Case Discussion

ALL with Renal

insufficiency

Karina Nilasari
Moderator :
dr. Dian Sukma Hanggara, M Biomed, Sp.PK

1
Data Base
Male / 16 y.o
Chief Complaint : Gum bleeding
Present Medical History :
The patient had suffered from gum pain since 1 week before
admission and it was bleeding when he brush his teeth.
The patient also complained of abdominal discomfort and pain,
nausea and vomiting. The patient also complained of being pale
since he was admitted at the Al-Huda Hospital. He had lost his
appetite and body weight in this last week.
The conjungtiva of the patient was red, and he also had dark
stool since 4 days before admission.
2
Past medical history :
Data Base
• The patient was reffered from Al Huda Hospital Banyuwangi, with
diagnosis suspected ALL.

Family medical History :

• There were no family suffer from the same illness

Social and family history

• He is the first child, the second child is a girl, 7yo. His mother 40
yo and his father is 47 yo

3
• Birth history : spontaniously crying by mid wife.
• ANC history : routinely control in midwife and sometimes in
obstetrician.
• Nutrient history : within normal limit
• Develompment history : within normal limit
• Immunizasion history : complete until 9 months

4
 Physical Examination
General status Moderately ill, GCS : 4-5-6
BW: 57kg H: 165cm ( BMI:normal)
Vital sign BP : 110/70 mmHg HR : 80 bpm
RR : 24 tpm T : 36,7°C (axilla)
Head & Neck Anemic conjunctiva +/+, Conjungtiva bleeding +/+, Icteric sclera -/-
JVP : R+2 cmH2O
Thorax P : symmetrical, VBS +/+, Rh -/-, Wh -/-
C : ictus at 5th ICS, 1 cm lateral of MCL, single S1/S2, murmur -, gallop -

Abdomen Flat, Soefl (+), Liver : unpalpable, Lien : schuffner I, meteorimus (-),
traube space tympani

Extremities Warm acral, edema -/-

5
HEMATOLOGY 22-07 23-07 26-07 Reference
Hemoglobin 9,40 7,90 9,60 13,4 – 17,7 g/dL
CHEMO
PRC+TC
Erythrocyte 3,70 3,18 3,77 4,0 – 5,5 . 106 /µL

Leucocyte 75,00 66,16 5,21 4,3 - 10,3 .103 /µL

Hematocrit 27,10 23,70 29,10 40 – 47 %
Thrombocyte 41 42 89 142 – 424 . 103 /µL
MCV 73,20 74,50 77,20 80 - 93 fL
MCH 25,40 24,80 25,50 27 – 31 pg
MCHC 34,70 33,30 33,00 32 - 36 g/dL
RDW 16,00 16,40 16,90 11,5-14,5
LED 85 2-30 mm/jam
Diff.count:
0-4/0-1/0/51-67/25-33/2-
Eo/Baso/Neut/ 0/0/0/8/58/34 0/0/0/6/87/7 0/0/0/38/58/4
5
Lymph/Mono

6
 22-07 23-07 Normal range

Retikulosit 0,0178 . 106 /uL 0,0114 . 106 /uL

Absolut

Retikulosit 0,48 0,36 0,5 – 2,5%

Immature 2,6 1,1 – 6,1%

Platelet
Fraction

7
Evaluasi Hapusan 22-07 (00:53:18) 23-07
Darah
Lain-lain Hasil Diff Count: 0/0/2/6/3/1 Hasil Diff Count: 0/0/0/9/9/0
Mielosit : 1% Limfoblas: 82%
Sel blas : 87%
Eritrosit Hipokrom Anisopoikilositosis, Hipokrom Anisopoikilositosis,
Mikrositik, Eliptosit +, Makroovalosit +, tear drop cell +
Makroovalosit +
Lekosit Kesan Jumlah sangat meningkat, Kesan Jumlah sangat meningkat,
sel blas + didominasi oleh limfoblas

Trombosit Kesan Jumlah menurun Kesan Jumlah turun

8
 22/07 Reference
PPT (sec) 11,40 9,3 – 11,4 sec
Control (sec) 11,1
INR 1,10 < 1,5
APTT 28,50 24,6 – 30,6 sec
Control (sec) 25,14
Conclusion Normal

