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Ann Thorac Surg 2002;74:372-377
© 2002 The Society of Thoracic Surgeons

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Original article: cardiovascular

Leukodepletion reduces renal injury in coronary revascularization: a prospective randomized study

^a Wessex Regional Cardiac and Thoracic Unit, Southampton General Hospital, Southampton, United Kingdom

* Address reprint requests to Dr Tang, Department of Cardiac Surgery, Southampton General Hospital, Tremona Rd, Southampton SO16 6YD, United Kingdom
e-mail: gus{at}tang-family.org

Presented at the Thirty-eighth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 28–30, 2002.

	Abstract

Top Abstract Introduction Patients and methods Results Comment Acknowledgments Discussion References

 
Background. Cardiopulmonary bypass (CPB) is an important contributor to renal failure, which is a well-recognized complication after coronary artery bypass grafting (CABG). Leukodepletion reduces CPB-associated inflammation and resultant end-organ injuries. However, its effectiveness in renal protection has not been evaluated in a prospective randomized clinical setting.

Methods. Forty low-risk patients awaiting elective CABG with normal preoperative cardiac and renal function were prospectively randomized into those undergoing nonpulsatile CPB without (group A: n = 20) and with leukodepletion (group B: n = 20). Renal glomerular and tubular injury were assessed by urinary excretion of microalbumin and retinol binding protein (RBP) indexed to creatinine (Cr), respectively. Daily measurements were taken from admission to postoperative day 5. Fluid balance, serum creatinine, and blood urea were also monitored.

Results. No mortality or renal complication occurred. Both groups had similar demographic makeups, Parsonnet scores, extents of coronary revascularization and, durations of CPB and aortic cross-clamping. Daily fluid balance, serum creatinine, and blood urea remained comparable in both groups throughout the study period. From equal preoperative values, a significantly higher release of urinary RBP:Cr (7,807 ± 2,227 vs 3,942 ± 2,528; p < 0.001) and urinary microalbumin:Cr (59.4 ± 38.0 vs 4.7 ± 6.7; p < 0.0001) occurred in group A, peaking on day 1 before returning to approximate baseline levels.

Conclusions. Although clinically overt renal complications were absent, sensitive indicators revealed significantly more injury to both renal tubules and glomeruli after nonpulsatile CPB without leukodepletion. These data suggest that leukocytes play an important role in post-CPB renal dysfunction, and leukodepletion may offer some renal protection in low-risk patients during CABG.

	Introduction

Top Abstract Introduction Patients and methods Results Comment Acknowledgments Discussion References

 
Coronary revascularization (coronary artery bypass grafting [CABG]) is now firmly established as the gold standard treatment for ischemic heart disease, conferring both symptomatic and prognostic benefits. Overall mortality has progressively declined over the decades despite an increasing proportion of higher-risk procedures being performed. However, kidney dysfunction remains a significant contributor to postoperative morbidity and mortality. Central to the complex etiology of perioperative renal damage is a process of systemic inflammation induced by cardiopulmonary bypass (CPB). The important role of leukocyte activation in CPB-associated inflammation has been universally recognized. More recently, effective removal of activated leukocytes during CPB by mechanical filtration has been demonstrated both in vitro and in vivo. Although the clinical benefits of leukodepletion have already been documented in the heart and lungs, its renoprotective effect so far has not been evaluated. This study aimed to investigate the influence of leukodepletion on differential renal injury in low-risk patients undergoing coronary revascularization.

	Patients and methods

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Patient recruitment
Consecutive patients awaiting elective CABG at the Southampton General Hospital were prospectively screened according to entry criteria (Table 1). Suitable candidates were counseled before offering informed consent. Patients were randomized on the day before surgery to either those undergoing CPB alone (control group A) or with leukodepletion instituted during CPB (group B). This study was approved and monitored by the Southampton and South West Hants Joint Local Research Ethics Committee.

Surgical techniques and myocardial protection
Coronary anastomoses were performed sequentially during a single period of aortic cross-clamping. Myocardial protection was achieved by combining intermittent antegrade cold blood cardioplegia (4°C) and topical cooling. The cardioplegic mixture consisted of 20% St. Thomas’ Hospital No. 2 solution (Martindale Pharmaceuticals, Essex, UK) and 80% autologous blood. Diastolic cardiac arrest was induced with 12 mL/Kg body weight of cardioplegia supplemented at 20-minute intervals by further doses of the solution at 3 mL/Kg. With the heart reperfused after cross-clamp removal, anastomoses of vein grafts to the ascending aorta were performed using the tangential technique of applying an occlusive side-biting vascular clamp to the aorta.

