dependent.4,5 Although historically fewer than 10% of children with SSNS continue to have
relapses in adulthood,6 contemporary cohorts suggest higher proportions of 16∙4–42%.
Frequency of relapses during childhood and the need for non-steroid immunosuppressants such
as cyclophosphamide or ciclosporin are predictive of active disease as young adults.7,8 Among
287 children followed up for over 15 years, 85% achieved long-term remission. Despite ongoing
relapses, kidney outcomes remain excellent, with risk of progression to chronic kidney disease
estimated to be less than 5% in those with SSNS at 10 years after diagnosis.2 In contrast, SRNS is
associated with increased risk of progression to end-stage renal disease (ESRD). Children with
SRNS on biopsy might have minimal change or focal segmental glomerulosclerosis (FSGS). Owing
to the heterogeneity of SRNS, only 50% are at risk of progressing to ESRD in 5 years; typically
those children who do not achieve complete or partial remission.9 Long-term prognosis in adults
with paediatric onset NS is not well studied and would provide important information on risk for

2
families. Standard definitions are established and highlighted in the 2012 Kidney Disease
Initiatives: Global Outcomes (KDIGO; panel 1).10

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 CHAPTER II
CASE PRESENTATION

This case reported a 6-years and 5-months old boy admitted in Kariadi Hospital with
steroid-resistant nephrotic syndrome, dengue haemoragic fever and diarhhea.

Present Illness
Based on the history of the parents and from the medical records, information was
obtained about the child being taken to RSUP Dr. Kariadi Semarang with the main complaint of
diarhhea. The boy with idiopathic steroid-resistant nephrotic syndrome was admitted to our
Pediatric Department because of vomiting, diarrhea, abdominal pain and oliguria. On admission,
he was febrile 39’C, with congested eyes without any systemic signs and bleeding
manifestations. Additionally, he has had several episodes of nonbloody, nonbilious vomiting and
watery diarrhea. His pulse was 108 beats/min, respiratory rate 22x/min and blood pressure was
90/50 (P50)mm of Hg. Pulse was reguler with sufficient volume and pressure. He was breathing
spontaneously, oxygen saturation 98%. Initial investigation on admission showed Hb 18,1g/dL,
Ht 56,4%, RBC 6,68 x 107/uL, MCH 27,1 pg, MCV 84,3 fL, WBC 11,3 x 103/uL, Platelet 79 x 103/uL.
Eosinophil 0%, Basophil 0%, Staff 4%, Segment 77%, Lymphocyte 12%, Monocyte 7%.
Laboratory tests, performed on admission, showed an ongoing CKD stage I with GFR 148,5
ml/menit/1,73 m2 with , Ureum 55 mg/dL, Creatinine 0,4 mg/dL, diuresis 0,3cc/kg/hr, albumin
1,2 g/dL, urid acid 7,8 mg/dL, magnesium 0,8 mmol/L, Calcium 1.6 mmol/L, phosphat anorganic
4,9 mg/dL, Sodium 125 mmol/L, Potassium 6.1 mmol/L, Chloride 99 mmol/L.
Urinalysis from the urine shown cloudy red with pH 6, protein concentration 1.000
mg/dL, and sediments: epithelial cell 828/uL, epithelial tubulus 201,8/uL, oval fat bodies (+),
leucocytes 15/uL, erythrocyte 7,2/uL, calcium oxalate was positive, and the other sediments
were negative. Bacterial 768,1/uL and yeast cell 73,4/uL. Routine stool specimen tested showed
no entamoeba or parasit infection.
An i.v. infusion of albumin 20% (100 ml in 4 h) was started immediately after admission
while an infusion of saline 720 ml/24 hrs was added only five hours later; because of vomiting

4
the incoming oral fluid in the first 24 hrs was below 500 ml. On the second day, severe oliguria
was not present. Intravenous ampicillin sulbactam 200 mg/6 hr, intravenous methyprednisolon
40mg/24 hr (for 3 days), cyclophosphamide 25mg-0-25mg PO, lisinopril 2,5 mg/24 PO,
paracetamol 200 mg/4-6 hr (T≥38oC) PO, zink 20mg/24 hr PO.
Past medical history: The boy suffered from nephrotic syndrome and hypertensi when he
was 1 year 6 months. He started to get a full dose prednison (60mg/bsa) and captopril
0,1mg/kg/8hr and never get remision. When he was 2 years old, he was given Cyclophosphamide
(CPA) 2 cycles, but the urinalysis were found proteinuria +2 and the tension is higher. The boy is
programmed with cyclosporine therapy and get additional valsartan therapy. Last relapsed 6
months ago when he was get cough. Captopril was replaced by Lisinopril because the boy
repeatedly experienced coughing which caused relapse.
Perinatal history: He was born post term, sectio caesarea from G3P1A1 33 year old
mother. Birth weight was 3500 gr and birth lenght was forgotten. Her mother had routine
antenatal care in midwife more than 4 times during pregnancy, was received vitamin, iron
supplementation, and TT injection for twice. There was no history of TB and any other illness
during pregnancy.
Sosio-economic and family history: Both her parents worked as bakers with average
monthly income ± Rp 4.000.000,-. Hospital cost was covered by class one independent BPJS.
Family medical history: No history of kidney disease, no history of the same disease.
Pedigree

5
 Developmental history: He is normal developmental status. He is able to walk, run, jump,
talking, helping the household activities. He was attending kindergarten A. He could follow
school lessons and playing round with friends.
Growth history: Body weight 1 month before admission was 17 kg. On admission, body
weight was 18 kg, 108 cm in height, 51 cm for head circumference, 19 cm for upper arm
circumference. No history of weight loss was noted.
Immunization history: Basic immunization was completed appropriate for her age.

