Anesth Analg 2003;97:1582-1589
© 2003 International Anesthesia Research Society
CARDIOVASCULAR ANESTHESIA
Kidney-Specific Proteins in Elderly Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass
Joachim Boldt, MD*,
Torsten Brenner*,
Johannes Lang, MD*,
Bernhard Kumle, MD*, and
Frank Isgro, MD
*Department of Anesthesiology and Intensive Care Medicine and the
Clinic of Cardiac Surgery, Klinikum der Stadt Ludwigshafen, Ludwigshafen, Germany
Address correspondence and reprint requests to Prof. Dr. Joachim Boldt, Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Bremserstr. 79, D-67063 Ludwigshafen, Germany. Address email to BoldtJ{at}gmx.net
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Abstract
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In cardiac surgery, acute renal failure (ARF) is more likely in elderly patients than in younger patients. We assessed whether kidney function is different between elderly and younger cardiac surgery patients by measuring kidney-specific proteins. Forty consecutive patients aged <60 yr and 40 patients aged >70 yr without preoperative kidney dysfunction undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) were included. Creatinine clearance and fractional excretion of sodium, as well as urine concentrations of N-acetyl-ß-D-glucosaminidase, -1-microglobulin, glutathione transferase-pi (GST-pi), and glutathione transferase- (GST- ) were measured after induction of anesthesia, at the end of surgery, and at the first and second postoperative days (PODs) on the intensive care unit. Patients ages were 54 ± 4 and 77 ± 3 yr, respectively. Preoperative creatinine concentrations were without significant differences between the two groups. Fractional excretion of sodium was significantly higher after bypass in the elderly than in the younger patients. Urine concentrations of all kidney-specific proteins increased after CPB in the elderly (e.g., GST-pi from 16.2 ± 3.4 to 27.7 ± 3.9 µg/L), whereas they remained almost unchanged in the younger patients. Concentrations of all kidney-specific proteins were significantly larger in the elderly than in the younger patients even at the second POD. Although none of our patients suffered ARF requiring dialysis, increased post-CPB urine concentrations of kidney-specific proteins in the elderly suggest discrete and transient alterations in kidney integrity in comparison with a younger patient population undergoing cardiac surgery.
IMPLICATIONS: Measurement of kidney-specific proteins demonstrated that patients >70 yr (mean, 77 ± 3 yr) undergoing cardiac surgery with cardiopulmonary bypass had moderate and transient alterations in kidney integrity compared with patients aged <60 yr (mean, 54 ± 4 yr). These abnormalities were not detected with standard measures of kidney function (e.g., creatinine concentrations).
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Introduction
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Improvements in surgical techniques, cardiopulmonary bypass (CPB) equipment, and anesthetic management have facilitated expansion of cardiac surgery to more elderly patients (1,2). Perioperative mortality in the elderly undergoing coronary artery bypass surgery, however, is more frequent than in younger patients (2). Elderly patients tend to have less physiologic organ reserve (3), consequently, elderly patients are at increased risk of perioperative morbidity and mortality. This difference is most likely attributable to the frequent incidence of coexisting diseases (4).
