Urinary Insulin-like Growth Factor-binding Protein 7 Research Articles

Tissue Inhibitor of Metalloproteinase 2 and Insulin-Like Growth Factor-Binding Protein 7 in Pediatric Diabetic Ketoacidosis

Abstract Background Diabetic ketoacidosis (DKA) is one of the main causes of end-stage kidney disease (ESKD). Urinary concentration of tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) are well known urinary acute kidney injury (AKI) biomarkers. Objectives to determine the level of urinary TIMP-2 and IGFBP7 as markers of acute kidney injury (AKI) in children with T1DM during and after the resolution of diabetic ketoacidosis. Patients and Methods A prospective longitudinal study was conducted over 1 year, where we have included children with T1DM presented to Emergency Department (ED) at Children’ s Hospital, Faculty of Medicine, Ain Shams University, with moderate and severe DKA, where we followed them at presentation and day 14, and determined those who developed AKI and measured urinary TIMP-2 and IGFBP7 to detect it AKI. Results We have included 40 pediatric patients with T1DM with mean (±SD) age of 10.59 ± 2.17 years, with a female predominance (90%). Among our patients, 18 patients (45%) had AKI at presentation, where they had a significantly elevated urinary level of both TIMP-2 and IGFBP7 than without AKI (TIMP-2 (ng/ml):112.58(13.76 - 190.1) versus 33.53 (17.27 - 149.65), IGFBP7(ng/ml) :77.42(0.57 - 164.3) versus 1.41(0.67 - 82.63) (p < 0.001). Follow up at day 14, after recovery from DKA, we had no patients with AKI, with significant decrease in the same urinary biomarkers (TIMP-2(ng/ml) :11.35 (8.13 - 25.03) versus 9.62 (7.67 - 17.02), IGFBP7(ng/ml) :0.94(0.51 - 2.34) versus 0.78 (0.43 - 1.34) (p < 0.005). Conclusion The level of urinary TIMP-2 and IGFBP7 increased in children and adolescent with T1DM who developed AKI at the time of presentation of DKA, and normalized after the resolution of DKA and the recovery from AKI.

Urinary beta-2 microglobulin increases whereas TIMP-2 and IGFBP7 decline after unilateral nephrectomy in healthy kidney donors

Early kidney injury may be detected by urinary markers, such as beta-2 microglobulin (B2M), tissue inhibitor of metalloproteinases-2 (TIMP-2), insulin-like growth factor-binding protein 7 (IGFBP7), kidney injury molecule-1 (KIM-1) and/or neutrophil gelatinase-associated lipocalin (NGAL). Of these biomarkers information on pathophysiology and reference ranges in both healthy and diseased populations are scarce. Differences in urinary levels of B2M, TIMP-2, IGFBP7, KIM-1 and NGAL were compared 24 h before and after nephrectomy in 38 living kidney donors from the REnal Protection Against Ischaemia–Reperfusion in transplantation study. Linear regression was used to assess the relation between baseline biomarker concentration and kidney function 1 year after nephrectomy. Median levels of urinary creatinine and creatinine standardized B2M, TIMP-2, IGFBP7, KIM-1, NGAL, and albumin 24 h before nephrectomy in donors were 9.4 mmol/L, 14 μg/mmol, 16 pmol/mmol, 99 pmol/mmol, 63 ng/mmol, 1390 ng/mmol and 0.7 mg/mmol, with median differences 24 h after nephrectomy of − 0.9, + 1906, − 7.1, − 38.3, − 6.9, + 2378 and + 1.2, respectively. The change of donor eGFR after 12 months per SD increment at baseline of B2M, TIMP-2, IGFBP7, KIM-1 and NGAL was: − 1.1, − 2.3, − 0.7, − 1.6 and − 2.8, respectively. Urinary TIMP-2 and IGFBP7 excretion halved after nephrectomy, similar to urinary creatinine, suggesting these markers predominantly reflect glomerular filtration. B2M and NGAL excretion increased significantly, similar to albumin, indicating decreased proximal tubular reabsorption following nephrectomy. KIM-1 did not change considerably after nephrectomy. Even though none of these biomarkers showed a strong relation with long-term donor eGFR, these results provide valuable insight into the pathophysiology of these urinary biomarkers.

Cell cycle arrest biomarkers for the early detection of acute allograft dysfunction and acute rejection in living donor kidney transplantation: a cross-sectional study from Egypt.

Urinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) are G1 cell arrest biomarkers that have demonstrated accuracy and validity in predicting and diagnosing acute kidney injury (AKI). This study aimed to evaluate the validity of [TIMP-2]×[IGFBP7] in diagnosing acute allograft dysfunction and its utility in distinguishing acute rejection (AR) from nonrejection causes in kidney transplantation. This study included 48 adult living donor kidney transplant recipients (KTRs; 18 with AR, 15 with nonrejection causes of AKI, and 15 with stable grafts). Urinary TIMP-2 and IGFBP7 were measured, and [TIMP-2]×[IGFBP7] was calculated in all subjects. IGFBP7, TIMP-2, and [TIMP-2]×[IGFBP7] were statistically significantly higher in KTRs with acute allograft dysfunction than in those with stable grafts. [TIMP-2]×[IGFBP7] was statistically significantly higher in KTRs with AR than in those with nonrejection AKI. [TIMP-2]×[IGFBP7] at a cutoff level of 0.278 (ng/mL)2/1,000 had an area under the curve (AUC) of 0.99 with a sensitivity of 100% and a specificity of 93.3% in diagnosing acute allograft dysfunction, while at a cutoff level of 0.803 (ng/mL)2/1,000 had an AUC of 0.939 with a sensitivity of 94.4% and a specificity of 83.3% in diagnosing AR. Besides its role in the early detection of acute allograft dysfunction, [TIMP-2]×[IGFBP7] may help to differentiate between AR and nonrejection causes in KTRs. However, whether and how urinary [TIMP-2]×[IGFBP7] can be used in clinical diagnosis still requires further research.

Urinary Insulin-Like Growth Factor-Binding Protein 7 (IGFBp7), Urinary Tissue Inhibitor of Matrix Metalloproteinase 2 (TIMP2), and Serum Transgelin as Novel Biomarkers of Kidney Injury in Multiple Myeloma.

Renal dysfunction is a common complication of MM and is associated with poor prognosis, particularly when progressive. Early identification of renal dysfunction is essential for prompt treatment for disease control and restoration of renal function. Urinary insulin-like growth factor-binding protein 7 (IGFBP-7), urinary tissue inhibitor of matrix metalloproteinase 2 (TIMP-2), and serum transgelin levels were measured using enzyme-linked immunosorbent assays and evaluated as biomarkers for the prediction of renal impairment in patients with multiple myeloma. U IGFBP-7/creatinine ratio, U TIMP2/creatinine ratio, and serum transgelin levels were higher in patients with MM than healthy controls, and predicted renal insufficiency in MM. Serum transgelin, urinary IGFBp7, and TIMP2 levels may have utility as biomarkers of renal tubular injury and predict future renal impairment in patients with MM.

Urinary cell cycle biomarkers for the prediction of renal non-recovery in patients with septic acute kidney injury: a prospective study.

Poor prognosis has been associated with the absence of renal recovery after acute kidney injury (AKI). This study aimed to investigate whether urinary biomarkers at 0 and 24h could be used independently or in conjunction with a clinical model to predict renal non-recovery in septic AKI. A prospective observational study was conducted to measure the urinary levels of insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinase-2 (TIMP-2) at the time of AKI diagnosis (0h) and 24h later. Renal non-recovery within 7 days was defined as the outcome. The predictive value of urinary biomarkers for renal non-recovery in septic AKI was assessed using the area under the curve (AUC). A total of 198 individuals with septic AKI were included in the final analysis. Among them, 38.9% (n = 77) did not experience renal recovery within 7 days. The combination of urinary IGFBP7 and TIMP-2 at the initial time point demonstrated prognostic value for non-recovery of renal function, with an AUC of 0.782. When [TIMP-2]*[IGFBP7] was measured at 0h, the clinical prognostic model, incorporating AKI stage 2-3 and the non-renal sequential organ failure assessment score, showed an improved AUC of 0.822 (with a sensitivity of 88.3% and specificity of 59.5%). The combination of urinary [TIMP-2]*[IGFBP7] at 0h exhibited moderate predictive ability for renal non-recovery in cases of septic AKI. However, there is potential to enhance the prognostic capabilities of the [TIMP-2]*[IGFBP7]-clinical prediction model.

Marathon running and cell-cycle arrest biomarkers of acute kidney injury.

