1 Department of Diagnostic Radiology and 2 Department of Nephrology and Rheumatology, Heinrich-Heine-University, Düsseldorf, Germany
Correspondence and offprint requests to: Jens-Albrecht Koch, MD, Department of Diagnostic Radiology, Heinrich-Heine-University, Moorenstraße 5, D-40225 Düsseldorf, Germany.
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Abstract |
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Methods. 130 patients with renal impairment (serum creatinine 1.5 mg/dl) were included in the study prior to intravascular RCM injection. The patients received one of three different doses of PGE1 (10, 20, or 40 ng/kg bodyweight/min) or placebo (physiologic sodium chloride solution) intravenously over a time period of 6 h (beginning 1 h prior to RCM application). Serum creatinine was measured 12, 24, and 48 h post RCM-application and creatinine clearance was determined with two 12 h collection periods, as well as one 24 h collection within 48 h post RCM administration. Adverse events during PGE1 administration were recorded.
Results. In the placebo group, the mean elevation of serum creatinine was markedly higher (0.72 mg/dl) 48 h after RCM administration compared with the three PGE1 groups (0.3 mg/dl in the 10 ng/kg/min group, 0.12 mg in the 20 ng/kg/min group, and 0.29 mg/dl in the 40 ng/kg/min group). No clinically relevant changes were seen regarding the creatinine clearance in the four groups examined.
Conclusions. Results from this pilot-study suggest that intravenous PGE1 may be used efficaciously and safely to prevent RCM-induced renal dysfunction in patients with pre-existing impaired renal function.
Keywords: contrast media; renal function; prostaglandin E1
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Introduction |
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One of the changes by which ARF clinically manifests itself is an elevation of serum-creatinine levels usually within 25 days post-RCM administration. In most cases, this elevation is reversible, at least among patients with initially normal renal function. The incidence of the need for dialysis after RCM application is approximately 1.4% [5]. However, in a retrospective study, Levy and co-workers showed that even moderate elevations of serum-creatinine levels (>25% of initial levels) were associated with longer hospitalization time and higher mortality rates [6].
Among causes discussed for RCM-induced renal deterioration are damages resulting from ischemia due to vasoconstrictive effects and direct toxic effects on renal tubular cells [7,8]. Animal experiments show that renal vasoconstriction in vivo results in a high production of prostaglandin E2 and that prostaglandins and endothelin have vasodilatory and vasoconstrictive effects, respectively [9]. Moreover, one group demonstrated that prostaglandin E1 (PGE1) and prostaglandin E2 (PGE2) are able to inhibit the transcription of endothelin [10,11] and that PGE1 has a cytoprotective effect [12].
Therefore, enhancing PGE1 may have a protective effect on renal function since the RCM-induced vasoconstriction is counteracted by the vasodilatory effects of PGE1. The goal of this study was to examine the effectiveness and compatibility of PGE1 in the prevention of ARF after administration of radiocontrast media, as well as to find the most appropriate dose.
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Patients and methods |
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Patients
Adult patients (>18 years of age) who received intravascular administration of RCM for various diagnostic purposes (coronary angiographies and peripheral angiographies: 81.5%; computer assisted tomographies and intravenous urograms, etc.: 18.5%) were included in the study. Furthermore, all patients had a stable, but already impaired renal function with a serum-creatinine 1.5 mg/dl (133 µmol/l) prior to RCM administration.
Clinically relevant criteria for exclusion included: myocardial infarction, cerebral stroke, chronic cardiac insufficiency (NYHA IV) or unstable angina pectoris, significant arrhythmias, intake of digitalis, clinically relevant respiratory, gastrointestinal, haematologic, or neurologic illness, haemodialysis or progressive renal failure, severe liver damage, multiple myeloma, autoimmune illnesses or severe allergies, severe uncontrollable hypertension (systolic >220 mmHg), arterial hypotension (systolic <80 mmHg), cardiogenic shock, infectious diseases or fever.
Treatment
One-hundred and thirty patients were randomized in a double blind manner to placebo (physiological saline solution) or PGE1 (Alprostadil; Schwarz Pharma, Monheim, Germany) at the following doses: group 1, placebo; group 2, 10 ng/kg/min PGE1; group 3, 20 ng/kg/min PGE1 or group 4, 40 ng/kg/min PGE1. The intravenous administration of the study-medication was started 1 h prior to RCM application and was administered for a total of 6 h.