Physical Examination on February 24th 2019 in C1L1 pediatric ward:

Six years and five month boy with 18 kg body weight, 108 cm height, with fluid balance
+20 cc/d and diuresis 1 cc/kg/hr. General conditions were conscious GCS E4M6V5. The patient’s
complain diarhhea 8 times a day, no fever, no vomiting. He was oriented to time, place and
person. He was breathing spontaneously, no breathlessness. Heart rate was 100 beats per
minute, regular rhythm with good pulse, respiratory rate was 24 times/minute, body
temperature 39oC, and blood pressure was 90/50 mmHg (P50). He had edema in his palpebra,
sclera did not shown any sign of anemia, nor jaundice. No abnormalities in ear, nose and throat.
No enlargements of lymph nodes were found in the neck. Symmetrical respiration on static and
dynamic setting, no retraction was found and no shotness of breath. Heart sounds was normal,
no heart murmurs. Auscultation of the lungs showed normal vesicular sound, no additional
sound was found. Abdominal examination showed bulging flanks, no enlargement of liver and
spleen. All extremities were not cyanotic, capillary refill was <2”.
Anthropometric score: WAZ -1,19 SD, HAZ -1,86 SD, BMI for age 0,07 SD. He gaining
weight 1 kg since previous month. Nutritional status impression were well nourished, normal
stature, and normo growth.

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Laboratory findings:
The result of laboratory examinations on admission February 23th 2019 were Hb 18,1g/dL, Ht
56,4%, RBC 6,68 x 107/uL, MCH 27,1 pg, MCV 84,3 fL, WBC 11,3 x 103/uL, Platelet 79 x 103/uL.
Eosinophil 0%, Basophil 0%, Staff 4%, Segment 77%, Lymphocyte 12%, Monocyte 7%. albumin
1,2 g/dL, Ureum 55 mg/dL, Creatinine 0,4 mg/dL, urid acid 7,8 mg/dL, magnesium 0,8 mmol/L,
Calcium 1.6 mmol/L, phosphat anorganic 4,9 mg/dL, Sodium 125 mmol/L, Potassium 6.1 mmol/L,
Chloride 99 mmol/L. Urinalysis from the urine shown cloudy red with pH 6, protein
concentration 1.000 mg/dL, and sediments: epithelial cell 828/uL, epithelial tubulus 201,8/uL,
oval fat bodies (+), leucocytes 15/uL, erythrocyte 7,2/uL, calcium oxalate was positive, and the
other sediments were negative. Bacterial 768,1/uL and yeast cell 73,4/uL.
Diagnosis:
The boy was diagnosed with steroid-resistant nephrotic syndrome relaps, hypertension
(controlled by medication), diarhhea acute dehydration.
Therapy :
The boy was admitted to the C1L1 ward, given infusion saline 0,9% 50 ml/jam (3cc/kg/h),
injections of: ampicillin sulbactam 200mg/6 jam, inj methylprednisolone 40mg/24 hr, tranfusion
albumin 20% 100ml And oral medications: lisinopril 2,5mg/24 hr, cyclosporine 25mg-0-25mg,
zink 20mg/24 hr
Progress note:
On the first day in the pediatric ward, he had diarrhea 8 times a day. He was
composmentis, still had palpebra edema, no shortness of breathing, vital sign: blood pressure
90/50 mmHg, heart rate 112x/minute, normal volume and pressure, respiratory rate
24x/minute, body temperature 38,5oC, fluid balance -25 cc/12 hours, diuresis 1.38 cc/kg/hour.
Albumin result after tranfusion was 1,4 g/dL
On the 2rd day, he had diarrhea 10 times a day, patient gets tranfusion of Albumin 100ml
and Albumin result after tranfusion was 1,7 g/dL. The evaluation of laboratory on February 25th
2019 were Hb 14,7g/dL, Ht 43,8%, RBC 5,32 x 107/uL, MCH 27,6 pg, MCV 82,3 fL, WBC 3,3 x
103/uL, Platelet 219 x 103/uL, Ig M dengue (+), Ig G dengue (-). From these findings, the platelet
increased and infus replaced to infus D5 ¼ NS 20ml/hr.

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 1st week of admission, patient get total albumin transfusion 4X100ml. Edema started to
alleviate. He was composmentis, and the edema was reduced. Vital sign: blood pressure 80/60
mmHg, heart rate 102x/minute, normal volume and pressure, respiratory rate 22x/minute, body
temperature 36,8oC. The evaluation of laboratory were Hb 13g/dL, Ht 47,9%, RBC 4,7 x 107/uL,
MCH 27,7 pg, MCV 80,6 fL, WBC 5,4 x 103/uL, Platelet 210 x 103/uL, Albumin 2.4g/dL. Urinalysis
from the urine shown clear yellow urine with pH 7, protein concentration 30 mg/dL, and
sediments: epithelial cell 2,6/uL, epithelial tubulus 1,8/uL, leucocytes 0,6/uL, erythrocyte 0,8/uL,
calcium oxalate was positive, and the other sediments were negative. Bacterial 5,8/uL and yeast
cell 0,2/uL. The boy was permitted to leave the hospital. Outpatient medication include
methyprednisolone mg/m2/days (full dose) : 16mg-16mg-0,lisinopril 2,5mg/24 jam, calk 1
tab/24 jam, cyclosporine 25mg-0-25mg

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 CHAPTER III
CASE ANALYSIS
Chronic Kidney Disease
Adverse outcomes of CKD can often be prevented or delayed through early detection and
treatment. Earlier stages of CKD can be detected through routine laboratory measurements.11

• The presence of CKD should be established, based on presence of kidney damage and level of
kidney function (glomerular filtration rate [GFR]), irrespective of diagnosis.

• Among patients with CKD, the stage of disease should be assigned based on the level of kidney
function, irrespective of diagnosis, according to the K/DOQI CKD classification (Table 1).