Endurance exercise is known to cause a rise in serum creatinine. It is not known to what extent this rise reflects renal stress and a potential acute kidney injury (AKI). Increases in Insulin Like Growth Factor Binding Protein 7 (IGFBP7) and Tissue Inhibitor of Metalloprotinases-2 (TIMP-2), urinary biomarkers of cell cycle arrest and renal stress, are associated with the development of AKI in clinical populations. Repeated measures study. Runners were recruited at the 2019 Brighton Marathon (UK) and provided urine and blood samples at baseline, immediately post-race and 24 h post-race. Serum creatinine, urinary creatinine and urinary IGFBP7 and TIMP-2 were analysed from the samples. Seventy nine participants (23 females, 56 males), aged 43 ± 10 yrs. (mean ± SD), finish time 243 ± 40mins were included for analysis. Serum creatinine increased over the race by 40 ± 26% (p < 0.001), TIMP-2 increased by 555 ± 697% (p < 0.001) and IGFBP7 increased by 1094 ± 1491% (p < 0.001) over the race. A subset of twenty-two participants supplied samples 24 h post-race, reporting values similar to baseline for all variables. This study is the first to report large rises in IGFBP7 and TIMP-2 following marathon running. This suggests that rises in creatinine are not fully explained by changes in production and clearance and marathon running induces a state of kidney stress and potential injury.

Kidney injury molecule type-1, interleukin-18, and insulin-like growth factor binding protein 7 levels in urine to predict acute kidney injury in pediatric sepsis.

This study aimed to observe the role of urinary kidney injury molecule (KIM-1), interleukin (IL-18), and insulin-like growth factor-binding protein 7 (IGFBP-7) levels in predicting acute kidney injury (AKI) in children with sepsis. This prospective cohort observational study was conducted at Dr. RSUP. Wahidin Sudirohusodo, Makassar, South Sulawesi, from January to December 2021. Inclusion criteria were septic patients treated in the pediatric intensive care unit (PICU) aged 1 month to 18 years with normal serum creatinine or normal urine output (>5 ml/kg/body weight (BW)/h in 6-12 h). Patients with a history of kidney disease, prior urinary tract infection, or history of using nephrotoxic drugs were excluded. There was a significant difference in urinary KIM-1, IL-18, and IGFBP-7 levels between septic patients with and without AKI. The cut-off point for urinary KIM-1 level in sepsis with and without AKI was 1.666 ng/ml, with sensitivity of 82.5%, specificity of 82.2%, and a relative risk (RR) [95% confidence interval (CI)] of 6.866 (95% CI, 3.329-14.165). The cut-off point for urinary IL-18 levels was 3.868 ng/ml, with sensitivity of 92.50%, specificity of 91.78%, and RR of 20.078 (95%CI, 6.593-61.142). The cut-off point for urinary IGFBP-7 levels was ≥0.906 ng/ml with a sensitivity of 75.00%, specificity of 75.34%, and RR of 4.063 (95% CI, 2.206-7.483). Urinary KIM-1, IL-8, and IGFBP-7 levels could be used to predict AKI in septic patients. Urinary IL-8 has a higher sensitivity and specificity as a predictor of AKI in patients with sepsis.

Urinary Tissue Inhibitor of Metalloproteinase-2 and Insulin-Like Growth Factor-Binding Protein 7 Enhanced Risk Prediction for Initiation of Renal Replacement Therapy in Postoperative Patients with Acute Kidney Injury: A Prospective Cohort Study

Abstract Introduction: The current study is to identify the performance of urinary tissue inhibitors of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) for predicting renal replacement therapy (RRT) initiation and mortality in postoperative acute kidney injury (AKI) patients. Methods: Postoperative AKI patients were prospectively and consecutively enrolled. The biomarkers of urinary TIMP-2 and IGFBP7 were detected at the time AKI diagnosed (day 0) and 24 h later (day 1). The primary endpoint was the initiation of RRT, and the secondary endpoint was 30-day mortality. The receiver operating characteristic (ROC) curve was used to assess the performance of biomarkers for the prediction of RRT requirement. Results: There were 220 AKI patients enrolled in this study. Among the 220 patients, 33 (15.0%) initiated RRT during intensive care units period. Urinary (TIMP-2) × (IGFBP7), TIMP-2 and IGFBP7 on day 1 had fair performance for predict RRT initiation, the predictive area under the ROC curve (AUC) were 0.792 (0.732, 0.843), 0.784 (0.724, 0.837), and 0.770 (0.709, 0.824), respectively, with no significant difference. When they combined with clinically independent risk factors (nonrenal sequential organ failure assessment score, duration of surgery procedure, and serum creatinine at the time of AKI diagnosed) to construct predictive models for predicting RRT. The AUCs were greatly improved to be good. The best AUC was achieved by TIMP-2, which was 0.866 (0.814, 0.908). All of the biomarkers performed poor predictive values for predicting 30-day mortality. Conclusion: Urine concentrations of (TIMP-2) × (IGFBP7), TIMP-2 alone, and IGFBP7 alone on AKI day 1 show fair value for prediction of RRT initiation. However, they fail to predict 30-day mortality.

