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Eur J Cardiothorac Surg 1999;15:717-722
© 1999 Elsevier Science NL


The effect of `renal-dose' dopamine on renal tubular function following cardiac surgery: assessed by measuring retinol binding protein (RBP)1

Augustine T.M. Tanga, Ahmed El-Gamela, Brian Keevilb, Nizar Yonana, Abdullah K. Deiraniyaa

a Department of Cardiothoracic Surgery, Wythenshawe Hospital, Manchester, M23 9LT, UK
b Department of Biochemistry, Wythenshawe Hospital, Manchester, M23 9LT, UK

Received 23 September 1998; received in revised form 1 February 1999; accepted 10 February 1999.

Corresponding author. Wessex Regional Cardiac and Thoracic Unit, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD UK. Tel.: +44-1703-777-222; fax: +44-1703-796-614; email: gustmtang@aol.com


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Appendix A. Conference...
 References
 
Objective: Acute renal failure complicating open heart surgery is not uncommon. Dopamine infusion (2.5–4.0 µg/kg per min) has often been advocated for prophylactic `renal protection' in this setting despite little objective evidence of real benefit. We aimed to investigate whether dopamine offers any `renal protection' in patients with normal heart and kidney functions undergoing routine coronary artery bypass grafting (CABG). Urinary excretion of retinol-binding protein (RBP), previously validated as a sensitive and accurate marker of early renal tubular injury, was used to assess the renal effects of dopamine during the first postoperative week. Methods: Forty consecutive patients from the elective waiting list were prospectively randomized into two equal groups: those in Group A received dopamine infusion at `renal dose' (2.5–4.0 µg/kg per min) starting from induction of anaesthesia for 48 h, whereas those in Group B served as untreated controls. Daily measurements were made of weight-adjusted urine output (ml/kg), fluid balance (input/output), serum creatinine, blood urea and urinary RBP. Statistical comparisons were made using Mann–Whitney U-test. Results: The two groups matched in terms of age, time and temperature on cardiopulmonary bypass, number of grafts performed and perioperative haemodynamic status. No differences were detected in the weight-adjusted urine output, fluid balance, serum creatinine and blood urea between the groups. Control subjects (Group B) showed an increase in urinary RBP during the first and second postoperative days (323±4 µg/mmolCr and 50±3 µg/mmolCr; mean±SD). However, patients treated with dopamine (Group A) demonstrated much greater urinary excretion of RBP over the same period (1257±15 µg/mmolCr and 449±21 µg/mmolCr; P=0.0006 and 0.03) than those in Group B. Conclusions: Dopamine given at `renal-dose' appears to offer no renal protection in patients with normal heart and kidney functions undergoing elective coronary surgery. On the contrary, it exacerbates the severity of renal tubular injury during the early postoperative period. Based on these findings we do not recommend the use of dopamine for routine renal prophylaxis in this group of patients.

Key Words: Dopamine • Coronary artery bypass grafting • Acute renal failure • Retinol-binding protein • Renal tubular injury


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Appendix A. Conference...
 References
 
Renal dysfunction complicating open heart surgery is not uncommon. Multiple aetiological factors lead to renal hypoperfusion and ischaemic injury to the kidney [1]. Renal blood flow decreases approximately 30% during cardiopulmonary bypass (CPB) accompanied by an increase in renal vascular resistance. The consequent ischaemia impairs both glomerular and tubular functions. The use of `low-dose' dopamine infusion has been advocated for `renal protection' in this setting [2] based on, amongst others, its purported ability to induce receptor-mediated renal vasodilation [3]. However, there is no reliable data available to claim preservation of renal function or improved patient survival as a result of dopamine treatment following cardiac, aortic or liver transplantation surgery [4] [5] [6]. Urinary excretion of retinol-binding protein (RBP) has been validated as a sensitive and accurate marker of early tubular dysfunction [7]. We have performed a prospective randomized controlled study to investigate the effects of perioperative `renal-dose' dopamine on renal tubular function as measured by urinary RBP.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Appendix A. Conference...
 References
 
Patient selection and randomization
Consecutive patients on the elective coronary artery bypass grafting (CABG) waiting list were screened according to the exclusion criteria listed in Table 1. Forty patients selected on such criteria (24 males and 16 females) were prospectively randomized into two equal and independent groups after having given informed consent. In essence we aimed to select subjects with normal cardiac and renal functions prior to surgery. Group A patients received an intravenous infusion of dopamine administered at a rate of 2.5–4.0 µg/kg per min starting from induction of general anaesthesia for 48 h, whereas, Group B patients served as untreated controls. The study was approved and monitored by the Research Ethics Committee at the South Manchester University Hospitals.


