Pediatric Case Discussion (1)

Chronic Kidney Disease (CKD)

in a-7-Year-Old Boy

Hariogie Putradi

Moderator:
Moderator : dr. Anik Widijanti, Sp. PK(K)
Data Base

• Boy, 7 y.o
• Chief complaint : swelling
• History of present illness (Heteroanamnesis) :
 Patient suffered from swelling in both her legs
since 3 days before admission, followed by
swelling in his face since 2 days ago.
 Low grade fever since 4 days ago.
 He also had shortness of breath since 2 days
before admission. Cough (-).
 Nausea (-), vomiting (-), decreased of appetite (-).
 Defecation and urination were normal.
2
• History of Past Illness :
• Patient had been diagnosed with nephrotic
syndrome when he was 3 years old (in 2017).
• He got therapy prednisone and
cyclophosphamide for 6 months in RSSA.
• His last control to hospital about one year ago.

• History of Family Disease : -

• Pregnancy History :
• ANC by midwife every month, DM (-), HT (-),
Bleeding (-).
3
• Birth, Growth & Developmental and Immunization:
• He was delivered spontaneously by midwife, aterm.
• His weight 3200 gr and cried immediately after
birth & received a complete course of basic
immunization.
• Had normal development.

• History of Social : 1st child

Father 35 y.o / laborer; Mother 28 y.o / housewife.
General appearance : moderately ill, GCS = 456

Weight 18 kg HR 86 x/min RR 20 x/min

Height 103 cm
BMI 16,98 BP 140/100 Tax 36,3 o C
normoweight mmHg

Head Anemic (+/+), icteric sclerae (-/-), cervical lymph

nodes enlargement (-), edema palpebra +/+.
Thorax Cardiovascular:
ictus invisible, single S1 & S2, murmur (-),
Lungs: simetris, rhonchi (-), wheezing (-),
Abdomen flat, soefl
Liver & lien : unpalpable, bowel sound (+) normal
Extremities warm acral, edema +/+
Hematology 17/02/ 20/02/ - Reference
20 PRC 20 range
Hb 5,60 3420 cc
days
11,80 - 10.7 – 14.7 g/dL
RBC 2,01 4,40 - 3.7 – 5.7 x 106/μL
Hct 16,80 34,30 - 31 – 43%
MCV 83,60 78,00 - 72 – 88 fL
MCH 27,90 26,80 - 23 – 31 pg
MCHC 33,30 34,40 - 32 – 36 g/dL
RDW 15,90 18,60 - 11.5-14.5%
WBC 16,15 11,19 - 5.0 – 14.5 x 103/μL
Thrombocyte 297 292 - 229 – 553 x 103/μL
Diff.count -/-/-/ -/-/-/ - 1-5/0-1/3-6/
85/9/6 65/29/6 25-60/25-50/1-6
Parameter 17/02/ 20/02/ 22/02/ 25/02/ Reference
20 20 20 20 Range
AST/ SGOT 25 22 - - <52 U/L
ALT/ SGPT 9 Alb 25% 9 - - <40 U/L
60 cc
Albumin 2,07 3 days 2,99 - - 3.8– 5.4 g/dL
RBG 106 - - - <200 mg/dL
Ureum 184,3 191,1 192,3 206,2 15-36 mg/dL
Creatinine 12,45 12,37 11,08 10,96 <0.47 mg/dL
E-GFR 3 3 4 4 mL/min/1.73 m2
(schwartz)
SI 61 - - - 53-167 ug/dL
TIBC 154 - - - 300-400 ug/dL
Transferin 40 - - - 16-45%
saturation
 Parameter 17/02/ 20/02/ 22/02/ Reference
20 20 20 Range
Natrium 133 134 131 132 – 141 mmol/L
Kalium 4,07 3,84 4,17 3.3 – 4.6 mmol/L
Chloride 114 113 113 97 – 107 mmol/L
Corr Corr
Calcium 4,1 5,64 4,9 - 8.8 – 10.8 mg/dl
5,7
Phosphate 7,4 7,6 - 3.3 – 5.6 mg/dl

Procalcitonin 0,21 - - <0,5 low risk severe

sepsis/septic shock
>2 high risk
ANA test - 0,40 - Negative: <1
Positive: >1,2
IgG Anti-dsDNA - 3,40 - Negative: <20 IU/mL
Positive: ≥20 IU/mL
IgM Anti-dsDNA - 7,70 - Negative: <20 IU/mL
Positive: ≥20 IU/mL
Hemostasis
PPT 17/02/20 Reference range
Patient 10,10 second 9,4 – 11,3
Control 10,8 second -
INR 0,97 < 1,5
APTT
Patient 28,10 second 24,6 – 30,6
Control 24,4 second -

Conclusion: normal
9
 Urinalysis 21/02/20 Ref.Range
Turbidity Rather cloudy
Colour Yellow
pH 6,0 4,5 – 8,0
Specific 1.015 1,005 – 1,030
Grafity
Glucose Negative Negative
Protein 3+ Negative
Keton Negative Negative
Bilirubin Negative Negative
Urobilinogen 3,2 <17 umol/L
Nitrite Negative Negative
Leukocyte 1+ Negative
Blood 1+ Negative
 Urinalysis 21/02/20 Ref.Range
10x:
Epithel 9,7 ≤ 3/ LPF
Cast : Negative
40x:
Erythrocyte 5,1 ≤ 3 /HPF
- Eumorphic - %
- Dysmorphic - %
Leukocyte 35,1 ≤ 5 /HPF
Crystal -
Bacterial 8,4 ≤ 23 x103/mL
Other examinations :
• Renal Doppler USG (20-02-2020) :
• Conclusion :
-there is no evidence of bilateral renal artery stenosis
-bilateral renal parenchymal disease

Therapy :
- O2 nasal canule 1 L/’
- Inj. Ceftriaxone 2x900 mg
- Inj. Furosemide 3x20 mg
- po: Nifedipine 3x 2 mg
- po: Prednisone 4-2-1 tab
 Data Interpretation
• Laboratory results showed :
normochromic anisocytosis anemia then normal,
leukocytosis with diff. count neutrophilia then
normal, hypoalbuminemia, azotemia, low e-GFR,
normal SI, low TIBC, hyperchloremia,
hypocalcemia, hyperphosphatemia,
UL: proteinuria, hematuria,
leukocyturia, Renal Doppler USG:
no evidence of bilateral renal artery stenosis,
bilateral renal parenchymal disease.
 Data Interpretation
From history taking, physical examination, laboratory
results & other examinations indicated :
• Chronic Kidney Disease (CKD) nephrotic phase.
• Hypertension stage 2 d.t. CKD dd. Essential
Hypertension
• Anemia of chronic disease d.t. CKD

• Suggestion : peripheral blood smear, reticulocyte, count,

Bilirubin T/D/I, ALP, GGT, coagulation test, lipid profile,
vit. D, SPE, BGA.
• Monitoring : CBC, ureum, creatinine, albumin, SI, TIBC,
serum electrolyte, urinalysis, e-GFR, Urine output.
Discussion
•Establishment of Diagnosis

•Hyperphosphatemia and Hypocalcemia

 Establishment of Diagnosis
Glomerular Disease
• Disorders that affect the structure & function of the renal
glomerular apparatus

Lerma EV, Berns JS, Nissenson AR, editors. CURRENT Diagnosis and Treatment: 17
Nephrology & Hypertension, 1st ed. New York: McGraw-Hill. 2009.
 Chronic Kidney Disease (CKD)
• CKD  defined as abnormalities of kidney structure or function,
present for >3 months, with implications for health.
• Criteria for CKD (either of the following present for >3 months)
Markers of kidney • Albuminuria (AER ≥30 mg/24 hours; ACR ≥30 mg/g [≥3
damage mg/mmol])
(one or more) • Urine sediment abnormalities
• Electrolyte and other abnormalities due to tubular
disorders
• Abnormalities detected by histology
• Structural abnormalities detected by imaging
• History of kidney transplantation

Decreased GFR GFR <60 ml/min/1.73 m2 (GFR categories G3a–G5)

KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management
18
of Chronic Kidney Disease; Kidney International Supplements (2013) 3, 5–14.
 CKD
Staging of CKD
GFR category GFR (ml/min/1,73 m2 Terms
G1 ≥ 90 Normal or high
G2 60-89 Mildly decreased
G3a 45-59 Mildly to
moderately
decreased
G3b 30-44 Moderately to
severely decreased
G4 15-29 Severely decreased
G5 <15 Kidney Failure

KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management
19
of Chronic Kidney Disease; Kidney International Supplements (2013) 3, 5–14.
 Epidemiology of CKD
• CKD has a prevalence of 1.5 to 3.0 per 1,000,000 among
children younger than the age of 16 years.

