Trial document




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  DRKS00012446

Trial Description

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Title

Prediction of AKI with the need for RRT by the use of cell cycle arrest biomarkers in patients with sepsis or septic shock.

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Trial Acronym

PredARRT-Sep-Trial

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URL of the Trial

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Brief Summary in Lay Language

In this clinical trial, the diagnostic value of two renal damage biomarker “insulin like growth factor binding protein-7” (IGFBP-7) and “tissue inhibitor of metalloproteinase-2” (TIMP-2) is evaluated in patients with sepsis or septic shock and associated acute kidney injury (AKI). Therefore, 200 patients are supposed to be recruited. The aim is to establish a IGFBP-7xTIMP-2 cut-off value to predict AKI stage III with need for renal replacement therapy with high sensitivity and specificity. This cut-off might serve as decision guidance for RRT timing and might help to predict (long-term) outcomes. In addition, other AKI biomarkers in blood and urine are analyzed in the same context.

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Brief Summary in Scientific Language

The acute kidney injury (AKI) is a relevant disease entity with a high incidence and mortality on intensive care units (ICU). 50% of AKI are thereby sepsis-related. Even moderate serum creatinine (SCr) rises correlate with adverse outcomes like chronic kidney disease (CKD) or end-stage renal disease (ESRD). Apart from prevention, risk stratification and RRT-independent therapies, the adequate timing of RRT is of great relevance. Despite several studies the optimal RRT timing is discussed controversially and the related data is inconclusive. A general problem across all studies remains the distinction between beneficial and unnecessary or even harmful “early” RRT due to spontaneous renal recovery. In addition, there is evidence of a delayed renal recovery after “early” RRT. Previously published date from Gaudry et al., Jamale et al. and Wald et al. support this issue [1-3]. In this context, the implementation of innovative biomarkers into the therapeutic concept might be beneficial. The two G1-cell cycle inhibitors “insulin like growth factor binding protein-7” (IGFBP-7) and “tissue inhibitor of metalloproteinase-2” (TIMP-2) proved enormous diagnostic potential regarding the prediction of moderate and severe AKI 12h after ICU admission [4-6]. On this basis, the aim of this study is to establish a IGFBP-7xTIMP-2 cut-off value to predict AKI stage III with need for renal replacement therapy with high sensitivity and specificity. The latter might serve as decision guidance for RRT timing in the further clinical course and might help to predict (long-term) outcomes (mortality, renal recovery, CKD, ESRD) and to clarify AKI-Pathogensis. For this purpose 200 patients with sepsis or septic shock are supposed to be recruited. In addition, other soluble and cell-bound biomarkers in blood and urine are analyzed in the same context.

[1] Gaudry S, Hajage D, Schortgen F, et al. Initiation Strategies for Renal-Replacement Therapy in the Intensive Care Unit. N Engl J Med 2016;375:122–33.
[2] Wald R, Adhikari NKJ, Smith OM, et al. Comparison of standard and accelerated initiation of renal replacement therapy in acute kidney injury. Kidney Int 2015;88:1–8.
[3] Jamale TE, Hase NK, Kulkarni M, et al. Earlier-start versus usual-start dialysis in patients with community-acquired acute kidney injury: a randomized controlled trial. Am J Kidney Dis 2013;62:1116–21.
[4] Kashani K, Al-Khafaji A, Ardiles T, et al. Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury. Crit Care 2013;17:R25
[5] Bihorac A, Chawla LS, Shaw AD, et al. Validation of cell-cycle arrest biomarkers for acute kidney injury using clinical adjudication. Am J Respir Crit Care Med 2014;189:932–9.
[6] Hoste EAJ, McCullough PA, Kashani K, et al. Derivation and validation of cutoffs for clinical use of cell cycle arrest biomarkers. Nephrol Dial Transplant 2014;29:2054–61.