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Table 1. A list of the exclusion criteria for recruitment into the study

 
Anaesthesia
A standard protocol was followed in which fentanyl based anaesthesia was used in combination with benzodiazepine and vecuronium as a muscle relaxant. Each patient had a pulmonary artery balloon catheter inserted for perioperative monitoring of haemodynamic status. Patients were ventilated with 10 ml/kg tidal volume and 5 cm H2O of PEEP were applied, respiratory rate and O2 fraction were adjusted to maintain normal oxygenation and acid base status. Anyone who subsequently developed poor cardiac output requiring inotropic support was excluded from the study. Alpha-stat management of acid-base status during CPB was used. No vasoactive agent was administered other than for maintenance of perfusion pressure during CPB (see under Section 2.3).

Surgical procedure
CABG was performed in each case with the institution of CPB. The latter was accomplished by the use of a single 2-stage venous cannula (Medtronic dlp, Medtronic UK) inserted into the right atrium/inferior vena cava and an arterial cannula (Medtronic dlp, Medtronic UK) placed in the ascending aorta. The procedure was conducted under moderate hypothermia (32°C) with myocardial protection provided by intermittent antegrade cold-blood cardioplegia and topical cooling. Flow was controlled at 2.5 l/min per m2 during CPB with judicious use of metaraminol to maintain a perfusion pressure of 65 mmHg (14 patients received 1–10 mg during bypass and after administration of protamine, patients were distributed adequately between the two groups).

Infusions and medications
Antibiotics
All patients received three doses of netilmicin 3 mg/kg and 2 g of flucloxacillin for 48 h in divided doses.

Infusions
Maintenance fluid until oral fluid intake is satisfactory: 1 ml/kg of Dextrose 5% in 1/2 normal saline. Central venous pressure was maintained between 8 and 12 mmHg with the use of Gelofusin. Donor blood transfusion was only indicated when haematocrit is below 28%.

Assessment of renal function
Daily measurements were taken during the first postoperative week of the following parameters: (i) weight-adjusted urine output (ml/kg) (ii) fluid balance (input/output) (iii) serum creatinine (µmol/l) (iv) blood urea (mmol/l) (v) urinary RBP (µg/mmolCr). Measurements of creatinine and urea were made in venous blood samples. Twenty-millilitre aliquots of urine were collected in sterile tubes and stored in a refrigerator until analysis.

Analysis of RBP
Urinary excretion of RBP was assessed using a commercial reagent kit (Randox Laboratories, Antrim, UK) employing an ELISA technique.

The calibrators and diluted samples were added to microtitre plate wells precoated with antibody specific for RBP. After incubation for 2 h the plate was washed and antibody conjugated to horse radish peroxidase was added for a further 1 h incubation. Following a final wash step, substrate solution was incubated in the wells resulting in a coloured product which was measured at 450 nm after quenching with dilute sulphuric acid. The colour intensity is proportional to the amount of RBP present. All samples and calibrators were analyzed in duplicate and the mean absorbance results for the calibrators were plotted against calibrator concentration, using semi-logarithmic graph paper. Any samples with an absorbance greater than the top calibrator were re-assayed using a greater dilution. The within batch coefficient of variation was less than 9% and the between batch coefficient of variation was less than 10%, across the assay range [8].

Statistical analyses
Data are presented as the mean±SD. For each parameter comparisons between the two groups were made using Mann–Whitney U-test, and a statistically significant difference was considered when P<0.05.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Appendix A. Conference...
 References
 
Group characteristics
There were no significant differences between the groups in terms of age, time on CPB, number of coronary artery bypass grafts performed, and their perioperative haemodynamic status (Table 2).


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Table 2. Comparison of specific characteristics between the control and dopamine-treated groups. No statistical significant difference was found in any of the parameters

 
Renal functions
No significant difference was detected between the two groups in the serum creatinine, blood urea, weight-adjusted urine output and fluid balance during the first postoperative week (Table 3). Serum creatinine remained within the normal range throughout the duration of the study in both groups. Control subjects demonstrated a significant level of urinary RBP on the first and second postoperative days ( Fig. 1 ). However, those who were given a perioperative dopamine infusion showed a much greater release of RBP in the urine over the same period. The amount of this protein detectable in urine subsequently returned to baseline in both groups and remained so for the rest of the study period.