Urinary NGAL, IGFBP-7, and TIMP-2: novel biomarkers to predict contrast medium-induced acute kidney injury in children

Background Serum creatinine (SCr) is unreliable in detecting acute changes in kidney function. Early recognition of contrast-induced acute kidney injury (CI-AKI) can provide better opportunities for preventive interventions. Therefore, the purpose of this study is to examine the value of the combined detection of urinary neutrophil gelatinase-associated lipocalin (NGAL), insulin-like growth factor binding protein-7 (IGFBP-7), and tissue inhibitor of metalloproteinase-2 (TIMP-2) in the early diagnosis of children with CI-AKI. Methods A prospective, single-center clinical trial was performed and included 172 children aged 0–18 years. The dynamic changes of urinary NGAL, IGFBP-7, and TIMP-2 levels in children with intravascular injection of contrast medium were investigated to determine whether they can diagnose CI-AKI early. Results CI-AKI occurred in 20 of 137 enrolled patients, and the incidence was 14.59%. In the CI-AKI group, urinary levels of NGAL, IGFBP-7, TIMP-2, and [IGFBP-7]*[TIMP-2] were significantly increased 2 h after angiography and remained at high levels at 6 h. Using a cutoff value of 36.274 ng/mL, the specificity was 70.0%, and the sensitivity was 68.4% for the prediction of CI-AKI, which was excellent for urinary NGAL. When both urinary IGFBP-7 and TIMP-2 were used together, urinary [IGFBP-7]*[TIMP-2] at 0.417(ng/mL)2/1000 was regarded as the cutoff value. The specificity was 80.0%, and the sensitivity was 81.2%. Conclusions NGAL, IGFBP-7, and TIMP-2 concentrations in the urine of children after receiving injections of contrast medium increased faster than SCr and had good clinical value for the early diagnosis of CI-AKI in children. The combination of IGFBP-7 and TIMP-2 was better than either analyte alone.

Elevated Urinary Tissue Inhibitor of Metalloproteinase-2 and Insulin-Like Growth Factor Binding Protein-7 Predict Drug-Induced Acute Kidney Injury

Urinary tissue inhibitor of metalloproteinase-2 (TIMP2) and insulin-like growth factor binding protein-7 (IGFBP7) predict severe acute kidney injury (AKI) in critical illness. Earlier but subtle elevation of either biomarker from nephrotoxicity may predict drug-induced AKI. A prospective study involving serial urine collection in patients treated with vancomycin, aminoglycosides, amphotericin, foscarnet, or calcineurin inhibitors was performed. Urinary TIMP2 and IGFBP7, both absolute levels and those normalized with urine creatinine, were examined in days leading to AKI onset by KDIGO criteria in cases or at final day of nephrotoxic therapy in non-AKI controls, who were matched for age, baseline kidney function, and nephrotoxic exposure. Urinary biomarker analyses were performed in 21 AKI patients and 28 non-AKI matched-controls; both groups had comparable baseline kidney function and duration of nephrotoxic drug therapy. Significantly higher absolute, normalized, and composite levels of TIMP2 and IGFBP7 were observed in AKI cases versus controls as early as 2-3 days before AKI onset (all P<0.05); >70% of patients with corresponding levels above 75th percentile developed AKI. Normalized TIMP2 at 2-3 days pre-AKI predicted AKI with the highest average AUROC of 0.81, followed by that of composite [TIMP2]x[IGFBP7] (0.78) after cross-validation. [TIMP2]x[IGFBP7] >0.01 (ng/mL)2/1000 predicted AKI with a sensitivity of 79% and specificity of 60%. Elevated urinary TIMP2 or IGFBP7 predicts drug-induced AKI with a lead-time of 2-3 days; an opportune time for interventions to reduce nephrotoxicity.

Elevated Levels of Urinary Biomarkers TIMP-2 and IGFBP-7 Predict Acute Kidney Injury in Neonates after Congenital Heart Surgery.