9
BMP (23 July 2020)
• Selularitas : Hiperseluler
• Rasio M:E : 1:1
• Eritropoiesis : Aktivitas turun
• Granulopoisis : Aktivitas turun
• Megakariopoisis : Aktivitas turun
• Cadangan Fe : Negative
• Lain-lain : terdapat proliferasi limfoblas 90%, dengan morfologi
homogen, bulat, anak inti +/-, sitoplasma scanty
• Kesimpulan : Acute Lymphoblastic Leukemia (ALL) L1 dengan Fe
depletion
10
Darah Tepi

Limfoblas Limfoblas 11
Sumsum Tulang

Hiperseluler Limfoblas
12
Sumsum Tulang

ST : Fe -
13
 Clinical 22/07 23/07 26-07 Normal reference
chemistry
Chemo

Urea 99,3 157,2 117,6 16,6 – 48,5 mg/dL

Creatinine 8,13 7,11 2,24 < 1,2 mg/dL

Uric acid 30,5 32,5 6,8 3,4-7 mg/dL

eGFR 9 10 42 ml/min/1,73m²

Fe 228 116 53-167 μg/dL

TIBC 237 248 300-400 μg/dL

Saturasi 96 47 16-45%
Transferin
RBS 135 154 < 200mg/dL

Albumin 4,19 4,44 3,5- 5,5 g/dL

14
 Clinical chemistry 22/07 26/07 Normal reference

AST/SGOT 333 35 0 – 32 U/L

ALT/SGPT 49 22 0 – 33 U/L

INFLAMATION 22/07 Normal reference

CRP 11,34 <0,3 mg/dL

Immunoserology and others 22/07

Ferritin 1207,00 14-152 ng/mL

Procalsitonin 2,13 <0,5 Low risk sepis

>2 High risk sepsis
15
LABORATORY RESULT

Electrolyte 22/07 26/07 Normal reference

Chemo

Natrium 130 142 133- 148 mmol/L

Kalium 4,73 4,78 3,5 – 5,0 mmol/L

Chloride 101 112 101 – 105 mmol/L

Calsium 9,6 5,7 7,6-11,0 mg/dL

Phosphor 1,9 7,1 2,7-4,5 mg/dL

16
 Urinalysis 22/07 23/07 Reference
Turbidity Cloudy Clear
Color Yellow Yellow
pH 5,5 6,0 4,5-8,0
SG 1,025 ≤1,005 1,005-1,030
Glucose Negative Negative Negative
Protein 1+ Negative Negative
Keton Negative Negative Negative
Bilirubin Negative Negative Negative
Urobilinogen 16 3,2 <17μmol/L
Nitrite Negative Negative Negative
Leucocyte 1+ Trace Negative
Blood Trace Trace Negative
17
 Microscopic
urine exam 22-07 23-07 Reference
Epithel 10,8 1,8 ≤3/lpf
Cast
10x Hyaline Negative Negative ≤2/lpf
Granular Negative Negative Negative
Other Negative Negative
Erythrocyte 1,8 0,4 ≤3/hpf
Eumorphic - %
Dysmorphic - %
40x
Leucocyte 16,6 1,7 ≤5/hpf
Crystal -
Bacteria 594,7 41,8 ≤23x103/mL
18
Stool Analysis 22-07 25-07 26-07 Reference
Colour Yellow Yellow Brown
Consistency Liquid Liquid Mushy
Element Negative Negative Negative
Epithel + + + Negative – 1+ /HPF
Leucocyte 1-2 0-2 0-2 ≤ 5 /HPF
Erythrocyte 1-2 Negative 0-2 Negative /HPF
Parasite - - Negative /HPF
Food remnants Positive Positive Positive
Muscle fiber Negative Negative Negative < 10 /HPF
Plant fiber Positive Positive Positive -/+
Amylum Negative Negative Negative -/+
Fat Negative Negative Negative Steatorhoe > 60
Others Bacteria (++) Bacteria (++) Bacteria (++)
FOBT T1 positive Negative -

