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The incidence of perioperative renal injury appears to be increasing in the ever more complex elderly population presenting for cardiac surgery. More often than not acute kidney injury (AKI) is associated with well-defined risk factors that precede the surgical event. AKI complicates cardiovascular surgery in as many as 30% of all procedures, leading to dramatically worse outcomes, including increased mortality and substantial financial cost.
The incidence of AKI requiring dialysis among patients who undergo coronary artery bypass grafting alone is roughly 1%. However, when valve surgery or coronary artery bypass grafting and valve surgery occur concomitantly, the risks of AKI requiring dialysis are 1.7 and 3.3%, respectively. The risks for AKI rise substantially if there is pre-existing chronic kidney disease (CKD), which afflicts as many as 30 million people in the USA.
Definitions
Lack of a universally accepted definition of the syndrome of acute renal failure has hampered the study, understanding, management, and prevention of this disastrous complication. The complexities of the accompanying fluid, electrolyte, acid–base, and azotemic solute accumulation have led to approximately 50 different diagnostic criteria for acute renal failure to be cited in the literature.
A subgroup of intensivists and critical care nephrologists has formed the AKI Outcomes and Quality Study Group. This group has agreed upon a new definition of acute renal injury, acute kidney injury (AKI) which replaces the term “acute renal failure” and enhances the recent Risk, Injury, Failure, Loss, End-stage (“RIFLE”) criteria.
AKI is generally defined as an abrupt decline in kidney function over less than 48 hours with an increase in serum creatinine of 0.3 mg/dl (greater than 25 μmol/l) or a 50% increase over baseline, accompanying a urine output of less than 0.5 ml/kg/hour.
Stage I – An increase in serum creatinine of greater than 0.3 mg/dl or greater than 150% increase in baseline and urine output of 0.5 ml/kg/hour for 6 hours.
Stage II – A serum creatinine increase of greater than 200–300% over baseline with concomitant decreased urine output to < 0.5 ml/kg/hour for the past 12 hours.
Stage III – An increase in serum creatinine greater than 300% over baseline, or an absolute level of greater than 4 mg/dl, accompanying a urine output of < 0.3 ml/kg/hour) for the past 12 hours. Also included within the stage III definition would be any patient who requires renal replacement therapy.
However, even this new definition is limited by the utilization of increasing creatinine as the serum marker of decreased renal function (decreased glomerular filtration rate, GFR). Increased serum creatinine is well known to lag significantly behind the development of acute injury, and is confounded by its dependence on tubular secretion and relationship to muscle mass and catabolism. Biomarkers of AKI, including serum and urine neutrophil gelatinase-associated lipocalin (NGAL), serum cystatin C, interleukin 17 (IL-17) and kidney injury marker-1 (KIM-1), are relatively new markers of kidney injury and poor kidney function. NGAL has been shown to be an excellent predictor of AKI in the pediatric population, specifically in the cardiovascular surgical population. Serum and urinary increases in NGAL preceded increase in creatinine by over 2 days. Recent data has suggested that NGAL may also be of value in adult perioperative patients.
Outcomes associated with AKI
It is difficult to overstate the negative clinical impact of AKI on outcome after cardiovascular surgery. Any AKI occurring in the perioperative period carries an accompanying mortality rate of 15–30%, increasing substantially to at least 50% when dialysis is required. In fact, an adjusted covariant-independent observation of an eight-fold increase in death rate has been reported among a large cohort of cardiovascular surgical patients (see Table 13.1).
| Mortality (%) | ICU LOS (days) | Hospital LOS (days) | |
|---|---|---|---|
| Normal renal function | 0.9 | 3.1 | 10.6 |
| Renal dysfunction | 19.0 | 6.5 | 18.2 |
| AKI | 63.0 | 14.9 | 28.8 |
Even slight decreases in GFR imply an increased mortality risk: an increased mortality risk of four- to five-fold with any increase in serum creatinine has been reported among patients followed for 1 year. A 30% decrease in GFR during the perioperative period is associated with a 6% overall morality over the subsequent year, as compared with 0.4% mortality without an accompanying AKI. When dialysis is required for AKI, recovery of renal function sufficient to discontinue chronic dialysis occurs in less than half of these patients. This obviously leads to a dramatic decrease in quality of life and longevity (20% mortality rate per year).
The cause of death associated with AKI is most often infection. In fact, approximately 58% of patients with AKI requiring perioperative dialysis in the cardiovascular surgery arena have a diagnosis of sepsis as compared to 3.3% of those without AKI. Whether the sepsis was the cause or result of the AKI is not determined in these studies.
The risks for bleeding, wound complications, and nutritional compromise are also increased among patients with AKI.
Risk factors for AKI
Generally, the risk factors for developing AKI can be separated into those that are patient related versus those that are procedure related. Patient-related factors are predominant, once again emphasizing the overwhelming consequences of the ageing population with their concomitant increased burden of chronic illness. The most important patient-related issue predicting AKI is pre-existing chronic kidney disease. There is an overall 10–20% risk of AKI requiring dialysis among cardiac surgical patients with a serum creatinine preoperatively of 2–4 mg/dl, and the risk of requiring dialysis increases to nearly 28% with a preoperative serum creatinine of greater than 4 mg/dl.
