Chronic Kidney Disease and Adverse Outcomes in the Perioperative Period

C h ro n i c K i d n e y D i s e a s e and Adverse Outcomes in the Pe ri o p er at i ve Pe ri o d Adam C. Schaffer,

MD

KEYWORDS  Chronic kidney disease  Preoperative evaluation  Estimated glomerular filtration rate  Perioperative outcomes  Medication dosing  Acute kidney injury

HOSPITAL MEDICINE CLINICS CHECKLIST

1. All 3 risk assessment tools recommended for use in the 2014 American College of Cardiology/American Heart Association guidelines on perioperative cardiovascular evaluation take into account renal function. 2. Current clinical practice guidelines recommend assessing for chronic kidney disease (CKD) using estimated glomerular filtration rate (eGFR) rather than simply using serum creatinine values, given the risk that a normal serum creatinine can be falsely reassuring, particularly in the elderly. 3. The Kidney Disease Improving Global Outcomes scheme is used to classify CKD severity. 4. The Cockcroft-Gault formula, the Modification of Diet in Renal Disease formula, and the Chronic Kidney Disease Epidemiology Collaboration formula are 3 commonly used tools for calculating eGFR. 5. Studies examining the relationship between eGFR and cardiovascular outcomes generally have found that decrements in eGFR are associated with an increased risk of cardiovascular (and all-cause) mortality in the perioperative setting (and generally). 6. The magnitude of the increased risk of postoperative death associated with CKD is comparable to other commonly used risk factors for adverse postoperative outcomes, such as diabetes mellitus. CONTINUED

Disclosure: The author has nothing to disclose. Hospital Medicine Unit, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA 02115, USA E-mail address: [email protected] Hosp Med Clin 5 (2016) 478–491 http://dx.doi.org/10.1016/j.ehmc.2016.05.006 2211-5943/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.

Chronic Kidney Disease and Perioperative Outcomes

CONTINUED

7. CKD appears to be an independent risk factor for adverse events in the perioperative setting. CKD is a significant predictor of postoperative mortality in multivariate models, and, as the severity of CKD worsens, so do postoperative outcomes. 8. Higher rates of bleeding, an increased infection risk, and incorrect dosing of medications are 3 possible mechanisms by which CKD could result in adverse perioperative outcomes. 9. Among patients with CKD, medication dosing in the perioperative setting can be a challenge, and medications requiring adjustment for impaired renal function are often dosed incorrectly. Collaboration with a clinical pharmacist to help ensure correct dosing of medications is useful. 10. Hospitalists need to appreciate that CKD is an important perioperative risk factor and assess a patient’s renal function as part of a preoperative evaluation. 11. Patients with perioperative acute kidney injury (AKI) superimposed on CKD have particularly poor outcomes. Specific actions hospitalists should take to avoid perioperative AKI in the CKD population are to avoid those causes of AKI known to occur in this setting: hemodynamic stress/hypotension, administration of intravenous contrast material, and administration of nephrotoxic medications.

BACKGROUND

The importance of kidney disease to perioperative outcomes is demonstrated by its inclusion in the commonly used tools for assessing perioperative cardiovascular risk. All 3 risk assessment tools recommended for use in the 2014 American College of Cardiology/American Heart Association guidelines on perioperative cardiovascular evaluation take into account renal function.1 The older revised cardiac risk index, designed to predict major perioperative cardiac complications, has a preoperative serum creatinine level greater than 2.0 mg/dL as 1 of its 6 risk factors.2 Using a serum creatinine threshold of 1.5 mg/dL, the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) cardiac risk calculator counts renal function among the 5 factors that it considers in predicting the risk of perioperative myocardial infarction (MI) or cardiac arrest.3 Finally, the ACS NSQIP Surgical Risk Calculator—another of the newer risk prediction instruments that predicts multiple domains of perioperative risk, including the risk of cardiac complications—considers both whether the patient has acute renal failure and whether the patient is on dialysis.4 Current clinical practice guidelines recommend assessing for chronic kidney disease (CKD) using estimated glomerular filtration rate (eGFR) rather than simply using serum creatinine values, given the risk that a normal serum creatinine level can be falsely reassuring, particularly in the elderly.5 Recent studies assessing the association between CKD and clinical outcomes, including perioperative outcomes, use the Kidney Disease Improving Global Outcomes (KDIGO) scheme to classify CKD severity. Therefore, understanding the KDIGO nomenclature is necessary in order to examine the association between CKD and perioperative cardiac risk. The KDIGO scheme has 6 categories, based on eGFR, as shown in Table 1.5,6

479

480

Schaffer

Table 1 Kidney Disease: Improving Global Outcomes nomenclature for chronic kidney disease Glomerular Filtration Rate Category

eGFR (mL/min/1.73 m2)

Description

G1

90

Normal or high

G2

60–89

Mildly decreased

G3a

45–59

Mildly to moderately decreased

G3b

30–44

Moderately to severely decreased

G4

15–29

Severely decreased

G5

<15

Kidney failure

Adapted from Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int 2013;3(1):1–150; and Stevens PE, Levin A. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med 2013;158(11):825–30.