The Work Group defined CKD as the presence of kidney damage or GFR 60 mL/min/1.73
m2 for 3 months or more, irrespective of diagnosis (Table 2). Kidney damage is usually identified
by the presence of markers of disease that are present in blood, urine, or imaging studies, rather
than by kidney biopsy. The CKD guidelines emphasize persistent proteinuria as a particularly
important marker of kidney damage. The rationale for including individuals with normal GFRs is
that substantial kidney damage often occurs before this pivotal component of kidney function
declines, and that these individuals are at increased risk for adverse outcomes of CKD.12 The
rationale for including individuals with GFR 60 mL/ min/1.73 m2 without any other evidence of
kidney damage is that reduction in kidney function below this level represents loss of at least
50% of normal kidney function, a level at which the prevalence of complications of CKD begins to
increase. The 5 different CKD stages shown in Table 1 generally correspond to both the severity
and the nature of the expected complications of CKD. Kidney failure (CKD stage 5) is defined as

9
either 1) GFR 15 mL/min/1.73 m2, or 2) need for the initiation of kidney replacement therapy
(dialysis or transplantation).13

The decision to use the level of GFR as the primary focus in this guideline was made
because GFR provides the best measure of overall kidney function. However, correct
interpretation of GFR values in individual patients, especially children and adolescents, requires a
clear understanding that the normal level of GFR varies according to age, gender, and body size.
The normal GFR in young adults is 120 to 130 mL/min/1.73 m2, whereas the normal level of GFR
is much lower than this in early infancy, even when corrected for body surface area, and
subsequently increases in relationship to body size for up to 2 years.14 Hence, the GFR ranges
that are used to define the 5 CKD Stages in Table 1 apply only to children 2 years of age and
above. The normal range of GFRs at different ages is given in Table 3.15

10
 Some individuals without kidney damage and with normal or elevated GFR are at
increased risk for development of CKD.
• All individuals should be assessed, as part of routine health encounters, to determine if they
are at increased risk of developing CKD, based on clinical and sociodemographic factors.
• Individuals at increased risk of developing CKD should undergo testing for markers of kidney
damage and to estimate the level of GFR.
• Individuals found to have CKD should be evaluated and treated.
• Individuals at increased risk, but found not to have CKD, should be advised to follow a
program of risk factor reduction, if appropriate, and undergo repeated periodic evaluations.
The prevalence of children and adolescents at increased risk for CKD has not been
studied systematically. It is likely that the number of individuals at risk for CKD exceeds the
number of patients known to have CKD. Pediatric patients who are at increased risk of
developing CKD include those with disorders such as those shown in Table 4.

11
 Normal individuals usually excrete very small amounts of protein in the urine. Persistently
increased protein excretion is usually a marker of kidney damage. The excretion of specific types
of protein, such as albumin or low molecular weight globulins, depends on the type of kidney
disease that is present. Increased excretion of albumin is a sensitive marker for CKD attributed to
diabetes, glomerular disease, and hypertension. Increased excretion of low molecular weight
globulins is a sensitive marker for some types of tubulointerstitial disease. In this guideline, the
term “proteinuria” refers to increased urinary excretion of albumin, other specific proteins, or
total protein; “albuminuria” refers specifically to increased urinary excretion of albumin.
“Microalbuminuria” refers to albumin excretion above the normal range but below the level of
detection by dipstick for total protein.
• Under most circumstances, untimed (“spot”) urine samples should be used to detect and
monitor proteinuria in children and adolescents.
• It is usually not necessary to obtain a timed urine collection (overnight or 24-hour) for these
evaluations.
• First morning specimens are preferred, but random specimens are acceptable if first morning
specimens are not available.
• In most cases, screening with urine dipsticks is acceptable for detecting proteinuria:
1. Standard urine dipsticks are acceptable for detecting increased total urine protein.
2. Albumin-specific dipsticks are acceptable for detecting albuminuria.
3. Patients with a positive dipstick test (1 or greater) should undergo confirmation of proteinuria
by a quantitative measurement (protein-to-creatinine ratio or albumin-to-creatinine ratio) within
3 months.
• Patients with 2 or more positive quantitative tests temporally separated by 1 to 2 weeks should
be diagnosed as having persistent proteinuria and undergo further evaluation.16
Patients diagnosed with nephrotic syndrome from the age of 1 year and 6 months.
Relaps often occurs with clinical anasarca edema and massive proteinuria. Patients can be
clasificate with CKD because kidney damage > 3 month. Because of LFG is still normal (148) it
can be said to be stage 1 chronic kidney failure.

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Nephrotic Syndrome
Nephrotic syndrome (NS) is characterized by massive proteinuria (> 40 mg/m2/h), heavy
hypoalbuminemia (< 2,5 g/dL), edema, and usually accompained by hypercholesterolemia > 200
mg/dL, based on the International Study of Kidney Disease in Children (ISKDC) criteria.1 (table
1)17

Table 1. Definitions .
Term Definition
Nephrotic syndrome Proteinuria > 40mg/m2/hr , plasma albumin <25g/L,
edema or protein : creatinine ratio > 200 mg/mmol
Remission Urinary protein excretion < 4 mg/ m2/ hr or albustix 
0/trace for 3 consecutive days
Steroid responsive Remission achieved with steroid therapy alone
Late responder Remission occuring after 4 weeks prednisolone
60mg/m2/day without other drugs
Relapse Urinary protein excretion > 40 mg/ m2/ hr or albustix  +
+ or more for 3 consecutive days, having previously been
in remission
Frequent relapse Two or more relapses within 6 months of initial response
or 4 or more relapses within any 12-month period
Steroid dependence Two consecutive relapse occuring during corticosteroid
treatment or within 14 days of its cessation
Steroid resistance Failure to achieve response in spite of 4 weeks’
prednisolone 60mg/m2/day
Early nonresponder Steroid resistance in the initial episode
Late nonresponder Steroid resistance developing in a patient who had
previously been steroid responsive