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Table 3. Comparison of indices of renal function between the control and dopamine-treated groups during the first postoperative week. No statistical significant difference was found in any of the parameters

 


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Fig. 1. Comparison of urinary excretion of retinol-binding protein between the control and dopamine-treated groups during the first postoperative week. *Significant difference between the two groups: P=0.0006. **Significant difference between the two groups: P=0.03.

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Appendix A. Conference...
 References
 
In patients undergoing elective coronary surgery who have normal cardiac and renal functions preoperatively, administration of intravenous dopamine at `renal dose' (2.5–4.0 µg/kg per min) offered no prophylactic protection to the nephrons. Coronary surgery appeared to cause a degree of renal tubular injury during the first and second postoperative days as measured by urinary RBP. However, dopamine greatly exacerbated the extent of this injury in a comparable group of patients. This deleterious effect of dopamine on the kidney is otherwise clinically silent since neither oliguria nor a rise in serum creatinine occurred in the treatment group when compared with the control group.

The incidence of renal dysfunction following open-heart surgery varies between 0.1 and 39% according to the criteria employed [9]. When it does occur, the extent of dysfunction may vary from subclinical [10] to full-blown acute renal failure requiring replacement therapy. The aetiology is believed to be multifactorial but primarily related to techniques of cardiopulmonary bypass [11], peri- and postoperative renal insult [12] and postoperative cardiac dysfunction [13]. Some of these factors such as the conduct of cardiopulmonary bypass have been standardized in the present study. Furthermore, the perioperative haemodynamic status remained comparable between the two groups. It is unlikely, therefore, that any of these factors could have accounted for the impressive difference in the extent of renal dysfunction observed.

A review of the literature suggests that acute renal dysfunction secondary to cardiac surgery may have both glomerular and tubular components [9] [14]. Traditional tests of renal function such as serum creatinine and creatinine clearance used in clinical practice focus on glomerular filtration and are relatively insensitive indicators of early damage because of the existence of a large `renal functional reserve' [15]. Consequently the incidence of impaired glomerular function reported following open-heart surgery varied considerably and a raised serum creatinine may be observed in up to 30% of cases (12). The subjects in the present study were recruited on the basis that they were unlikely to compromise their renal reserve postoperatively as demonstrated by the maintenance of normal levels of serum creatinine following surgery. Until recently early injury to the renal tubule, on the contrary, has not been studied to the same detail since mild damage to that part of the nephron is difficult to assess using conventional indices. Accurate and sensitive methods of detecting tubular injury were developed during the 1980s which depend either on the ability of the proximal tubular cells to reabsorb low-molecular-mass proteins (e.g. ß2-microglobulin and RBP) or on the leakage of intracellular proteins of high-molecular-mass from the damaged tubules (e.g. N-acetyl-ß-D-glucosaminidase and {Gamma}-glutamyltranspeptidase). RBP is synthesized in the liver, freely filtered through the glomeruli and normally fully reabsorbed by the proximal tubules so that only trace amounts appear in the urine even in the presence of massive proteinuria. Consequently urinary RBP is considered an excellent marker of early tubular damage and has been shown to be a more sensitive and accurate index than measurements of other tubular enzymes because of its greater stability in acidic urine [7]. An increase in the urinary excretion of renal tubular enzymes indicating proximal tubular injury has been observed soon after CPB [14] [16] [17]. This is in agreement with our own observations in the control group. Such injury may increase tubular permeability and promote leakage of fluid from the tubular lumen into the peritubular circulation. Significant transtubular back-leak is strongly believed to contribute towards more severe forms of acute renal failure by compromising glomerular filtration rate [4]. However, this phenomenon is probably unimportant in the mild to moderate forms of renal dysfunction [18], such as that observed in the present study.

