TIMP2 and IGFBP7

1. P R O G R A M S T U D I I L M U P A T O L O G I K L I N I K
P R O G R A M P E N D I D I K A N D O K T E R S P E S I A L I S
F A K U L T A S K E D O K T E R A N U N I V E R S I T A S H A S A N U D D I N / R S U P D R . W A H I D I N S U D I R O H U S O D O
Jurnal Ginjal Hipertensi
Diana Tangdan Ampulembang
Pembimbing I : dr. Ani Kartini, M.Kes, Sp.PK
Pembimbing II : dr. Fitriani Mangarengi, Sp.PK(K)
Moderator : Dr. dr. Rachmawati A. Muhiddin,Sp.PK(K)
CELL CYCLE ARREST BIOMARKERS FOR PREDICTING
RENAL RECOVERY FROM ACUTE KIDNEY INJURY:
A PROSPECTIVE VALIDATION STUDY

2. ABSTRACT
1
Background: Acute kidney injury (AKI) is a common disease in the intensive care unit
(ICU). AKI patients with nonrecovery of renal function have a markedly increased risk of
death compared with patients with recovery. The current study aimed to explore and
validate the utility of urinary cell cycle arrest biomarkers for predicting nonrecovery in
patients who developed AKI after ICU admission.
Methods: We prospectively and consecutively enrolled critically ill patients who developed AKI after
admission to the ICU, which were divided into a derivation cohort (194 AKI patients) and a validation
cohort (185 AKI patients). The biomarkers of urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and
insulin-like growth factor-binding protein 7 (IGFBP7) were detected at inclusion immediately after AKI
diagnosis (day 0) and 24 h later (day 1). The optimal cut-off values of these biomarkers for predicting
nonrecovery were estimated in the derivation cohort, and their predictive accuracy was assessed in the
validation cohort. The primary endpoint was nonrecovery from AKI (within 7 days).

3. ABSTRACT
1
Results: Of 379 patients from 2 ICU’s (Chao-yang and Lu-he Hospital in Beijing),
159 (41.9%) patients failed to recover from AKI onset, with 79 in the derivation
cohort and 80 in the validation cohort. Urinary [TIMP-2]*[IGFBP7] on day 0 showed
a better prediction ability for nonrecovery than TIMP-2 and IGFBP7 alone, with an
area under the receiver operating characteristic curve (AUC) of 0.751 [95%
confidence interval (CI) 0.701–0.852, p < 0.001] and an optimal cut-off value of 1.05
((ng/mL)2/1000). When [TIMP-2]*[IGFBP7] was combined with the clinical factors of
AKI diagnosed by the urine output (UO) criteria, AKI stage 2–3 and nonrenal SOFA
score for predicting nonrecovery, the AUC was significantly improved to 0.852 (95%
CI 0.750–0.891, p < 0.001), which achieved a sensitivity and specificity of 88.8%
(72.9, 98.7) and 92.6% (80.8, 100.0), respectively. However, urine [TIMP-
2]*[IGFBP7], TIMP-2 alone, and IGFBP7 alone on day 1 performed poorly for
predicting AKI recovery.

4. ABSTRACT
1
Conclusion: Urinary [TIMP-2]*[IGFBP7] on day 0 showed a fair performance for
predicting nonrecovery from AKI. The predictive accuracy can be improved when
urinary [TIMP-2]*[IGFBP7] is combined with the clinical factors of AKI diagnosed by
the UO criteria, AKI stage 2–3 and nonrenal SOFA score.