The KDIGO nomenclature, which requires that the diminished renal function be present for more than 3 months for a diagnosis of CKD to be made, also includes the degree of albuminuria as another dimension to be used in categorizing the extent of the CKD. Two of the most widely used equations for quantitatively estimating renal function are the older Cockcroft-Gault formula,7 which estimates creatinine clearance, and the newer abbreviated Modification of Diet in Renal Disease (MDRD) formula,8 which estimates GFR.9 The even newer Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula10 also estimates GFR and appears to be superior in many populations and more accurate than the abbreviated MDRD equation at higher eGFR values.11,12 Box 1 shows these 3 different formulae for estimating patients’ renal function. The eGFR from the abbreviated MDRD equation is included with the reports of some electrolyte panels. However, it is important to keep in mind that the eGFR is just that,

Box 1 Formulae used to quantify renal function Formula

Parameter Estimated

Cockcroft-Gault7 5 (140 age)  lean body weight (kg)/Cr (mg/dL)  72 Modification of diet in renal disease (abbreviated)8 5 175  Scr 1.154  age 0.203  1.212 (if black)  0.742 (if female) Scr, serum creatinine (in mg/dL). Chronic Kidney Disease Epidemiology Collaboration10 5 141  min(Scr/k, 1)a  max(SCr/k, 1) 1.209  0.993Age  1.018 (if female)  1.159 (if black) Scr, serum creatinine (in mg/dL). k is 0.7 for women and 0.9 for men; a is 0.329 for women and 0.411 for men. min, the minimum of Scr/k or 1; max, the maximum of Scr/k or 1.

Creatinine clearance (in mL/min) Glomerular filtration rate (in mL/min/1.73 m2) Glomerular filtration rate (in mL/min/1.73 m2)

Data from National Kidney Foundation. GFR calculator. Available at: www.kidney.org/ professionals/KDOQI/gfr_calculator. Accessed March 20, 2016.

Chronic Kidney Disease and Perioperative Outcomes

an estimate, and so may be inaccurate in certain circumstances.13 For example, in certain patient populations, such as the elderly, the abbreviated MDRD equation tends to overestimate GFR.14,15 One systematic review and meta-analysis compared the use of eGFR cutoffs calculated using either the Cockcroft-Gault or MDRD equations to dichotomize patients as having CKD or normal renal function, and this review concluded that which equation was used did not significantly affect the relative risk of the clinical outcomes that were measured.9

ESTIMATED GLOMERULAR FILTRATION RATE AND CLINICAL OUTCOMES: SYSTEMATIC REVIEWS AND META-ANALYSES

Studies examining the relationship between eGFR and cardiovascular outcomes generally have found that decrements in eGFR are associated with an increased risk of cardiovascular mortality.16 In one meta-analysis including 105,872 subjects, the hazard ratio for cardiovascular death increased once the eGFR decreased to 60 mL/min/1.73 m2 and continued to increase as eGFR decreased. Once eGFR decreased to 15 mL/min/1.73 m2, the hazard ratio for death was greater than 4. Higher levels of proteinuria were also associated with a higher risk of death, particularly at higher eGFR values.17 There have been 2 systematic reviews and meta-analyses looking at the effect of CKD specifically on perioperative outcomes.9,18 One systematic review and metaanalysis, performed by Mathew and colleagues,18 included 31 cohort studies encompassing 153,885 patients, 27,955 of whom had CKD. Pooled unadjusted odd ratios were determined for each category of surgery studied. Among patients undergoing thoracoabdominal/abdominal aortic aneurysm surgery, the risk of postoperative mortality among CKD patients was 9.2%, compared with 3.2% among patients with normal renal function. Among patients undergoing lower extremity revascularization/ amputation, the risk of postoperative mortality among CKD patients was 7.2%, compared with 3.7% among patients with normal renal function. Among patients undergoing carotid endarterectomy, the risk of postoperative mortality among CKD patients was 4.0%, compared with 1.5% among patients with normal renal function. Among patients undergoing other types of general surgery, the risk of postoperative mortality among CKD patients was 11.3%, compared with 3.1% among patients with normal renal function. The differences in the risk of postoperative mortality between those patients with CKD and those with normal renal function were statically significant in all 4 categories of surgery studied. There was a dose-response effect, such that, as renal function worsened, the risk of postoperative mortality increased. Looking at cardiovascular outcomes specifically, this systematic review and metaanalysis did not calculate pooled odds ratios due to heterogeneity among the studies assessing cardiovascular events.18 However, in 10 of the 13 studies that looked at cardiovascular outcomes, the odds ratio for postoperative cardiovascular events was significantly higher among patients with CKD than among patients with normal renal function. In the 3 studies that used adjusted odds ratios for cardiovascular events, 2 found a significantly higher risk of cardiovascular events among CKD patients, and one study2 found a significantly higher risk in the derivation but not the validation cohort.18 The included study that found the greatest increase in cardiac risk among CKD patients examined 497 patients undergoing carotid endarterectomy, using a serum creatinine level of 1.8 mg/dL as the breakpoint for CKD, and excluded hemodialysis patients from the analysis.19 Patients in this study with CKD had perioperative cardiac events rate of 28.6%, versus 5.4% among patients without CKD.