The proportional impact of pre-existing subclinical renal insufficiency is extremely well illustrated by the decade-old study by Chertow. In a study of 43 000 patients, Chertow used multivariate analysis to identify independent risk factors for dialysis in cardiac surgical patients. A fraction of his data is presented in Table 13.2. Of greatest importance is the profound effect of moderately reduced creatinine clearance (CrCl) on the likelihood of postoperative dialysis. In this study, approximately 60% had a CrCl less than 80 ml/minute resulting in an odds ratio for dialysis similar to the odds ratio for dialysis in patients who have had prior heart surgery. The weight of the numbers is astonishing. Anesthetists and surgeons think of prior heart surgery as a profound risk factor, but Chertow demonstrates that moderate decreases in preoperative CrCl are as potent a predictor of postoperative dialysis. Even more important, there are five times as many patients with subclinical renal insufficiency as those who undergo redo operations. Given the “normal” declines in CrCl seen as adults age from 65 to 80 years, the importance of this risk factor cannot be overestimated.
| Prerenal | Intrinsic renal | Postrenal | |
|---|---|---|---|
| BUN/Cr ratio | > 20 | 10–20 | 10–20 |
| Urine specific gravity | > 1.020 | ~ 1.010 | > 1.010 early, < 1.0101 late |
| Uosmol (mosmol/kg) | > 350 | ~ 300 | > 400 early, ~ 300 late |
| U Na (mEq/l) | < 20 | > 30 | < 20 early, > 40 late |
| FE Na (%) | < 1* | > 2–3 | < 1 early, > 3 late |
| U Cr/P Cr ratio | ≥ 40 | ≤ 20 | > 40 early, ≤ 20 late |
| Urine microscopy | Normal, hyaline casts | ATN: dark granular casts, hyaline casts, renal epithelial cells/casts | |
| GN: RBCs, dysmorphic RBCs (> 20%), RBC casts, WBC/WBC casts, proteinuria | |||
| AIN: urine eosinophilia, WBC, WBC casts, hyaline casts (consider CES) |
AIN = acute interstitial nephritis; ATN = acute tubular necrosis; BUN = blood urea nitrogen; CES = cholesterol emboli syndrome; Cr = creatinine; FE Na = fractional excretion of sodium (calculated as: U Na/P Na × P Cr/U Cr × 100); GN = glomerulonephritis; P Cr = plasma creatinine; P Na = plasma sodium; U Cr = urinary creatinine; U Na = urinary sodium; Uosmol = urinary osmolality.
* Falsely low FE Na seen occasionally with acute GN, radiocontrast nephropathy, rhabdomyolysis.
Other associated patient-related risk factors include pre-existing diabetes mellitus, female gender, increasing age, preoperative congestive heart failure, peripheral vascular disease, preoperative balloon pump requirements, chronic obstructive pulmonary disease, emergency surgery, anemia, and, although somewhat controversial, decreased serum ferritin level.
Whether on-pump versus off-pump cardiac surgery may lead to increased risk for AKI has continued to spur controversy. A meta-analysis of randomized controlled trials (4819 patients) determined a 40% relative risk reduction of AKI when defined as an increase in serum creatinine greater than 50% at 30 days. However, no difference was noted in the combined risk of death, MI, stroke or in the requirements for new dialysis (13%). Long-term renal outcomes have recently been published, showing no long-term benefit from off-pump CABG versus on-pump CABG. Subset analysis suggested a potential benefit among CKD patients managed with an off-pump strategy; however this has yet to be proven in a randomized prospective fashion. Difficulties in weaning from CPB and postoperative intra-aortic balloon pump (IABP) are intuitive additional risks for AKI.
No single etiological factor is responsible for the development of postoperative AKI, but a number of related factors certainly interact to contribute to cause renal injury.
Etiology of AKI
In this context, the principal etiological factors are reduction in renal blood flow during CPB, the mediators generated by the systemic inflammatory response syndrome (SIRS) accompanying CPB, and the translocation of endotoxins from the gastrointestinal tract.
Under normal circumstances blood flow to the kidney remains constant despite variations in blood pressure in the range from 80 to 200 mmHg; the kidney thus autoregulates its blood supply. The kidney receives approximately 20% of the total cardiac output (about 1 l/minute). Oxygen delivery thus exceeds 80 ml/minute/100 g tissue. The distribution of blood flow within the kidney is not uniform, with the cortex receiving more than 90% of total blood flow.
Oxygen consumption, however, is less than 10% of total body utilization, and thus there is a low arteriovenous oxygen content difference (1.5 ml oxygen per 100 ml blood). The low oxygen extraction by the kidney suggests that supply exceeds demand and that there should be an adequate oxygen reserve. However, the kidney is highly sensitive to reduction in perfusion, with AKI being a frequent complication of hypotension. The sensitivity of the kidney to damage as a result of hypoperfusion, despite its low overall oxygen consumption, is related to the physiological gradient of intrarenal oxygenation. Within the kidney the cortex and medulla have widely disparate blood flows and patterns of oxygen extraction.
Although a high percentage of blood goes to the cortex (about 5 ml/minute/g), the cortex extracts only about 18% of total oxygen delivered to it. On the other hand, the medullary region has a far smaller blood flow (0.03 ml/minute/g), but has a far greater extraction (about 79% of the delivered oxygen), as a result of the high oxygen requirement for tubular reabsorption of sodium and chloride ions.
Medullary oxygenation is normally strictly balanced by a series of control mechanisms, which match regional oxygen supply and consumption. Failure of these controls renders the outer medullary region susceptible to acute or repeated episodes of hypoxic injury, which may lead to acute tubular necrosis (ATN).
Hypoxia and renal damage
The differing requirements of cortex and medulla for blood flow and oxygen result in an oxygen tension in the cortex of about 50 mmHg higher than that of the inner medulla. This explains why renal tubules are extremely vulnerable to hypoxic injury and why ATN can be induced by as little as a 40–50% decrease in renal blood flow.
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