Pre-Interventional Kynurenine Predicts Medium-Term Outcome after Contrast Media Exposure Due to Coronary Angiography

Background/Aims: Contrast induced acute kidney injury (CI-AKI) remains a serious complication of contrast media enhanced procedures like coronary angiography. There is still a lack of established biomarkers that help to identify patients at high risk for short and long-term complications. The aim of the current study was to evaluate plasma kynurenine as a predictive biomarker for CI-AKI and long-term complications, measured by the combined endpoint "major adverse kidney events" (MAKE) up to 120 days after CM application. Methods: In this prospective cohort study 245 patients undergoing coronary angiography were analyzed. Blood samples were obtained at baseline, 24h and 48h after contrast media (CM) application to diagnose CI-AKI. Patients were followed for 120 days for adverse clinical events including death, the need for dialysis, and a doubling of plasma creatinine. Occurrence of any of these events was summarized in the combined endpoint MAKE. Results: Preinterventional plasma kynurenine was not associated with CI-AKI. Patients who later developed MAKE displayed significantly increased preinterventional plasma kynurenine levels (p<0.0001). ROC analysis revealed that preinterventional kynurenine is highly predictive for MAKE (AUC=0.838; p<0.0001). The optimal cutoff was found at ≥3.5 µmol/L Using this cutoff, the Kaplan-Meier estimator demonstrated that concentrations of plasma kynurenine ≥3.5 µmol/L were significantly associated with a higher prevalence of MAKE until follow up (p<0.0001). This association remained significant in multivariate Cox regression models adjusted for relevant factors of long-term renal outcome. Conclusion: Preinterventional plasma kynurenine might serve as a highly predictive biomarker for MAKE up to 120 days after coronary angiography

Urinary Vitamin D Binding Protein and KIM-1 Are Potent New Biomarkers of Major Adverse Renal Events in Patients Undergoing Coronary Angiography

Background Vitamin-D-binding protein (VDBP) is a low molecular weight protein that is filtered through the glomerulus as a 25-(OH) vitamin D 3/VDBP complex. In the normal kidney VDBP is reabsorbed and catabolized by proximal tubule epithelial cells reducing the urinary excretion to trace amounts. Acute tubular injury is expected to result in urinary VDBP loss. The purpose of our study was to explore the potential role of urinary VDBP as a biomarker of an acute renal damage. Method We included 314 patients with diabetes mellitus or mild renal impairment undergoing coronary angiography and collected blood and urine before and 24 hours after the CM application. Patients were followed for 90 days for the composite endpoint major adverse renal events (MARE: need for dialysis, doubling of serum creatinine after 90 days, unplanned emergency rehospitalization or death). Results Increased urine VDBP concentration 24 hours after contrast media exposure was predictive for dialysis need (no dialysis: 113.06 ± 299.61ng/ml, n = 303; need for dialysis: 613.07 ± 700.45 ng/ml, n = 11, Mean ± SD, p<0.001), death (no death during follow-up: 121.41 ± 324.45 ng/ml, n = 306; death during follow-up: 522.01 ± 521.86 ng/ml, n = 8; Mean ± SD, p<0.003) and MARE (no MARE: 112.08 ± 302.00ng/ml, n = 298; MARE: 506.16 ± 624.61 ng/ml, n = 16, Mean ± SD, p<0.001) during the follow-up of 90 days after contrast media exposure. Correction of urine VDBP concentrations for creatinine excretion confirmed its predictive value and was consistent with increased levels of urinary Kidney Injury Molecule-1 (KIM-1) and baseline plasma creatinine in patients with above mentioned complications. The impact of urinary VDBP and KIM-1 on MARE was independent of known CIN risk factors such as anemia, preexisting renal failure, preexisting heart failure, and diabetes. Conclusions Urinary VDBP is a promising novel biomarker of major contrast induced nephropathy-associated events 90 days after contrast media exposure