481

482

Schaffer

The second large systematic review and meta-analysis assessing the effect of CKD on postoperative outcomes, performed by Mooney and colleagues,9 included 46 studies that looked predominantly at patients undergoing vascular and cardiac surgery. Patients with an eGFR of less than 60 mL/min/1.73 m2 had an adjusted relative risk of all-cause short-term postoperative mortality of 2.98 (95% confidence interval [CI] 1.95–4.96). As was the case in the systematic review and meta-analysis performed by Mathew and colleagues,18 as the eGFR decreased, the risk of postoperative mortality increased. Relative to patients with an eGFR of 90 mL/min/1.73 m2, patients with eGFRs of 60, 30, and 15 had odds ratios for 30-day mortality of 2.04, 4.17, and 6.00, respectively.9 Studies including 8388 patients reported data on long-term cardiovascular events postoperatively, and the adjusted relative risk for long-term cardiovascular events among patients with an eGFR of less than 60 mL/min/1.73 m2 was 1.49 (95% CI 1.32–1.67). The largest individual study included in the systematic review and meta-analysis by Mooney and colleagues9 was a cohort of 483,914 patients who underwent coronary artery bypass surgery.20 Compared with patients with an eGFR greater than or equal to 90 mL/min/1.73 m2, patients with an eGFR of less than 30 (although not yet dialysis dependent) have a risk-adjusted odds ratio for operative mortality of 2.87 (95% CI 2.61–3.16), for stroke of 1.76 (95% CI 1.55–2.01), of a hospital stay more than 14 days of 2.82 (95% CI 2.64–3.02), and for becoming dialysis-dependent postoperatively of 20.37 (95% CI 16.68–24.87). For all of these outcomes, the adjusted odds ratio increased as the severity of the CKD increased.20 The magnitude of the increased risk of postoperative death associated with CKD was comparable in multiple studies to other commonly used risk factors for adverse postoperative outcomes.18 For instance, in a study of 3518 patients who underwent lower extremity amputations conducted at Veterans Affairs hospitals, the odds ratio in a multivariate analysis for 30-day mortality for patients with a serum creatinine level greater than 1.2 mg/dL was 1.45 (95% CI 1.09–1.93), and for patients on dialysis, it was 2.50 (95% CI 1.62–3.86).21 This finding compares to an odds ratio for 30-day mortality for patients with diabetes mellitus of 1.40 (95% CI 1.06–1.86). In a study of 2310 patients who underwent major noncardiac vascular surgery in the Netherlands that derived multivariate predictors of 30-day mortality, the odds ratio for renal dysfunction (defined as a preoperative serum creatinine level > 2.0 mg/dL) was 5.2 (95% CI 2.6– 10.2) in the derivation cohort (n 5 1537) and 6.7 (95% CI 2.9–15.1) in the validation cohort (n 5 773).22 By way of comparison, the odds ratio for ischemic heart disease was 3.5 (95% CI 2.1–6.0) and for chronic pulmonary disease was 2.0 (95% CI 1.1– 3.4). In a cohort of 857 patients who underwent carotid endarterectomy, in which the outcome was 30-day mortality, patients with a serum creatinine level greater than or equal to 1.5 mg/dL had an odds ratio of 3.76 (95% CI 1.12–12.61) in a multivariate analysis.23 This odds ratio was higher than the one for diabetes mellitus (2.98, 95% CI 0.98–9.04). ESTIMATED GLOMERULAR FILTRATION RATE AND CLINICAL OUTCOMES: INDIVIDUAL AND SURGERY-SPECIFIC STUDIES

Several investigators have examined the relationship between CKD and adverse postoperative outcomes in specific surgical populations; a select sample of the more recent studies is presented here. In a retrospective analysis of a group of 2323 patients who had undergone noncardiac (predominantly orthopedic and general/gastrointestinal) surgery, perioperative outcomes were stratified by the KDIGO eGFR categories (see Table 1).5,24,25

Chronic Kidney Disease and Perioperative Outcomes

Analyzing perioperative outcomes that occurred during the surgery and subsequent hospitalization, the investigators looked at all-cause mortality, major adverse cardiovascular and cerebrovascular events (MACCE), and length of hospital stay. There was a trend toward increased all-cause mortality as patients’ CKD became more advanced, although this association did not reach statistical significance (P 5 .071). There was a statistically significant increase in the odds ratios for any MACCE and length of hospital stay with more advanced KDIGO CKD stage. The rates of specific subtypes of perioperative MACCE were also studied, including cardiac death, noncardiac death, nonfatal cardiac arrest, angina, acute MI, congestive heart failure, arrhythmia or atrioventricular block, and acute cerebrovascular event. There was a statistically significant association between more severe CKD and a higher rate of all the MACCE subtypes except for acute cerebrovascular events. Although the number of patients in the most advanced CKD categories was modest, the rates of adverse events in these groups were quite high. Among the 57 patients with KDIGO stage 4 CKD (eGFR 5 15–29 mL/min/1.73 m2), 10.6% died and 29.8% had a MACCE. Among the 39 patients with KDIGO stage 5 CKD (eGFR < 15 mL/min/1.73 m2), 7.7% died and 17.9% had an MACCE. In a cohort of 3646 patients who underwent vascular surgery at a single center, the effect of both CKD and acute kidney injury (AKI) on surgical outcomes was examined.26 Compared with patients without kidney disease, patients with CKD had a significantly higher hospital mortality (7.3%, compared with 0.8% in patients without kidney disease) and significantly higher rates of cardiovascular complications (38.9%, compared with 31.3% in patients without kidney disease). Patients with AKI superimposed on CKD had the worst outcomes, with hospital mortality of 14.6% and a cardiovascular complication rate of 63.4%. Patients with CKD also had significantly higher hospital costs than patients without kidney disease. CKD patients had a risk-adjusted relative cost ratio of 1.23 (95% CI 1.13–1.33) (representing $8900 in additional costs). Patients with AKI superimposed on CKD had a risk-adjusted relative cost ratio of 1.49 (95% CI 1.38–1.60; representing $19,100 in additional costs). Using data from the ACS NSQIP, Cloyd and colleagues27 examined the outcomes of 24,572 patients who underwent nonemergent major gastrointestinal surgeries, who were stratified by hemodialysis status and, for those patients not on hemodialysis, eGFR (calculated using the CKD-EPI formula; see Box 1). Patients on hemodialysis had a significantly higher risk of death (odds ratio 7.99, 95% CI 4.89–13.05), MI (5.36, 95% CI 1.30–22.14), and sepsis (2.60, 95% CI 1.60–4.23) compared with patients not on hemodialysis. Compared with patients with an eGFR of 75 to 90 mL/min, once patients’ eGFR decreased to less than 60, the odds ratio for 30-day mortality was significantly increased. Patients with an eGFR of 45 to 60 mL/min (KDIGO class 3a) have an odds ratio for death of 1.6 (95% CI 1.3–2.1). The risk of death increased as eGFR decreased, such that patients with an eGFR of 15 to 30 mL/min (KDIGO class 4) had an odds ratio for death of 5.6 (95% CI 4.3–7.2), corresponding to a 30-day mortality of 13.3%. BASIS FOR THE ASSOCIATION BETWEEN CHRONIC KIDNEY DISEASE AND ADVERSE PERIOPERATIVE OUTCOMES