Renal monitoring
Urine and blood samples were collected daily from each patient commencing on surgical admission (baseline) until postoperative day 5. Differential injury to the renal tubules and glomeruli were detected, respectively, by urinary excretion of retinol binding protein (RBP) and microalbumin (MA). These highly sensitive markers were indexed to urinary excretion of creatinine (Cr) to adjust for variations in the glomerular filtration rate. The scientific rationale for monitoring urinary RBP:Cr as a parameter for early renal tubular injury had previously been discussed [1]. Assessment of glomerular injury by measuring urinary MA:Cr has also been validated to be both accurate and sensitive in cardiac surgical patients [2]. In essence, these urinary indices allow for very early detection of differential renal injury at a stage long before conventional parameters such as blood urea and serum creatinine become abnormal. Aliquots of urine (20 mL) were collected in sterile tubes and stored frozen (-40°C) until analysis. Urinary RBP was analyzed using a very sensitive latex-enhanced immunoassay technique with nephelometric detection, which has been custom developed in our own laboratory [3]. Urinary microalbumin and creatinine were measured using a turbimetric assay. Changes in clinical indices of renal function were assessed by measuring blood urea and serum creatinine. A loop diuretic was routinely administered daily from the first postoperative day. This was generally stopped once the patient regained baseline preoperative body weight.

Data collection
Patient characteristics, perioperative variables, and daily fluid balance were prospectively recorded.

Statistical analysis
Data are presented as mean ± standard deviation. Renal outcome data were naturally transformed and analyzed using repeated-measures analysis of covariance with Bonferroni correction to adjust for any potential baseline differences. Differences in categorical variables between groups were compared using Fisher’s exact test. The Mann-Whitney U test was used to compare other nonparametric data. A statistical significance was applied to any difference when p < 0.05.

	Results

Top Abstract Introduction Patients and methods Results Comment Acknowledgments Discussion References

 
Patient characteristics
Forty-four patients meeting entry criteria offered informed consent and were randomized into two equal groups. Four patients, 2 in each group, were subsequently excluded from the study because of perioperative inotrope dependency. Noradrenaline was the only vasoactive agent used in 3 cases to overcome perioperative vasodilation, whereas the remaining patient received dopamine for 16 hours. No significant difference was observed between the groups in the distribution of age, gender, New York Heart Association (NYHA) functional class, Canadian Cardiac Society (CCS) angina grade, Parsonnet score, left internal thoracic artery usage, extent of coronary revascularization, duration of CPB, and aortic cross-clamping (Table 2). No mortality or major morbidity, including renal impairment, was encountered postoperatively.

View larger version (17K): [in this window] [in a new window]   Fig 1. Renal tubular marker increased significantly from baseline to postoperative day (POD) 1 (p < 0.001) in both groups followed by full recovery by day 5. Group A (nonpulsatile cardiopulmonary bypass [CPB]) sustained significantly greater renal tubular injury than group B (leukodepletion [LEUKO]) (p < 0.01). (RBP:Cr = retinal binding protein:creatinine.)

View larger version (15K): [in this window] [in a new window]   Fig 2. Renal glomerular marker increased significantly from baseline to postoperative day (POD) 1 (p < 0.001) in both groups followed by full recovery by day 5. Group A (nonpulsatile cardiopulmonary bypass [CPB]) sustained significantly greater renal glomerular injury than group B (leukodepletion [LEUKO]) (p < 0.0001). (MA:Cr = microalbumin:creatinine.)

	Comment

Top Abstract Introduction Patients and methods Results Comment Acknowledgments Discussion References

 
The findings in this study clearly demonstrated significant injury to both renal glomeruli and tubules in low-risk patients undergoing CABG. This damage was likely to be intraoperative as it occurred early after CPB and was fully reversed without specific intervention by the fifth postoperative day. Such findings concur well with previous observations [1, 4]. As indicated by the sensitive biochemical markers, addition of leukodepletion during nonpulsatile CPB significantly reduced the extent of differential renal injury and demonstrated for the first time its renoprotective benefits.

Renal dysfunction is an important complication after CPB. Its overall incidence, depending on study criteria, has been reported as high as 40% in the series [5]. Full-blown acute tubular necrosis necessitating renal replacement therapy has fortunately been a rare event (1%) but is potentially associated with substantial mortality (60%) [6]. Survivors of this dreadful complication may develop chronic renal failure and face the prospects of long-term dialysis with all the attendant morbidities.