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Organizational Data

  •   DRKS00012446
  •   2017/05/16
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  •   yes
  •   Approved
  •   S-200/2017, Ethik-Kommission I der Medizinischen Fakultät Heidelberg
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Secondary IDs

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Health Condition or Problem studied

  •   N17.9 -  Acute renal failure, unspecified
  •   A41.9 -  Sepsis, unspecified
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Interventions/Observational Groups

  •   AKI with need for RRT.
  •   No AKI or AKI Stage I (mild AKI), KDIGO AKI-Guidelines 2012.
  •   AKI stage II or III without need for RRT (moderate or severe AKI), KDIGO AKI-Guidelines 2012.
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Characteristics

  •   Non-interventional
  •   Other
  •   Non-randomized controlled trial
  •   Open (masking not used)
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  •   Other
  •   Diagnostic
  •   Other
  •   N/A
  •   N/A
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Primary Outcome

* Establishment of a IGFBP-7xTIMP-2 cut-off value for the prediction of AKI stage III with need for RRT in patients with sepsis or septic shock on ICU with high sensitivity and specificity.

* Evaluation of IGFBP-7xTIMP-2 (cut-off) levels in relation to disease severity (SOFA-Score, APACHE-II-Score, SAPS-Score), survival after 30d, 60d and 365d, RRT-dependency after 30, 60 and 365d and length of hospital stay.

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Secondary Outcome

* Evaluation of other soluble and cell-bound biomarkers of sepsis and AKI concerning disease course, mortality, RRT-dependency as well as renal and general long-term prognosis and AKI pathogenesis

* Ability of IGFBP-7xTIMP-2 concentrations to distinguish between moderate, severe AKI and AKI with need for RRT (KDIGO 2012).

* Evaluation of changes in IGFBP-7xTIMP-2 levels over the disease course and the correlation with AKI with need for RRT and RRT-dependency and mortality after 30,60 and 365d.

* Correlation of IGFBP-7xTIMP-2 concentrations and established markers of renal function (SCr, Cystatin C).

* Correlation of IGFBP-7xTIMP-2 concentrations and composite endpoint MAKE30 („major adverse kidney events“): combination of death, RRT-dependency and persistent renal dysfunction on day 30, 60, 365 after admission.

* Time correlation of IGFBP-7xTIMP-2 levels, application of nephrotoxic drugs and potential renal dysfunction.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2017/05/22
  •   200
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   99   Years
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Additional Inclusion Criteria

* Written consent form of study participant or his appointed representative
Sepsis criteria have to be fulfilled (sepsis-3 definition, Singer et al.):
* Suspected infection
* SOFA-Score ≥ 2
and further for septic shock:
* need for vasopressors to maintain a sufficient hemodynamic state (MAP≥65mmHg) despite adequate volume replacement
* serum lactate > 2mmol/l

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Exclusion Criteria

* non-fulfillment of inclusion criteria
* no urinary catheter
* refusal of participation in the study
* pre-existing RRT dependency or immediate need for RRT on admission

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Addresses

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    • Universitätsklinikum Heidelberg Klinik für Anästhesiologie, Nierenzentrum Heidelberg
    • Im Neuenheimer Feld 110 und 162
    • 69120  Heidelberg
    • Germany
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    • Universitätsklinikum Heidelberg, Klinik für Anästhesiologie
    • Mr.  PD, Dr. med.  Thorsten  Brenner 
    • Im Neuenheimer Feld 110
    • 69120  Heidelberg
    • Germany
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    • Nierenzentrum Heidelberg
    • Mr.  Dr. med.  Christian  Nusshag 
    • Im Neuenheimer Feld 162
    • 69120  Heidelberg
    • Germany
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    • Nierenzentrum Heidelberg
    • Mr.  Dr. med.  Christian  Nusshag 
    • Im Neuenheimer Feld 162
    • 69120  Heidelberg
    • Germany
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Sources of Monetary or Material Support

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    • Universitätsklinikum Heidelberg, Klinik für Anästhesiologie
    • Im Neuenheimer Feld 110
    • 69120  Heidelberg
    • Germany
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    • Nierenzentrum Heidelberg
    • Im Neuenheimer Feld 162
    • 69117  Heidelberg
    • Germany
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Status

  •   Recruiting complete, follow-up continuing
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Trial Publications, Results and other Documents

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