Given the data pointing to a strong association between CKD and adverse perioperative outcomes, a question that logically follows is whether this association is because CKD is a marker for other well-established risk factors, such as diabetes mellitus and coronary artery disease, or whether CKD is an independent risk factor for poor outcomes perioperatively. Although existing data do not allow us to answer this question

483

484

Schaffer

definitively, substantial evidence exists that CKD is an independent risk factor for adverse events in the perioperative setting.12 In the 4 studies in the systemic review by Mathew and colleagues18 in which CKD was one risk factor in a multivariate model predicting postoperative mortality, CKD had significant predictive value for at least some of the surgical cohorts examined in each of these studies.21–23,28 In an analysis of a Canadian cohort of 1,268,029 patients, in a multivariate model that included both CKD (defined as an eGFR of <60 mL/min/1.73 m2) and diabetes mellitus (defined as a hemoglobin A1c of >6.5%), CKD was an independent predictor of both hospital admission for MI and all-cause mortality.29 Moreover, the rate of both MI and all-cause mortality was higher in patients with CKD (and not diabetes) than in patients with diabetes (but not CKD). Patients with both CKD and diabetes had higher rates of hospital admission for MI and all-cause mortality than patients with either condition alone. Strengthening the case for CKD being an independent predictor of adverse outcomes in the postoperative setting is the observation in multiple studies that, as the severity of CKD worsens, so too do the postoperative outcomes.9,20,24 Multiple plausible mechanisms exist by which CKD could lead to cardiac and other adverse events postoperatively.30 One important possible mechanism is the increased bleeding risk that results from patients’ CKD. A systematic review and meta-analysis of the risk of perioperative bleeding, stratified by whether CKD was present, synthesized 23 studies from 10 countries encompassing 418,846 patients with CKD and 260,327 with normal renal function.31 The unadjusted odds ratio for the risk of perioperative blood transfusions in cardiac surgery for patients with CKD compared with patients with normal renal function was 2.7 (95% CI 2.1–3.4). The unadjusted odds ratio for requiring greater than or equal to 4 units of blood perioperatively was 2.5 (95% CI 1.7–3.6) for cardiac surgery and 2.7 (95% CI 1.6–4.5) for noncardiac surgery. For patients on dialysis, the unadjusted odds ratio for bleeding after cardiac surgery was 2.7 (95% CI 1.6–4.4). In the 4 studies that adjusted for baseline characteristics (which were not pooled due to heterogeneity), the presence of CKD was still associated with a significantly higher perioperative bleeding risk.32–35 Regarding bleeding severity, in all 5 studies that compared the number of units of red blood cells transfused in CKD patients with patients with normal renal function, the CKD patients required a significantly higher number of units of red blood cells.31,32,36–39 After risk adjustment, the presence of CKD was not associated with a higher risk of reoperation.31 With the increased bleeding and resultant anemia, there can be volume overload associated with the need for transfusion as well as increased cardiac events resulting from anemia-induced ischemia. There are also data suggesting that blood transfusions are associated with an increased risk of infection.40–43 Infection itself is another possible reason for the increase in adverse perioperative events seen among CKD patients, who are effectively immunosuppressed.44 Nearly all the data on infection risk in patients with kidney disease have been generated from patients with end-stage renal disease (ESRD) rather than CKD not yet requiring renal replacement therapy. However, with the exception of infections related to hemodialysis vascular access, the increase in infection risk seen among ESRD patients is very likely also to apply to CKD patients who are not on dialysis. Based on an analysis of population data from the US Renal Data System and National Center for Health Statistics, the annual death rate from sepsis was approximately 100 times greater in dialysis patients (both hemodialysis and peritoneal dialysis patients were included) compared with the general population.45 The annual death rate from sepsis among dialysis patients remained 30 to 50 times higher than in the general population even after stratifying patients by whether they had diabetes and after performing sensitivity