Different approaches have been tried in order to prevent renal dysfunction following cardiac surgery with variable outcome. These primarily involve modifying aspects of cardiopulmonary bypass such as the temperature employed, pump-priming with crystalloid to achieve haemodilution and the use of pulsatile flow [17]. Among the pharmacological agents on trial, dopamine infused at low to intermediate rates of 2.5–4.0 µg/kg per min has gained popularity over the years. The perceived benefits include raised cardiac output, improved renal perfusion from receptor-mediated renal vasodilation [3], reduced renal metabolic activity, diuresis and natriuresis [19]. However, no reliable data exists to claim preservation of renal function or improved patient survival as a result of dopamine treatment following cardiac, aortic and liver transplantation surgery [4] [5] [6]. A recent review concluded that dopamine should not be used as a prophylactic agent except in specific situations in which there is some evidence of benefit, such as when its diuretic and inotropic properties might be of use [19]. More importantly, if adverse effects are experienced, or no beneficial effects are derived, the infusion should be stopped [20]. In this context our findings have conclusively demonstrated for the first time that dopamine used at the `renal dose' not only afforded no prophylactic benefit to the nephrons but was indeed grossly harmful to renal tubular function. This observation could partially account for the diuretic action of dopamine although the precise mechanism of enhanced tubular injury remains to be elucidated.

There has been a distinct lack of objective evidence from randomized controlled trials to confirm the purported benefits of using low dose dopamine for renal prophylaxis in the variety of settings in which it is commonly indicated. Consequently advocates of `renal dose' dopamine inevitably base their recommendations more on opinions than facts. The present study has gone some way to clarify this issue in a well defined population of cardiac surgical patients. Given the wide spectrum of potential adverse effects associated with the use of dopamine [21] [22] our findings fundamentally altered the benefit to risk ratio of this drug in a group of patients who are otherwise at low risk of developing renal dysfunction. Based on such principles, we do not recommend the use of dopamine for routine renal prophylaxis in this group of cardiac surgical candidates. It remains to be seen however, whether dopamine could still be an effective prophylactic agent in patients who may be at higher risk of acquiring acute renal failure following cardiac surgery, such as those with pre-existing renal impairment [23] and cardiac dysfunction [9].


    Footnotes
 
Presented at the 12th Annual Meeting of the European Association for Cardio-thoracic Surgery, Brussels, Belgium, September 20–23, 1998. Back


    Appendix A. Conference discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Appendix A. Conference...
 References
 
Dr U. Von Oppell (Cape Town, South Africa): Is the release of retinol binding protein related to urine volume, and thus the higher urine volume in the renal dopamine group a cause for the increased release of retinol binding protein? Secondly, would you consider doing a similar study but in a high risk group?

Mr. Tang: The answer to your first question is, no, the level of retinol binding protein in the urine is not dependent on the actual volume urine output. It is very difficult to see, but in fact if you look at the unit used on the y-axis when I showed you the difference between two curves, it is actually corrected for the amount of creatinine excreted in the urine as well. So it's all standardized. And the answer to your second question is, yes, we are in the process of doing a study, which we call phase II, looking at whether dopamine is an effective prophylactic agent in patients who are considered at higher risk of developing acute renal dysfunction following coronary surgery.

Dr L. von Segesser (Lausanne, Switzerland): Can you tell us something about hemolysis; was this evenly distributed in the two groups?

Mr Tang: You mean in terms of the serological markers of hemolysis?

Dr von Segesser: One could imagine that a lot of hemoglobin, which is free in the plasma, could saturate the kidney from one group and less in the other, because there were differences there.

Mr Tang: Right. I think what you are trying to get at is that some of these toxins can affect renal tubular function. We haven't actually specifically looked at the level of microglobulin or haptoglobin between the two groups, but effectively there were no differences in any of the other parameters we looked at, such as perioperative hemodynamic status and the requirement for transfusion, etc.

Mr J. Kuo (Plymouth, UK): I enjoyed your study because I have a similar interest and I did an identical study 2 years ago looking at a similar group of patients, but we came to a different conclusion. We actually monitored renal function during bypass, measuring RBP levels at intervals during bypass, and we found that the RBP levels are lower in the dopamine group compared with the nondopamine group, and we back up our data with a second renal marker, the alpha-1-microglobulin.

My question to you is, did you actually measure retinol binding protein during bypass, and if you haven't, can you actually draw any conclusion as to whether or not dopamine offers any advantage to this group of patients during bypass?

Mr Tang: No. Retinol binding protein was basically measured on a daily basis in 20-ml aliquots of urine which is collected from day zero onward during the 1st postoperative week. We didn't actually collect specimens while the patient was on bypass. And I think you mentioned that you assess renal function using beta-2-microglobulin.

Dr Kuo: Alpha-1-microglobulin, not beta.

