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

The predictive value of asymmetric dimethylaginine for the renal outcome after radiocontrast exposure - a prospective clinical study

Einleitung: Asymmetrisches Dimethylarginin (ADMA) ist ein kompetitiver Inhibitor der Stickstoffmonoxid-Synthase und ein wichtiger Faktor in der Gefäßregulation. Es wird durch posttranslationale Modifikation von Proteinen gebildet und durch Proteolyse im Körper freigesetzt. In der Literatur wurde beschrieben, dass Patienten mit chronischer Niereninsuffizienz oder Dialysepflichtigkeit erhöhte ADMA-Spiegel aufweisen. Iodierte Kontrastmittel können die Funktion der Niere schwer beeinträchtigen und zu einem terminalen Insuffizienzstadium führen. Besonders renal vorgeschädigte Patienten haben hierfür ein hohes Risiko. Aufgrund der stetig steigenden Anzahl an Kontrastmitteluntersuchungen wird das Verlangen nach einem Prognosemarker bei Kontrastmittelgabe größer. Da die Beteiligung des ADMA-NO-Systems bei der Pathogenese einer kontrastmittelinduzierten Nephropathie möglich ist, soll in dieser Arbeit das Verhalten und die Aussagekraft des ADMA bei Kontrastmittelgabe in Bezug auf renale Ereignisse untersucht werden. Methoden: Zu diesem Zweck wurde eine prospektiven Studie mit 330 Patienten, die einen Diabetes mellitus oder eine eingeschränkte Nierenfunktion vorwiesen und Kontrastmittel appliziert bekamen, durchgeführt. Dabei wurde den Patienten sowohl vor als auch 24 Stunden nach Kontrastmittelgabe Blut abgenommen und Kreatinin, Cystatin c und ADMA bestimmt. Um den Verlauf zu dokumentieren wurde Kreatinin zusätzlich nach 48 Stunden und bei einem Follow up nach 3 Monaten bestimmt. Beim Follow up wurden zusätzlich klinisch relevante Ereignisse seit Aufnahme in die Studie abgefragt. Ergebnisse: In der Auswertung zeigte sich, dass die ADMA-Spiegel nach Kontrastmittelgabe stiegen. Jedoch konnte kein Zusammenhang zwischen dem ADMA und dem Auftreten eines akuten Nierenversagens gesehen werden. Für das langfristige Outcome zeigten sich die ADMA-Spiegel vor und nach Kontrastmittelgabe prädiktiv für Dialysen und als „major adverse renal event“ (MARE) zusammengefasste renale Ereignisse. Zudem zeigten Patienten mit MARE einen signifikant höheren Anstieg des ADMA nach Kontrastmittelgabe. Diabetes mellitus, Anämie, Herzinsuffizienz und die Wässerung von Patienten stellten sich dabei als wichtige Einflussfaktoren bei der Beurteilung des ADMA bei Kontrastmittelgabe heraus. Konklusion: In der Zusammenschau kommt man zu dem Schluss, dass die ADMA-Regulation durch die Kontrastmittelgabe beeinflusst wird. Patienten mit einem ungünstigeren Outcome unterscheiden sich dabei durch einen höheren Anstieg des ADMA von Patienten mit besserem Outcome, wobei die kurzfristige renale Prognose scheinbar weniger durch das ADMA angezeigt wird.Introduction: Asymmetric dimethylarginine is a competitive inhibitor of the NO-sythase and an important factor of the regulations of vessels. It is synthesized through posttranslational modification of proteins and released by proteolyses into circulation. In literature patients with chronic kidney disease or dialysis had higher ADMA levels. Iodonated radiocontrast media can heavily damage the kidney, which can lead to a complete loss of kidney function. Especially patients with predamaged kidneys have a higher risk. Because of the rising usage of radiocontrast media, the importance of identification of biomarkers for the prognosis after application rises as well. The ADMA-NO-System might be taking part in the pathogenesis of a contrast induced nephropathy. So this work examines the behavior and the force of expression of ADMA to renal events. Methods: Therefore 330 patients with preexisting diabetes mellitus or renal impairment, who were undergoing a percutanous coronary angiography, were included and the levels of ADMA, creatinine and cystatin c before and 24 hours after contrast media application were measured. To determine the development creatinine was also measured 48 hours and tree months after the application. At three month follow up data about clinical relevant events were collected, too. Results: As result ADMA rises after contrast media application. But there was no relationship between ADMA and the incidence of an acute renal failure. For longer prognosis ADMA levels before and after contrast media application were predictive for dialysis and major adverse renal events (MARE). Additional patients with MARE had a significant higher increase of the ADMA levels than other patients. Diabetes mellitus, anemia, congestive heart failure and the hydration of patients emerged as important influencing factors in the assessment of ADMA. Conclusion: In conclusion the ADMA-regulation is influenced by contrast media. Patients with poorer prognosis demonstrated a different behavior by a higher increase of ADMA. For the short term outcome ADMA seems to be less relevant

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