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 Nephrotic syndrome is a common chronic illness in childhood, reports from the USA and
UK showed that NS affects 2-7/100,000 children per year; whereas a report from Indonesia
showed that NS affects 6/100,000 children under 4 years of age per year. The ratio of boys
to girls was reported to be 2:1.18 The peak age of onset occur at 2 – 3 years except for the rare,
congenital type of nephrosis. Approximately 50% of affected children are ages 1 to 4 years; 75%
are younger than age 10 years.19 In children younger than 8 years at onset, the ratio of males to
females is 2:1 to 3:2. In older children and adolescent, the male-to-female prevalence is
approximately equal. Approximately 75% of children who developed nephrotic syndrome is
younger than 6 years of onset.19 According to the International Study of Kidney Diseases in
Childhood (ISKDC), 84.5% of all children have minimal-change nephrotic syndrome (MCNS), 9.5%
have focal segmental glomerulosclerosis (FSGS), 2.5% have mesangial proliferation, and 3.5%
have membranous nephropathy or other etiologies.1
The causes of the primary and most of the secondary glomerular disorders associated
with the nephrotic syndrome are largely unknown. By far, the most common form of nephrotic
syndrome is that associated with “nil disease,” or minimal change on renal biopsy. It is also called
idiopathic nephrosis of childhood and accounts for 80% of pediatric cases. There is no definite
association with antecedent bacterial (e.g., streptococcal) or viral infections, although the
presenting illness and episodes of clinical relapse are often associated with upper respiratory or
GI infections. Some have postulated an imunologic mechanism : 1) persistently elevated serum
IgM levels, 2) circulating immune complexes, 3) spontaneous remissions with natural measles
infections (which are known to induce suppression of cell-mediated immunity), 4) suppression of
lymphocyte proliferative responses in vitro by serum from patients with nephrotic syndrome, 5)
hyperactivity of lymphocytes from patients when exposed to renal antigens in vitro, and 6)
response of some patients to immunosuppressive agents. The strongest argument against an
immunologic factor as a cause of nephrotic syndrome has been the failure to find immune
reactants or inflammation in kidney biopsies, despite repeated studies of these patients.20 A
comprehensive list of causes are listed in (table 2).

14
Idiopathic Minimal-change nephrosis
Focal segmental glomerulosclerosis
Idiopathic
Obesity
Unilateral renal agenesis
Glycogen storage disease
Post infectious glomerulonephritis
Obstructive uropathy
Lupus nephropathy
Sickle cell disease
Alport syndrome
Membranous glomerulonephritis
Idiopathic
Lupus nephropaty
Sickle cell disease
Sarcoidosis
Hashimoto tyroiditis
Heavy metal toxicity
Captopril
Penicillamine
NSAID
Syphilis
Hepatitis B and C
Membranoproliferative Glomerulonephritis
Chronic bacterial or viral infection
Lupus nephropathy
Rheumatoid arthritis
Chronic liver disease
Sickle cell disease
Renal transplant
Bone marrow transplant
Table 2. Primary and secondary glomerulopathies

The patient is a 6 year 5 month old boy, complaining of diarhhea. He is diagnosed with
steroid-resistant nephrotic syndrome when he was 6 year 7 month old. The boy was given
prednisone with a daily dose of 60 mg / day for 6 weeks but persistent proteinuria 500 mg / dL
was remained. Based on the response to glucocorticoid therapy, nephrotic syndrome is classified
as steroid resistant nephrotic syndrome (SRNS). SRNS is defined as failure to achieve remission
despite daily therapy of oral prednisone at full dose (2 mg/kg/day) for 4 weeks.21

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 Patient with nephrotic syndrome typically present with periorbital swelling (puffiness),
more noticeable in the morning, which progress to generalized edema over days or weeks.
Edema is gravity dependent, localized to the lower extremity in upright position. Abdominal wall
edema and ascites or pleural effussions and scrotal or vulval edema may be seen. This edema is
soft and pitting, keeping the marks of clothes or finger pressure. Microscopic hematuria is found
in up to 30% patients, but gross hematuria is unusual in idiopathic nephrotic syndrone and
suggest an alternative primary diagnosis. Intravascular volume depletion may happen despite a
fluid gain up to 20% of body weight. Cardiovascular shock is not unusual, secondary to sudden
fall of plasma albumin, with abdominal pain and symptoms of peripheral circulatory failure with
cold extremities and hypotension. Blood pressure is usually normal but sometimes elevated.22,23
This patient had symptoms of edema of the palpebral, hypertension; laboratory investigations
revealed significant proteinuria, hypoalbuminemia that treated with tranfusion of albumin. While
the diagnosis of steroid-resistant was based on the response to steroid therapy, this patient
achieved no remission despite having a 4-week course of prednisone full dose (FD). The patient
was given prednisone with a daily dose of 60 mg / day for 6 weeks but persistent proteinuria 500
mg / dL was remained. Based on the response to glucocorticoid therapy, nephrotic syndrome is
classified as steroid sensitive nephrotic syndrome (SSNS) and steroid resistant nephrotic
syndrome (SRNS). SRNS is defined as failure to achieve remission despite daily therapy of oral
prednisone at full dose (2 mg/kg/day) for 4 weeks.21 Urinary protein carbonyl content (UPCC)
examined before starting steroid therapy can be used to predict the steroid dependence and
resistance in children with idiopathic nephrotic syndrome. Using cutoff limit of 5.10 nmoles/mg
of protein, UPCC can predict steroid dependence or resistance cases with 83.3% sensitivity and
85.2% specificity.24 When the patient was first diagnosed at previous health care facility, UPCC
assay was not measured before starting steroid therapy.
Nephrotic syndrome patients should undergo urinalysis and microscopy, urinary protein
to creatine ratio (Upc) or 24-h urinary protein estimation, serum albumin, total protein,
cholesterol, and creatinine. Infectious disease workup including PPD (mantoux) skin test and
chest x ray in the epidemic areas, and HIV, HBV, or HCV serology or PCR for patient at risk.
Kidney biopsy is reserved for infant and older children, and those with “atypical” presentation