Various factors have been consistently associated with progression to postoperative renal failure in this setting. Among these are old age (>70 years), poor left ventricular function, preexisting renal disease, and diabetes [7, 8]. The common pathophysiology through which these factors mediate is likely to be complex, with multiple processes acting synergistically. Systemic inflammation, renal ischemia, and global hypoperfusion are universally regarded as the central mechanisms of renal injury [6, 9]. Exclusion of patients with chronic hypertension, preexisting renal disease, and abnormal serum indices from our study aimed to minimize the likelihood of any observed differences in renal outcome being attributable to the differential prevalence of subclinical renal ischemia in the two groups. Likewise, rejection of candidates with poor preoperative left ventricular function (ejection fraction <40%) together with standardization of flow characteristics and perfusion pressure during CPB would help to eliminate global hypoperfusion as a confounding factor when interpreting these results. Our study was essentially designed to specifically investigate the extent to which systemic inflammation associated with CPB alone could be responsible for renal glomerular and tubular injury. In this regard, perioperative administration of dopamine has previously been shown to exacerbate the release of urinary RBP:Cr after CABG even when recognized risk factors of renal dysfunction were notably absent [1]. This would create great difficulties in dissecting out the elements of renal injury attributable to systemic inflammation and dopamine, respectively. As there is no contrary evidence to support the use of related inotropic agents in this setting, we took the necessary precaution to exclude patients who subsequently became inotrope dependent from the study. Because the numbers involved were identical in each group, interpretation of our findings is unlikely to be affected.

Based on an understanding of the pathophysiology, attempts to modulate renal dysfunction after CPB have been made with varying degrees of success. No single method has so far emerged with consistent benefits for patients with widely differing risk profiles. Pharmacological measures included the addition of mannitol to pump-prime, loop diuretics, calcium channel blockers, and perioperative infusion of low-dose dopamine [1, 9, 10]. Far from being renoprotective, the latter has been shown to enhance renal tubular injury in the perioperative period [1]. Nonpharmacological approaches predominantly involved modifications to the conduct of CPB, such as the temperature employed, pump-priming with crystalloid to achieve hemodilution, and the use of pulsatile flow [11]. However, one such aspect that has remained unexplored is modulation of leukocyte activation during CPB. The crucial role of activated leukocytes in the pathogenesis of post-CPB systemic inflammation with resultant end-organ damage is universally recognized [12]. A series of immunological changes including complement activation and cytokine release triggered by CPB ultimately lead to endothelial adherance of leukocytes followed by margination, degranulation, and tissue destruction. Limiting the effects of activated leukocytes would therefore reduce the extent of inflammatory injury. Pharmacological modulation of leukocyte activities has been limited to the use of high-dose systemic steroid (eg, 1 g of methylprednisolone) and protease inhibitor (aprotinin). Commonly administered before institution of CPB, these agents reduce chemotatic sensitization of leukocytes and subsequent tissue sequestration [12]. However, the antiinflammatory actions of steroid and aprotinin owe much more to direct inhibition of complement and cytokine activation. An alternative strategy is to remove activated leukocytes from circulation. Because chemical leukodepletion is not feasible in clinical practice, mechanical removal of the white blood cells by appropriate filters has been developed. Early attempts relying on cell separator technology and transfusion line filters produced inconsistent results with variable leukodepletion efficiency whether circulating or activated leukocytes were measured [13, 14]. Further research and development led to the introduction of a dedicated leukodepletion filter intended for CPB (LG6 LeukoGuard; Pall, Portsmouth, UK). Findings from our own research and others suggested that the LG6 filter is highly effective in removing activated granulocytes whether placed in the arterial or venous side of the extracorporeal circuit [15, 16]. In a recirculating microcircuit standardized to 36°C, we demonstrated that the LG6 installed in the arterial limb of the extracorporeal tubing can remove approximately 60% of circulating leukocytes and over 99% of the activated fraction [15]. The clinical effectiveness matched the in vitro findings and significantly lowered total leukocyte count throughout CPB when compared with controls [15, 17]. There have also been concerns with saturation of the leukofilter after an "avalanche" of trapped leukocytes during the initial stages of CPB, thus rendering it subsequently ineffective. In this regard, a stable state of leukodepletion does indeed occur after 20 to 30 minutes of CPB due primarily to all of the nonspecific adsorptive sites being filled [18]. However, further challenging the filter with activated white cells still leads to a complete removal of this subsequent leukocyte population from the circulating blood. The latter observation offers some reassurance that the LG6 filter retains its effectiveness after the early stages of CPB. Evidence for a reduction in reperfusion endothelial injury and the release of proteolytic enzymes, superoxides, and cytokines with mechanical leukodepletion exists but is not always reproducible [19–22]. Such inconsistencies may reflect differences in the filters used in addition to variations in the technical aspects of leukodepletion during CPB.