Etiology of CKD

Pediatrics in ReviewVol.29 No.10 October 2008

 Patophysiology of CKD

• The kidney initially adapts to damage by increasing the

filtration rate in the remaining normal nephrons, a process
called adaptive hyperfiltration.
• As a result, patients with mild chronic kidney disease often
have a normal or near-normal serum creatinine
concentration.
• Additional homeostatic mechanisms permit the serum
concentrations of sodium, potassium, calcium, and
phosphorous and total body water to also remain within the
reference range, particularly among those with mild to
moderate stages of chronic kidney disease.

Sanjeev Gulati. 2018. Chronic Kidney Disease in Children. Medscape

 Patophysiology of CKD

• Adaptive hyperfiltration, although initially beneficial,

appears to result in long-term damage to the
glomeruli of the remaining nephrons, which is
manifested by pathologic proteinuria and
progressive kidney insufficiency.
• Increasing protein in the urine (proteinuria) 
is caused either by damage to the glomerular
capillary wall or by decrease in tubular reabsorption
of protein leading to further destruction of the renal
tubular cells.

Sanjeev Gulati. 2018. Chronic Kidney Disease in Children. Medscape

 Patophysiology of CKD

• Proteinuria  is common in pediatric CKD.

• 62% of the CKiD cohort was found to have significant
proteinuria associated with a lower GFR.
• This irreversibility appears to be responsible for the
development of end-stage kidney failure.

Sanjeev Gulati. 2018. Chronic Kidney Disease in Children. Medscape

 Hypertension and CKD

• The Kidney Disease Outcome and Quality Initiative

(KDOQI)  the prevalence of hypertension in children
with CKD to be 70%, and it may even be as high as 80%
in those with stage IV and V CKD.
• Uncontrolled hypertension in children with CKD  has
been identified as one of the main factors contributing
to progression of CKD and increased risk for
cardiovascular disease.
• The diagnosis of hypertension  is based on the child’s
age, sex, and height percentile.
Int J Nephrol Renovasc Dis. 2017; 10: 205–213.
2017 AAP Guidelines for Childhood Hypertension
 Hypertension and CKD

2017 AAP Guidelines for Childhood Hypertension

 Pediatric Hypertension
• Hypertension  can be primary (ie, essential)
or secondary.
• In general, the younger the child and the higher
the blood pressure (BP), the greater the
likelihood that hypertension is secondary to an
identifiable cause.
• A secondary cause of hypertension  is most
likely to be found before puberty;
• After puberty, hypertension is likely to be
essential.

Edwin Rodriguez-Cruz. 2017. Pediatric Hypertension. Medscape.

 Common Causes of Hypertension by Age
Children
Infants Adolescents
1-6 y 7-12 y

•Thrombosis of
renal artery or •Renal artery •Renal
stenosis
vein parenchymal •Essential
•Congenital •Renal disease hypertension
parenchymal
renal disease •Renovascular •Renal
anomalies abnormalities parenchymal
•Coarctation of •Wilms tumor •Endocrine disease
aorta •Neuroblastom causes •Endocrine
a
•Bronchopulm •Essential causes
onary •Coarctation of hypertension
aorta
dysplasia

Edwin Rodriguez-Cruz. 2017. Pediatric Hypertension. Medscape.

 Anemia in CKD
• Anemia  is defined as a reduction in red blood cell
volume or hemoglobin concentration below the normal
range for a healthy person.
• Anemia in CKD  is caused by either an insufficient
production of erythropoietin by the diseased kidneys or
by iron deficiency.
• Morbidity, mortality, and quality of life data from the
KDOQI guidelines  suggest that maintaining the
hematocrit in the range of 33% to 36% (0.33 to 0.36) and
the hemoglobin at 11.0 to 12.0 g/dL (110.0 to 120.0 g/L)
is important for children who have CKD.

Pediatrics in Review Vol.29 No.10 October 2008

Anemia In this Patient
Hematology 17/02/20 20/02/20 Reference range
Hb 5,60 PRC 11,80 10.7 – 14.7 g/dL
420 cc
RBC 3 days
2,01 4,40 3.7 – 5.7 x 106/μL

Hct 16,80 34,30 31 – 43%

MCV 83,60 78,00 72 – 88 fL

MCH 27,90 26,80 23 – 31 pg

MCHC 33,30 34,40 32 – 36 g/dL

RDW 15,90 18,60 11.5-14.5%

SI 61 N: 53-167 Anemia of
ug/dL normochromic
chronic
TIBC 154 N: 300-400 anisocytosis
disease
ug/dL anemia +
d.t. CKD
chronic disease
Patient’s Diagnosis; Boy, 7 y.o •CKD nephrotic phase
• Lab: normochromic anisocytosis •Hypertension stage 2
anemia then normal, d.t. CKD dd. Essential
leukocytosis with diff. count Hypertension
neutrophilia then normal, •Anemia of chronic
hypoalbuminemia, azotemia, low disease d.t. CKD
e-GFR, low TIBC, hyperchloremia,
hypocalcemia,
hyperphosphatemia, UL: • Suggestion : peripheral
proteinuria, hematuria, blood smear, reticulocyte
leukocyturia, Renal Doppler USG: count, Bilirubin T/D/I, ALP,
bilateral renal parenchymal GGT, coagulation test, lipid
disease. profile, vit.D, SPE, BGA.
• Edema in the leg and face • Monitoring : CBC, ureum,
• History of nephrotic syndrome in creatinine, albumin, SI,
2017 (therapy: prednisone and TIBC, serum electrolyte,
cyclophosphamide for 6 months) urinalysis, e-GFR, Urine
output.
 Hyperphosphatemia and
Hypocalcemia
• Hyperphosphatemia

• Most patients are asymptomatic.

• Symptoms : muscle cramps, tetany, and perioral
numbness or tingling. Other symptoms : bone and
joint pain, pruritus, and rash.
• Symptoms related to the underlying cause of the
hyperphosphatemia  Uremic symptoms (fatigue,
shortness of breath, anorexia, nausea, vomiting, sleep
disturbances).
Medscape. 2018. Hyperphosphatemia, Eleanor Lederer, MD 31
 Phosphate Metabolism

Patient :
Hyperphosphatemia
32
33
 Hyperphosphatemia
• Hyperphosphatemia  is treated with
administration of a phosphate binder with meals to
facilitate bonding of phosphorus within the
gastrointestinal tract, thereby increasing phosphate
elimination.

• Commonly used binders are calcium-containing

agents such as calcium carbonate and calcium
acetate and other non calcium-containing binders.

Pediatrics in Review Vol.29 No.10 October 2008

This patient :
Boy, 7 yo
Parameter 17/02/ 20/02/ 22/02/ Reference
20 20 20 Range
Phosphate 7,4 7,6 - 3.3 – 5.6
mg/dl

Hyperphosphatemia
dt. CKD
• Monitoring :
serum electrolyte 35
 Hypocalcemia

• In children, hypocalcemia  is defined as a total

serum calcium concentration less than 8.5 mg/dL
(2.1 mmol/L).

• Severe hypocalcemia with serum calcium

< 7 mg/dL (< 1.75 mmol/L)  may cause
hyperreflexia, tetany, laryngospasm, or
generalized seizures.

36
Yogangi Malhotra. 2016. Pediatric Hypocalcemia. Medscpae
 Hypocalcemia
• Serum calcium levels are  regulated by 3 main
calcium-regulating hormones—parathyroid hormone
(PTH), vitamin D, and calcitonin—through their
specific effects on the bowel, kidneys, and skeleton.
• Approximately half of the total serum calcium is
bound to protein, and the remaining free ionized
calcium is physiologically active.
• Serum calcium levels must be corrected for the
albumin level before confirming the diagnosis of
hypercalcemia or hypocalcemia.
37
Can Fam Physician 2012;58:158-62
 Hypocalcemia
Pathophysiology
• Hypocalcemia  manifests as central nervous system
(CNS) irritability and poor muscular contractility.
• Low calcium levels  decrease the threshold of
excitation of neurons, causing them to have repetitive
responses to a single stimulus.
• Because neuronal excitability occurs in sensory and motor
nerves, hypocalcemia produces a wide range of peripheral
and CNS effects, including paresthesias, tetany (i.e.,
contraction of hands, arms, feet, larynx, bronchioles),
seizures, and even psychiatric changes in children.
38
Yogangi Malhotra. 2016. Pediatric Hypocalcemia. Medscpae
 Calcium
Test principle
• Method according to Schwarzenbach with o-cresolphthalein
complexone.
• Calcium ions react with o-cresolphthalein complexone (o-CPC)
under alkaline conditions to form a violet colored complex. The
addition of 8-hydroxyquinoline prevents interference by
magnesium and iron.

• The color intensity of the complex formed is directly

proportional to the calcium concentration and is measured
photometrically.
39
Cobas
 Calcium
Sample:
Serum: Fresh serum collected in the fasting state is the preferred
specimen.
Plasma: Li-heparin plasma.