16
and for SRNS. Kidney biopsy is necessary to exclude secondary causes of nephrotic syndrome,
and assess the extent of interstitial and glomerular fibrosis.22,25 In this case kidney biopsy is not
done.
Currently, there is no consensus about the most appropriate secondline agent for
treating children with refractory childhood nephrotic syndrome. Immunosuppressive agents (ie,
cyclophosphamide, cyclosporine, tacrolimus and mycophenolate mofetil) are the commonly
used as second-line therapeutic agents for refractory childhood nephrotic syndrome. According
to KDIGO 2012, treatment recommendation for SRNS are calcineurin inhibitor (CNI) as initial
therapy for children with SRNS (LoE 1B) for a minimum of 6 months and then stopped if a partial
or complete remission of proteiunuria is not achieved (2C), and be continued for a minimum of
12 months when at least a partial remission is achieved by 6 months with low dose
corticosteroid theraphy be combined with CNI theraphy. Additional to this regimens is ACEI or
ARBs for children with SRNS.18 These patients received ACEI and ARB therapy to control the
blood pressure and to reduce proteinuria. Hypertension in this patient has been improved
captopril, because the patient had repeated coughing, captopril administration was changed to
lisinopril. In addition to medical treatment, this patient is also encouraged to modify lifestyles
changes such as having regular exercise, maintaining ideal body weight and reducing salt
consumption to 1.5g/day.11
Systematic review report that cyclosporin significantly increased the number with
complete or partial remission compared with IV cyclophosphamide (RR 3.40, 95% CI 1.12 to
10.28). There was no significant difference in the number who achieved complete remission
between oral cyclophosphamide with prednisone versus prednisone alone (RR 1.06, 95% CI 0.61
to 1.87), IV versus oral cyclophosphamide (RR 3.13, 95% CI 0.81 to 12.06), IV cyclophosphamide
versus oral cyclophosphamide with IV dexamethasone (RR 1.13, 95% CI 0.65 to 1.96), tacrolimus
versus cyclosporin (RR 0.86, 95% CI 0.44 to 1.66) and azathioprine with prednisone versus
prednisone alone (RR 0.94, 95% CI 0.15 to 5.84). ACEi significantly reduced proteinuria.26
Systematic review and metaanalysis found that treatment with mycophenolate mofetil
had the greatest odds of relapse compared with tacrolimus, cyclophosphamide or cyclosporine.
Rank probability analysis found that cyclophosphamide was the best treatment with the lowest

17
relapse rate as compared with other treatments, and tacrolimus was ranked as the second best
with respect to relapse.27 Another systematic review and metaanalysis suggest that tacrolimus
and cyclosporine may be preferred initial treatments for children with SRNS. MMF may be
another option for this patient population.28
Treatment for steroid-resistant nephrotic syndrome (SRNS) is challenging and children
who suffer from SRNS require aggressive treatment to achieve remission. Thus, when
intravenous high-dose methylprednisolone does not work, calcineurin inhibitors, such as
cyclosporine, is used as the first line of treatment.29 Cyclosporine has shown to have higher rate
of remission as compared to other immunosuppressant therapies used for the treatment of
SRNS.30 Calcineurin inhibitors have been used more in an empirical manner than on the basis of
clear rationale.29 It was in 1984 when cyclosporine was first considered for the treatment of
SRNS. Till now many studies have been conducted to determine dosages, duration of therapy,
side effects and advantages of cyclosporine.31 Cyclosporin is a calcineurin inhibitor that
suppresses immune response by downregulating the transcription of multiple cytokine genes.
The most significant of these cytokines is interleukin-2, which serves as the major activation
factor for T cells in numerous immunologic processes. Cyclosporin inhibits cytokine production
from T helper cells and also has an inhibitory effect on antigen presenting cells which are the
main agents of T cell stimulation. A further effect of IL-2 inhibition is a reduction in B-cell
activation and subsequent antibody production. IL-2 levels are known to become elevated during
proteinuria and to normalize during remission in adults with idiopathic nephrotic syndrome and
in children with Minimal change Nephrotic Syndrome (MCNS) or FSGS.29 However, this pattern of
interleukin-2 activity is felt to be part of a more widespread disorder of cellular immunity that
results in nephrotic syndrome rather than being causal of proteinuria.It has been reported that
cyclosporin has some antiproteinuric action on glomerular perm-selectivity to proteins that is
unrelated to its immunosuppressive properties. Among these are an influence on perm-
selectivity and charge selectivity and impairment of GFR. These data come from various human
studies and animal models with no immunologically mediated disease. Some studies revealed
that lesions from the primary glomerular disease had either not regressed or had continued to
progress.32