a prospective clinical trial

Hintergrund: Kontrastmittelgestützte Untersuchungsverfahren finden in steigender Zahl Anwendung. Kontrastmittelinduziertes Nierenversagen (CIN) ist dabei eine unerwünschte Wirkung. Risikofaktoren hierfür sind, z.B. hohes Alter, Diabetes mellitus, Herz- oder Niereninsuffizienz. Diese Risiken nehmen aufgrund des demographischen Wandels zu. Die CIN ist mit einem schlechteren Kurz- und Langzeit-Outcome der betroffenen Patienten verbunden. Die gängige Definition der CIN basiert auf der Messung des Serum-Kreatinin, durch die das Nierenversagen jedoch erst 24-72h nach Kontrastmittelgabe angezeigt wird. Angesichts der sehr kurzen mittleren Krankenhausverweildauer von Patienten, stellt sich die Frage nach einem Biomarker, der eine CIN früher diagnostiziert. S100a12 und Calprotectin sind S100-Proteine, die in hoher Konzentration in aktivierten Granulozyten vorkommen, aber auch im Gewebe induzierbar sind. Sie gehören zu den „Damage-associated molecular pattern proteins“ (DAMP). Intrazellulär erfüllen sie Aufgaben der Zellhomöostase. Bei einem Zellschaden werden sie jedoch frei und verursachen die Aktivierung und Aufrechterhaltung einer Immunantwort. Ziel dieser Arbeit ist, Calprotectin und S100a12 im Urin als Biomarker für eine CIN zu untersuchen. Zusätzlich wird ein Zusammenhang mit dem Outcome der Patienten drei Monate nach Kontrastmittelgabe anhand sekundärer Endpunkte betrachtet. Methode: Basis dieser Arbeit ist eine prospektive Studie an 314 Patienten mit erhöhtem Risiko für eine CIN. Alle Patienten erhielten eine elektive Herzkatheteruntersuchung. Aus Urinproben vor und 24h nach KM wurde S100a12 und Calprotectin bestimmt. Gleichzeitig erfolgte eine Serum-Kreatininmessung. Zusätzlich wurde Kreatinin nach 48h bestimmt. Drei Monate nach Kontrastmittelgabe wurden die Probanden in einer Follow-up- Untersuchung auf die Endpunkte: „Verdopplung des Serumkreatinins“, „Dialyse“, „weitere Krankenhausaufenthalte“ und „Tod“ hin untersucht und erhielten eine weitere Serum-Kreatininmessung. Ergebnisse: 21 (7,4%) von 283 Patienten der Studienkohorte erlitten eine CIN. Die Analyse der Biomarker zeigte, dass CIN- Patienten 24h nach Kontrastmittelgabe signifikant höhere S100a12-Werte haben, als Patienten ohne CIN. Bei der Auswertung hinsichtlich der Calprotectin- Konzentration ergaben sich bei Patienten mit CIN nicht signifikant höhere Konzentrationen vor und 24h nach Kontrastmittelgabe. Patienten, die zum Zeitpunkt der Follow-up-Untersuchung einen Endpunkt erreicht hatten, wiesen jeweils vor und 24h nach Kontrastmittelgabe höhere S100a12- und Calprotectin- Konzentrationen auf, als Patienten, die keinen der beschriebenen Endpunkte erreichten. Dies erwies sich jedoch als nicht signifikant. Ein weiteres Ergebnis ist ein hoch signifikanter Unterschied der S100a12- und Calprotectin- Konzentrationen vor und 24h nach KM in Abhängigkeit vom Geschlecht. Die weiblichen Patienten wiesen hierbei höhere Werte auf als die männlichen. Schlussfolgerung: S100a12 eignet sich potentiell als Biomarker für die Diagnostik der CIN. Calprotectin erscheint in diesem Zusammenhang ungeeignet. Es sollten ergänzende Studien durchgeführt werden, um dies zu bestätigen. Im Bezug auf das Outcome der Patienten anhand der sekundären Endpunkte ergaben sich für S100a12 und Calprotectin keine signifikanten Ergebnisse.Background: There are a rising number of patients undergoing radiocontrast media-enhanced examinations. Contrast media-induced kidney injury (CIN) is a side effect of the radiocontrast agent. Due to demographic changes, the incidence of risk factors for CIN-, such as advanced age, diabetes mellitus and cardiac or renal failure will increase. CIN is associated with worse short-and long-term outcomes. Today's common definition of CIN is based on measurement of the serum creatinine, which only indicates renal failure 24-72hrs after administration of radiocontrast media. It is necessary to find an earlier biomarker to indicate CIN. S100a12 and calprotectin are proteins that occur in high concentrations in activated granulocytes and can be induced in tissue. They belong to the "Damage-associated molecular pattern proteins" (DAMP) and fulfill the duties of intracellular homeostasis. During tissue or cell damage they are responsible for the activation and amplification of an immune response. The goal of this paper is to examine calprotectin and S100a12 in urine as a biomarker for CIN. Additionally, calprotectin and S100a12 are analyzed regarding the outcome based on specific endpoints three months after the administration of the contrast medium. Methods: We performed a prospective study on 314 patients with an increased risk for CIN undergoing percutaneous coronary angiography. Urine samples before and 24h after contrast media application were collected. S100a12 and calprotectin were measured. At the same time, creatinine samples were taken from the blood. Three months after administration of the contrast medium, data regarding the endpoints: "doubling of serum creatinine", "dialysis", "non-elective hospitalizations" and "death" were collected and another blood sample for creatinine measurement taken. Results: 21 (7,4%) out of 283 patients developed CIN. The results show that patients who developed CIN had significantly higher S100a12-levels than patients without CIN, 24hrs after administration of contrast medium. The calprotectin-level was not significantly higher before and 24hrs after contrast administration in patients with CIN. The patients who reached an endpoint, had higher S100a12- and calprotectin-levels before and 24hrs after contrast administration, compared to patients who did not reach an endpoint. However, this difference proved to be statistically insignificant. There is also strong evidence for a gender-dependent difference of S100a12- and calprotectin-levels before and 24hrs after contrast administration, with women having higher levels. Conclusion: S100a12 has the potential to be a promising biomarker detecting CIN. Calprotectin is as a biomarker rather unsuitable in this context. It is necessary to carry out further studies to confirm this. In terms of patient outcome on the basis of secondary endpoints no significant results for S100A12 and calprotectin were found