Interference :
Serum/plasma
Icterus: No significant interference up to an I index of 60 (approximate
conjugated and unconjugated bilirubin concentration: 1026 μmol/L (60
mg/dL)).
Hemolysis: No significant interference up to an H index of 1000
(approximate hemoglobin concentration: 621 μmol/L (1000 mg/dL)).
Lipemia (Intralipid): No significant interference up to an L index
of 2000. There is a poor correlation between the L index (corresponds
to turbidity) and triglycerides concentration.
40
Cobas
 Calcium
Other:
• the blood should be drawn following an overnight fast
because the daily intake of calcium may contribute to the
serum calcium concentration as much as 0.15 mmol/L.
• Intravenously administered contrast media for MRI
(Magnetic Resonance Imaging) contain chelating complexes
which may interfere with the determination of calcium.
• A sharp decrease in calcium values was observed when
gadodiamide (GdDTPA-BMA) was administered.
• In very rare cases gammopathy, in particular type IgM
(Waldenström’s macroglobulinemia), may cause unreliable
results.
41
Cobas
This patient : Parameter 17/02/ 20/02/ Reference
Boy, 7 yo 20 20 Range
Corr Corr
5,64 5,7
Calcium 4,1 4,9 8.8 – 10.8 mg/dl

False low hypocalcemia d.t. pre analytic dd.

True hypocalcemia d.t. CKD
Pre analytic: Analytic: Post analytic:
Suitable sample identity  QC in  LIS
Proper urine sample range
condition ??
• Patient fasting ? • Suggestion : vit D, lipid
• Lipemia ? profile
• Hemolysis X • Monitoring : serum calcium
• Icteric X
(fasting, proper sample) 42
 Conclusion
It has been discussed Boy, 7 y.o with :
•Chronic Kidney Disease (CKD) nephrotic phase.
•Hypertension stage 2 d.t. CKD dd. Essential Hypertension
•Anemia of chronic disease d.t. CKD
•Hyperphosphatemia in this patient dt. renal impairment.
• False low hypocalcemia d.t. pre analytic dd.
True hypocalcemia d.t. CKD

•Suggestion : peripheral blood smear, reticulocyte count,

Bilirubin T/D/I, ALP, GGT, coagulation test, lipid profile, vit. D,
SPE, BGA.
•Monitoring : CBC, ureum, creatinine, albumin, SI, TIBC,
serum electrolyte, urinalysis, e-GFR, urine output. 43
Thank
You
Problem’s Cues and Clues Problem List Initial Diagnosis Planning Diagnosis

1. Boy, 7 y.o Azotemia CKD nephrotic • Suggestion :

Lab: phase peripheral
normochromic blood smear,
anisocytosis anemia reticulocyte,
then normal, count, lipid
hypoalbuminemia, profile, vit. D,
azotemia, low e-GFR, SPE, BGA.
low TIBC,
hyperchloremia,
hypocalcemia, • Monitoring :
hyperphosphatemia, CBC, ureum,
UL: proteinuria, creatinin,
hematuria, albumin, SI,
leukocyturia, Renal TIBC, serum
Doppler USG: electrolyte,
bilateral renal urinalysis.
parenchymal
disease.
45
Problem’s Cues and Clues Problem List Initial Diagnosis Planning Diagnosis

1. Boy, 7 y.o

Ax:
Edema in the leg and
face
History of nephrotic
syndrome when he
was 3 years old (in
2017).
History of therapy:
prednisone and
cyclophosphamide for
6 months

46
Problem’s Cues and Clues Problem List Initial Diagnosis Planning Diagnosis

2. Boy, 7 y.o Hyper- Hyper- • Suggestion :

tension tension stage 2 lipid profile.
BP: 140/100 mmHg d.t. No. 1.
Lab: dd. Essential
Hypertension • Monitoring :
hypoalbuminemia, blood
azotemia, low e-GFR, pressure
low TIBC,
hyperchloremia,
hypocalcemia,
hyperphosphatemia,

UL: proteinuria,
hematuria,
leukocyturia, Renal
Doppler USG:
bilateral renal
parenchymal
disease. 47
 Problem’s Cues and Problem List Initial Planning
Clues Diagnosis Diagnosis
3. Boy, 7 y.o Hyperphos- Hyperphos- Monitoring :
phatemia phatemia dt serum
Lab: no. 1 electrolyte
P: 7,4

Ur 184,3
Cr 12,45
eGFR 3

48
 Problem’s Cues and Problem List Initial Planning
Clues Diagnosis Diagnosis
4. Boy, 7 y.o Hypocal- False Low Suggestion :
cemia Hypo- vit D, lipid
Lab: calcemia d.t. profile
Ca: 4,1 Pre analytic
Monitoring :
dd. serum calcium
Ur 184,3 True hypo- (fasting,
Cr 12,45 calcemia d.t. proper
eGFR 3 CKD sample)

49
Problem’s Cues and Clues Problem Initial Planning
List Diagnosis Diagnosis
5. Boy, 7 y.o Normo- Anemia of Suggestion:
chromic chronic PBS,
Lab: anisocyto disease d.t. Reticulocyte
Hb 5,6 sis CKD count
MCV 83,60 anemia
MCHC 27,90 Monitoring:
RDW 15,90 CBC, SI, TIBC
Ur 184,3
Cr 12,45
eGFR 3
SI 61
TIBC 154
Transferin saturation 40

50
 Nephrotic Syndrome
Typical features Atypical features
Age 1-10 years <1 year, > 10 years
Normotensive Hypertensive
Normal renal function Elevated creatinine
+/- microscopic hematuria Macroscopic hematuria
Responsive to steroid Unresponsive to steroid
treatment treatment
Renal biopsy: minimal Renal biopsy : FSGS or one of the
change nephrotic other forms of nephrotic
syndrome syndrome
Started on steroid without Need renal biopsy before
renal biopsy receiving steroid treatment
52
 NEPHROTIC SYNDROME
• An injury to podocyte
• Changed architecture : scarring, deposition of matrix or
other elements
Etiology

Primary Secondary

• Membranous nephropathy • Diabetic

• Focal segmental nephropathy
glomerulosclerosis (FSGN) • Systemic Lupus
• Minimal change disease Erythematosus
• Membranoproliferative • Renal amyloidosis
glomerulonephritis • Fabry’s disease

Lerma EV, Berns JS, Nissenson AR, editors. CURRENT Diagnosis and Treatment: Nephrology &
Hypertension, 1st ed. New York: McGraw-Hill. 2009. 54
Diagnostic criteria for nephrotic Syndrome
Factors Criteria
Heavy proteinuria spot urine showing a protein to creatinine
ratio > 3 to 3.5 mg protein/mg creatinine
(300 to 350 mg/mmol), or 24 hour urine
collection showing > 3 to 3.5 g protein

Hypoalbuminemia serum albumin < 2.5 g per dL (25 g per L)*

Edema clinical evidence of peripheral edema
Hyperlipidemia Severe hyperlipidemia, total cholesterol is
often > 350 mg per dL (9.06 mmol per L)

*some expert use a cutoff <3.0 g per dL(30 g per L)

Adapted with permission from Hull RP, Goldsmith DJ.Nephrotic syndrome in
adult.BMJ.2008;336(7654):1185
55
Kidney Disease: Improving Global Outcomes , Kidney International Supplements 2012; 2:163–171
 Bilirubin
• Increased concentrations of serum bilirubin have long been
used as a marker of liver dysfunction.

• In addition, serum bilirubin is not merely an end product of

heme degradation but is also a potent antioxidant that acts
via inhibitions of NADPH oxidase, a key source of oxidants
in phagocytic and non-phagocytic cells, and of protein
kinase C activity.

• In addition to being an antioxidant, bilirubin also has

anticomplement properties that protect against
inflammation.

Shinetal.BMCNephrology2011,12:29
 Bilirubin
• Furthermore, bilirubin has been suggested to have
cytoprotective properties through its influence on protein
kinase C. Through these mechanisms, bilirubin could
protect diabetic patients from the development and
progression of diabetic nephropathy.

• In this study, serum bilirubin concentration correlated

negatively with proteinuria and positively correlated with
renal function, and total cholesterol in the normal
proteinuria group level was lower than that in the abnormal
proteinuria group.

Shinetal.BMCNephrology2011,12:29
• This study demonstrated that serum total bilirubin concentration was
negatively correlated with 24-hour urine protein and was positively
correlated with eGFR in Korean non-diabetic and diabetic adults.

