Prostaglandin E1: a new agent for the prevention of renal dysfunction in high risk patients caused by radiocontrast media?

Jens-Albrecht Koch1, Jörg Plum2, Bernd Grabensee2, Ulrich Mödder and PGE1 Study Group1

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.



   Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Background. Acute renal failure following the administration of radiocontrast media (RCM) is a complication found especially in patients with impaired renal function. Within the limits of a pilot study, the objective was to (a) show the effectiveness and compatibility of prostaglandin E1 (PGE1=Alprostadil) in preventing acute renal failure in patients with elevated levels of serum creatinine and (b) to identify the most appropriate PGE1-dose.

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



   Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Deterioration of renal function is a serious and common complication after administration of radiocontrast media (RCM). In unselected groups, 2–6% [1] of all patients develop acute renal failure (ARF). In higher risk groups, ARF has been reported with a frequency varying between 9.5 and 50% [2,3]. Risk factors known to make a patient more prone to contrast induced ARF include pre-existing renal impairment, diabetes mellitus, cardiovascular diseases, the use of diuretics, multiple myeloma, hypertension, hyperuricaemia, volume depletion and advanced age as well as high doses of RCM [4].

One of the changes by which ARF clinically manifests itself is an elevation of serum-creatinine levels usually within 2–5 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.



   Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Design of study
The evaluations were performed as part of an international, multicentre, double-blind, randomized pilot study in the clinical phase II with parallel-group-design. The study was conducted according to the guidelines of the declaration of Helsinki. The protocol was examined by the ethics committee of each participating centre prior to the begin of the study. Before inclusion into the study, informed written consent was obtained from each patient.

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 1Go)
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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Fig. 1. Schematic study procedure.

 
At each visit (1, 2a, 2b, 3), blood and urine samples were obtained for a complete blood work-up at the hospital as well as for the clinical research laboratory (SmithKline Beecham clinical laboratories). A first 24-h urine sample was collected at this time. Serum creatinine was measured by the Jaffé-method with auto-analysing systems. Endogenous creatinine clearance was measured according to 12 or 24 h urine collection (supervised by medical staff or the research ward) using the standard formula ECC=UxV/PxT [U=urinary concentration (mg/dl); V=urine volume (ml); P=plasma concentration (mg/dl); T=collection time (1440 min)]. Serum and urine osmolality were measured by the freezing point method and used to calculate osmolar and free water clearance.

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: 20–445 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.



   Results
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Thirteen of the 130 patients were not included in the final analyses. In six patients (placebo group; n=1; 10 ng group, n=1; 20 ng group, n=1; 40 ng group, n=3), adverse events (arterial hypertension, arterial hypotension (2x), unstable angina pectoris, massive haematuria, atrial tachycardia) led to discontinuation of PGE1 administration. These cases were examined and it was found that a complete laboratory work-up was not available for three patients and that the other three patients received too small amounts of RCM (<75 ml). In one case, the study medication was only infused after RCM administration had already been initiated. Table 1Go shows the most important demographic data of the 117 patients included in the final analyses.


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Table 1. Demographic data (n=117)
 
Serum creatinine
Serum creatinine was measured at pre-defined periods and was obtained from 108 patients at the time of visit 3. There was a mean increase in serum creatinine of 0.72 mg/dl 48 h after beginning placebo administration. The corresponding increase was lower in the PGE1 groups: 0.3 mg/dl in the 10 ng/kg/min group, 0.12 mg/dl in the 20 ng/kg/min group, and 0.29 mg/dl in the 40 ng/kg/min group (Table 2Go). A statistically significant difference was found between the placebo and 20 ng/kg/min groups (P=0.0136). Figure 2Go and Table 3Go demonstrate changes in the serum creatinine.


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Table 2. Increase of serum-creatinine 48 h post RCM-application
 


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Fig. 2. Changes of serum creatinine post-RCM application compared with baseline.