19
 DATA INTERPRETATION 20

This is a case of a 16-year old male, with laboratory tests showed:

• Normochrom anisopoikilocytosis anemia, low reticulocyte, leukocytosis,
trombocytopenia
• Hyponatremia normal, hyperphosphatemia, hypocalsemia,
• Increased of Transferin Saturation and low TIBC
• Increased AST
• Azothemia, increased uric acid serum
• Blood smear : lymphoblast 82%
• Increased ferritin, CRP
• Increased Procalsitonin
• Leukocyturia, bacteriuria normal
• FOBT T1 +  negative
• BMP conclusion: Acute Lymphoblastic Leukemia (ALL) L1 dengan Fe depletion
 Data Interpretations
Based on medical history, physical & other supporting examinations
showed :
1. ALL-L1 and suspected Tumor Lysis Syndrome
2. Acute Kidney Injury due to SEPSIS dd Leukemia infiltration

• Suggestion: Immunophenotyping, Cytogenetic, Urine culture, faeces

culture
• Monitoring : CBC, Blood smear evaluation, Serum electrolyte,
Ureum, creatinin, uric acid, calsium, SI, TIBC, AST, ALT, Urynalisis

21
Establishment of diagnosis

AKI in this patient

22
Establishment of
diagnosis

23
Acute lymphoblastic leukemia (ALL)

• ALL is a malignant disorder that originates in a single B

or T lymphocyte progenitor
• Characterized by 20% or more lymphoblasts in the
bone marrow and/or the blood.
• The disease is most common in children but can be
seen in individuals of any age.
• Proliferation and accumulation of blast cells in the
marrow result in suppression of hematopoiesis and,
thereafter, anemia, thrombocytopenia, and
neutropenia

24
• Approximately 6000 cases of ALL are diagnosed in the United States
annually  half the cases occur in children and teenagers
• In the United States, ALL is the most common cancer among children
and the most frequent cause of death from cancer before 20 years of
age
• Presenting symptoms of ALL include bruising or bleeding due to
thrombocytopenia, pallor and fatigue from anemia, and infection
caused by neutropenia
• Leukemic infiltration of the liver, spleen, lymph nodes, and
mediastinum is common at diagnosis
25
• ALL comprises multiple entities with distinct constellations of somatic
genetic alterations
• These genetic alterations include aneuploidy (changes in
chromosome number), chromosomal rearrangements that
deregulate gene expression or result in expression of chimeric fusion
proteins, deletions and gains of DNA, and DNA sequence mutations

26
HUNGER, Stephen P.; MULLIGHAN, Charles G.
Acute lymphoblastic leukemia in children. New
England Journal of Medicine, 2015, 373.16:
1541-1552.

27
The following studies and procedures are used in the
workup for acute lymphoblastic leukemia (ALL):
• Complete blood count (CBC) with peripheral smear
• Coagulation studies (prothrombin time [PT], activated partial thromboplastin
time [aPTT], fibrinogen)
• Chemistry profile, including liver and kidney function studies
• Bone marrow aspiration and biopsy – Definitive diagnostic tests
• Cultures; in particular, blood cultures
• Chest radiography
• Chest computed tomography (CT) scan, as indicated by symptoms
• Multiple-gated acquisition (MUGA) scan or echocardiogram
• Lumbar puncture 
28
Classification (WHO)