Shinetal.BMCNephrology2011,12:29
 Stress Oxidative and CKD

• Oxidative stress has been reported in kidney disease, due to

both antioxidant depletions as well as increased ROS
production.
• The kidney is a highly metabolic organ, rich in oxidation
reactions in mitochondria, which makes it vulnerable to
damage caused by OS, and several studies have shown that
OS can accelerate kidney disease progression.
• Also, in patients at advanced stages of chronic kidney
disease (CKD), increased OS is associated with complications
such as hypertension, atherosclerosis, inflammation, and
anemia.

Pediatr Nephrol. 2019 Jun;34(6):975-991.

Pathogenesis
Pathogenesis
• Intrinsic Glomerular Disease (Nephritic or
Nephrotic)
• A nephrotic pattern is associated with proteinuria,
usually in the nephrotic range (greater than 3.5 gm
per 24 hours), and an inactive urine microscopic
analysis with few cells or casts.
• It is commonly caused by minimal change disease,
focal segmental glomerulosclerosis, membranous
GN, membranoproliferative GN (Type 1 and 2 and
associated with cryoglobulinemia), diabetic
nephropathy, and amyloidosis.
• Intrinsic Glomerular Disease (Nephritic or
Nephrotic)
• A nephritic pattern is suggested by abnormal urine
microscopy with red blood cell (RBC) casts and
dysmorphic red cells, occasionally white blood cells
(WBCs), and a variable degree of proteinuria.[6] The
most common causes are post-streptococcal GN,
infective endocarditis, shunt nephritis, IgA
nephropathy, lupus nephritis, Goodpasture
syndrome, and vasculitis.
 Calcium

• Serum or plasma should be separated from blood cells as

soon as possible, because prolonged contact with the clot
may cause lower calcium values.
• Sera from patients receiving EDTA (treatment of
hypercalcemia) are unsuitable for analysis, since EDTA will
chelate the calcium and render it unavailable for reaction
with o-cresolphthalein complexone.
• Co-precipitation of calcium with fibrin (i.e. heparin plasma),
lipids, or denatured protein has been reported with storage
or freezing.
False high Ca

• Venous occlusion of the arm during venipuncture

may increase the total concentration of serum
calcium by up to 0.3 mmol/L.
• This results from an increase in plasma protein
concentration caused by hemodynamic changes.
• Another source of error is posture.
• If the patient stands up from a supine position,
there may be an increase of 0.05 to 0.20 mmol/L in
serum calcium.
• Still another possible source of error is hemolysis.
False high Ca

• If an error is suspected and the measurement is to

be redone, the blood should be drawn following an
overnight fast because the daily intake of calcium
may contribute to the serum calcium concentration
as much as 0.15 mmol/L.
False high Ca

• Exercise just before venipuncture tends to increase

serum calcium, so the patient should be rested for
at least 15 minutes prior to sampling.
• Men tend to have a higher serum calcium by 0.02 to
0.04 mmol/L during summer versus winter.
• Postmenopausal women, however, have higher
levels of calcium in winter as compared to summer.
• Men 15 to 45 years of age tend to have serum
calcium levels 0.02 to 0.05 mmol/L higher than
similarly aged women.
Calcium
• Serum Ionized Calcium
• Ionized calcium is the definitive method for diagnosing
hypocalcemia. A serum calcium level less than 8.5 mg/dL or
an ionized calcium level less than 1.0 mmol/L is considered
hypocalcemia.
• Analysis for the ionized calcium level must be performed
rapidly with whole blood to avoid changes in pH and anion
chelation. Blood should be drawn in an unheparinized
syringe for best results.
• Falsely elevated calcium levels may be seen with elevated
acetaminophen levels, alcohol, hydralazine, and hemolysis.
Falsely depressed levels can be seen with heparin, oxalate,
citrate, or hyperbilirubinemia.
Calcium
• About 90% of the protein-bound calcium is linked to albumin
with the remaining 10% bound to a variety of globulins.
There are 12 binding sites on each albumin molecule and
only about 10 to 15% are utilized under normal conditions.
Therefore, when an excess of calcium in the blood occurs,
each of the three calcium fractions (i.e., ionized, complexed,
protein-bound) increases in the same ratio, resulting in a
constant proportion of ultrafilterable calcium.
 Erythropoietin
• Erythropoietin can be administered subcutaneously to
children who have CKD, including those undergoing
peritoneal dialysis, or intravenously for those receiving
hemodialysis.
• Erythropoietin can be given one, two, or three times per
week.
• The initial dose ranges between 30 and 300 units/kg per
week, with the usual maintenance dosage between 60 and
600 units/kg per week.
• The maintenance dose is determined and adjusted based on
monthly hemoglobin values.
• A new form of erythropoietin, darbepoetin alfa, which has a
longer half-life andrequires dosing once every 2 weeks to
once monthly, is being investigated for use in children.
Renal Osteodystrophy
• Calcium, phosphorus, and magnesium balance are
maintained by the kidney when people have normal
renalfunction.
• In CKD, hypocalcemia and hyperphosphatemia
occur.
• The normal kidney converts 25-dihydroxyvitamin D3
into 1,25-dihydroxyvitamin D3 when stimulated by
hypocalcemia, parathyroid hormone (PTH) release,
and decreased dietary intake of phosphate.
• PTH is degraded and removed by the kidney
Renal Osteodystrophy
• In renal disease, 1,25-dihydroxyvitamin D3
production decreases, intestinal absorption of
calcium decreases, and hypocalcemia develops.
• This series of events, in turn, causes an increase in
PTH formation.
• However, PTH has little effect due to low vitamin D
and high serum phosphate concentrations
(phosphorus cannot be secreted by the diseased
kidneys) as well as down regulation of PTH
receptors.
• Abnormal bone mineralization with resultant
fractures and osteitis fibrosa can occur
• GFR values for CKD staging are for children older
than 2 years of age because the GFRvalues for
younger children are low due to ongoing renal
maturation.
• Podocytes are cells in the
Bowman's capsule in the
kidneys that wrap around
capillaries of the glomerulus.
Podocyte cells make up the
epithelial lining of Bowman's
capsule, the third layer
through which filtration of
blood takes place.[1] The
Bowman's capsule filters the
blood, retaining large
molecules such as proteins
while smaller molecules such
as water, salts, and sugars are
filtered as the first step in the
formation of urine.
 Hypocalcemia
• Hypocalcemia  is common in the nephrotic
syndrome, but rather than being a true hypocalcemia,
it is usually caused by a low serum albumin level.
• Nonetheless, low bone density and abnormal bone
histology are reported in association with nephrotic
syndrome.
• This could be caused by urinary losses of vitamin D–
binding proteins, with consequent hypovitaminosis D
 as a result, reduced intestinal calcium absorption.

Medscape. 2019. Eric P Cohen, MD. Does nephrotic syndrome increase the risk for
82
hypocalcemia?
 Hypocalcemia

• Tessitore et al  when the GFR was reduced, bone

mineralization defects were found by biopsy.
• Low bone mass  may be found in relation to
cumulative steroid dose.
• It is possible that long duration of either the
nephrotic syndrome or treatments for it  are the
important risk factors for bone disease in these
patients.

Medscape. 2019. Eric P Cohen, MD. Does nephrotic syndrome increase the risk for
83
hypocalcemia?
 Steroid Resistant Nephrotic Syndrome (SRNS)
and End Stage Renal disease (ESRD)
• SRNS  is associated with increased risk of complications
due to persistent proteinuria and therapeutic drug side
effects.
• The most prevalent histological pattern in SRNS is FSGS
(Focal Segmental Glomerulosclerosis)  which is the major
glomerular etiology of ESRD in children.
• The probability of occurrence of ESRD in 10 years in
children with SRNS varies between 34-64%.
• Several risk factors for progression to chronic renal failure or
ESRD  as persistent proteinuria, older age at onset, initial
renal impairment, and extensive focal sclerosis in biopsy
specimens have been reported in the literature.
J. Bras. Nefrol. vol.35 no.3 São Paulo July/Sept. 2013
 SRNS and ESRD
• According to the recent Practical Guidelines from KDIGO, the
recommendations for the treatment of SRNS are:

1) Calcineurin inhibitors (CsA and tacrolimus) associated

with steroids must be the first line drugs to treat patients
with SRNS.

2) Mycophenolate mofetil (MMF) may be indicated in

children who did not respond to CsA (low evidence).

3) Cyclophosphamide (CP) is not suggested for the treatment of

SRNS (moderate evidence).

J. Bras. Nefrol. vol.35 no.3 São Paulo July/Sept. 2013

 SRNS and ESRD
• According to the recent Practical Guidelines from KDIGO, the
recommendations for the treatment of SRNS are:

4) Rituximab is still not recommended as a treatment

option for SRNS due to the lack of RCTs and risk of serious
adverse events.
5) Angiotensin-converting enzyme inhibitors (ACE-i) and
angiotensin receptor blockers (ARB) are recommended for
treatment (moderate evidence).

• The response to therapeutic drugs is a good predictor of a

long-term renal survival in children with FSGS.

