BJA Advance Access published July 10, 2014

British Journal of Anaesthesia Page 1 of 4 doi:10.1093/bja/aeu222


Chronic kidney disease: a gateway for perioperative medicine G. L. Ackland 1* and C. M. Laing 2 1 2

Wolfson Institute for Biomedical Research, University College London, Cruciform Building, Wing 1.1 Gower Street, London WC1E 6BT, UK Royal Free Hospital, London, UK

* Corresponding author. E-mail: [email protected]

across a broad range of populations.8 The measurement of cystatin C—which provides a measure of renal reserve that is independent of age, sex, and lean muscle mass—may further refine risk assessment in CKD.9 Since the categorization by the National Kidney Foundation of CKD into five stages of increasing severity (Table 1), CKD has consistently been associated—in a ‘dose-dependent’ fashion—with excess allcause mortality and cardiovascular pathology in the general population of all healthcare systems/countries examined.10 UK-specific epidemiology makes similarly sobering reading. The NEOERICA (New Opportunities for Early Renal Intervention by Computerised Assessment) project found that the age-standardized prevalence of stage 3– 5 CKD is 10.6% for females and 5.8% for males in the UK.11 The key repeated finding is that the majority of patients with CKD do not progress to end-stage renal failure, but rather sustain fatal cardiovascular complications prematurely. Most alarmingly, despite the clear association with excess morbidity and mortality, patients are frequently unaware of CKD as exemplified by the US REGARDS (REasons for Geographic And Racial Differences in Stroke) cohort study.12 In REGARDS, ,10% of 3803 adults with coronary artery disease—and in routine contact with tertiary level medical providers—were aware of having CKD.

Impact of CKD on cardiovascular disease Compelling epidemiological data show that CKD confers increased risk of cardiovascular morbidity and mortality, irrespective of age, gender, and ethnic group. While CKD in the UK population certainly associates with increased risk of hypertension, diabetes, and cardiovascular disease, an important recent study interrogating a large (1 268 029) patient cohort showed the true importance of recognizing CKD in relation to cardiovascular morbidity and mortality.13 In this cohort, the rate of myocardial infarction was lower in those with diabetes—without CKD—than in those with CKD without diabetes. The rate of incident myocardial infarction in people with diabetes was substantially lower than for those with CKD when defined by eGFR of ,45 ml min21 1.73 m22, severely increased proteinuria, or both. Thus, CKD increasingly takes centre stage for defining patients at the highest risk of future coronary and all-cause cardiovascular events. Although heavily biased towards cardiac and vascular surgery, the

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In this issue of the BJA, Mases and colleagues1 on behalf of the Spanish ANESCARDIOCAT perioperative research group2 add important data to the expanding perioperative literature describing chronic kidney disease (CKD) as a consistent associate with postoperative morbidity. This post hoc observational study confirms the findings of a previous meta-analysis, showing an increased risk of perioperative major cardiovascular events in patients with estimated glomerular filtration rate (eGFR) ,45 ml min21 1.73 m22.3 These data extend the perioperative CKD literature by assessing major adverse cardiac and cerebrovascular events (MACCE) in surgical populations other than vascular surgery,3 the chief focus of previous studies primarily due to the perceived higher event rate for MACCE in this population. At this juncture, it is worth bearing in mind that the ANESCARDIOCAT study defined MACCE without routine high-sensitivity troponin sampling—which may therefore underestimate the true magnitude of the association between CKD and cardiac ischaemic events.4 Indeed, the first cohort of the international VISION study (Vascular Events in Noncardiac Surgery Patients Cohort Evaluation Study) suggests an association between postoperative troponin leak and degree of chronic renal dysfunction in 15 000 patients.5 Both studies therefore reinforce the consistently negative impact of CKD on outcomes after non-cardiac surgery. Taken together with other recent studies, it is clear that even asymptomatic preoperative kidney impairment is associated with clinically significant increases in postoperative morbidity and mortality, as demonstrated in elective orthopaedic6 and major abdominal surgery.7 Thus, CKD defines a significant but substantial minority of patients who can be readily identified with real-time, objective, cheap, and prognostically important renal function tests that should be a key feature of every preoperative assessment. By virtue of several creatinine-based prediction equations, the robust assessment of renal function is readily available (several web-based resources and apps are available; the calculators provided by the National Institute of Health National Kidney Disease Education Program are an excellent resource: Of the purely creatinine-based equations, CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula has emerged as the most robust calculator. CKD-EPI classifies fewer individuals as having CKD and is superior for quantifying the risk for mortality compared with the MDRD (Modification of Diet in Renal Disease) study equation