29
 Classification (FAB)

ALL L1 ALL L2 ALL L3 30

 Tumor Lysis Syndrome (TLS)
• Oncometabolic emergency
• It can occur as a consequence of tumor targeted therapy or
spontaneously
• Characterized by a massive destruction tumor cell and release
their contents into the bloodstream, leading to the development
of metabolic derangements and target organ dysfunction
• Laboratory finding  hyperuricemia, hyperkalemia,
hyperphosphatemia, and hypocalcemia
• Blood cancers constitute the vast majority of TLS cases because of
the sensitivity to therapy and rapid division rates
• Management of established TLS includes intravenous hydration,
urate lowering therapies, management of hyperkalemia and
hemodialysis in refractory cases.
31
Solh M, Appel. Tumor Lysis Syndrome. Resident Grand Round. www.turner-white.com
 This case
• Male 16 yo
• Spontaneous bleeding history
• Anemia, thrombocytopenia, neutropenia, Acute
hyperleukocytosis, peripheral blood smear Lymphoblastic
showed lymphoblas 82% Leukemia (ALL) – L1
• BMA  Infiltration and proliferation of and suspected
lymphoblas 90% with homogen morphology, Tumor Lysis
rounded, nucleolus +/-, scanty cytoplasm  Syndrome
ALL-L1
• Azotemia, Decreased eGFR, increased uric
acid  normal Suggestion :
• Increased CRP, ferritin Immunophenotyping,
• Hyperphosphatemia, hypocalsemia Cytogenetic
Monitoring : CBC, Blood smear
evaluation, Serum electrolyte,
Ureum, creatinin, uric acid,
calsium 33
AKI in this patient

34
 ACUTE KIDNEY INJURY
Acute Kidney Injury (AKI)Rapid decrease of GFR which in
commonly reversible, followed by renal failure with/without
electrolyte imbalance
Etiology: pre renal, renal, post renal

AKI is defined as any of the following ( Not Graded ):

1. Increase in SCr by ≥ 0.3 mg/dl ( ≥ 26.5 mol/l) within 48 hours; or
2. Increase in SCr to ≥ 1.5 times baseline, which is known or presu-
med to have occurred within the prior 7 days; or
3. Urine volume < 0.5 ml/kg/h for 6 hours
35
(KDIGO Clinical Practice Guideline for Acute Kidney Injury,2012)
36
 AKI From Kidney Infiltration

• The kidney is the most common extrahematopoietic organ infiltrated by leukemia

• The rate of infiltration parallels with the stage and grade of disease
• Prevalence of kidney infiltration was 54% in acute lymphoblastic leukemia (ALL)
• AKI from infiltration is seen in only 1% of cases of all patients with acute leukemias and
even less commonly in chronic leukemia
• Symptoms and signs that may be associated with infiltration include flank pain,
hematuria, abdominal distension, or hypertension
• Kidney biopsy is often useful to :
• Find location of infiltration to influence prognosis.
• Differentiate subtype leukemia  alter disease treatment

37
Luciano and Brewster. Kidney Manifestations of Hematologic Malignancy
SIRS
• Systemic Inflammatory Response Syndrome (SIRS) is an
inflammatory state affecting the whole body, frequently a
response of the immune system to infection, but not
necessarily so.
• SIRS must first be diagnosed by finding at least any two of
the following:
• Tachypnea (high respiratory rate) > 20 breaths per minute, or
on blood gas, a PCO2 less than 32 mmHg signifying
hyperventilation.
• White blood cell count either significantly low, < 4000
cells/mm3 or elevated > 12000 cells/mm3.
• Heart rate > 90 beats per minute
• Temperature: Fever> 38.0 °C (100.4 °F) or hypothermia < 36.0 °C
(96.8 °F)
38
Score: 4 39
 This Patient
• Male 16 yo, nausea, vomiting
• Tachypnea
• Hyperleukocytosis, trombocytopenia, BMP  ALL-L1
• Serum creatinine (7.11  2.24 in 3 days without dialysis), Hyponatremia
• Increased CRP, Ferritin, LED, Procalsitonin 2,13
• Increased AST
• Leukocyturia, bacteriuria
• FOBT T1 +  negative

Acute Kidney Injury due to volume depletion dd SEPSIS dd Leukemia infiltration

• Suggestion : Billirubin T/D/I, urine culture, faeces culture

• Monitoring: CBC, Ureum, creatinin, Urine volume, serum
electrolyte, urynalisis, ASL, ALT 40
CONCLUSION
• It has been discussed, male 16 years old with ALL-L1 and Suspected Tumor
Lysis Syndrome with Acute Kidney Injury due to volume depletion dd
SEPSIS dd Suspected Leukemia infiltration
• Tumor Lysis Syndrome in this patient was still suspected, because the
kalium and uric acid was still normal, so the kalium serum, uric acid and
creatinin should be monitored.
• Suggestion : Immunophenotyping, Cytogenetic, Billirubin T/D/I, urine
culture, faeces culture
• Monitoring: CBC, Blood smear evaluation, Serum electrolyte, Ureum,
creatinin, uric acid, calsium, SI, TIBC, AST, ALT, Urynalisis