A sufficient quantity of fluid was made available to all patients, either orally or intravenously, for 24 h before and after the intervention. The amount of i.v. fluids was 2000 ml (1000 ml NaCl solution/100 ml 5% glucose solution) before and after the RCM procedure.
Registration of clinical and laboratory parameters/Study procedure (Figure 1)
Twenty-four to 48 h before RCM diagnostics, the patient history was taken, a physical examination was performed and a 12-lead ECG was evaluated by a cardiologist. Medications taken up to 4 weeks prior to the exam as well as during the entire study were recorded.
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Over the course of 8 h, beginning 1 h (±30 min) prior to i.v. administration of the study medication, continuous monitoring of heart rate, blood pressure, as well as 12-lead-ECG were performed. This monitoring was continued for 1 h (±30 min) post-administration of PGE1. Every 15 min, blood pressure measurements were automatically taken and registered in a computer. Since PGE1 can lower blood pressure, special attention was given to this parameter. A decrease of more than 20 mmHg systolic pressure and/or diastolic pressure reduction of more than 10 mmHg were considered clinically relevant. Dependant upon clinical intervention, blood pressure monitoring was performed and registered at shorter intervals. Subsequently, a blood pressure curve was established and several diastolic and systolic values were documented in the protocol. The patients remained under physician surveillance for the complete 8 h of examination. The patients were hospitalised for a total of 4 days. A prolonged hospital stay or outpatient surveillance only followed if serum-creatinine was elevated more than 25% of the initial level after the examination.
Further blood samples were drawn 12 h (visit 2a), 24 h (visit 2b), and 48 h (visit 3) after RCM administration.
Twelve hour urine collections were obtained 12 and 24 h post-radio-contrast media administration. A final urine collection was attained at visit 3.
Radiocontrast media
Of the 130 patients examined, 112 (86.15%) received non-ionic RCM and 15 patients (11.54%) received ionic RCM. In one case, ionic as well as non-ionic RCM was administered. Two cases were not documented. The average iodine content of the non-ionic and ionic radio-contrast media was 340 mg/ml and 320 mg/ml, respectively. The average applied RCM volume was 158.5 ml per patient (range: 20445 ml; standard deviation: 73.86 ml).
Statistical analyses
This study was intended as a pilot study to determine an appropriate dose for PGE1 and to attain information about the effectiveness and its dependancy on dosage. (Since substantial information concerning possible doses for the substance used in this study already existed, the pilot-phase and dose-finding-phase could be combined.) Changes in serum creatinine were used as the primary variable for verifying the effectiveness of dosage. Furthermore, variables attained on the basis of clearance measurements were used. Explorative statistical methods were primarily used to compare the different patient groups. Differences in the distribution between the groups were evaluated by the Fisher exact test. In comparison with the placebo group after 48 h the P values were calculated on the basis of the 2-sample-two-sided t-test.
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Results |
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In reference to the osmolar and `free water clearance', a significant difference was not found between the various groups during the course of the study.
Sub-group analysis: diabetics
Of the 117 patients in the study population, 61 had a standing diagnosis of diabetes mellitus (type I and II): Placebo, n=17; 10 ng/kg/min, n=18; 20 ng/kg/min, n=14, 40 ng/kg/min, n=12. A mean increase in serum creatinine of 0.96 mg/dl 48 h after RCM administration was observed in the placebo group of diabetic patients. The increase in serum creatinine was less pronounced in all three PGE1 groups: 0.53 mg/dl (10 ng/kg/min), 0.07 mg/dl (20 ng/kg/min), and 0.66 mg/dl (40 ng/kg/min) (Figure 3). The most favourable result in terms of the lowest increase of serum creatinine was also found to be in the 20 ng group in this sub-analysis. A statistically significant difference between the PGE1- and placebo-groups was not found due to the relatively low number of patients per group.
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Further adverse events corresponded to those observed in previous studies after intravenous application of PGE1 such as isolated cases of nausea, vomiting, fatigue, or moderate skin symptoms.
Dialysis
One patient from the 40 ng-group was temporarily treated with dialysis due to ARF. No patients in the other three groups required dialysis.
Extended in-patient hospitilization/surveillance periods
An extension of in-patient hospitalization time or outpatient surveillance up to a maximum of 7 days post RCM administration became necessary in the different groups. Details are as follows (treatment group percentage of total patients, absolute number of patients, average increase in length of stay): placebo group 24.1%, n=7, 2 days; 10 ng-group 15.6%, n=2, 2.6 days; 20 ng-group 6.1%, n=2, 3 days and 40 ng-group 13.0%, n=3, 2.6 days.