J. Bras. Nefrol. vol.35 no.3 São Paulo July/Sept. 2013

 This Patient

• Boy, 7 y.o
hypoalbuminemia, azotemia,
low e-GFR, hyperchloremia,
hypocalcemia, hyperphosphatemia, CKD st V newly
UL: proteinuria, hematuria, diagnosed
leukocyturia, Renal Doppler USG: d.t. Steroid Resistant
bilateral renal parenchymal disease. Nephrotic Syndrome
• Edema in the leg and face
• History of nephrotic syndrome when
he was 3 years old (in 2017).
Monitoring : ureum,
• History of therapy: prednisone and creatinine, serum
cyclophosphamide for 6 months electrolyte, urinalysis.
 Hypertension in Nephrotic Syndrome

Shatat IF, Becton LJ and Woroniecki RP (2019) Hypertension in Childhood Nephrotic Syndrome.
Front. Pediatr. 7:287.
 Hypertension in Nephrotic Syndrome
• Synthetic steroids (prednisolone, prednisone, and
methylprednisone)  are central in the treatment regimens of
patients with NS.
• Synthetic steroids may play a role in BP regulation via other
mechanisms  such as
• fluid shifts from interstitial to the intravascular compartment
• elevated plasma renin activity
• increased sympathetic nerve activity
• altered prostaglandin biosynthesis
• enhanced vascular smooth muscle responsiveness to
catecholamines and angiotensinogen II
• impaired vasodilation, and nitric oxide synthase activity

Shatat IF, Becton LJ and Woroniecki RP (2019) Hypertension in Childhood Nephrotic Syndrome.
Front. Pediatr. 7:287.
 Anemia in Nephrotic Syndrome

• Commonly normochromic normocytic anemia 

develops from decreased renal synthesis of erythropoietin

• Decreased erythropoietin production, secretion, and

hyporesponsiveness  can contribute to anemia in
nephrotic patients.

Review of clinical signs. The nephrotic syndrome. 2007.

 Establishment of Diagnosis
Nephrotic Syndrome
• Nephrotic syndrome (NS) 
• is one of the most common childhood kidney diseases
worldwide.
• clinical condition caused by an increase in glomerular
permeability of plasma proteins that causes proteinuria,
hypoalbuminemia, hyperlipidemia and edema.

• In Indonesia  reported 6 per 100,000 per year in children

aged less than 14 years. Comparison of boys and girls 2:1.

Medula, Volume 2, Nomor 4, Juni 2014

 Nephrotic syndrome in children

• Edema, massive proteinuria (≥40 mg/m2/h or uACR

>2.0 mg/dL), hypoalbuminemia (≤2.5 g/dl) and
hypercholesterolemia.
• Development of structural and functional defects in
the glomerular filtration barrier  inability to
restrict urinary loss of protein.
• The great majority of cases are steroid responsive,
with only <20% of children with NS being steroid
resistant.

Shatat IF, Becton LJ and Woroniecki RP (2019) Hypertension in Childhood Nephrotic Syndrome.
Front. Pediatr. 7:287.
 Steroid Resistant Nephrotic Syndrome (SRNS)

• Steroid resistance  defined as the absence of

remission despite 4 weeks of therapy with daily
prednisone at a dose of 2 mg/kg/d.
• Patients with steroid-resistant nephrotic syndrome
(SRNS)  have proven more difficult to treat, with
36%–50% progressing to end-stage renal disease
within 10 years.
• Mutations in genes coding for key podocyte proteins
(NPHS2, PLCE1, ACTN4, and TRPC6)  cause FSGS, the
histopathologic finding most commonly associated
with SRNS.

Pediatric Health Med Ther. 2017; 8: 29–37.

Classification Nephrotic Syndrome

• Primary Nephrotic Syndrome

• Most often, Nephrotic Syndrome is defined by its
primary diseases that attack the kidney’s filtering
system. Doctors often call these diseases “idiopathic,”
which means that they have arisen from an unknown
cause.
• Minimal Change Disease (MCD) – most common in
children
• Focal Segmental Glomerulosclerosis (FSGS)
• Membranous Nephropathy (MN) – most common in
adults
• Other Glomerular Diseases
Classification Nephrotic Syndrome

Secondary Nephrotic Syndrome

• Secondary NS is associated with an underlying cause or condition.
You may have secondary nephrotic syndrome if you have also been
diagnosed with one of the following:
• Vasculitis: Lupus
• Infection: Hepatitis, HIV, CMV, others
• Metabolic disorder: Diabetes
• Cancer: Lymphoma
• Amyloidosis
• Renal Vein Thrombosis
• Heart Failure: Constrictive Pericarditis
• Medications, toxins, IV drug abuse
 Lupus Nephritis
Table: 2. International Society of Nephrology Society 2003 Classification of
LUPUS NEPHRITIS on Kidney Biopsy 1,2,4
• Class I Minimal mesangial LN
• Class II Mesangial proliferative LN
• Class III Focal LN (50% of glomeruli)
          III (A): active lesions
          III (A/C): active and chronic lesions
          III (C): chronic lesions
• Class IV Diffuse LN (> 50% glomeruli)
          IV (S) Diffuse segmental
          IV (G) LN : Global
          IV (A): Active lesions
          IV (A/C): Active and chronic lesions
          IV (C): Chronic lesions
• Class V Membranous LN+
• Class VI Advanced sclerosing LN (>90% globally sclerosed glomeruli without
residual activity)
 Renal Biopsy
• Given the larger proportion of patients with FSGS who
progress to end-stage renal disease (ESRD) and the higher
likelihood of a relapsing course based on histopathology,
many nephrologists face the difficult decision of
determining optimal timing of initial biopsy in initial
nonresponders with new-onset nephrotic syndrome.

• ISKDC data suggest that absence of response to steroid

therapy at 8 weeks indicates nonresponse; however, given
the 6-week high-dose steroid course endorsed by numerous
programs, a lack of response at completion of 6 weeks
often prompts many nephrologists to pursue renal biopsy.
 Renal Biopsy
• Renal histology is also an important predictor of long-term
outcome.
• FSGS is associated with worse outcomes: only 20% to 30% of
children with FSGS respond to steroids, and 25% to 62% of
children with FSGS develop ESRD within 5 to 10 years.28
• It is difficult to compare the present data on long-term
outcomes of children with INS with those obtained from
other studies, as most of those studies enrolled patients who
had steroid-resistant INS or FSGS.
• Cohort studies have reported that renal survival at 5 and 10
years was 75% to 92% and 50% to 86%, respectively, in
patients with steroid-resistant nephrotic syndrome.

J Epidemiol. 2012; 22(6): 517–522.

 SRNS and ESRD

• SRNS  is associated with increased risk of complications

due to persistent proteinuria and therapeutic drug side
effects.
• The most prevalent histological pattern in SRNS is FSGS,
which is the major glomerular etiology of ESRD in children.
• The probability of occurrence of ESRD in 10 years in
children with SRNS varies between 34-64%.
• Several risk factors for progression to chronic renal failure or
ESRD  as persistent proteinuria, older age at onset, initial
renal impairment, and extensive focal sclerosis in biopsy
specimens have been reported in the literature.

J. Bras. Nefrol. vol.35 no.3 São Paulo July/Sept. 2013

 SRNS and ESRD
• According to the recent Practical Guidelines from KDIGO,4the
recommendations for the treatment of SRNS are:

• 1) Calcineurin inhibitors (CsA and tacrolimus) associated

with steroids must be the first line drugs to treat patients
with SRNS.

• 2) Mycophenolate mofetil (MMF) may be indicated in

children who did not respond to CsA (low evidence).

• 3) Cyclophosphamide (CP) is not suggested for the

treatment of SRNS (moderate evidence).

J. Bras. Nefrol. vol.35 no.3 São Paulo July/Sept. 2013

 SRNS and ESRD
• According to the recent Practical Guidelines from KDIGO,4the
recommendations for the treatment of SRNS are:

• 4) Rituximab is still not recommended as a treatment

option for SRNS due to the lack of RCTs and risk of serious
adverse events.

• 5) Angiotensin-converting enzyme inhibitors (ACE-i) and

angiotensin receptor blockers (ARB) are recommended for
treatment (moderate evidence). The response to therapeutic
drugs is a good predictor of a long-term renal survival in
children with FSGS.