Table 1 Stages of chronic (chronic is defined as either renal damage or GFR,60 present for ≥3 months) kidney disease. *Renal damage is defined as pathological abnormalities or markers of damage identified through imaging studies, blood or urine tests GFR (ml min21 1.73 m22)




Renal damage* with normal GFR



Renal damage* with mild decrease in GFR

60 –89


Moderate decrease in GFR

30 –59


Severe decrease in GFR

15 –29


Renal failure

,15 (or dialysis)

Immediate perioperative challenges associated with CKD The Journal has previously published an extensive review of how CKD may affect anaesthetic practice, with detailed anaesthetic scrutiny of fluid balance, haemodynamic monitoring, and autonomic dysfunction clearly becoming increasingly important in patients with minimal renal reserve.16 Since that review, a recent meta-analysis has confirmed that CKD confers an increased risk of perioperative bleeding, as has been reported for bleeding in non-surgical settings.17 Furthermore, it has become evident that the acquisition of, and mortality from, sepsis is also higher in patients with CKD— including those patients with eGFR above end-stage disease. The Third National Health and Nutrition Examination Survey (NHANES III) focused on CKD beyond the dialysis subpopulation. NHANES III found that compared with individuals with eGFR ≥60 ml min21 1.73 m22, infection-related mortality was progressively more likely as eGFR declined, with a significantly elevated risk even for eGFR of 45–60 ml min21 1.73 m22.18 Similar graded relationships for urinary albumin (albumin-to-creatinine ratio) were found. While plausible mechanisms of acquiring sepsis in end-stage renal failure have been explored, the predisposition to infectious complications in less severe grades of CKD remains mechanistically unclear. However, laboratory models certainly confirm that

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The dangers of CKD preceding end-stage renal failure The dose –response relationship between CKD, significant noncardiac postoperative morbidity associated and prolonged hospital stay mirrors similar studies in the general medical population, where CKD increases the risk of adverse outcomes after percutaneous coronary intervention23 24 and accelerates the progression of chronic heart failure.25 These associations are not surprising, given that the spectrum of pathophysiological features described in CKD includes increased levels of inflammatory mediators, elevated plasma homocysteine, hypercoagulability, arterial calcification, and endothelial dysfunction.25 What remains unclear is how these pathological features map to clinically relevant grades of CKD severity. Most of the literature focuses on end-stage renal failure, rather than the comparative or sequential study of pathophysiological changes and mechanisms associated with progressive worsening of renal function.

A critical opportunity for perioperative medicine The early identification of individuals with CKD, especially those populations with a high risk for CKD and related adverse outcomes, is a major public healthcare challenge. Both the identification and subsequent implementation of evidence-based interventions may slow or prevent the progression to advanced stages of the disease, reduce the risk of cardiovascular disease, multiple other complications, and improve quality of life.26 Given the scale of non-cardiac surgery, particularly in an ageing population with frequently undiagnosed or unrecognized CKD, a role for perioperative medicine in deciphering the impact of progressive stages of CKD on postoperative and general healthcare outcomes is self-evident. The NEOERICA study of computerized records

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perioperative literature mirrors these findings. Operative mortality after coronary artery bypass graft surgery increases dramatically with worsening degrees of kidney disease, particularly those patients with CKD stages 3–5.14 15 Meta-regression analysis of five retrospective studies conducted exclusively in major vascular surgery similarly suggests a graded relationship between severity of CKD and postoperative death.2 Further examination of the recently completed Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) Study will provide definitive contemporary data to substantiate the relationship between CKD stages and (higher sensitivity) troponin-defined perioperative cardiovascular events. Importantly, this 40 000 patient observational study enrolled patients undergoing a broad range of non-cardiac surgical procedures, not just non-vascular surgery.