Acute renal dysfunction (ARF) is one of the most serious complications of cardiac surgery. ARF requiring dialysis after cardiac surgery occurs in up to 8% of patients and the mortality rate of patients with ARF is frequent (5,6). Severe alterations in renal function (i.e., ARF) are rare, but many patients suffer from altered renal function that does not meet the criteria for ARF (7). The definition of ARF and/or acute renal dysfunction is significant reduction in glomerular filtration rate (GFR) that occurs over a period of 2 wk or less (8), but the definition of postoperative renal failure varies from study to study (9). From 978 patients aged 5090 yr undergoing all types of cardiac surgery, 5.3% suffered renal failure, defined as a >50% increase in serum creatinine, at postoperative day 6 (9). In a retrospective study in 591 patients undergoing various cardiac surgery procedures, in approximately 15% of the patients plasma creatinine increased by >20% (10). In a prospective study in patients undergoing normothermic CPB, 112 of 649 patients suffered from kidney dysfunction defined as a >30% increase in serum creatinine levels (11). Non-dialysis-dependent, more moderate and transient alterations in kidney function have been reported to occur with a frequency rate of up to 30% after cardiac surgery using CPB (12). Age increases the risk of postoperative organ failure and the elderly cardiac surgery patient appears to be particularly vulnerable to development of postbypass renal dysfunction (5,6,13). Damage to the renal tubules precedes biochemical evidence of decreased renal function; consequently, sensitive biologic markers of tubular injury are needed to measure early alterations of kidney integrity (14). Kidney-specific proteins, e.g., N-acetyl-ß-D-glucosaminidase (ß-NAG), -1-microglobulin ( -1-M), glutathione transferase-pi (GST-pi), and glutathione transferase- (GST- ), may be useful in identifying patients at risk of developing impairment of renal functional reserve and tubular function. In the present study, changes of kidney function in elderly patients undergoing cardiac surgery was assessed by measuring kidney-specific proteins and comparing them with changes in a younger patient population.
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Methods
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Forty consecutive patients aged <60 yr and 40 consecutive patients aged >70 yr undergoing elective cardiac surgery were included. The study was approved by the Ethics Study Committee and informed consent was obtained from all patients. Exclusion criteria were renal insufficiency (serum creatinine >150 µmol/L), liver insufficiency (aspartate aminotransferase >40 U/L, alanine aminotransferase >40 U/L), insulin-dependent and non-insulin dependent diabetes mellitus, reduced ventricular function (left ventricular ejection fraction <30%), and use of corticosteroids, nonsteroid antiinflammatory substances, diuretics, and other nephrotoxic substances (e.g., aminoglycosides). In all patients, cardiac catheterization using radiocontrast dye was performed more than 1 wk before surgery. Except for aspirin and other platelet-inhibiting substances, preoperative medication was continued until the morning of the operation.
All patients underwent surgery on the morning of the operation day (first case). In all patients, standardized general anesthesia was used based on weight-related doses of sufentanil, midazolam, and pancuronium bromide. CPB was performed using a nonpulsatile pump, venous reservoir (Capiox; Terumo, Frankfurt, Germany), membrane oxygenator (Quadrox 10/10 Safeline; Jostra, Hirrlingen, Germany), and arterial microfilters (Quart Safeline; Jostra). The (noncoated) circuit was primed with 1000 mL of Ringers lactate (RL) solution and 500 mL gelatin. Standard "large-dose" aprotinin regimen ("Hammersmith" regimen, initial loading dose: 2 million U followed by 500,000 U/h until the end of surgery) was used in all patients. Mild hypothermia (bladder temperature always kept >33°C) and a flow rate of 2.4 L/min/m2 were maintained. To guarantee filling volume of the circuit, gelatin and/or RL were added. When hemoglobin (Hgb) was less than 70 g/L, packed red blood cells (PRBC) were added. When necessary, norepinephrine was given as a bolus to maintain mean arterial blood pressure (MAP) between 50 and 70 mm Hg. During weaning off bypass, pump blood was given as necessary to keep pulmonary artery occlusion pressure (PAOP) between 10 and 14 mm Hg. Blood remaining in the CPB circuit after weaning off bypass was salvaged by a cell-saving device and retransfused after protamine had been given to antagonize heparin effects. Collected shed mediastinal blood was not retransfused postoperatively. All patients were transferred to the intensive care unit (ICU) and controlled mechanical ventilation was continued for at least 3 h. After hemodynamic variables were stable for at least 30 min, temperature was >36°C, and the patient was breathing spontaneously and had satisfactory blood gas analyses, tracheal extubation was performed.