5. INTRODUCTION
1
• Acute kidney injury (AKI)  carries a significant risk of chronic kidney
disease (CKD)
• AKI patients (nonrecovery renal function) risk of death compared with
recovery patients
• Cell cycle arrest of urinary (TIMP-2) and (IGFBP7)  upregulated early
after AKI and has been confirmed to be superior in the early detection
of AKI
• Predict patients who will fail to recover in early AKI  effective
supportive measures may be implemented early before irreversible
recovery occur

6. 6
MATERIAL & METHODS

7. 7
MATERIAL & METHODS
3
Study Design
Prospective cohort study
and consecutively
sampling method
Samples
379
Patients
Derivation Cohort
194
Patients
Validation Cohort
185
Patients

8. 8
MATERIAL & METHODS
3
INCLUSION EXCLUSION
1. Patients stayed in the ICU longer than 24 h 1. Age < 18 years
2. Patients who developed AKI after ICU
admission
2. Developed AKI before ICU admission
3. Acquired insufficient urine samples at
enrolment

9. 9
MATERIAL & METHODS
3
Definition
1. The diagnosis of AKI was dependent on the serum creatinine and urine output (UO) criteria
proposed by the KDIGO as any of the following: increase in serum creatinine by ≧ 0.3 mg/dl (≧
26.5 μmol/L) within 48 h; increase in serum creatinine to ≧ 1.5 times baseline; or UO < 0.5
ml/kg/h for > 6 h
2. Renal recovery was defined as the absence of any stage of AKI by either serum creatinine criteria
or UO criteria.
3. Patients requiring renal replacement therapy (RRT) until the 7th day after AKI or who died within 7
days were regarded as nonrecovery patients.
4. The primary endpoint was nonrecovery from AKI.
5. The secondary endpoints were the use of RRT in the ICU period, hospital mortality and 30-day
mortality.

10. 10
MATERIAL & METHODS
3
Human Ethics Committee of Beijing Chao-
yang Hospital, Capital Medical University
(Beijing, China), and the ethics number
was 2018-117.
ETHICAL CLEARANCE Chi-square test
Repeated measurement
analysis of variance
Categorical
variables compared
Compared between two
groups (recovery group
& nonrecovery group)

11. 11
MATERIAL & METHODS
3
NephroCheck™ VITROS 5600

12. 12
MATERIAL & METHODS
3

13. 13
MATERIAL & METHODS
3
DATA COLLECTION
Clinical patient variables included patient demographic characteristics, prior health history,
diagnosis, comorbidities, use of vasopressors, and mechanical ventilation
Serum creatinine was detected and recorded at ICU admission and every 12 h thereafter
until the 7th day after AKI
UO was measured hourly from the urinary catheter in the ICU period
The Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ
Failure Assessment (SOFA) scores were assessed on the day AKI was diagnosed
Furthermore, the use of RRT in the ICU period, duration of ICU stay, hospital stay, and death
in the hospital and 30 days after AKI development were recorded

14. 14
RESULT
3154 critically ill patients
stayed > 24 h after ICU
admission
 Urinary TIMP-2 and IGFBP7 on day 0 were obtained from all
379 patients.
 Among the 379 patients, 17 patients were lost from day 0 to
day 1 (anuria) , and 11 patients died within 24 h.

15. 15
RESULT

16. 16
RESULT

17. 17
R
E
S
U
L
T

18. 18
RESULT

19. 19
RESULT
Characteristics and outcomes of
AKI patients with and without
renal recovery in the derivation
cohort
Predicting nonrecovery from
AKI in the derivation cohort
 Recovery patients showed concentrations of [TIMP-2]*[IGFBP7] = 0.3
[(ng/mL)2/1000], TIMP-2 = 3.3 ng/mL, and IGFBP7 = 35.2 ng/mL.
 Patients who failed to recover showed higher concentrations of 1.1
[(ng/mL)2/1000], TIMP-2 = 8.5 ng/mL and IGFBP7 = 100.9 ng/mL.
 Urinary [TIMP-2]*[IGFBP7] on day 0  AUC of 0.751 (95% CI 0.701–
0.852, p < 0.001) with an optimal cutoff value of 1.05
[(ng/mL)2/1000].
 Urinary [TIMP-2]*[IGFBP7], TIMP-2 and IGFBP7 on day 1 performed
poorly for predicting nonrecovery.