 

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Table 3. Changes in serum creatinine post-RCM application compared with baseline
 
For further evaluations, maximum creatinine increase over 48 h was separated according to the following cut-off values: >=0.5 mg/dl, >=1.0 mg/dl, and >=1.5 mg/dl. In the four patient groups, varying frequencies were clearly seen among these values. An increase in serum creatinine of at least 0.5 mg/dl was seen in 51.7% of the placebo group; 31.3% was seen in the 10 ng/kg/min group, 18.2% of the 20 ng/kg/min group, and 34.8% of the 40 ng/kg/min group. The percentage of patients belonging to the groups formed by the other serum creatinine cut-off values also was lower in the prostaglandin-treated groups than placebo. The 20 ng/kg/min dosage of PGE1 also showed favourable results compared to the other two PGE1-and placebo groups (Table 4Go).


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Table 4. Increase of serum creatinine above predefined values 48 h post-RCM application
 
Clearance measurements
No clinically relevant changes were observed in creatinine clearance among all four groups after RCM application (Table 5Go).


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Table 5. Follow-up of creatinine clearance (ml/min/1.73m2)
 
Creatinine clearance was not only measured from urine, but was also calculated from serum samples by the `Cockcroft-Gault' formula. A comparison of both methods yielded only a weak correlation of both values (Pearson correlation coefficient, e.g. at baseline 0.51).

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 3Go). 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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Fig. 3. Diabetics: changes of serum creatinine post-RCM application compared with baseline.

 
Tolerability
The most essential adverse event was a clinically relevant drop in blood pressure. Since it is already known that PGE1 can cause a drop in blood pressure when given in high doses, this parameter was—as mentioned earlier—monitored with special care over the 6 h period of i.v. application. Clinically relevant decreases in blood pressure were seen more often in the 40 ng group than in the other groups (40 ng group, seven of 30 patients=23.3%; placebo, two of 31 patients=6.5%; 10 ng/kg/min, two of 33 patients=6.1%; 20 ng/kg/min, two of 36 patients=5.5%).

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.



   Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
The mechanisms responsible for renal dysfunction caused by RCM-application are not yet entirely understood. According to present literature, two main factors play a decisive role. Both a direct toxic effect on tubule cells and the induction of renal vasoconstriction with possible ischemia are believed to be responsible [1315]. Pre-existing renal insufficiency as well as the administration of large doses of RCM are major contributors to further renal impairment [1619].

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 balance—a 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.



   Conclusion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 
Our pilot study showed that prostaglandin E1 (doses: 10 ng/kg/min; 20 ng/kg/min; 40 ng/kg/min) was able to lower the rate of increase in serum-creatinine in patients with pre-existing renal impairment undergoing intravascular iodinated RCM-application compared to patients treated with placebo. In the case of the middle dose of 20 ng/kg/min, the difference was significant (P=0.0136). The 20 ng dosage proved to be the most promising in terms of effectiveness (nephroprotectivity) and tolerability (neutrality towards blood pressure).

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.



   Acknowledgments
 
The following clinical centres participated in the study programme: Heinrich-Heine-Universität Düsseldorf, Radiology/Nephrology; Allgemeines Krankenhaus Hamburg-Harburg, Radiology; RWTH Aachen, Internal Medicine/Nephrology; Universitätsklinikum Essen, Cardiology, Germany; Martini Ziekenhuis Groningen, Cardiology; Reinier de Graaf Gasthuis, Locatie Bethel, Delft, Cardiology, Netherlands; Johns Hopkins Medical Center Baltimore MD, Cardiology; Duke University Medical Center Durham NC, Cardiology; Washington Hospital Center Washington DC, Cardiology; The Cleveland Clinic Foundation Cleveland OH, Nephrology; Rush-Presbyterians-St. Luke's Medical Center Chicago IL, Cardiology; The New York Hospital, Cornell Medical Center New York NY; Elmhurst Hospital Center Elmhurst NY, Cardiology; Cardiology Associates PC Washington DC, Cardiology; St. Lukes Medical Center Milwaukee WI, Cardiology, USA.



   References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 Conclusion
 References
 

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Received for publication: 10. 2.99
Accepted in revised form: 13. 9.99