Gelatin solution and RL were infused to keep PAOP or central venous pressure (CVP) between 10 to 14 mm Hg. PRBC were given when Hgb was <90 g/L and fresh-frozen plasma (FFP) was given only to maintain adequate hemostasis (when activated partial thromboplastin time was >70 s, fibrinogen was <2 g/dL, antithrombin III was <40%, and bleeding was present). Epinephrine was administered when MAP was <60 mm Hg and cardiac index (CI) was <2.5 L/min/m2 despite sufficient filling pressures (target for CI: 2.53.0 L/min/m2). Norepinephrine was administered when systemic vascular resistance (SVR) was <600 dyn · sec · cm-5 and MAP was <60 mm Hg (target for SVR: 6001000 dyn · sec · cm-5). Dopamine and fursemide were not given within the study period. All patients were managed by physicians who were not involved in the study.
Hemodynamic monitoring consisted of measurement of HR, MAP, pulmonary artery pressure, PAOP, and CVP using a pulmonary artery catheter (Baxter, Irvine, CA). Cardiac output (CO) was discontinuously measured by thermodilution technique and a bedside microprocessor (ExplorerTM, Baxter, Irvine, CA).
From arterial blood samples or urine specimen, creatinine levels (using Jaffé reaction), Hgb, blood gases, and electrolytes were measured by routine laboratory techniques. Creatinine clearance (UcreaxUvol/Pcreaxduration of urine collection period; [Ucrea: urine creatinine concentration; Uvol: urine volume during the collection period; Pcrea: serum creatinine concentration] and fractional sodium clearance were also measured. Blood sampling and hemodynamic measurements were performed after induction of anesthesia (T0), at the end of surgery (T1), and at 8:00 AM on the first POD (T2) and the second POD (T3). Collecting periods for urine was defined as follows: 1: T01 (400 min) finished at the end of surgery, 2: T12 (20 h) finished 8 AM first POD, 3: T23 (24 h) finished 8 AM second POD.
ß-NAG urine concentrations were measured by a spectrophotometric method (Hoffmann La-Roche, Basel, Switzerland) (normal values in healthy volunteers: 07 U/L), -1-M urine concentrations were analyzed by immunonephelometry (Behring Werke, Marburg, Germany) (normal values in healthy volunteers: <14 mg/L), GST-pi urine concentrations were measured by enzyme immunoassay (NephkitTM-Pi, Biotrin International, Sinsheim-Reihen, Germany) (normal values in healthy volunteers: 1215 µg/L), and GST- urine concentrations were analyzed by enzyme immunoassay (NephkitTM-Alpha, Biotrin International) (normal values in healthy volunteers: 3.5 ± 11.1 µg/L).
A formal sample-size calculation was performed before the study based on data from a previous study on the release of GST- (15). A 50% increase of urinary GST- concentration was assessed to be of clinical importance. The approximate standard deviation of urinary GST- excretion has been found to be approximately 20 µg/L. The error was set at 0.05 (two-sided) and type II error was at 0.2. Based on this assumption, a minimum of 39 patients per group was required.
All data are expressed as mean and standard deviation unless otherwise indicated. A SPSS/PC+ software package was used for statistical analyses (version 4.0, SPSS, Chicago, IL). Categorical variables were tested by 2 test; normally distributed data (tested by Kolmogorov-Smirnov test) were analyzed using Students t-test. One-way and two-way analysis of variance with repeated measures and post hoc Scheffés test were used to determine the effects of group, time, and group-time interaction. The Mann-Whitney U-test or the Kruskal-Wallis H test were also used when appropriate. A P value <0.05 was considered significant.
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Results
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Patients ages were 54 ± 4 yr (range, 4359 yr) and 77 ± 3 yr (range, 7381 yr), respectively (Table 1). The other biometric data and data from the perioperative period were without significant differences between groups (Table 1). Blood loss, urine output, and volume input did not differ significantly between the two groups (Table 2). Use of epinephrine and norepinephrine (Table 3), as well as hemodynamics and serum creatinine levels (Table 4), were without differences between groups. At baseline, Hgb was slightly (but not significantly) less in the elderly group (11.5 ± 0.7 g/dL) than in the younger group of patients (12.6 ± 1.0 g/dL); no more significant differences in Hgb were seen until the end of the study. Significantly more PRBC and FFP were given in the elderly patients than in the younger patients (Table 2). No platelet concentrates were administered. No patient suffered from ARF requiring dialysis/hemofiltration or severe low output syndrome requiring intraaortic balloon pump.