20. 20
RESULT
Predicting nonrecovery
from AKI in the Derivation
Cohort
When [TIMP-2]*[IGFBP7] on day 0 was combined with the clinical risk
prediction model to predict nonrecovery, the power was significantly improved,
resulting in the best predictive AUC of 0.852
The optimal cut off probability value was 0.290 (ng/mL)²/1000 . AKI patients
who had a probability value greater than 0.290 (ng/mL)²/1000 may fail to
recover.

21. 21
RESULT
DERIVATION COHORT

22. 22
RESULT
Predictive accuracy of urinary
[TIMP-2]*[IGFBP7] for nonrecovery
from AKI in the validation cohort
 In the validation cohort, 79/194 (40.7%) patients failed to recover from AKI
 Urinary [TIMP-2]*[IGFBP7] on day 0 showed the best predictive accuracy for
nonrecovery compared with urinary TIMP-2 and IGFBP7 alone, with sensitivity 82.3% ,
specificity 76.9% , PPV 65.0%, and NPV 88.5%.
 The sensitivity, specificity, PPV and NPV increased to 88.8%, 86.2%, 80.0% and
92.6% respectively.

23. 23
RESULT

24. 24
DISCUSSION
The SAPPHIRE study identified their ability
to predict the development of KDIGO stage
2 or 3 AKI within 12 h in high-risk patients
(2013, north America & europe)
The TOPAZ study  Validate the
performance of [TIMP-2] · [IGFBP7] with
clinical adjudication (2014,US)
Urine TIMP-2 & IGFBP7, inducers of G1
cell cycle arrest  renal tubular cells.
AKI  inflammation, oxidative stress,
and apoptosis in cellular & molecular
pathways. AKI may occur following
ischaemic or toxic insults.
TIMP-2 and IGFBP7 participate in these
mechanisms and reflect early damage
to the kidney
The OPAL study  Derivated and validate
two different cutoff values of [TIMP-2] ·
[IGFBP7] (2014,US)

25. 25
DISCUSSION
The main findings were as follows:
1. Urine [TIMP-2]*[IGFBP7], TIMP-2 alone, and IGFBP7 alone on day 0 showed
fair value for predicting nonrecovery from AKI.
2. When adding urinary [TIMP-2]*[IGFBP7] on day 0 to the clinical risk
prediction model, the predictive value was greatly improved to 0.852. The
utility of the [TIMP-2]*[IGFBP7] day 0 clinical risk prediction model was
confirmed in the validation cohort, with a sensitivity and specificity of
88.8% and 92.6%, respectively;
3. Urine [TIMP- 2]*[IGFBP7], TIMP-2 alone, and IGFBP7 alone on day 1
performed poorly for predicting AKI recovery

26. 26
KESIMPULAN
• Urine [TIMP-2]*[IGFBP7]  Biomarker Prediksi AKI Penelitian
SAPPHIRE,TOPAZ,OPAL (biomarker AKI lainnya - NGAL,KIM-1,Cystatin
C,IL-18,L-FABP)
• 2 ICU RS Chao-yang and Lu-he di Beijing-China (2018-2020)
• Prospektif Kohort  Derivasi (nilai cut off)  Validasi (Sensitivitas,
spesitifitas,NPV,PPV)
• Urine [TIMP-2]*[IGFBP7],TIMP-2,IGFBP7 hari 0  kemampuannya paling
baik dibanding hari 1
• Urine [TIMP-2]*[IGFBP7] hari 0 + Risiko Klinis (kriteria UO, SOFA skor
nonrenal, Aki st.2-3)  Sensitivitas, spesitifitas,NPV,PPV makin
meningkat/paling baik.
• Pemakaian agent nefrotoksik, memaksimalkan resusitasi hemodinamik

27. THANK YOU