J. Bras. Nefrol. vol.35 no.3 São Paulo July/Sept. 2013

SRNS

• The genetics of SRNS has focused on genes

playing a role in cell–cell signaling at the
podocyte slit membrane (NPHS1, NPHS2,
CD2AP, and PTPRO/GLEPP1), regulation of
foot process actin network (ACTN4 and INF2),
or foot process–glomerular basement
membrane interaction (LAMB2 and ITGA3).12
• More recently, podocyte cell migration has
been implicated in the pathogenesis of SRNS.
SRNS

• It is clear that the worst outcomes occur in SRNS,

with 34–64% progressing to ESRD within 10 years of
diagnosis (5–8).
• The majority of SRNS patients are treated with
second-line agents, such as calcineurin inhibitors
and other immunosuppressant medications.
• There is a highly variable response, which may
depend upon the population studied.
• For example, studies of calcineurin inhibitors report
divergent response rates of between 25 and 75% in
children with SRNS (9).
SRNS

• This variability in response to calcineurin inhibitors

likely reflects in part differences dependent on the
underlying histopathology of the SRNS, with MCD
more likely to respond than FSGS.
• Other factors, such as race or ethnicity of the
population being studied, may also affect likelihood
of response (10).
• In particular, African-American and Hispanic
children with FSGS have poorer outcomes, with one
study demonstrating 50% progress to ESRD within 3 
years
 Biomarker SRNS

• More recently, the soluble urokinase-type plasminogen activator

receptor (suPAR) has been suggested as a potential circulating factor
in FSGS.37
• Reiser et al38 reported that circulating suPAR could activate B3
integrin on podocytes as a means of inducing proteinuria. suPAR
concentrations correlated directly with the activity of podocyte B3
integrin.
• Conversely, inhibition of suPAR by antibodies against suPAR and/or
plasmapheresis could lower B3 integrin activity.38
• Serum suPAR concentrations were significantly elevated in persons
with FSGS, compared to those with MCD, membranous
nephropathy, and healthy subjects.
• In summary, Reiser et al were able to establish and identify the
important role of suPAR in the pathogenesis of FSGS.
Remission Urine albumin nil or trace (or proteinuria <4
mg/m2/h) for 3 consecutive early morning
specimens.
Relapse Urine albumin 3+ or 4+ (or proteinuria >40
mg/m2/h) for 3 consecutive early morning
specimens, after having been in remission
previously.
Frequent relapses Two or more relapses in initial 6-month
period or more than 3 relapses in any 12
months.
Steroid dependence Two consecutive relapses when on alternate
day steroid therapy or within 14 days of its
discontinuation.

Steroid resistance Absence of remission despite therapy with

daily prednisolone at a dose of 2 mg/kg/d
for 4 weeks.
• Schematic drawing of the glomerular barrier. Podo = podocytes;
GBM = glomerular basement membrane; Endo = fenestrated
endothelial cells; ESL = endothelial cell surface layer (often
referred to as the glycocalyx).

• Primary urine is formed through the filtration of plasma fluid

across the glomerular barrier (arrows); in humans, the
glomerular filtration rate (GFR) is 125 mL/min.
• The plasma flow rate (Qp) is close to 700 mL/min, with the
filtration fraction being 20%.
• The concentration of albumin in serum is 40 g/L, while the
estimated concentration of albumin in primary urine is 4 mg/L, or
0.1% of its concentration in plasma.

• Courtesy of the American Physiological Society (www.the-aps.org) and reproduced from

Haraldsson B, Nystrom J, Deen WM. Properties of the glomerular barrier and mechanisms of
proteinuria. Physiol Rev. 2008 Apr;88(2):451-87.
Nephrotic Syndrome: Pathogenesis and Management. Pediatr. Rev. 2002
Nephrotic Syndrome: Pathogenesis and Management. Pediatr. Rev. 2002
 Albuminuria and Hypertension in NS
• These findings suggest that pathways leading to
albuminuria such as endothelial dysfunction,
impaired kidney function and decreased ability to
excrete sodium may contribute to the pathogenesis
of HTN.
• Although the study was not conducted in a NS
cohort, it does represent an additional significant
step toward our understanding of the effects of
albuminuria (the primary protein lost in patients with
NS) on BP and highlights the need for further studies
to better understand this complex interplay between
albuminuria and HTN (29).
 Theory
Nephrotic Syndrome Nephritic Syndrome
• Massive proteinuria • 1–2 g/24 h of proteinuria
(>3.0g/24 h) • Hematuria with RBC casts
• Hypoalbuminemia and/or dysmorphic red
• Edema blood cells
• Hyperlipidemia • Pyuria
Complications: Ascites, Anemia, • Hypertension
Infection, Tubular dysfunction, • Fluid retention
Renal dysfunction, • Increase serum creatinine
Hypercoagulable state, Bone dt reduction in
disorder, CAD glomerular filtration
 Sepsis

• Sepsis is defined as life-threatening organ dysfunction

caused by a dysregulated host response to infection.

• Organ Dysfunction Criteria

Organ dysfunction includes cardiovascular system
dysfunction, respiration, haematological, central
nervous system, and renal.
Organ dysfunction is established based on PELOD-2
scores. The diagnosis of sepsis is established if the
score is ≥11 (or ≥7).

115
Konsensus Diagnosis dan Tata Laksana Sepsis pada Anak, IDAI 2016
 Sepsis

GCS: 456

MAP:
113,33

0
116
Konsensus Diagnosis dan Tata Laksana Sepsis pada Anak, IDAI 2016
 Sepsis
0

Creatinine:
2 1100,58 umol/L

? ?

0 WBC: 16,15

PELOD-2 Score: 2 T: 297

Predicted Death Rate: 0.3 %
117
Konsensus Diagnosis dan Tata Laksana Sepsis pada Anak, IDAI 2016
 118
Konsensus Diagnosis dan Tata Laksana Sepsis pada Anak, IDAI 2016
 • Kecurigaan disfungsi organ (warning signs) bila
ditemukan salah satu dari 3 tanda klinis:
• penurunan kesadaran (metode AVPU)
• gangguan kardiovaskular (penurunan kualitas
nadi, perfusi perifer, atau tekanan arterial rerata)
• gangguan respirasi (peningkatan atau penurunan
work of breathing, sianosis)

119
Konsensus Diagnosis dan Tata Laksana Sepsis pada Anak, IDAI 2016
 UTI in nephrotic syndrome (NS) patient

• 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
• Besides the loss of immunoglobulin via urine, UTI may
result from T cell dysfunction, ascites, and relative
malnutrition in NS patients
• Patricia et all (2016) reported UTI occurred in 34 of 74
NS patients (46%). Arcana et all (2009) reported UTIs in
42% and 66.7%. Moorani et all (2012) reported found
only 25%.
 Principle: Blood in dipstick

Reagents Diisopropylbenzene dehydroperoxide

tetramethylbenzidine
Sensitivity 5 – 20 RBCs/mL, 0.015 – 0.062 mg/dL Hb
Interference False (+): strong oxidizing agents, bacterial
peroxidases, menstrual contamination
False (-): specific gravity /crenated cells
>>, formalin, captopril, nitrite
concentration >>, ascorbic acid > 25
mg/dL, unmixed specimens

Correlations with other Protein, microscopic

tests
Algorithm Hematuria
 Hematuria
 American Urological Association : hematuria defined by the presence
of > 3 RBCs/HPF in 2-3 urine samples
 The dipstick test for blood detects peroxidase activity of erythrocytes
 Myoglobin and hemoglobin also will catalyze this reaction, so a
positive test result may indicate hematuria, myoglobinuria, or
hemoglobinuria
Glomerular Renal non Urological
glomerular
Proteinuria Significant Significant Absent or
minimal
RBC form Dysmorphic Isomorphic Isomorphic
RBC cast + - -
Cause(s) Most prominent: Tubulointerstitial, Tumors, calculi,
IgA nephropathy renovascular, or and infections
metabolic disorders
Simmerville JA, Maxted WC, Pahira JJ. Urinalysis: A comprehensive review. Am Fam Physician. 2005 Mar 15;71(6):1153-
1162. http://www.aafp.org/afp/2005/0315/p1153.html
 Hematuria, Hemoglobinuria and
Myoglobinuria

Hematuria Hemoglobinuria Myoglobinuria

Color Red Red Brown

Supernatan Clear / less Equally Equally
after colored discolored discolored
centrifugation
Dipstick (+) (+) (+)
Presence of (+) (-)/few (-)/few
RBC in
microscopic
examination
 Spectrum of glomerular diseases

nephrotic manifest : nephritic manifest :

massive proteinuria, hematuria, oliguria,
hypoalbuminemia, edema, azotemia, hypertension.
hyperlipidemia.
128
Pendahuluan
Spektrum penyakit glomerolus
Methods Of Phosphorus Analysis

131
132
 Interferences Of Phosphorus
Analysis
• Compounds such as citrate, fluoride, oxalate, tartrate, and EDTA can
form complexes with molybdate and decrease color development.
• Heparin is the preferred anticoagulant.
• Leakage of phosphate from cells falsely increases serum or plasma
concentrations. Whereas losses from erythrocytes produce a positive
influence, hemoglobin will produce a strong negative photometric
influence. For these reasons, the preferred methods of phosphate
analysis require correct blanking of the individual sera. Use of 340- and
380-nm filters and 340-nm monitoring with blanking is optimum.
• Icteric sera should be properly blanked. Blanking with use of bichromatic
analysis with 340- and 380-nm wavelengths is helpful. Lipemic sera,
whose absorbance is higher at the shorter wavelengths, can produce a
positive bias with some methods.