41
THANK YOU

42
43
Cairo-Bishop Definition of laboratory tumor
lysis syndrome
Variable Value Change from This
baseline value Patient
Uric acid ≥ 8 mg/dL (476 25% increase
mmol/L) √
Potassium ≥ 6.0 mEq/L (or 6 25% increase
mmol/L)
Phosphorus ≥ 4.5 mg/dL (1.45 25% increase
mmol/L) for adults and √
≥ 6.5 mg/dL (2.1
mmol/L) for children
Calcium ≤ 7 mg/dL (1.75 25% decrease
mmol/L)
√
47
48
49
50
 FOBT
• Noninvasive test to detect the presence • FOBT Rapid Test: Qualitative
of hidden (occult) blood in the stool.
• Methods: chemical, hemoporphyrin or
immunologic.
• Causal: malignancy, bleeding from
esophageal varices/ polyps/
inflammation, hemorroids or fisures,
inflammatory bowel disease, peptic ulcer
disease etc.
immunochromatographic assay for
the determination of specific human
hemoglobin (cutoff of 100ng/ml
feces) and/or transferrin (cutoff of
40ng/ml) in feces.
• Interpretation:
• T1 zone: transferrin (+)
• T2 zone: hemoglobin (+)

Henry’s Clinical Diagnosis and Management by Laboratory Methods. 22nd ed. 51

2011.
 • Esophageal varises
• Ulcus peptikum
• Gastritis erosive
Upper GI tract • Gastropathy hipertensi porta
• Esophagitis
• Malignancy
• Angiodysplasia
FOBT Positive (+)
• Colitis
(infection,radiation,ischemic)
• Malignancy
Lower GI tract • Diverticulosis
• Inflammatory Bowel Disease
• Hemorrhoid
GI complication in ALL
• Gastrointestinal (GI) complications are common in patients with
ALL.
• Enterocolitis, a necrotizing inflammatory lesion involving the
terminal ileum, cecum, and ascending colon, can be a
presenting syndrome or can occur during treatment.
• Intestinal perforation, an inflammatory mass, and associated
infection with enteric gram-negative bacilli or clostridial species
are often associated with a fatal outcome.

Gamal Abdul Hamid, Acute Leukemia Clinical Presentation.2009

For optimal risk stratification and treatment planning, the
NCCN advises the tests, as follows :
• Cytogenetics – Karyotyping of G-banded metaphase chromosomes
• Interphase fluorescence in situ hybridization (FISH, ALL panel to include testing
for  BCR-ABL1,  MLL,  TEL/AML - ETV6/RUNX1, CEP4 and CEP10)
• Reverse transcriptase polymerase chain reaction (RT-PCR) for fusion genes
(eg,  BCR-ABL1), including determination of transcript size; in  BCR-ABL1–negative
cases, testing for other fusions that are associated with Ph-like ALL may be
considered
• Additional assessment (array comparative genomic hybridization [cGH]) may be
considered in cases of aneuploidy or failed karyotype

[Guideline] NCCN Clinical Practice Guidelines in Oncology: Acute Lymphoblastic Leukemia. National
Comprehensive Cancer Network. Available at 
http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Version 1.2020 — January 15, 2020; 54
Accessed: February 20, 2020.
Clinical Features of Adult ALL

55
Acute Leukemia Clinical Presentation. http://dx.doi.org/10.5772/53531
 Diagnostic Approach for Adult ALL

• Medical history
• Physical examination
• Laboratory studies
• Complete blood count & peripheral smear,
• Coagulation studies, fibrinogen level, serum chemistry, ABO and Rh
blood group,
• human leukocyte antigen typing
• Lumbar puncture
• Bone marrow aspiration and biopsy
• Cytochemical stains,
• cytogenetic analysis,
• Immunophenotype analysis,
• BCR-ABL molecular analysis
• Chest radiograph or computed tomography 56
 Acute Kidney Injury (AKI)