pre-existing CKD promotes further sepsis-induced acute kidney injury and increases mortality.19 Drug clearance, which is usually proportional to GFR, presents a particular challenge in CKD patients during the perioperative period. The vast majority of manufacturers’ dosing recommendations are based on the use of measured GFR or creatinine clearance estimated by the Cockcroft – Gault formula. Very few studies have directly linked dosing by eGFR with pharmacokinetic or clinical outcomes.20 An exception is the finding that abnormal platelet function in response to clopidogrel is associated with worse outcomes after percutaneous coronary intervention in patients with CKD.21 Factors other than renal drug clearance can also alter drug effects, including a substantially higher frequency of adverse drug reactions to water-soluble drugs in elderly patients with unrecognized CKD. As proof of principle, interventional studies in separate healthcare systems have demonstrated that clinical decision support systems targeted at appropriate drug dosing in CKD reduce the hospital length of stay.22



Declaration of interest G.L.A. is supported by Academy of Medical Sciences/Health Foundation Clinician Scientist fellowship.

References 1 Mases A, Sabate´ S, Guilera N, et al. Preoperative estimated glomerular filtration rate and the risk of subsequent perioperative major adverse cardiovascular and cerebrovascular events in non-cardiac surgery. Br J Anaesth 2014, in press 2 Sabate S, Mases A, Guilera N, et al. Incidence and predictors of major perioperative adverse cardiac and cerebrovascular events in noncardiac surgery. Br J Anaesth 2011; 107: 879– 90 3 Mathew A, Devereaux PJ, O’Hare A, et al. Chronic kidney disease and postoperative mortality: a systematic review and meta-analysis. Kidney Int 2008; 73: 1069– 81 4 Vascular Events in Noncardiac Surgery Patients Cohort Evaluation Study I, Devereaux PJ, Chan MT, et al. Association between




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20 21



postoperative troponin levels and 30-day mortality among patients undergoing noncardiac surgery. J Am Med Assoc 2012; 307: 2295– 304 Botto F, Alonso-Coello P, Chan MT, et al. Myocardial injury after noncardiac surgery: a large, international, prospective cohort study establishing diagnostic criteria, characteristics, predictors, and 30-day outcomes. Anesthesiology 2014; 120: 564–78 Ackland GL, Moran N, Cone S, Grocott MP, Mythen MG. Chronic kidney disease and postoperative morbidity after elective orthopedic surgery. Anesth Analg 2011; 112: 1375– 81 Cloyd JM, Ma Y, Morton JM, Tamura MK, Poultsides GA, Visser BC. Does chronic kidney disease affect outcomes after major abdominal surgery? Results from the National Surgical Quality Improvement Program. J Gastrointest Surg 2014; 18: 605–12 Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009; 150: 604–12 Shlipak MG, Matsushita K, Arnlov J, et al. Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med 2013; 369: 932–43 Tonelli M, Wiebe N, Culleton B, et al. Chronic kidney disease and mortality risk: a systematic review. J Am Soc Nephrol 2006; 17: 2034– 47 Stevens PE, O’Donoghue DJ, de Lusignan S, et al. Chronic kidney disease management in the United Kingdom: NEOERICA project results. Kidney Int 2007; 72: 92–9 McClellan WM, Newsome BB, McClure LA, et al. Chronic kidney disease is often unrecognized among patients with coronary heart disease: the REGARDS Cohort Study. Am J Nephrol 2009; 29: 10–7 Tonelli M, Muntner P, Lloyd A, et al. Risk of coronary events in people with chronic kidney disease compared with those with diabetes: a population-level cohort study. Lancet 2012; 380: 807–14 Hillis GS, Croal BL, Buchan KG, et al. Renal function and outcome from coronary artery bypass grafting: impact on mortality after a 2.3-year follow-up. Circulation 2006; 113: 1056– 62 Holzmann MJ, Hammar N, Ahnve S, Nordqvist T, Pehrsson K, Ivert T. Renal insufficiency and long-term mortality and incidence of myocardial infarction in patients undergoing coronary artery bypass grafting. Eur Heart J 2007; 28: 865–71 Craig RG, Hunter JM. Recent developments in the perioperative management of adult patients with chronic kidney disease. Br J Anaesth 2008; 101: 296–310 Acedillo RR, Shah M, Devereaux PJ, et al. The risk of perioperative bleeding in patients with chronic kidney disease: a systematic review and meta-analysis. Ann Surg 2013; 258: 901– 13 Wang HE, Gamboa C, Warnock DG, Muntner P. Chronic kidney disease and risk of death from infection. Am J Nephrol 2011; 34: 330– 6 Doi K, Leelahavanichkul A, Hu X, et al. Pre-existing renal disease promotes sepsis-induced acute kidney injury and worsens outcome. Kidney Int 2008; 74: 1017–25 Fink JC, Joy MS, St Peter WL, Wahba IM. Finding a common language for patient safety in CKD. Clin J Am Soc Nephrol 2012; 7: 689– 95 Morel O, El Ghannudi S, Jesel L, et al. Cardiovascular mortality in chronic kidney disease patients undergoing percutaneous coronary intervention is mainly related to impaired P2Y12 inhibition by clopidogrel. J Am Coll Cardiol 2011; 57: 399– 408 Mason NA. Polypharmacy and medication-related complications in the chronic kidney disease patient. Curr Opin Nephrol Hypertens 2011; 20: 492–7 Bae EH, Lim SY, Cho KH, et al. GFR and cardiovascular outcomes after acute myocardial infarction: results from the Korea Acute