Objectives This article investigated the utility of urine biomarkers tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein-7 (IGFBP-7) in identifying acute kidney injury (AKI) in neonates after congenital heart surgery (CHS). TIMP-2 and IGFBP-7 are cell cycle arrest proteins detected in urine during periods of kidney stress/injury. Methods We conducted a single-center, prospective study between September 2017 and May 2019 with neonates undergoing CHS requiring cardiopulmonary bypass (CPB). Urine samples were analyzed using NephroCheck prior to surgery and 6, 12, 24, and 96 hours post-CPB. All patients were evaluated using the Acute Kidney Injury Network (AKIN) criteria. Wilcoxon rank sum tests were used to compare the medians of the [TIMP-2*IGFBP-7] values in the AKIN negative and positive groups at each time point. Receiver operating characteristic curves were used to measure how well the [TIMP-2*IGFBP-7] values predict AKIN status. Results Thirty-six patients were included. No patients met the AKIN criteria for AKI preoperatively. Postoperatively, 19 patients (53%) met the AKIN criteria for AKI diagnosis: 13 (36%) stage 1, 5 (14%) stage 2, and 1 (3%) stage 3. None required renal replacement therapy. At the 24-hour time points, patients who met the AKIN criteria for AKI had a statistically significantly higher [TIMP-2*IGFBP7] values than the patients without AKI (1.1 vs. 0.27 [ng/mL] 2 /1,000) at 24 hours (adj- p = 0.0019). Conclusion AKI is a serious complication associated with adverse outcomes in patients undergoing cardiac surgery. [TIMP-2*IGFBP-7] urinary level 24 hours after CPB is a good predictor of AKI in this population.

Renal Impairment Detectors: IGFBP-7 and NGAL as Tubular Injury Markers in Multiple Myeloma Patients.

Background and Objectives: Urine insulin-like growth factor-binding protein 7 (IGFBP-7), tissue inhibitor of matrix metalloproteinase 2 (TIMP-2), and neutrophil gelatinase-associated lipocalin (NGAL) monomer are novel tubular kidney injury biomarkers. In multiple myeloma (MM), immunoglobulin free light chains (FLCs) play an integral role in renal impairment. This study aimed to investigate the correlation between new biomarkers and acclaimed parameters of renal failure, MM stage, and prognosis. Materials and Methods: The examined parameters included: urinary and serum cystatin-C, IGFBP-7, and TIMP-2, and urinary NGAL monomer in 124 enrolled patients. Results: Urinary and serum IGFBP-7 and urinary NGAL were higher among patients with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2, and positively correlated with urine light chains. Serum and urine IGFBP-7 and urine NGAL were greater among patients with a higher disease stage. In the whole study group, urinary concentrations of the studied markers were positively correlated with each other. In multiple linear regression, urinary IGFBP-7 and NGAL were associated with lower eGFR, independently of other urinary markers. Conclusions: Urinary IGFBP-7 and NGAL monomer may be useful markers of tubular renal damage in patients with MM. Biomarker-based diagnostics may contribute to earlier treatment that may improve renal outcomes and life expectancy in MM.

Tissue inhibitor metalloproteinase 2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) best predicts the development of acute kidney injury

BackgroundAcute kidney injury (AKI) is routinely diagnosed by creatinine-based guidelines, which is sub-optimal marker after injury due to renal and non-renal factors. This has necessitated the need for more specific and sensitive biomarkers for early detection of AKI in at risk patients. This prospective cross-sectional study used the biomarkers of cell cycle arrest and Neutrophil Gelatinase Associated Lipocalin (NGAL) to assess AKI among hospitalized patients. MethodsWe conveniently enrolled 151 in-patients at the Trauma and Specialist Hospital, Winneba in Ghana. Socio-demographic and clinical information were collected using structured questionnaires. Blood samples were collected for the estimation of serum creatinine, and AKI diagnosed and staged using the KDIGO guideline. Fresh urine samples were collected and urinary NGAL, TIMP-2 (tissue inhibitor metalloproteinase 2) and IGFBP-7 (insulin-like growth factor binding protein 7) were estimated using ELISA kits. ResultsThe cell cycle arrest biomarkers and NGAL were significantly (P < 0.001) higher among participants with AKI than those without AKI. [TIMP-2]∗[IGFBP-7] showed the best diagnostic performance (AUC = 0.94, CI = 0.90–0.98) followed by [IGFBP-7]∗NGAL] (AUC = 0.93, CI = 0.87–0.99), with NGAL having the least (AUC = 0.62, CI = 0.46–0.78). The cut-off for [TIMP-2]∗[IGFBP-7] showed the best predictive ability (95.8% sensitivity, 77.2% specificity, 44.2% PPV and 99% NPV). The cut-off for NGAL, on the other hand, showed the least predictive ability (62.5% sensitivity, 42.5% specificity, 17.0% PPV and 85.7% NPV). ConclusionTissue inhibitor metalloproteinase 2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP7) best predicts the development of AKI, and can be used in high risk patients for early diagnosis of AKI.