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Discussion |
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The kidneys play an important role in the synthesis, metabolism, and excretion of prostaglandins. PGE1 is a natural prostaglandin with numerous pharmacologic effects including the well-known vasodilatative effect. In the kidney, PGE1 plays a role in the upkeep of blood-flow, the intrarenal distribution of blood, and the excretion of electrolytes and water. It has been shown that PGE1 has a protective effect on the kidneys when non-steroidal anti-inflammatory drugs (NSAID) are given [1,10,20]. Due to the vasodilatative (in the sense of an antagonistic effect to the RCM- induced vasoconstriction) and cytoprotective effects of PGE1 [12], it may provide a potential nephroprotective effect following RCM administration. All of the results of this study support a potential nephroprotective effect for PGE1 when administered with iodinated RCM in the presence of renal insufficiency.
ARF caused by RCM is most commonly defined as the increase of serum creatinine within 48 h after RCM application (>25% of initial level, >50% of initial level, >0.5 mg/dl, or >1.0 mg/dl) [4,19,21,22]. Alternatively, the creatinine-clearance can be determined as a marker for glomerular filtration. It is well acknowledged that in individuals with normal renal function, the creatinine-clearance adequately reflects the glomerular filtration rate (GFR). However, in patients with renal dysfunction, the GFR is over-estimated [23] since in this case creatinine is not only filtered but also undergoes tubular secretion. Furthermore, creatinine clearance is unreliable since urine-collections are frequently imprecise [24]. These findings were confirmed in this pilot study since a small degree of correlation was found between the creatinine-clearance measured from urine versus serum samples (calculated by the Cockcroft-Gault formula). None of the four groups demonstrated a significant change in creatinine-clearance after RCM application.
Due to the above mentioned considerations, only high-risk patients were included into this study, i.e., patients with pre-existing renal dysfunction (serum creatinine >1.5 mg/dl). Serum creatinine was chosen as the primary parameter in evaluating the course of drug effectiveness.
In order to show the prophylactic potential of PGE1, i.v. PGE1 was started before RCM-administration and was continued for 6 h. The time interval for the infusion of PGE1 was chosen based on the knowledge of the half-life of RCM excretion [25]. Since one of the criteria for inclusion into the study was based on the minimum application of 75 ml of iodinated RCM, the results were evaluated independent of RCM-type, the applied volume, as well as the place of application. The effectiveness of PGE1 was evaluated within 48 h after RCM application. This time period is considered clinically relevant for the further treatment of the patient [9].
In a contemporary survey study, complications and possible prophylactic measures concerning the application of RCM are discussed [26]. The authors Liebl and Krämer mention the prophylactic use of calcium antagonists, theophylline, endothelin receptor antagonists, as well as the atrial natriuretic factor (ANF). Of these substances, calcium antagonists are attributed with the highest degree of certain nephroprotective potential. According to the authors, in high-risk patients the most important preventive measure in terms of nephroprotectivity is a sufficient positive water balancea point that was also stressed in this study. The above cited publication does not recommend any routine prophylaxis except for volume expansion and does not mention prostaglandins as a potential prophylactic agent [26]. To the best of our knowledge, there exist no further publications in the current literature with representative patient numbers of a convincing study that deals with the nephroprotective potential of PGE1 and the application of iodine-based RCM. Abe and colleagues described a beneficial effect for PGE1 on renal function in patients with normal renal function undergoing cardiac surgery. The most effective dose was 20 ng/kg/min, as this study also showed [27].
The increase in serum creatinine of greater than 0.5 mg/dl in 51.7% of the patients in the placebo group corresponds with the increased rates found in current literature [2,3]. The lower rates of increases in serum-creatinine with PGE1 administration indicate that the nephroprotective potential of PGE1 reaches its maximum at the dosage of 20 ng/kg/min. Since it is well known that PGE1 lowers blood pressure via vasodilation, this substance might possibly aggravate contrast media nephrotoxicity by severly dropping the blood pressure. The greater number of clinically relevant reductions in blood pressure seen in the 40 ng group may explain why a better protective effect was observed in the 20 ng group. In accordance with other studies, the increase of serum creatinine was higher among placebo patients who had diabetes is compared to placebo patients without diabetes [28]. This underlines the clinical importance of this risk factor anew.
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Conclusion |
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Due to the relatively small number of patients per treatment group, the interpretation of the results warrant caution. Further studies with larger patient groups are now necessary to validate the results of this pilot study.
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Acknowledgments |
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References |
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