Chronic Kidney Disease and Perioperative Outcomes

analyses. Another study, also using the US Renal Data System, examined the incidence, risk factors, and prognosis of sepsis in a cohort of 4005 hemodialysis patients, 11.7% of whom had an episode of sepsis requiring hospitalization (a comparison group with normal renal function was not included).46 Even after adjusting for comorbidities and demographic factors, hemodialysis patients who had an episode of sepsis had a risk ratio of 2.40 (95% CI 2.12–2.72) of death from all causes. Among patients with CKD, medication dosing in the perioperative setting can be a challenge, and medications requiring adjustment for impaired renal function are often dosed incorrectly, setting the stage for adverse outcomes due to medication errors.47 Incorrect dosing of medications in CKD patients can arise from inattention to the need to adjust medications for abnormal renal function, faulty assessment of renal function (eg, not appreciating that an elderly patient has CKD because of a serum creatinine level within the reference range), and inadequate availability of information on how a medication should be adjusted for impaired renal function. A study cohort of 164 inpatients with serum creatinine values greater than or equal to 1.7 mg/dL were ordered 1469 medications during their hospitalizations, 886 of which (60.3%) required dosing adjustments for impaired renal function.48 Dosing adjustments were not performed, or done incorrectly, in 301 of these 886 medications (34.0%). Of these inappropriate orders, 3% were judged as having potentially fatal or severe consequences, and 9% had the potential for serious consequences. Another study examined 169 adult inpatients in a teaching hospital who had an estimated creatinine clearance of less than 40 mL/min and who were not on dialysis.49 Sixty (35.5%) of these patients were prescribed a medication for which dosing adjustment for impaired renal function was indicated, and in 45% of cases the medication doses were not adjusted appropriately. SUMMARY, PERFORMANCE IMPROVEMENT, AND IMPLICATIONS FOR HOSPITALISTS

Multiple studies have demonstrated an association between the presence of CKD and adverse postoperative outcomes—both increased mortality and a higher rate of cardiovascular events. This association is very likely causal because it holds up in multivariate analyses, which control for other risk factors for adverse postoperative events. In addition, several studies have shown a dose-response relationship between eGFR and adverse outcomes, such that, as eGFR worsens, the risk of postoperative events increases. One important implication for hospitalists is that CKD should be appreciated as an important risk factor for adverse outcomes in the perioperative setting, and hospitalists should assess a patient’s renal function as part of a preoperative evaluation. Although renal function is included in the formal risk assessment instruments recommended in the 2014 American College of Cardiology/American Heart Association guidelines on perioperative cardiovascular evaluation, CKD nonetheless is often not considered by many clinicians to be an important risk factor on par with diabetes mellitus or ischemic heart disease. However, studies that have assessed the magnitude of CKD as a risk factor have shown advanced CKD to be a risk factor that is roughly as important as diabetes mellitus or ischemic heart disease. In addition to its importance in predicting commonly used outcomes, such as cardiovascular events, CKD is also a predictor of outcomes that are of particular interest to hospitalists, such as length of stay. One possible reason that CKD has received only modest attention as a risk factor for adverse postoperative events is there is no straightforward intervention to markedly reduce the risk associated with CKD, once this risk is identified. There is no way to

485

486

Schaffer

“fix” CKD, comparable to the ability to perform preoperative revascularization in a patient who is found to have significant coronary artery disease. However, there are measures hospitalists can take in patients with CKD who are undergoing surgery to address some of the CKD-associated perioperative risks. As has been discussed, the need to adjust medication doses for reduced renal function is important and often neglected. Hospitalists must be attentive to the need to adjust renal medications and should collaborate closely with clinical pharmacists in this effort. Physician education and presenting estimated creatinine clearance values have been shown to be beneficial in increasing the proportion of medications that are dosed appropriately for renal function.50 In addition, having a pharmacist make rounds with the team helps ensure medications are dosed appropriately for the patients’ renal function.51 Another important consideration for hospitalists in perioperative patients with CKD is the need to take measures to prevent the development of AKI superimposed on the patients’ pre-existing CKD.52 A full discussion of preventing perioperative AKI is beyond the scope of this article, and several informative reviews exist on this topic.53–55 However, a concise review of this area is important to the care of perioperative CKD patients, because patients with CKD are at higher risk for AKI, and patients who develop AKI on CKD have especially poor outcomes (as well as longer lengths of stay and higher costs).26,56,57 In a study of 3500 patients who underwent cardiac surgery, of the 119 of them who had a greater than 75% decrease in their eGFR or who ended up on dialysis, 59% has pre-existing CKD (defined as an eGFR < 60 mL/min).58 In a smaller study of geriatric patients who underwent surgical repair of their hip fracture, eGFR was the only predictor of AKI that was statistically significant in a multivariate analysis.56 In the perioperative setting, patients with AKI have worse outcomes than those patients who do not develop AKI—including a 6.8-fold increase in the mortality and a 2.1-day increase in length of stay, both of which were statistically significant.59 Specific actions hospitalists should take to avoid perioperative AKI in the CKD population is to avoid those causes of AKI known to occur in the perioperative setting: hemodynamic stress/hypotension, administration of intravenous (IV) contrast material, administration of nephrotoxic medications, and, as discussed above, failure to dose medications appropriately for patients’ renal function. Avoiding hemodynamic stress by ensuring patients remain intravascularly replete and providing appropriate transfusion support, ideally starting in the preoperative setting, is effective at reducing the incidence of AKI.60 Patients with CKD are at significantly elevated risk of developing contrast-induced nephropathy (CIN) (also referred to as contrast-induced AKI),61,62 and the most effective way to avoid CIN is to avoid exposure to IV contrast agents to begin with. It is imperative to avoid multiple IV contrast studies in a short period of time, which necessitates being aware of whether the surgical procedure itself involved the administration of IV contrast, such as typically occurs with endovascular aortic aneurysm repair.63 If perioperative patients with CKD must receive IV contrast, then it is important that these patients be intravascularly volume replete. If there is no contraindication, then administration of isotonic IV fluids to ensure volume repletion should occur starting before the study in which IV contrast will be used and continuing for at least 4 hours after the study.64,65 What role, if any, there exists for specific medications to prevent CIN, such as N-acetylcysteine and statins, remains controversial.66,67 Consideration should be given to holding certain medications on the day of surgery with the goal of reducing the risk of AKI in patients with CKD. Renin-angiotensinaldosterone system antagonists, which include angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers, have been shown to lead to increased