Serum creatinine levels and creatinine clearance were not influenced by age and showed no significant differences between groups within the study period (Table 4, Fig. 1). Fractional excretion of sodium was normal at baseline but was significantly more post-CPB in the elderly patients (6.3% ± 1.3%) (Fig. 1).

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Figure 1. Changes in creatinine clearance (normal value: 70110 mL/min) and fractional excretion of sodium (normal value: <1%) in the two groups. CPB = cardiopulmonary bypass; POD = postoperative day. Values are mean ± SD. +P < 0.05 different to baseline data; *P < 0.05 different to the other group. Dotted lines indicate the range of normal values.
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Beta-NAG and -1-M urine concentrations were normal at baseline (Fig. 2). Both increased after CPB in the elderly and were significantly higher than in the younger patients until the end of the study period (ß-NAG: from 3.6 ± 1.1 to 10.9 ± 1.7 U/L at the first POD; -1-M: from 12.2 ± 2.4 to 22.8 ± 3.2 mg/L at the first POD).
GST- and GST-pi urine concentrations were within normal range in both groups at baseline (Fig. 3). GST- increased in both groups; in the younger patients, however, GST- urine concentrations remained within normal range. Post-CPB and in the ICU, GST- and GST-pi urine concentrations were significantly larger in the elderly than in the younger patients (GST- : from 5.8 ± 2.2 to 15.2 ± 2.9 µg/L at the first POD; GST-pi: from 16.2 ± 3.4 to 27.7 ± 3.9 µg/L at the first POD).
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Discussion
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Post-CPB alterations in renal function range from occult reductions of renal reserve through moderate renal dysfunction with increased creatinine levels to ARF requiring dialysis (16). Subclinical alterations in renal function detected by sensitive markers of tubular damage have been reported in the absence of overt changes in creatinine concentration and creatinine clearance (17,18). In a study in intensive care patients, approximately 30% of patients with normal GFR showed pathological excretion of kidney-specific proteins (e.g., -1-M) (19). In trauma patients, monitoring of standard kidney function (serum creatinine) was not an effective way to detect moderate and transient changes in kidney integrity assessed by kidney-specific proteins (20). Thus we have measured kidney-specific proteins to detect discrete and transient alterations in tubular function. Urinary excretion of -1-M is a marker of proximal tubular dysfunction and indicates mild and reversible tubular lesions even when no histologic damage is seen (21), D-acetyl-ß-glucosaminidase (NAG) is a sensitive marker of lysosomal tubular damage (22), urine GST- is a marker of proximal tubular cell injury (20), and urine GST-pi indicates distal tubular damage (23,24). GST enzymes appear to be more specific for renal tubular injury than other proteins found in the urine (25). We measured both isoenzymes of GST because they are different with regard to size and charge: there may be some filtration of the -form, but is hardly any filtration of the negatively charged pi-enzyme through the glomerulus (26).
Fractional excretion of sodium in the present study was significantly increased in the elderly patients compared with the younger patients. An increase in fractional excretion of sodium may result from renal dysfunction or may be the appropriate homeostatic response to water and osmolar load (27). Volume input was similar in both groups; thus the differences were not likely attributable to different water and osmolar load.
The major result of our study is that urine concentrations of all measured kidney-specific proteins were significantly larger in the patients aged >70 years than in the patients aged <60 years. These differences were identified at the end of surgery and persisted until the second POD. Our results suggest that younger cardiac surgery patients without preexsisting renal disease and without postoperative low CO syndrome did not suffer from postbypass alterations in renal function, whereas the elderly also without preexsiting renal dysfunctions have a risk of discrete and transient alterations in kidney integrity.