The Association between Urinary Tissue Inhibitor Metalloproteinase 2 (TIMP-2) and Insulin-like Growth Factor Binding Protein 7 (IGFBP-7) and Renal Recovery in Acute Kidney Injury

Background. Acute kidney injury (AKI) is a common and serious medical condition associated with significant increases in morbidity, mortality, cost of care and non recovery of kidney function that leads to progression to chronic kidney disease. Cell cycle arrest is implicated in the pathogenesis and repair process following AKI. The urinary cell-cycle arrest markers tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor binding protein 7 (IGFBP-7) have been utilized to predict the risk of AKI in many studies from specific population with good performance. However, their use in predicting recovery is still lacking. The aim of this study was to determine the association between two novel AKI biomarkers, urinary TIMP2 and IGFBP7 and renal recovery after 7 days of treatment in AKI patients at Dr. Mohammad Hoesin Hospital Palembang.&#x0D; Method. This was a prospective cohort study conducted in dr. Mohammad Hoesin Hospital Palembang from January 2021 until March 2021. Subjects enrolled in this study were patients whom diagnosed AKI based on KDIGO 2012 criteria. Urine samples were collected upon patients’ enrollment within 24 hours of AKI diagnosis. We utilized Sandwich Enzyme Linked Immunosorbant Assay (ELISA) method to detect urinary TIMP-2 and IGFBP-7 levels. The primary outcome is recovery from AKI after 7 days of treatment. Chi square test is used to analyze the association between urinary TIMP-2 and IGFBP-7 levels and renal recovery.&#x0D; Results. There were 70 subjects, only 22 of them were recovered after 7 days (31%). Median of urinary TIMP-2 and IGFBP-7 was 0,0047(0,0001-0,1439) [(ng/ml)2/1000]. There was significant association between urinary TIMP2 and IGFBP7 and renal recovery (p=0,027; OR 3,19; 95% CI 1,116-9,128).&#x0D; Conclusion. There was significant association between urinary TIMP2 and IGFBP7 and renal recovery in AKI patients.

The predictive value of TIMP-2 and IGFBP7 for kidney failure and 30-day mortality after elective cardiac surgery

Acute kidney injury (AKI) is an important risk factor for chronic kidney disease, renal replacement therapy (RRT), and mortality. However, predicting AKI with currently available markers remains problematic. We assessed the predictive value of urinary tissue inhibitor of metalloprotease-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) regarding the need for RRT, and 30-day mortality, in elective cardiac surgery patients. In 344 elective cardiac surgery patients, we measured urinary TIMP-2 and IGFBP7 and serum creatinine at baseline and directly after surgery. Discrimination of both urinary biomarkers was assessed by the C-statistic. Model improvement for each biomarker when added to a basic model containing serum creatinine and duration of surgery was tested by the net-reclassification index (cf-NRI) and integrated discrimination index (IDI). At baseline, mean age was 66 years and 67% were men. Of all patients, 22 required RRT following surgery. IGFBP7 pre- and post-surgery and change in TIMP-2 during surgery predicted RRT with a C-statistic of about 0.80. However, a simple model including baseline serum creatinine and duration of surgery had a C-statistic of 0.92, which was improved to 0.93 upon addition of post-surgery TIMP-2 or IGFBP7, with statistically significant cf-NRIs but non-significant IDIs. Post-surgery TIMP-2 and IGFBP predicted 30-day mortality, with C-statistics of 0.74 and 0.80. In conclusion, in elective cardiac surgery patients, pre- and peri-operative clinical variables were highly discriminating about which patients required RRT after surgery. Nonetheless, in elective cardiac surgery patients, urinary TIMP-2 and IGFBP7 improved prediction of RRT and 30-day mortality post-surgery.

Application value of urinary IGFBP7 and TIMP-2 in acute kidney injury with decompensated hepatitis B virus-related liver cirrhosis