18
 According to a study, renal insufficiency developed in 6% and hypertension in 10% of
patients (most patients with FSGS).33 This analysis of the long-term risks of cyclosporin for
childhood NS has identified two important findings:34 combined cyclosporin and alternate-day
steroids can be highly effective in inducing complete remission in patients with SRNS and biopsy-
proven IgM nephropathy, and long-term use of cyclosporin in moderate doses with closely
monitored levels can result in a relatively low incidence of nephrotoxicity.35 There was a higher
incidence of cyclosporin dependence among young responders.
This patient is treated with cyclosporine at dose of 3mg/kg/day twice a day with oral
methylprednisolone 60mg/m2 daily and tappering off for 1 month according to the protocol CPA
for SRNS.3 In the recent years, experts of the Indian Society of Pediatric Nephrology effective
therapy regimens include treatment with calcineurin inhibitors (Cyclosporine), combination of
pulse corticosteroids with oral cyclophosphamide or intra-venous cyclophosphamide, tapering
doses of alternate day corticosteroids. Supportive management comprises therapy with
angiotensin converting enzyme inhibitors and statins. These guidelines are expected to enable
standardization of care for patients with SRNS worldwide.36
KDIGO Clinical Practice Guideline for Glomerulonephritis published in 2012, suggested
treatment recommendations for SRNS. These were calcineurin inhibitor (CNI) as initial therapy
which should be continued for atleast 6 months and discontinued only if partial or complete
remission of proteinuria is not observed; In case partial remission is achieved by 6 months then
CNIs can be continued for minimum of 12 months. Other suggestions in these guidelines were
low dose corticosteroid therapy with CNI therapy and ACE-I or ARBs were also recommended. In
children who fail to respond to CNI therapy can be treated with mycophenolate mofetil, high-
dose corticosteroids, or a combination of these agents in children who fail to achieve complete
or partial remission with CNIs and corticosteroids. It was suggested to not to use
cyclophosphamide in these children. These guidelines also mentioned treatment for patients
with a relapse of nephrotic syndrome after complete remission, in which therapy should be
restarted using oral corticosteroids, returning to previous successful immunosuppressive agent
or an alternative immunosuppressive agent to minimize potential cumulative toxicity (Clinical
Practice Guidelines KDIGO, 2012).18

19
 Systemic corticosteroids are used for the treatment of nephrotic syndrome in initial
phase and maintenance phase. Therapy in this patient is a full dose of methylprednisolone
because it is relaps (periorbita edema, proteinuria 1000 mg / dL and hypoalbuminemia 1.2 mg /
dL). Despite the beneficial effects, long term systemic use of these agents is associated with well-
known adverse events (Aes) including: cushingoid feature (19,4%), behavioral changes (8,1%),
increase appetite (18,5%), weight gain (21,1%), hypertension (5,6%), infection (8,7%), growth
retardation (18,1%), gastrointestinal upset (15,8%), hyperglycaemia (3,4%),
hypercholesterolaemia, fatigue (2,0%), myopathy (3,0%), insomnia (9,9%), headache (4,3%),
cataracts (5,9%), gastric wall abnormalities (10,4%), osteoporosis (0,8%), dizziness (4,3%), edema
(0.8%), acne (10,8%), skin striae (4,4%), hirsutism (12,1%), HPA axis suppression (58,6%), fever
(3,2%), pigmentation, rash (5,8%), and other rare advers event increase intraocular pressure,
pancreatitis, obstructive sleep apnoea, oral ulceration, hypocalcemia, hypokalemia.
Glucocorticosteroid (GC)-associated toxicity appears to be related to both the average dose and
cumulative duration of GC use. The adverse events of corticosteroid use should be monitored
regularly. Spesific recommendation for the assessment and monitoring of bone mineral density
(BMD) and fracture risk, diabetes, CV risk and dyslipidemia, adrenal supression, growth and
ophthalmologic event.37,38 This patient had received high-dose corticosteroid therapy for 1.5
months. Side effects encountered in the form of increased appetite, cushingoid feature, skin
striae, hypertension, and hypercholesterolemia. While hypertension and hypercholesterolaemia
are the symptoms of the nephrotic syndrome.

The contribution of renal biopsy (RB) is of major importance in the management of many
renal diseases in children. Specific indications for performing biopsy in children include steroid-
resistant nephrotic syndrome (NS) and secondary nephropathies. The anatomical pathology
results obtained from most nephrotic syndromes in children are abnormalities minimum, the
ISKDC no longer recommends biopsy was performed in all nephrotic syndrome patients. Kidney
biopsy is recommended in cases of syndrome nephrotic which is resistant to steroids or at the
initial presentation has a component of nephritis, namely, real hematuria, increase in creatinine
urea levels or decreased kidney function, which is found to be hypertension settled, and
decreased C3 levels. Next because it turns out that the prognosis determination is better done

20
with an assessment of the response to steroids rather than picture of PA, then finally division
classification Nephrotic syndrome is a steroid-sensitive nephrotic syndrome (SNSS) and steroid-
resistant nephrotic syndrome (SNRS). In a large multicenter cohort, the International Study of
Kidney Disease in Children (ISKDC) demonstrated that 77% of children with incident idiopathic NS
had MCD, suggesting that the majority of children at diagnosis should not need a biopsy.3
Subsequent studies have shown that approximately 90% of children with MCD respond to
corticosteroid therapy and, furthermore, approximately 90% of all children with NS who respond
to treatment will have MCD.3

These observations suggest that response to therapy is a useful measure of underlying

histopathology. While these studies have informed clinical practice, there continues to be a lack
of consensus among nephrologists or evidence-based guidelines regarding the specific
indications for performing kidney biopsies in children with NS. In fact, in a number of case series
of children with NS who underwent kidney biopsy, MCD continues to be the most common
pathological diagnosis.39 While the ISKDC studies provided important information about the
clinical characteristics of the different forms of INS, they were not able to use these
characteristics to differentiate between MCD and FSGS at diagnosis.3
Focal segmental glomerulosclerosis (FSGS) is a frequent glomerular kidney disease that
is revealed by proteinuria or even nephrotic syndrome. A diagnosis can be established from a
kidney biopsy that shows focal and segmental glomerulosclerosis. This histopathological lesion
may be caused by a primary podocyte injury (idiopathic FSGS) but is also associated with other
pathologies (secondary FSGS). The first-line treatment for idiopathic FSGS with nephrotic
syndrome is a prolonged course of corticosteroids. However, steroid resistance or steroid
dependence is frequent, and despite intensified immunosuppressive treatment, FSGS can lead to
end-stage renal failure.40

Hypertension On Therapy

21
 Hypertension often occurs in children with nephrotic syndrome, where steroid use can
exacerbate hypertension. Two main hypotheses have been posited to explain the development
of sodium retention in nephrotic syndrome: the underfill hypothesis and the overfill hypothesis.
The premise of the underfill hypothesis is that sodium retention in nephrotic syndrome is
primarily due to decreased effective circulating volume caused by fluid shifts from the
intravascular to the interstitial compartment as a direct consequence of a decrease in plasma
oncotic pressure by hypoalbuminemia. These changes activate sodium and water retention in
the kidney. The overfill hypothesis postulates that sodium retention reflects an intrinsic defect in
kidney sodium handling, which in turn causes volume expansion.