The negative influence of CPB on kidney function has been demonstrated by Ascione et al. (28). Comparison of off-pump coronary artery bypass surgery revealed increased urinary concentrations of kidney-specific proteins (NAG) only in CPB-based cardiac surgery.
Postcardiovascular surgery nephropathy may be related to several mechanisms including atheroembolism, inflammation, ischemia-reperfusion, disturbed microcirculatory blood flow, and use of nephrotoxic substances (16,29). The inflammatory response after CPB may also contribute specifically to development of organ dysfunction (16). An imbalance of immune response with increasing age has been demonstrated in previous studies (30). The kidney is not passive in the evolving inflammatory response. The kidney is actively involved in the control of inflammation; however, the kidney is also very vulnerable to this inflammatory process (31,32). Although filtration of proinflammatory mediators by the kidney could help to reduce inflammation, these substances may be tubulotoxic (31,32). In cardiac surgery patients, a correlation between plasma levels of cytokines and tubular injury has been demonstrated by measuring kidney-specific proteins (urine NAG concentrations) (32).
The results of our study are in agreement with other studies examining more sensitive measures of alteration in kidney integrity in cardiac surgery patients. Hamada et al. (33) found a significant increase in ß-NAG in 9 patients undergoing cardiac surgery with CPB in comparison with 7 patients undergoing noncardiac surgery. Dehne et al. (34) demonstrated increased levels of kidney-specific proteins ( -1-M, ß-NAG) in 10 patients aged >70 years after CPB indicating tubular damage in the elderly.
Clinical relevance of increased levels of kidney-specific proteins remains uncertain (11). We did notice an increase in all measured kidney-specific proteins in the elderly; however, none of our patients suffered significantly increased serum creatinine or developed ARF requiring dialysis. Hamada et al. (33) also showed increased ß-NAG after cardiac surgery but failed to note a relationship between the appearance of increased NAG levels with development of postoperative renal failure. The aim of our study was not to identify patients with manifest postbypass ARF. Our patient population was much too small for us to draw definite conclusions with regard to development of ARF and age. Our study was only focused on early alterations in tubular integrity in elderly compared with younger cardiac surgery patients.
We have differentiated patients 70 years of age and older from the younger patient group based on previous studies that documented the increased likelihood of renal dysfunction after cardiac surgery in patients over 65 years of age (13). We selected groups of patients aged <60 years and >70 years to have a clear difference in age between the two groups. We strictly excluded patients with known preexisting renal dysfunction or with diseases that predispose to development of renal dysfunction such as diabetes mellitus. This strict preoperative selection should exclude other factors than CPB as possible causes for renal dysfunction. None of our patients suffered from severe cardiocirculatory failure and use of vasoactive catecholamines was similar in both groups. The amount of intravascular volume administration that may have influenced kidney function was similar in both groups. Although blood loss was not different, the use of PRBC and FFP was different between the two groups. It appears unlikely that this may have influenced kidney-integrity, as Provenchere et al. (11) found that advanced age, active endocarditis, and radiocontrast agent administration are more consistently predictive of postoperative renal dysfunction.
In all our patients, aprotinin was used routinely. Aprotinin may have protective effects on kidney function by attenuating the inflammatory process associated with CPB. However, aprotinin has been suspected to impair renal function (35). As all our patients received aprotinin, the differences in kidney integrity between the two groups do not appear to be attributable to aprotinin. Thus, age appears the most likely reason why differences in kidney integrity were observed in the postbypass period.
In summary, we found that urine concentrations of kidney-specific proteins were significantly increased in cardiac-surgery patients aged >70 yr than in a patient population aged <60 yr, indicating discrete and transient alterations in tubular damage or renal functional reserve in the elderly. The value of perioperative assessment of kidney-specific proteins in the elderly undergoing more complex cardiac surgery procedures to identify patients at risk to develop ARF and the value of kidney-specific proteins to assess possible renal protective strategies should be studied in future prospective trials.
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Accepted for publication July 23, 2003.
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