Urinary cGMP predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus before exposure to contrast medium.

The use of iodine-based contrast agents entails the risk of contrast induced nephropathy (CIN). Radiocontrast agents elicit the third most common cause of nephropathy among hospitalized patients, accounting for 11-12% of cases. CIN is connected with clinically significant consequences, including increased morbidity, prolonged hospitalization, increased risk of complications, potential need for dialysis, and increased mortality rate. The number of in-hospital examinations using iodine-based contrast media has been significantly increasing over the last decade. In order to protect patients from possible complications of such examinations, new biomarkers are needed that are able to predict a risk of contrast-induced nephropathy. Urinary and plasma cyclic guanosine monophosphate (cGMP) concentrations are influenced by renal function. Urinary cGMP is primarily of renal cellular origin. Therefore, we assessed if urinary cGMP concentration may predict major adverse renal events (MARE) after contrast media exposure during coronary angiography.Urine samples were prospectively collected from non-randomized consecutive patients with either diabetes or preexisting impaired kidney function receiving intra-arterial contrast medium (CM) for emergent or elective coronary angiography at the Charité Campus Mitte, University Hospital Berlin. Urinary cGMP concentration in spot urine was analyzed 24 hours after CM exposure. Patients were followed up over 90 days for occurrence of death, initiation of dialysis, doubling of plasma creatinine concentration or MARE.In total, 289 consecutive patients were included into the study. Urine cGMP/creatinine ratio 24 hours before CM exposure expressed as mean±SD was predictive for the need of dialysis (no dialysis: 89.77±92.85 μM/mM, n = 277; need for dialysis: 140.3±82.90 μM/mM, n = 12, p = 0.008), death (no death during follow-up: 90.60±92.50 μM/mM, n = 280; death during follow-up: 169.88±81.52 μM/mM, n = 9; p = 0.002), and the composite endpoint MARE (no MARE: 86.02±93.17 μM/mM, n = 271; MARE: 146.64±74.68 μM/mM, n = 18, p<0.001) during the follow-up of 90 days after contrast media application. cGMP/creatinine ratio stayed significantly increased at values exceeding 120 μM/mM in patients who developed MARE, required dialysis or died.Urinary cGMP/creatinine ratio ≥ 120 μM/mM before CM exposure is a promising biomarker for the need of dialysis and all-cause mortality 90 days after CM exposure in patients with preexisting renal impairment or diabetes

Model of megalin function in renal uptake and activation of 25-(OH) Vitamin D3. [11]

<p>Model of megalin function in renal uptake and activation of 25-(OH) Vitamin D3. [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0145723#pone.0145723.ref011" target="_blank">11</a>]</p

Course of the study.

<p>Course of the study.</p

Urinary cGMP predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus before exposure to contrast medium - Fig 3

<p><b>Distribution of urinary cGMP/creatinine ratios (μM/mM) before 24 hours after and 48h after contrast media application detected in patients without (No) or with (Yes) following adverse events: death(a), dialysis (b) or MARE (c).</b><i>cGMP</i>: <i>urinary cyclic guanosine monophosphate</i>, <i>MARE</i>: <i>major adverse renal event</i>, <i>*** p<0</i>.<i>001</i>, <i>** p<0</i>.<i>01</i>, <i>* p<0</i>.<i>05</i>.</p

Multivariate logistic regression analysis for predictors of MARE.

<p>Multivariate logistic regression analysis for predictors of MARE.</p