Hypertension that occurs in these patients has been controlled by administration of

lisinopril. Lisinopril is a medication of the angiotensin-converting enzyme (ACE) inhibitor class
used to treat high blood pressure, heart failure, and after heart attacks. Proteinuria appears to
be an important risk factor for renal function deterioration and for cardiovascular mortality. ACE
inhibitors have been shown to reduce proteinuria more effectively than other antihypertensives.
Their antiproteinuric effect seems to be independent of the underlying renal disease, and is
mediated by a specific, not yet fully elucidated mechanism.41 Urinary protein loss related
phenomena, such as hypoalbuminemia and aberrant lipoprotein profile, tend to improve also
during ACE inhibitor treatment. Furthermore, ACE inhibition has been shown to prevent the
renal function deterioration that is frequently observed in patients with renal disease.
Interestingly, it has recently been shown that in proteinuric patients with renal disease the initial
proteinuria lowering response to ACE inhibition predicts long-term renal function outcome
during this treatment the more proteinuna is lowered during the first months, the better renal
function will be preserved over the following years. Because of these favorable effects ACE
inhibitors have become a widely used class of agents in nephrology. They are not only prescribed
for lowering blood pressure in the hypertensive renal patient, but also as symptomatic treatment
of patients with proteinuria.42

Previously the patient was given captopil, but because the boy had a recurring cough
which caused relapse eventually captopril was replaced with lisinopril. Lisinopril is a drug used to
control high blood pressure (hypertension). The effect of two angiotensin-converting enzyme

22
(ACE) inhibitors, lisinopril and captopril, on proteinuria and renal haemodynamics was
investigated in 11 hypertensives (9 men, 2 women; mean age 46 +/- 16 years) with proteinuria (>
1.5 g/24 h) due to chronic glomerulonephritis and impaired renal function (glomerular filtration
rate < 75 ml/min). Protein excretion was not significantly reduced by either drug (placebo: 7.1
+/- 4.0 g/d; lisinopril: 5.1 +/- 2.8 g/d; captopril: 5.4 +/- 3.0 g/d). Albumin excretion and fractional
albumin clearance were significantly decreased only by lisinopril (P < 0.05), not by captopril.
Plasma-renin activity was increased more by lisinopril than captopril (Placebo: 1.0 +/- 0.9
ng/ml.h; lisinopril: 5.2 +/- 2.8 ng/ml.h [P < 0.05]; captopril: 1.8 +/- 1.3 ng/ml.h [P < 0.05]). The
renal haemodynamics was only slightly influenced by either drug, but captopril significantly
decreased the filtration fraction in the presence of chronic glomerulonephritis and renal
failure.41

Acute Diarrhea With Mild Dehydration

The management of dehydration in patients with NS must consider some particular
pathophysiological aspects of the underlying condition, including the serum albumin
concentration and the amount of proteinuria. In normal subjects, the increased oncotic pressure
related to acute dehydration and the consequent increase in plasma protein concentrations
shift water from the interstitial compartment to the vascular bed in proportion to the absolute
increase of plasma protein concentration. In a child with NS, an equal loss of water leads to a
smaller increase in absolute plasma protein concentration and in oncotic pressure. The result of
this altered pathophysiology is a reduced shift of water into the vascular system regardless of the
excess fluid in the extravascular system. This implies that the hemodynamic condition of patients
with ongoing NS is more precarious, thus making them a lot more susceptible to AKI.43
It may seem paradoxical to consider a child with edema as being dehydrated. However,in
our opinion, this overweight was disproportionately low with respect to the relatively low
albumin level (1,2 g/dL) and the high amount of proteinuria (1000 mg/dL). The pathophysiology
of AKI in NS patients can include one or more of the following mechanisms: low renal perfusion
pressure in the case of severe hypoprotidemia, acute tubular necrosis, high intratubular
pressure, interstitial nephritis and interstitial edema.44

23
 It may seem reasonable to treat a dehydrated child with severe hypoprotidemia by
administering albumin to mobilize the sequestered fluids thus avoiding to further increase the
already existing water excess.45 It must be kept in mind that administered albumin will eventually
lead to a massive increase in protein loss into the tubules.46 The disproportion between
hypoalbuminemia (NOT in nephrotic range) and protinuria (IN nephrotic range) should be
considered an indicator of a possible dehydration and discourage the clinician to approach the
child with NS recurrence and mild edema by administering albumin as the first line treatment. As
already reported by Koomans et al,47 in the dehydration and antidiuresis condition, a massive
infusion of albumin may induce a very high tubular protein concentration, with tubular clogging
and precipitation of protein casts in the tubules. This process may also be favored if acidosis and
aciduria coexist as commonly observed in dehydrated children.48

Urinary Tract Infection

Urinary tract infection (UTI) is an infection in any part of the urinary system: the kidneys,
ureters, bladder, or urethra. A diagnosis of UTI is made if urine culture results from midstream
urine reveal bacterial colonization >100,000 colonies/mL urine of a single bacterial type, or
>10,000 colonies/mL urine, but accompanied by specific clinical UTI manifestations.49 The
prevalence of UTI in NS patients is high, due to immunoglobulin loss, defective T-cell function,
the presence of ascites, and relative malnutrition. A study in Pakistan reported that UTI was the
second most common infection in NS patients (25.2%), after bronchopneumonia (46.6%).6
Another previous study found the prevalence of UTI in NS patients in Yogyakarta to be 25%.7.50