Mr Tang: Okay. As far as I am aware, studies which compared the use of different renal tubular enzymes as markers of early renal tubular injury have indicated that RBP is the most reliable and accurate marker of them all, partly because it is a stable protein, even in acidic urine, and I think partly also because of the dynamics of its reabsorption. And I don't think simply by altering the marker and using other tubular enzymes as our end point would actually alter our conclusion, if that is the right answer to your question.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Appendix A. Conference...
 References
 

  1. Krian A. Incidence, prevention and treatment of acute renal failure following cardiopulmonary bypass. Int Anesthesiol Clin 1976;14:87-101.[Medline]
  2. Davis R.F., Lappas D.G., Kirklin J.K., Buckley M.J., Lowenstein E. Acute oliguria after cardiopulmonary bypass: renal improvement with low dose dopamine infusion. Crit Care Med 1982;10:852-856.[Medline]
  3. Jose P.A., Raymond J.R., Bates M.D., Aperia A., Felder R.A., Carey R.M. The renal dopamine receptors (editorial). J Am Soc Nephrol 1992;2(8):1265-1278.[Abstract]
  4. Myers B.D., Chui F., Hilberman M., Michaels A.S. Transtubular leakage of glomerular filtrate in human acute renal failure. Am J Physiol 1979;237:F319.
  5. Baldwin L., Henderson A., Hickman P. Effect of postoperative low-dose dopamine on renal function after elective major vascular surgery. Ann Intern Med 1994;120(9):744-747.[Abstract/Free Full Text]
  6. Swygert T.H., Roberts L.C., Valek T.R., et al. Effect of intraoperative low-dose dopamine on renal function in liver transplant recipients. Anesthesiology 1991;75(4):571-576.[Medline]
  7. Bernard A.M., Vyskocil A.A., Mahieu P., Lauwerys R.R. Assessment of urinary retinol-binding protein as an index of proximal tubular injury. Clin Chem 1987;33(6):775-779.[Abstract/Free Full Text]
  8. El-Gamel A., Yonan N., Keevil B., et al. Measurement of microalbumin and retinol binding protein in cardiac and lung transplant recipients. Transplant Proc 1995;27:1969-1972.[Medline]
  9. Leurs P.B., Mulder A.W., Fiers A., Hoorntje S.J. Acute renal failure after cardiovascular surgery. Current concepts in pathophysiology, prevention and treatment. Eur Heart J 1989;10(suppl H):38-42.
  10. Mazzarella V., Gallucci M.T., Tozzo C., et al. Renal function in patients undergoing cardiopulmonary bypass operations. J Thorac Cardiovasc Surg 1992;104(6):1625-1627.[Abstract]
  11. Utley JR. Renal effects of cardiopulmonary bypass. In: Utley JR, editor. Pathophysiology and techniques of cardiopulmonary bypass. Baltimore: Williams and Wilkins, 1982:40–54.
  12. Abel R.M., Buckley M.J., Austen W.G., Barnett G.O., Beck C.H., Fischer J.E. Etiology, incidence, and prognosis of renal failure following cardiac operations. J Thorac Cardiovasc Surg 1976;71:323-333.[Abstract]
  13. Hilberman M., Derby G.C., Spencer R.J., Stinson E.B. Sequential pathophysiological changes characterizing the progression from renal dysfunction to acute renal failure following cardiac operation. J Thorac Cardiovasc Surg 1980;79:838-844.[Abstract]
  14. Hashimoto K., Miyamoto H., Suzuki K., et al. Evidence of organ damage after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1991;104:666-673.[Abstract]
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  16. Ip-Yam P.C., Murphy S., Baines M., Fox M.A., Desmond M.J., Innes P.A. Renal function and proteinuria after cardiopulmonary bypass: the effects of temperature and mannitol. Anesth Analg 1994;78:842-847.[Abstract/Free Full Text]
  17. Regragui I.A., Izzat M.B., Birdi I., Lapsley M., Bryan A.J., Angelini G.D. Cardiopulmonary bypass perfusion temperature does not influence perioperative renal function. Ann Thorac Surg 1995;60:160-164.[Abstract/Free Full Text]
  18. Donohoe J.F., Venkatachalam M.A., Bernard D.B., Levinsky N.G. Tubular leakage and obstruction after renal ischemia. Structural-functional correlations. Kidney Int 1978;13:208-222.[Medline]
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