Clinically superior organ protection by leukodepletion has been consistently demonstrated in the myocardium (using leukodepleted cardioplegia) and the lung parenchyma, resulting in better cardiac output and gas exchange perioperatively. The blood-gas interface is particularly vulnerable to injury caused by sequestrated pulmonary leukocytes, and remains the focus of much leukodepletion research. In contrast, the renoprotective effect of leukodepletion has so far received little attention despite the crucial role played by systemic inflammation in renal injury after CPB. The latter was elegantly illustrated in a clinical study that found significant reductions in renal tubular damage after administration of elastase inhibitors [9]. Our results concur with such findings and confirm the importance of activated leukocytes in mediating both glomerular and tubular injury in the kidney. The renoprotective benefit of leukodepletion has otherwise not been demonstrated in a clinical setting. Although the inflammatory load was not directly measured, the conduct and duration of CPB were strictly similar in both groups, making it unlikely that the observed differences in renal damage were solely the result of differential inflammatory exposure. Using an identical leukocyte filter, an experimental study on neonatal piglets failed to show any additional recovery in renal blood flow after a 60-minute period of deep hypothermic circulatory arrest (DHCA) compared with controls [23]. The authors concluded that leukodepletion was ineffective in this setting. Although the inflammatory response, which was unquantified in this study, produced by DHCA in addition to over 120 minutes of CPB may have exceeded the protective limits of leukodepletion, the negative results may simply reflect that global renal blood flow was neither a sensitive nor accurate surrogate marker of early kidney damage.

In low-risk cohorts subjected to CABG, such as those in this study, the absence of clinically overt renal complication was naturally unremarkable. The significant biochemical injury revealed by our urinary markers was not matched by parallel changes in the commonly used clinical indices of renal function, namely serum creatinine and blood urea. While this may simply reflect the limitation of the latter parameters in assessing early kidney injury, it would be difficult to extrapolate from our results whether the observed biochemical "renoprotection" conferred by leukodepletion could translate into useful clinical benefit. This will best be demonstrated in candidates at high-risk of renal dysfunction after CABG where abnormal changes in both serum and urinary markers are likely to occur simultaneously and therefore render correlation possible. Furthermore, the antiinflammatory effect of leukodepletion is limited by its application being restricted to the duration of CPB and a failure to prevent initiation of the complement and other inflammatory cascades. Such factors may dampen its renoprotective capacity in higher-risk patients in whom more severe renal injury is known to occur [24]. Keeping these in mind, the influence of leukodepletion on perioperative renal injury in high-risk cardiac surgical candidates will therefore constitute the basis for further investigations.

	Acknowledgments

Top Abstract Introduction Patients and methods Results Comment Acknowledgments Discussion References

 
We are grateful for the generous financial assistance from the Royal College of Surgeons of Edinburgh that enabled this work to be completed.

	Discussion

Top Abstract Introduction Patients and methods Results Comment Acknowledgments Discussion References

 
DR PAUL FINNEGAN (New Haven, CT): I am just curious in terms of your ratio that you have presented, how does that correlate to sort of the long-term outcome, let us say 30 days and 180 days? Do you have any data for that?

DR OHRI: We did not set out to look at mid- or long-term, results, and therefore have no follow-up for these patients. But as stated in the results, there was no evidence of any clinical renal morbidity. The serum creatinine and urea was entirely normal for all these patients. This demonstrates that the sensitivity of the marker determines the incidence of subclinical renal injury.

DR FINNEGAN: And what is the cost of the leukodepletion filter approximately?

DR OHRI: In the UK, the cost of this filter is about 90 pounds ($130).

DR MASSIMO CAPUTO (Bristol, United Kingdom): There is some evidence showing that off-pump surgery reduces renal impairment, and we have shown some decrease, for example, in the release of NAG in the urine with off-pump compared with the on-pump. I was just wondering if you have any comparison of the off-pump surgery with some of your cardiopulmonary bypass leukodepletion data.

DR OHRI: We actually presented very recently in the European meeting another randomized study, which we undertook comparing OPCAB and on-pump surgery using the same renal parameters. And in contrast to the study that you published in the Annals from Bristol, we found no difference, actually, between the groups. The two groups were pulsatile perfusion as opposed to nonpulsatile perfusion on pump compared with OPCAB surgery, again in low-risk patients.

DR JOHN E. MAYER, JR. (Boston, MA): Do you have any intention of repeating this study in patients who are at high risk for renal failure? It would seem to me that you would have enough preliminary data based on what you have shown that this might be beneficial and certainly you would like to make the intervention in the group that is at the highest risk.

DR OHRI: Yes, I would entirely agree with your comments. Clearly, I think the issue is one of ethics committee approval and informed consent, which was brought up earlier. For this reason, in our institution we felt we should start with low-risk patients. Having established the protocol, we now intend to seek funding to move on to the high-risk group of patients.

	References

Top Abstract Introduction Patients and methods Results Comment Acknowledgments Discussion References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Augustine T.M. Tang Christos Alexiou Stuart V. Sheppard Marcus P. Haw Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tang, A. T.M. Articles by Ohri, S. K. Search for Related Content PubMed PubMed Citation Articles by Tang, A. T.M. Articles by Ohri, S. K. Related Collections Extracorporeal circulation