• Previously known as acute renal failure (ARF)

• AKI is defined as any of the following :
• Increase in SCr by ≥ 0.3 mg/dl (≥ 26.5 lmol/l) within 48 hours;
or
• Increase in SCr to ≥ 1.5 times baseline, which is known or
presumed to have occurred within the prior 7 days; or
• Urine volume < 0.5 ml/kg/h for 6 hours.
• Causes of AKI  prerenal azotemia, intrinsic renal
parenchymal disease, and postrenal obstruction
• AKI is staged for severity according to the following
criteria
57
Harrison’s Principles of internal Medicine 18 ed
RIFLE and AKIN Criteria For Diagnosis
And Classification Of AKI

58
Kidney International Supplements (2012) 2, 19–36
Transformation of Hematopoietic Cells in
the Pathogenesis of ALL.

59
Chronic Kidney Disease in Leukemia

60
61
• Leukemia-associated decreased kidney function is caused by
parenchymal infiltration of leukemia cells, tumor lysis, thrombotic
microangiopathy, radiation injury, or toxicity from chemotherapy
• Overproduction of lysozyme, an enzyme stored in myelomonocytic
cells, is released into the circulation, filtered by glomeruli, and taken
up by tubular cells. Tubule cells presumably undergo toxic injury
leading to atrophy, interstitial fibrosis, and progressive kidney disease

62
 Procalcitonin

www.procalcitonin.com
SEPSIS and AKI
 Prognostic Factor for Remission
Duration in Aduts ALL
Patient Features Prognostic
Age <30 Favorable
>30 Unfavorable
WBC 30.000 Favorable
Count x(106/ml) 30.000 (>100.000 for T cell) Unfavorable

Immunophenotype T-Cell ALL Favorable

Mature B-Cell ALL, early T-Cell ALL Unfavorable
Cytogenetics  12p abnormality; t(10;14)(q24;q11) Favorable
Normal; hyperdiploid intermediate
   t(9;22), t(4;11), t(1;19), hypodiploid, – Unfavorable
7, +8
Response to therapy Complete remission within 4 wk Favorable
  Persistent minimal residual disease Unfavorable

Wintrobe’s Clinical Hematology 12th Edition.2009

DIC in Acute Leukemia
• DIC commonly complicates AL because of the release of procoagulant
materials or enzymes from blasts;
• leukemic cells may also have fibrinolytic activity
• Leukemic cells produce inflammatory cytokines, including tissue
necrosis factor-α (TNF-α) and interleukin-1β (IL-1β)
• DIC may be worsened by the initiation of antileukemic therapy
FENa+

FE Na+ < 1% : prerenal AKI

FE Na+ > 1% : ATN
 Serum Osmolality
BUN = Ureum x 2,14
= 64,2 x 2,14
= 137,4
Serum osmolality = (2 x (Na+K)) + (BUN/
2,8) + (Glucose / 18)
= (2 x (129+3,54)) + 137,4 / 2,8) +
(98/18)
= 319,59 mOsm/kg Hypertonic
(normal 285-295mOsm/Kg)
http://bestpractice.bmj.com/best-practice/monograph/57/diagnosis.html
Na+ plasma < 135 mmol/L

77
 HYPOTONIC
HYPONATREMIA

78
The diagnostic approach to Hyponatremia

Hematologic maliganacy can caused

inapropriate vasopressin release
 Therapy Leukemia
Supportive care

●
Infection control, hyperleukocytosis, metabolic complication, hematologic support

Antileukemic therapy

●
B Cell ALL
●
B Cell Precursor and T Cell ALL
●
Remission induction  glucocorticoid (prednisone, prednisolone, or dexamethasone), vincristine, and L-asparaginase for children or an anthracycline for adults
●
Intensification (consolidation)
●
A very high dose of methotrexate (5 g/m 2) appears to improve the treatment outcome of patients with T cell ALL
●
patients with TEL-AML1 or E2A-PBX1 gene fusion benefit from a higher dose of methotrexate.
●
Prolonged continuation therapy