Objective: To investigate the application value of new urinary biomarkers insulin-like growth factor binding protein 7 (IGFBP7) and tissue matrix metalloproteinase inhibitor-2 (TIMP-2) in acute kidney injury with decompensated hepatitis B virus-related liver cirrhosis. Methods: 45 newly hospitalized cases with decompensated hepatitis B virus-related liver cirrhosis were selected. Among them, 19 cases were combined with AKI on admission (cirrhosis-AKI group), 26 cases without AKI (cirrhosis-non-AKI group), and 12 healthy cases (normal control group). First-morning urine samples were collected and IGFBP7 and TIMP-2 were detected by enzyme-linked immunosorbent assay (ELISA). Urinary IGFBP7 and serum creatinine (SCr) were dynamically monitored after hospitalization in cirrhosis-non-AKI group. Normally distributed measurement data were compared by t-test, and non-normally distributed measurement data were compared by rank sum test. The receiver operating characteristic (ROC) curve and area under the curve (AUC) were used to evaluate the diagnostic accuracy of the indicators. Results: Urinary IGFBP7, IGFBP7 with TIMP-2 (IGFBP7×TIMP-2) in cirrhosis-AKI group (n = 19) were equally higher than that of the cirrhosis-non-AKI group (P < 0.05). Urinary IGFBP7, TIMP-2 and IGFBP7×TIMP-2 in cirrhosis-AKI group or cirrhosis-non-AKI group were significantly higher than those of the normal control group (P < 0.01). The AUC of urinary IGFBP7 and urinary IGFBP7×TIMP-2 for diagnosis of AKI were 0.703 (95% CI 0.547-0.860) and 0.700 (95% CI 0.541-0.859), respectively. In the liver cirrhosis-non-AKI group (n = 26), 5 cases of AKI were newly diagnosed according to the changes in SCr during hospitalization (progressive group). Urinary IGFBP7 was significantly increased 2 days before the diagnosis of AKI. The concentration of urinary IGFBP7 at admission in the progressive group (n = 5) was higher than that of the non-progressive group (n = 21) (P < 0.05). Conclusion: Urinary IGFBP7 and TIMP-2 concentrations were significantly increased in patients with decompensated hepatitis B virus-related liver cirrhosis. When AKI occurred, urinary IGFBP7 and IGFBP7×TIMP-2 was further increased. Urinary IGFBP7 is valuable for early AKI diagnosis, and may play a role in predicting AKI occurrence.

Increase of urinary TIMP-2 and IGFBP7 as potential predictor of acute kidney injury requiring renal replacement therapy and patients' outcome following complex endovascular and open thoracic abdominal aortic aneurysm surgery - a prospective observational study.

Background: Acute kidney injury (AKI) as complication after open and endovascular repair of thoracoabdominal aortic aneurysm (TAAA) is one major predictor of mortality and postoperative complications. We evaluated tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) as combined early biomarker for AKI detection and predictor of patients' outcome. Patients and methods: Between 2014 and 2015, 52 patients have been enrolled in this observational study, of whom 29 (55.8%) underwent elective open repair and 23 (44.2%) endovascular repair. TIMP2×IGFBP7 were measured until 48 hours after admission on intensive-care unit (ICU) and were analyzed regarding their predictive ability for AKI (defined according to the KDIGO criteria) requiring temporary renal replacement therapy (RRT) and 90-day mortality using ROC curves. Results: Mean patient age was 64.5 years (Min: 43, Max: 85), endovascular treated patients were older (p <0.0001). 40.4% (n = 21) developed AKI, and 21.2% (n = 11) required renal replacement therapy. In-hospital and total mortality rates were 7.7% (n = 4) and 9.6% (n = 5), respectively. At no time a significant difference in TIMP2×IGFB7 levels between patients undergoing open or endovascular surgery was observed. The predictive quality of the TIMP2×IGFBP7 value on ICU admission was sound regarding AKI requiring temporary renal replacement therapy (sensitivity: 55.56% [38.1-72.1%], specificity: 90.91% [58.7-99.8%] with an area under the curve [AUC]: 0.694 [0.543-0.820]). Mean follow-up was 13.2 months (Min: 2, Max: 20), regarding the 90-day mortality, the predictive property of the TIMP2×IGFBP7 value was not sufficient (sensitivity: 80% [28.4-99.5%], specificity: 52.38% [36.4-68%], and AUC: 0.607 [0.454-0.746]). Conclusions: TIMP2×IGFBP7 level measured 6-12 hrs postoperatively may be useful as an early detectable biomarker for AKI requiring temporary renal replacement therapy. It seems not suited to predict patients' outcome following complex thoracoabdominal aortic surgery, regardless if performed by open or endovascular repair.

Serial Measurement of Cell-Cycle Arrest Biomarkers [TIMP-2] · [IGFBP7] and Risk for Progression to Death, Dialysis, or Severe Acute Kidney Injury in Patients with Septic Shock