Chronic Kidney Disease and Perioperative Outcomes

hypotension, especially upon induction of anesthesia, which would be expected to increase the risk of AKI among CKD patients. The benefits of these medications in patients, such as those with congestive heart failure, should be weighed against the risks when deciding whether these medications should be held in the perioperative period.68–70 Nonsteroidal anti-inflammatory drugs (NSAIDs) are another medication class that, in many circumstances, should be held before surgery. NSAIDs increase the risk of AKI,71 and this risk is especially pronounced in patients with CKD.72 Moreover, NSAIDs are also associated with an increased risk of perioperative bleeding. Thus, holding NSAIDs before surgery in CKD patients is often warranted.73–75 Hospitalists need to be cognizant of the importance of CKD as a perioperative risk factor. By doing so, hospitalists can remain vigilant for the complications for which CKD patients are at high risk. Hospitalists must also take steps to avoid AKI in perioperative patients with CKD. CLINICAL GUIDELINES

1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int 2013;3(1):1–150. 2. Matzke GR, Aronoff GR, Atkinson AJ Jr, et al. Drug dosing consideration in patients with acute and chronic kidney disease—a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2011;80(11):1122–37. 3. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 2012;120(4):c179–84. REFERENCES

1. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;130(24): e278–333. 2. Lee TH, Marcantonio ER, Mangione CM, et al. Derivation and prospective validation of a simple index for prediction of cardiac risk of major noncardiac surgery. Circulation 1999;100(10):1043–9. 3. Gupta PK, Gupta H, Sundaram A, et al. Development and validation of a risk calculator for prediction of cardiac risk after surgery. Circulation 2011;124(4): 381–7. 4. Cohen ME, Ko CY, Bilimoria KY, et al. Optimizing ACS NSQIP modeling for evaluation of surgical quality and risk: patient risk adjustment, procedure mix adjustment, shrinkage adjustment, and surgical focus. J Am Coll Surg 2013;217(2): 336–46.e1. 5. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int 2013;3(1):1–150. 6. Stevens PE, Levin A. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med 2013;158(11):825–30. 7. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16(1):31–41.

487

488

Schaffer

8. Levey AS, Coresh J, Greene T, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med 2006;145(4):247–54. 9. Mooney JF, Ranasinghe I, Chow CK, et al. Preoperative estimates of glomerular filtration rate as predictors of outcome after surgery: a systematic review and meta-analysis. Anesthesiology 2013;118(4):809–24. 10. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150(9):604–12. 11. Stevens LA, Schmid CH, Greene T, et al. Comparative performance of the CKD Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) Study equations for estimating GFR levels above 60 mL/min/1.73 m2. Am J Kidney Dis 2010;56(3):486–95. 12. Ackland GL, Laing CM. Chronic kidney disease: a gateway for perioperative medicine. Br J Anaesth Dec 2014;113(6):902–5. 13. Stevens LA, Nolin TD, Richardson MM, et al. Comparison of drug dosing recommendations based on measured GFR and kidney function estimating equations. Am J Kidney Dis 2009;54(1):33–42. 14. Drenth-van Maanen AC, Jansen PAF, Proost JH, et al. Renal function assessment in older adults. Br J Clin Pharmacol 2013;76(4):616–23. 15. Douros A, Ebert N, Jakob O, et al. Estimating kidney function and use of oral antidiabetic drugs in elderly. Fundam Clin Pharmacol 2015;29(3):321–8. 16. Levey AS, de Jong PE, Coresh J, et al. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney Int 2011;80(1):17–28. 17. Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010; 375(9731):2073–81. 18. 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(9): 1069–81. 19. Ayerdi J, Sampson LN, Deshmukh N, et al. Carotid endarterectomy in patients with renal insufficiency: should selection criteria be different in patients with renal insufficiency? Vasc Surg 2001;35(6):429–35. 20. Cooper WA, O’Brien SM, Thourani VH, et al. Impact of renal dysfunction on outcomes of coronary artery bypass surgery: results from the Society of Thoracic Surgeons National Adult Cardiac Database. Circulation 2006;113(8):1063–70. 21. Collins TC, Johnson M, Daley J, et al. Preoperative risk factors for 30-day mortality after elective surgery for vascular disease in Department of Veterans Affairs hospitals: is race important? J Vasc Surg 2001;34(4):634–40. 22. Kertai MD, Boersma E, Klein J, et al. Optimizing the prediction of perioperative mortality in vascular surgery by using a customized probability model. Arch Intern Med 2005;165(8):898–904. 23. Debing E, Van den Brande P. Chronic renal insufficiency and risk of early mortality in patients undergoing carotid endarterectomy. Ann Vasc Surg 2006;20(5): 609–13. 24. Mases A, Sabate S, Guilera N, et al. Preoperative estimated glomerular filtration rate and the risk of major adverse cardiovascular and cerebrovascular events in non-cardiac surgery. Br J Anaesth 2014;113(4):644–51.