133
 Specimen Phosphorus Analysis
• Serum is preferred by some because it has been suggested that phosphate
concentration in plasma samples are approximately 0.2 to 0.3 mg/dL lower than in
serum [16]. The release of intracellular phosphate during clotting accounts for this
difference. However, others have found no significant difference between serum and
plasma [17]. No significant difference has been seen in concentrations from
specimens collected into plastic and those collected into glass serum separator tubes
[18]. Storage of whole-blood specimens at room or refrigerated temperatures for
prolonged periods will result in increased phosphate concentrations. Prompt
separation of serum or plasma following collection is necessary. Separated serum or
plasma is stable for 4 days at room temperature, 7 days at 4°C and indefinitely at
−20°C [19].
• Serum values will be lower after meals, and it is best that the patient be fasting
before the sample is drawn. Phosphate will also be lower during the menstrual
period. A diurnal variation has been found, with a minimum occurring at 8:00 am and
highest around 2:00 am [20]. Intravenous glucose and fructose also physiologically
lower phosphate.
• Urine may contain larger quantities of organic phosphates, which can decompose on
exposure to elevated temperatures. When acidified with HCl, urine phosphate is
stable for more than 6 months [12]. Urine samples are usually diluted 1:10 with
normal saline before analysis. 134
Hyperphosphatemia

Medscape. 2018. Hyperphosphatemia, Eleanor Lederer, MD 135

Hyperphosphatemia

136
 Hyperphosphatemia
• The vast majority of filtered phosphate is reabsorbed by type 2a
sodium phosphate cotransporters located on the apical
membrane of the renal proximal tubule.
• The expression of these cotransporters is increased by low
dietary phosphate intake and several growth factors to enhance
phosphate absorption.
• The expression is decreased by high dietary phosphate intake,
parathyroid hormone (PTH), FGF23, and dopamine.
• Phosphate absorption in the remainder of the nephron is
generally mediated by type 3 sodium phosphate cotransporters.
No direct evidence has been found related to the regulation of
these transporters in renal cells under physiologic conditions.
The absorption in the proximal tubule is regulated such that the
final excretion matches the dietary excess in order to maintain
homeostasis.
137
Hyperphosphatemia

138
Hyperphosphatemia

139
Hyperphosphatemia

140
Hyperphosphatemia

141
Hyperphosphatemia

142
Hyperphosphatemia
If renal function is normal, then more unusual disorders, such as the
following, may be the cause:
• Vitamin D intoxication
• Laxative (Phospho-soda) abuse
• Tumor lysis
• Rhabdomyolysis
• Isolated hypoparathyroidism
• Pseudohypoparathyroidism

143
144
Tumor lysis syndrome

• Phosphate shift from intracellular to extracellular

space
• This pathogenic mechanism alone is an uncommon
cause of hyperphosphatemia, but it can exacerbate
hyperphosphatemia produced by impaired renal
excretion. Clinical situations in which a shift to
extracellular space is the major cause of
hyperphosphatemia include rhabdomyolysis and
tumor lysis. Rarely, extracellular shifts of phosphate
occur with insulin deficiency or acute acidosis.

145
146
Anion Gap : 12,92 (Corr : 15,12)

• Anion gap : (Na+K) – (Cl+HCO3)

• : (131+5,82)- (106+17,9)
• : 136,82-123,9
• : 12,92

• Corrected Anion gap:

• Anion gap + 2,5 (4-Alb)
• : 12,92+ 2,5 (4-3,12)
• : 12,92+2,2
• : 15,12

147
• PCO2 yg dihrpkan: (1,5xHCO3)+8+/- 2
• : (1,5x17,9)+8 +/-2
• :26,85+8 +/-2
• :34,85 +/- 2
• : 32,85 s/d 36,85

• PCO2 terukur : 35,2

• Jk pCO2 terukur<= dihrp : komp resp alkalosis

• pCO2 terukur> Dihrp : mixed resp acidosis dan metabolik
asidosis

148
O2 : NRBM 10 L/’
 150
Konsensus Diagnosis dan Tata Laksana Sepsis pada Anak, IDAI 2016
BB dan TB ideal (CDC)

151
BMI

152
Hematuria Algorithm

Consider Renal Biopsy

153
Thaller and Wang. 1999. Evaluation of Asymptomatic Microscopic Hematuria In Adults
 Suggestion : Urine Culture
154
Thaller and Wang. 1999. Evaluation of Asymptomatic Microscopic Hematuria In Adults
155
Hypertensive encephalopathy in Nephrotic syndrome

• This condition has been reported in approximately 5% of

hospitalized children and is the most serious early
complication of this disease. In these patients,
hypertension is usually severe and is accompanied by signs
of central nervous system (CNS) dysfunction such as
headache, vomiting, depressed sensorium, confusion,
visual disturbances, aphasia, memory loss, coma, and
convulsions.
• The mechanism of hypertension is most likely retention of
sodium and water with resulting expansion of the
extracellular space. 
.
Hypertensive encephalopathy

• Hypertensive encephalopathy has been reported in the

occasional individual with minimal or no edema and with
minimal urinary abnormalities. Since the urinalysis in such
patients exhibits minimal abnormalities, the underlying
cause may not be readily apparent. A high index of
suspicion is required to make an appropriate diagnosis.
• Children with nephrotic syndrome occasionally present
with gross hematuria. The frequency of macrohematuria
depends on the histological subtype of nephrotic
syndrome.
• It is more common in patients with membranoproliferative
glomerulonephritis (MPGN) than in other causes, but its
frequency in minimal change nephrotic syndrome (MCNS)
has been reported to be as high as 3-4% of cases.
160
 PRINCIPLES: Leukocyte Esterase

Reagents Derivatized pyrrole amino acid ester, diazonium

salt
Sensitivity 5 – 15 WBC/hpf
Interference False (+): strong oxidizing agents, formalin,
pigmented urine >>, nitrofurantoin
False (-): protein, glucose, oxalic acid, ascorbic
acid, gentamicin, cephalosporins, tetracyclines,
inaccurate timing

Correlations Protein, nitrite, microscopic

with other tests
 PRINCIPLES: Blood

Reagents Diisopropylbenzene dehydroperoxide

tetramethylbenzidine
Sensitivity 5 – 20 RBCs/mL, 0.015 – 0.062 mg/dL Hb
Interference False (+): strong oxidizing agents, bacterial
peroxidases, menstrual contamination
False (-): specific gravity /crenated cells >>,
formalin, captopril, nitrite concentration >>,
ascorbic acid > 25 mg/dL, unmixed specimens

Correlations with Protein, microscopic

other tests
 Causes Of Reactive
Thrombocytosis
Acute Chronic
-Immediate postsurgical period -Iron deficiency anemia
-Bleeding -Surgical of functional aspenia
-Hemolysis -Metastatic cancer, lymphoma
-Infections Inflammations (rheumatoid
-Tissue damage (acute arthritis, vasculitis, allergies)
pancreatitis, myocardial infarction, -Renal failure, nephrotic
trauma,burns) syndrome
-Coronary artery bypass grafting
-Rebound effect from
chemotherapy or immune
thrombocytopenia
 Antibiotic Susceptibility
• The external face of the outer membrane of S. marcescens is formed
by lipopolysaccharide (LPS) which is responsible for the biological
activity of an endotoxin in its ability to cause disease. The outer
membrane that surrounds this gram negative bacterium cell protects it
from toxic agents by slowing their penetration and hindering their
access to the target site. LPS is composed of parts that include the O-
antigen, lipid A, and the core.
• S. marcescens can become resistant to pencillins via two methods.
• S. marcescens has been shown to decrease its outer-membrane
permeability
• this bacterium uses beta lactamase to cleave the beta lactam ring of
pencillin which inhibits the entry of the antibiotic.
 Steroid Resistent Nefrotic Syndrome
• SRNS is defined as NS that does not respond to one month’s treatment
with oral prednisolone at a dosage of 60 mg/m2/day.
• When SRNS is suspected, a meticulous search for the possibility of
concurrent infection (e.g., sinusitis and skin infection), drug interaction
(e.g., anti epileptic drugs), inappropriate dosage, or compliance
problem is necessary.
• If those possibilities are ruled out, tissue diagnosis from a kidney
biopsy is the next step. At the same time, mutational analysis for genes
known to cause SRNS is recommended.
• Mutations of WT1, INF2, LAMB2, ACTN4, NPHS1, and NPHS2 have
been found in Korean children with SRNS by Cheong et al.