Rationale: Urinary TIMP-2 (tissue inhibitor of metalloproteinases-2) and IGFBP7 (insulin-like growth factor-binding protein 7) can predict acute kidney injury (AKI) in patients with sepsis.Objectives: To address critical questions about whether biomarkers can inform the response to treatment and whether they might be used to guide therapy, as most sepsis patients present with AKI.Methods: We measured [TIMP-2] · [IGFBP7] before and after a 6-hour resuscitation in 688 patients with septic shock enrolled in the ProCESS (Protocol-based Care for Early Septic Shock) trial. Our primary endpoint was stage 3 AKI, renal replacement therapy, or death within 7 days.Measurements and Main Results: The endpoint was reached in 113 patients (16.4%). In patients with negative [TIMP-2] · [IGFBP7] at baseline, those who became positive (>0.3 U) after resuscitation had three-times higher risk compared with those who remained negative (21.8% vs. 8.5%; P = 0.01; odds ratio [OR], 3.0; 95% confidence interval [CI], 1.31-6.87). Conversely, compared with patients with a positive biomarker at baseline that were still positive at Hour 6, risk was reduced for patients who became negative (23.8% vs. 9.8%; P = 0.01; OR, 2.15; 95% CI, 1.17-3.95). A positive [TIMP-2] · [IGFBP7] after resuscitation was associated with worse outcomes in both patients with and without AKI at that time point. The clinical response to resuscitation, as judged by the Acute Physiology and Chronic Health Evaluation II score, was weakly predictive of the endpoint (area under the curve, 0.68; 95% CI, 0.62-0.73) and improved with addition of [TIMP-2] · [IGFBP7] (0.72; 95% CI, 0.66-0.77; P = 0.03). Different resuscitation protocols did not alter biomarker trajectories, nor did they alter outcomes in biomarker-positive or biomarker-negative patients. However, biomarker trajectories were associated with outcomes.Conclusions: Changes in urinary [TIMP-2] · [IGFBP7] after initial fluid resuscitation identify patients with sepsis who have differing risk for progression of AKI.Clinical trial registered with www.clinicaltrials.gov (NCT00510835).

Urinary tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7 as biomarkers of patients with established acute kidney injury.

Background/AimsUrinary tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) have been recently discovered and validated as sensitive biomarkers that can predict stage 2 or 3 acute kidney injury (AKI) development in high-risk patients. We aimed to assess whether these biomarkers could predict adverse outcomes and renal recovery in established AKI patients.MethodsThis was a single-center study prospectively enrolling 124 patients diagnosed with AKI. TIMP-2, IGFBP7, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule 1 (KIM-1) levels were measured at the time of diagnosis and the predictive performance of short-term outcomes and renal recovery was assessed.ResultsPatients were divided into 4 quartiles according to the initial urinary TIMP-2/IGFBP7 levels. Stage 3 AKI (odds ratio [OR], 17.86), classified by the Kidney Disease Improving Global Outcomes (KDIGO), as well as the third and fourth quartiles of TIMP-2/IGFBP7 (OR, 5.75 and 44.98, respectively), were found to be independent predictors of renal replacement therapy at the time of AKI diagnosis. In addition, KDIGO stage 3 AKI (OR, 2.468) or the third of fourth quartiles of urinary TIMP-2/IGFBP7 (OR, 1.896 and 3.622, respectively) were also found to be useful in predicting nonrecovery of renal function. In a separate analysis of patients with renal recovery at discharge, initial urinary TIMP-2/IGFBP7 or urinary IGFBP7 at discharge could also predict new-onset or progressive chronic kidney disease (CKD).ConclusionsIn AKI patients, urine TIMP-2/IGFBP7 could serve as a biomarker for predicting adverse outcomes, renal recovery, or the development and progression of CKD.

The effectiveness of urinary TIMP-2 and IGFBP-7 in predicting acute kidney injury in critically ill neonates.

Urinary tissue inhibitor of metalloproteinase-2 (TIMP-2), insulin-like growth factor binding protein-7 (IGFBP-7) and the combination of TIMP-2 and IGFBP-7 ([TIMP-2]•[IGFBP7]) are proposed to be predictive biomarkers for acute kidney injury (AKI). The intention of our study was to determine whether there is any significant predictive value of these biomarkers for the occurrence of AKI and severe AKI in critically ill neonates. Urinary samples were serially collected in 237 neonates during neonatal intensive care unit (NICU) stay for measurements of TIMP-2 and IGFBP-7 in this prospective study. AKI diagnosis was based on KDIGO classification without urine output or serum creatinine >1.2 mg/dL. Twenty neonates developed AKI, including 11 with KDIGO stage 1, defined as mild AKI, and 9 with stages 2 and 3, defined as severe AKI. Urinary IGFBP-7 and [TIMP-2]•[IGFBP7] remained associated with AKI after adjustment for gestational age, gender and illness severity. Urinary [TIMP-2]•[IGFBP7] achieved an AUC of 0.71 (P = 0.034) and displayed a sensitivity of 88.9% and a specificity of 50.9% for discriminating severe AKI at the optimal cut-off value of 0.045. The combination of TIMP-2 and IGFBP-7 had independent discriminative value for severe AKI in critically ill neonates.