Chronic Kidney Disease and Perioperative Outcomes

25. Sabate S, Mases A, Guilera N, et al. Incidence and predictors of major perioperative adverse cardiac and cerebrovascular events in non-cardiac surgery. Br J Anaesth 2011;107(6):879–90. 26. Huber M, Ozrazgat-Baslanti T, Thottakkara P, et al. Mortality and cost of acute and chronic kidney disease after vascular surgery. Ann Vasc Surg 2016;30: 72–81. 27. Cloyd JM, Ma Y, Morton JM, et al. Does chronic kidney disease affect outcomes after major abdominal surgery? Results from the National Surgical Quality Improvement Program. J Gastrointest Surg 2014;18(3):605–12. 28. Axelrod DA, Stanley JC, Upchurch GR Jr, et al. Risk for stroke after elective noncarotid vascular surgery. J Vasc Surg 2004;39(1):67–72. 29. 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(9844):807–14. 30. Tonelli M, Karumanchi SA, Thadhani R. Epidemiology and mechanisms of uremiarelated cardiovascular disease. Circulation 2016;133(5):518–36. 31. 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(6):901–13. 32. Ibanez J, Riera M, Saez de Ibarra JI, et al. Effect of preoperative mild renal dysfunction on mortality and morbidity following valve cardiac surgery. Interact Cardiovasc Thorac Surg 2007;6(6):748–52. 33. Al-Sarraf N, Thalib L, Hughes A, et al. The effect of preoperative renal dysfunction with or without dialysis on early postoperative outcome following cardiac surgery. Int J Surg 2011;9(2):183–7. 34. O’Brien MM, Gonzales R, Shroyer AL, et al. Modest serum creatinine elevation affects adverse outcome after general surgery. Kidney Int 2002;62(2):585–92. 35. O’Hare AM, Feinglass J, Sidawy AN, et al. Impact of renal insufficiency on shortterm morbidity and mortality after lower extremity revascularization: data from the Department of Veterans Affairs’ National Surgical Quality Improvement Program. J Am Soc Nephrol 2003;14(5):1287–95. 36. Anderson RJ, O’Brien M, MaWhinney S, et al. Renal failure predisposes patients to adverse outcome after coronary artery bypass surgery. VA Cooperative Study #5. Kidney Int 1999;55(3):1057–62. 37. Anderson RJ, O’Brien M, MaWhinney S, et al. Mild renal failure is associated with adverse outcome after cardiac valve surgery. Am J Kidney Dis 2000;35(6): 1127–34. 38. Charytan DM, Yang SS, McGurk S, et al. Long and short-term outcomes following coronary artery bypass grafting in patients with and without chronic kidney disease. Nephrol Dial Transplant 2010;25(11):3654–63. 39. Witczak B, Hartmann A, Svennevig JL. Multiple risk assessment of cardiovascular surgery in chronic renal failure patients. Ann Thorac Surg 2005;79(4):1297–302. 40. Bernard AC, Davenport DL, Chang PK, et al. Intraoperative transfusion of 1 U to 2 U packed red blood cells is associated with increased 30-day mortality, surgical-site infection, pneumonia, and sepsis in general surgery patients. J Am Coll Surg 2009;208(5):931–7. 41. Murphy GJ, Reeves BC, Rogers CA, et al. Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation 2007;116(22):2544–52.