Hee Gyung Kang, MD, PhD, Treatment of steroid-resistant pediatric nephrotic

syndrome, Korean Pediatric Journal, 2011
Nephrotic Syndrome
169
170
171
Anemia hypochromic micrositer
Iron Chronic Thalassemia Sideroblastic
Deficiency Inflammation Anemia
Smear Micro/ Normal Micro/hypo Variable
hypo micro/hypo with targeting

SI <30 <50 Normal to Normal to high

high
TIBC >360 <300 Normal Normal
Percent <10 10–20 30–80 30–80
saturation
Ferritin (g/L) <15 30–200 50–300 50–300
Hemoglobin Normal Normal Abnormal Normal
pattern on with
electrophore  thalassemia;
sis can be normal
with 172
thalassemia
Histologic Patterns and Features of Primary Nephrotic Synd

Histologic pattern Key pathologic features Key clinical features

Focal segmental Sclerosis and hyalinosis of May be associated with
glomerulosclerosi segments of less than 50 hypertension, renal insufficiency,
s percent of all glomeruli on and hematuria
electron microscopy

Membranous Thickening of the glomerular Peak incidence at 30 to 50 years of

nephropathy basement membrane on age; may have microscopic
electron microscopy; hematuria; approximately 25
immunoglobulin G and C3 percent of patients have underlying
deposits with systemic disease, such as systemic
immunofluorescent staining lupus erythematosus, hepatitis B, or
malignancy, or drug-induced
nephrotic syndrome

Minimal change Normal-appearing glomeruli Relatively mild or benign cases of

disease on renal biopsy microscopy; nephrotic syndrome; may occur
effacement of foot processes following upper respiratory infection
on electron microscopy or immunization
 Common Secondary Causes of Nephrotic Syndrome
Cause Key features
Diabetes mellitus Glucosuria, hyperglycemia, polyuria
SLE Anemia, arthralgias, autoantibodies, photosensitivity, pericardial
or pleural effusion, rash
Hepatitis B or C Elevated transaminases; high-risk sexual activity, history of
transfusion, intravenous drug use, or other risk factors for
disease transmission

Nonsteroidal anti- Causes minimal change disease

inflammatory drugs

Amyloidosis Cardiomyopathy, hepatomegaly, peripheral neuropathy

Multiple myeloma Abnormal urine protein electrophoresis, back pain, renal
insufficiency
HIV Pathologically similar to focal segmental glomerulosclerosis; risk
factors for HIV transmission, possible reduced CD4 cell count

Preeclampsia Edema and proteinuria during pregnancy; elevated blood

pressure
Proteinuria

177
Hematuria in Nephritic, Proteinuria in Nephrotic

• In nephritic syndrome the integrity of the entire wall of the glomerular

capillary membrane is affected, so porosity of the glomerular
capillaries is increased greatly, allowing RBCs to leak into the tubular
lumen during filtration. In addition to that, vasoactive mediators of
inflammation constricts the glomerular capillary, causing intravascular
pressure to rise and further facilitate filtration of RBCs into the tubular
lumen. Proteins escape into the tubular lumen as well but only in fair
quantities since the polyanionic nature of the GBM is still intact. The
low GFR in nephritic syndromes also means that not a lot of albumin is
filtered in the first place.
 Hematuria in Nephritic, Proteinuria in Nephrotic

• In nephrotic syndrome, the glomerular basement membrane is

affected, while the capillary wall is spared. When GBM is disrupted,
the polyanionic characteristic of the GBM is altered, so proteins (such
as albumin) can enter the lumen unopposed. Hematuria is not a
feature of nephrotic syndrome because the endothelial cells lining the
glomerular capillary are unaffected.
Edema in
Nephrotic
Syndrome
 Hematuria

• Hematuria = the presence of > 3 RBCs/HPF in 2-3 urine samples

(American Urological Association)
• The dipstick test for blood detects the peroxidase activity of
erythrocytes. However, myoglobin and hemoglobin also will catalyze
this reaction, so a positive test result may indicate hematuria,
myoglobinuria, or hemoglobinuria
• Visualization of intact erythrocytes on microscopic examination of the
urinary sediment can distinguish hematuria from other conditions.
Microscopic examination also may detect RBC casts or dysmorphic
RBCs
• Hematuria is divided into glomerular, renal (i.e., nonglomerular), and
urologic etiologies
Glomerular Hematuria
• With significant proteinuria, erythrocyte casts, and dysmorphic RBCs
• 20% of patients  hematuria alone
• IgA nephropathy is the most common cause

Renal (Nonglomerular) Hematuria

• Secondary to tubulointerstitial, renovascular, or metabolic disorders
• With significant proteinuria, without dysmorphic RBCs nor erythrocyte
casts
• Further evaluation of glomerular and nonglomerular hematuria should
include determination of renal function and 24-hour urinary protein or
spot urinary protein-creatinine ratio
Urologic Hematuria

Causes include tumors, calculi, and infections

Absence of proteinuria, dysmorphic RBCs, and erythrocyte
casts. Even significant hematuria will not elevate the protein
concentration to the 2+ to 3+ range on the dipstick test
Up to 20 % of patients with gross hematuria have urinary
tract malignancy; a full work-up with cystoscopy and upper-
tract imaging is indicated in patients with this condition.
Causes of Hematuria
Glomerular causes
Familial causes
Fabry’s disease, Hereditary nephritis (Alport’s syndrome),
Nail-patella syndrome, Thin basement-membrane disease

Primary glomerulonephritis
Focal segmental glomerulonephritis, Goodpasture’s
disease, Henoch-Schönlein purpura, IgA nephropathy
(Berger’s disease), Mesangioproliferative
glomerulonephritis, Postinfectious glomerulonephritis,
Rapidly progressive glomerulonephritis

Secondary glomerulonephritis
Hemolytic-uremic syndrome, Systemic lupus nephritis,
Thrombotic thrombocytopenic purpura, Vasculitis
Non-glomerular causes

Renal causes

Arteriovenous malformation, Hypercalciuria, Hyperuricosuria,

Loin pain-hematuria syndrome, Malignant hypertension,
Medullary sponge kidney

Metabolic causes

Papillary necrosis, Polycystic kidney disease, Renal artery

embolism, Renal vein thrombosis, Sickle cell disease or trait

Tubulointerstitial causes

Vascular cause
Urologic causes
Benign prostatic hyperplasia, Cancer (kidney, ureteral, bladder,
prostate, and urethral), Cystitis/pyelonephritis, Nephrolithiasis,
Prostatitis,
Schistosoma haematobium infection, Tuberculosis

Other causes
Drugs (e.g., NSAIDs, heparin, warfarin [Coumadin],
cyclophosphamide [Cytoxan]), Trauma (e.g., contact sports,
running, Foley catheter)
 The Nephritic and Nephrotic
Syndrome
• The nephritic syndrome typically presents • The nephrotic syndrome presents with:
with clinical findings of : • proteinuria (is the most
• hematuria, prominent feature (greater than
• proteinuria (can range from 3.5 g per 1.73 m2 per day) and
200 mg/day to heavy • edema.
proteinuria (> 10 g/day)), and • dysmorphic red blood cells and
• dysmorphic red blood cells casts are typically absent
and/or red blood cell casts. [except in focal segmented
• Clinically, it is accompanied by glomerulosclerosis (FSGS) and
hypertension and edema. IgA nephropathy].
• Renal insufficiency is common and
typically progressive. • hypercholesterolemia and
• hypoalbuminemia (serum
albumin < 3.0 mg/dL).
• The diseases that cause the nephrotic
syndrome can lead to chronic,
progressive renal injury, but typically
are more indolent than diseases that
Manual of Nephrology, 6th Edition lead to a nephritic syndrome.
• The flow of blood enters the kidneys through the afferent arterioles then
because of pressure into the glomerular capillary and exit through the
efferent arterioles
• If the antigen-antibody complex is trapped in the endothelium, the
characteristic clinical manifestation is usually that of hematuria
• If it is stuck in the podocytes, the result is protein loss and proteinuria will
ensue Fauci, Harisson internal medicine
Glomerular Disorders by Age and Manifestations
Age(yr) Nephritic Syndrome Nephrotic Syndrome

 Focal segmental
 IgA nephropathy glomerulosclerosis
 Thin basement  Lupus nephritis
membrane disease  Minimal change disease
15–40  Lupus nephritis  Membranous nephropathy
 Hereditary nephritis  Diabetic nephropathy
 RPGN  Preeclampsia
 PIGN  Late PIGN
 IgA nephropathy

GN = glomerulonephritis; PIGN = postinfectious glomerulonephritis;

RPGN = rapidly progressive glomerulonephritis.

Adapted from Rose BD: Pathophysiology of Renal Disease, ed. 2. New

York, McGraw-Hill, 1987, p. 167.