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found that for a general practice of 10 000 patients, around 150 patients with stages 3–5 CKD would be identified—over and above those patients already known to have CKD.11 Indeed, perioperative medicine finds itself in an unrivalled position to contribute in helping define a new strategy to address CKD progression. Central to this role is the use of standardized, population-based definitions to define CKD, which has often been lacking in previous perioperative studies. Understanding how immediate and longer-term postoperative outcomes impact on CKD progression can help elucidate mechanisms through which CKD alters renal and extra-renal disease. The perioperative environment provides an ideal, controlled human model to enable further mechanistic understanding of why CKD patients are more prone to cardiac, infectious, and drug/pharmacokinetic-related morbidity. In this way, experimental perioperative medicine can provide important mechanistic insights that translate to the wider CKD population. Thus, not only should CKD be regarded as a robust marker of increased perioperative risk of morbidity, but also a key element underlying the emergence of perioperative medicine as a preventive translational speciality. For example, the NEORICA study identified that arterial pressure was appropriately controlled in only 20% of diabetic patients with stage 3–5 CKD.11 The REGARDS study highlighted the need for subspeciality clinicians routinely assessing renal function to be cognizant of the wider implications of CKD in order to educate and inform their patient population.12 Effective perioperative medicine should be in the vanguard of directing readily available interventions and the targeting of specialist resources to address these clear deficiencies. Thus, both acute and longer-term outcomes for patients with CKD can be positively influenced by perioperative medicine. Adopting the routine practice of applying creatinine to calculate eGFR using the MDRD or CKD-EPI nomogram—or merely noting the increasingly commonly automated reporting of estimated GFR—can help firmly establish the contribution of academic and clinical perioperative medicine to surgical patient care well beyond the perioperative period.

BJA Myocardial Infarction Registry. Am J Kidney Dis 2012; 59: 795 – 802 24 Dohi T, Kasai T, Miyauchi K, et al. Prognostic impact of chronic kidney disease on 10-year clinical outcomes among patients with acute coronary syndrome. J Cardiol 2012; 60: 438– 42 25 McCullough PA, Kellum JA, Haase M, et al. Pathophysiology of the cardiorenal syndromes: executive summary from the eleventh


consensus conference of the Acute Dialysis Quality Initiative (ADQI). Contrib Nephrol 2013; 182: 82 –98 26 Fink HA, Ishani A, Taylor BC, et al. Screening for, monitoring, and treatment of chronic kidney disease stages 1 to 3: a systematic review for the U.S. Preventive Services Task Force and for an American College of Physicians Clinical Practice Guideline. Ann Intern Med 2012; 156: 570–81

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Chronic kidney disease: a gateway for perioperative medicine.

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