489

490

Schaffer

42. Braga M, Vignali A, Radaelli G, et al. Association between perioperative blood transfusion and postoperative infection in patients having elective operations for gastrointestinal cancer. Eur J Surg 1992;158(10):531–6. 43. Vamvakas EC. Possible mechanisms of allogeneic blood transfusion-associated postoperative infection. Transfus Med Rev 2002;16(2):144–60. 44. Dalrymple LS, Go AS. Epidemiology of acute infections among patients with chronic kidney disease. Clin J Am Soc Nephrol 2008;3(5):1487–93. 45. Sarnak MJ, Jaber BL. Mortality caused by sepsis in patients with end-stage renal disease compared with the general population. Kidney Int 2000;58(4):1758–64. 46. Powe NR, Jaar B, Furth SL, et al. Septicemia in dialysis patients: incidence, risk factors, and prognosis. Kidney Int 1999;55(3):1081–90. 47. Matzke GR, Aronoff GR, Atkinson AJ Jr, et al. Drug dosing consideration in patients with acute and chronic kidney disease—a clinical update from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2011;80(11):1122–37. 48. Salomon L, Deray G, Jaudon MC, et al. Medication misuse in hospitalized patients with renal impairment. Int J Qual Health Care 2003;15(4):331–5. 49. Cantu TG, Ellerbeck EF, Yun SW, et al. Drug prescribing for patients with changing renal function. Am J Hosp Pharm 1992;49(12):2944–8. 50. Falconnier AD, Haefeli WE, Schoenenberger RA, et al. Drug dosage in patients with renal failure optimized by immediate concurrent feedback. J Gen Intern Med 2001;16(6):369–75. 51. Hassan Y, Al-Ramahi RJ, Aziz NA, et al. Impact of a renal drug dosing service on dose adjustment in hospitalized patients with chronic kidney disease. Ann Pharmacother 2009;43(10):1598–605. 52. Meersch M, Schmidt C, Zarbock A. Patient with chronic renal failure undergoing surgery. Curr Opin Anaesthesiol 2016;29(3):413–20. 53. Borthwick E, Ferguson A. Perioperative acute kidney injury: risk factors, recognition, management, and outcomes. BMJ 2010;341:c3365. 54. Gross JL, Prowle JR. Perioperative acute kidney injury. BJA Education 2015; 15(4):213–8. Available at: http://bjaed.oxfordjournals.org/content/15/4/213. 55. Goren O, Matot I. Perioperative acute kidney injury. Br J Anaesth 2015;115(Suppl 2):ii3–14. 56. Ulucay C, Eren Z, Kaspar EC, et al. Risk factors for acute kidney injury after hip fracture surgery in the elderly individuals. Geriatr Orthop Surg Rehabil 2012;3(4): 150–6. 57. White SM, Rashid N, Chakladar A. An analysis of renal dysfunction in 1511 patients with fractured neck of femur: the implications for peri-operative analgesia. Anaesthesia 2009;64(10):1061–5. 58. Karkouti K, Wijeysundera DN, Yau TM, et al. Acute kidney injury after cardiac surgery: focus on modifiable risk factors. Circulation 2009;119(4):495–502. 59. Biteker M, Dayan A, Tekkesin AI, et al. Incidence, risk factors, and outcomes of perioperative acute kidney injury in noncardiac and nonvascular surgery. Am J Surg 2014;207(1):53–9. 60. Brienza N, Giglio MT, Marucci M, et al. Does perioperative hemodynamic optimization protect renal function in surgical patients? A meta-analytic study. Crit Care Med 2009;37(6):2079–90. 61. Lautin EM, Freeman NJ, Schoenfeld AH, et al. Radiocontrast-associated renal dysfunction: incidence and risk factors. AJR Am J Roentgenol 1991;157(1): 49–58. 62. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract 2012;120(4):c179–84.

Chronic Kidney Disease and Perioperative Outcomes

63. de Bruin JL, Vervloet MG, Buimer MG, et al. Renal function 5 years after open and endovascular aortic aneurysm repair from a randomized trial. Br J Surg 2013; 100(11):1465–70. 64. Brar SS, Shen AY, Jorgensen MB, et al. Sodium bicarbonate vs sodium chloride for the prevention of contrast medium-induced nephropathy in patients undergoing coronary angiography: a randomized trial. JAMA 2008;300(9):1038–46. 65. Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med 2002;162(3):329–36. 66. Subramaniam RM, Suarez-Cuervo C, Wilson RF, et al. Effectiveness of prevention strategies for contrast-induced nephropathy: a systematic review and meta-analysis. Ann Intern Med 2016;164(6):406–16. 67. Zacharias M, Mugawar M, Herbison GP, et al. Interventions for protecting renal function in the perioperative period. Cochrane Database Syst Rev 2013;(9):CD003590. 68. Bertrand M, Godet G, Meersschaert K, et al. Should the angiotensin II antagonists be discontinued before surgery? Anesth Analg 2001;92(1):26–30. 69. Rosenman DJ, McDonald FS, Ebbert JO, et al. Clinical consequences of withholding versus administering renin-angiotensin-aldosterone system antagonists in the preoperative period. J Hosp Med 2008;3(4):319–25. 70. Kheterpal S, Khodaparast O, Shanks A, et al. Chronic angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy combined with diuretic therapy is associated with increased episodes of hypotension in noncardiac surgery. J Cardiothorac Vasc Anesth 2008;22(2):180–6. 71. Ungprasert P, Cheungpasitporn W, Crowson CS, et al. Individual non-steroidal anti-inflammatory drugs and risk of acute kidney injury: a systematic review and meta-analysis of observational studies. Eur J Intern Med 2015;26(4):285–91. 72. Mahmoud LB, Pariente A, Kammoun K, et al. Risk factors for acute decompensation of chronic kidney disease in hospitalized patients in the nephrology department: a case-control study. Clin Nephrol 2014;81(2):86–92. 73. Robinson CM, Christie J, Malcolm-Smith N. Nonsteroidal antiinflammatory drugs, perioperative blood loss, and transfusion requirements in elective hip arthroplasty. J Arthroplasty 1993;8(6):607–10. 74. Connelly CS, Panush RS. Should nonsteroidal anti-inflammatory drugs be stopped before elective surgery? Arch Intern Med 1991;151(10):1963–6. 75. Whinney C. Perioperative medication management: general principles and practical applications. Cleve Clin J Med 2009;76(Suppl 4):S126–32.

491