Infection is easily occurs in NS patients as a result the leakage of IgG and complement B
and D factors in urine. Immunosuppressive agents also increase the risk of infection. Urinary
tract infection, in particular, is common in NS patients.51 Besides the loss of immunoglobulin via
urine, UTI may result from T cell dysfunction, ascites, and relative malnutrition in NS patients. 52
In addition to UTI, other infections commonly found in NS are peritonitis, pneumonia, cellulitis,
and fungal infection.3 In this study, UTI occurred in 34 of 74 NS patients (46%). Arcana et al. 8
and Adeleke et al. reported UTIs in 42% and 66.7%, of NS patients, respectively. However,
Moorani et al.50

24
 Urinary tract infection is caused by bacteria, viruses, or fungi. The most common etiology
of UTI, both symptomatic and asymptomatic, including in neonates, is Eschericia coli.49
Subandiyah found that Eschericia coli was the etiologic agent in 48.9% of UTIs in both outpatient
and hospitalized children in Saiful Anwar Hospital, Malang.53 Similiarly, the most common causes
of UTI were Eschericia coli and Citrobacter diversus (23% each, or 8/34 children) in our study.
However, Adeleke et al. found Staphylococcus aureus to be the most common cause of UTI in NS
patients (67.9%).51 This difference may be due to location, which may lead to variations in
bacterial trends. Eschericia coli is part of the colon’s normal flora. It can cause UTIs, but not all
types of Eschericia coli have the ability to colonize the urinary tract. Only the uropathogenic type
of Eschericia coli can invade anatomically normal urinary tracts.53 The goal of UTI treatment in
children is to eradicate the cause, eliminate clinical manifestations, and prevent kidney failure, as
early as possible.54

Pasien had fever 3 days before admission, Urinalisis from the urine shown many
epithel cell, leucocytes 15/uL and bacterial 768,1/uL.
in these patients, urine culture should be carried out to determine the type of suspected
bacterial that cause UTI. In evaluation the bacterial decresed and urine culture examination was
not done.
All killed vaccines included in Indonesian Pediatrician Society programme should be
offered to these children preferably while receiving alternate day prednisolone. Parents must be
made aware that live vaccines are contraindicated while on treatments with steroids.55 Live
vaccines are contraindicated in children receiving high dose systemic steroids (prednisolone 2
mg/Kg/day or 20 mg/day in children > 10 kg body weight) until the steroids have been
discontinued for 3 months.55 The patient is immunosupressed due to CPA and prednisone AD
therapy. Immunization should be given 3 months after the completion of therapy.

Children with SRNS generally have good survival rates, although during the course of the
disease they may develop decreased kidney function, leading to a condition where the kidney
function is not compatible with life, called ESRD. A retrospective cohort study in Department of
Child Health, Cipto Mangunkusumo Hospital showed that live survival rates of subject at the first,
second, third, fourth and fifth years after diagnosis were 93%, 84%,80%,72% and 61%

25
respectively. Kidney survival rates determined by the lack of doubling of base creatinine levels at
the first, second, third, fourth and fifth years were 92%, 72%, 56%,42% and 34% respectively,
while kidney survival rates determined by the lack of ESRD were 97%, 88%, 81%,70% and 58%
respectively. Age onset, initial kidney function, hypertension at onset and type of resistance, did
not significantly affect the survival of children with SRNS.56 prognosis of the patients with SRNS
is poor, with 30–40% developing ESRD and requiring dialysis and transplantation.57 The patient is
steroid-resistant nephrotic syndrome with adolescent onset and normal GFR. However, the
prognosis of SRNS patients is poor as 30-40% patients will develop into ESRD and require dialysis
and transplantation.

CHAPTER IV

RESUME
The case is about a 6 year and 5 months old boy with watery diarrhea, high grade fever,
with congested eyes without any systemic signs and bleeding manifestations. Laboratory tests,
performed on admission, showed an ongoing CKD stage I with GFR 148,5 ml/menit/1,73 m2,

26
hypoalbuminemia 1,2 g/dL and proteinuria 1.000 mg/dL. Routine stool specimen tested showed
no entamoeba or parasit infection. An i.v. infusion of albumin 20% (100 ml in 4 h) was started
immediately after admission while an infusion of saline 720 ml/24 hrs was added only five hours
later for mild dehydration. Because of vomiting the incoming oral fluid in the first 24 hrs was
below 500 ml. On the second day, severe oliguria was not present. Intravenous
methyprednisolon full dose 40mg/24 hr and cyclophosphamide 25mg-0-25mg PO is given
because of relaps.
On follow up, 1st week of admission, patient get total albumin transfusion 4X100ml.
Edema started to alleviate. He was composmentis, and the edema was reduced. The Boy was
discharged with improvement of 2.4 g / dL albumin levels and proteinuria 30 mg / dL. Oral dose
of full dose metylprednisolone and cyclosporine therapy continued.
The boy suffered from nefrotik syndrome when he was 1 year and 6 months old. When
he was 2 years old he diagnosed with resistant steroid nephrotic syndrome. Now He get
cyclosphorine and methylprednisolon. Captopril was replaced by Lisinopril because the boy
repeatedly experienced coughing which caused relapse. Renal biopsy has not been done
because there is no agreement from the family. In a large multicenter cohort, the International
Study of Kidney Disease in Children (ISKDC) demonstrated that 58,8% of children with resistant
steroid nephrotic syndrome had focal segmented glomerulosclerosis.
Children with SRNS generally have good survival rates. Live survival rates of subject at
the first, second, third, fourth and fifth years after diagnosis were 93%, 84%,80%,72% and 61%
while kidney survival rates determined by the lack of ESRD were 97%, 88%, 81%,70% and 58%
respectively. Age onset, initial kidney function, hypertension at onset and type of resistance, did
not significantly affect the survival of children with SRNS. prognosis of the patients with SRNS is
poor, with 30–40% developing ESRD and requiring dialysis and transplantation.
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