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Editorials: Editorials

Chronic Kidney Disease

The Silent Enemy?

Sladen, Robert N., MBChB, MRCP(UK), FRCP(C), FCCM

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doi: 10.1213/ANE.0b013e318217f828
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Chronic kidney disease (CKD) has become increasingly prevalent in our aging patient population, especially because glomerular filtration rate (GFR) and renal reserve decline progressively as we grow older.1 The presence of CKD has important implications for our patients undergoing surgery and anesthesia. These may range from impaired handling of anesthetic agents to multiorgan dysfunction and general debility, and specific problems associated with renal replacement therapy (RRT) and transplantation.

Our ability to evaluate renal function and diagnose CKD is largely dependent on measurement of the serum creatinine (SCr), which reflects the steady-state equilibrium between creatinine production from muscle and creatinine excretion by glomerular filtration.2 However, the SCr is a poor indicator of acute changes in the GFR because it may take hours to days before abrupt declines in GFR are matched by a commensurate increase in SCr. Even in steady-state situations, the SCr may be a misleading indicator of GFR because SCr may not increase above normal laboratory limits until the GFR declines below 50 mL/min. Thus, a 20-year-old patient, a 60-year-old patient, and an 80-year-old patient may all have an SCr in the normal range even though the average GFR for these age groups is 125 mL/min, 80 mL/min, and 60 mL/min, respectively. In a sense, the creeping decline in renal reserve is a silent enemy, because it is not diagnosed or even appraised by standard laboratory screening of renal function. Indeed, patients with malnutrition or cachexia produce so little creatinine from their depleted muscle mass that their SCr may remain in the normal range even when GFR declines to as low as 30 mL/min.3

A more meaningful assessment of renal function and reserve is obtained by an estimation of GFR using clearance techniques (creatinine, inulin), or by measuring plasma decay of isotopic markers. However, these are time consuming, involve a varying degree of complexity, and are themselves subject to error. In steady-state situations, nephrologists have long relied on a simple nomogram such as the Cockcroft–Gault equation to calculate an estimated GFR (eGFR), which is based upon patient gender, age, weight, and SCr.4 The Cockcroft–Gault equation has subsequently been displaced by the Modification of Diet in Renal Disease (MDRD) nomogram, which is independent of body weight, and is expressed per 1.73 M2 body surface area5:

The eGFR is modified by a factor of 0.742 for female patients and 1.212 for African-American patients.

Although the MDRD is a convenient and relatively reliable indicator of the severity of CKD, it has some inherent limitations. It is generally accepted that the MDRD provides accurate GFR assessment between 20 and 60 mL/min/1.73 M2 only. In general, there is so much variability in normal GFR that any eGFR calculated >60 mL/min/1.73 M2 is referred to as a “normal” GFR. Although it is weighted for age, the MDRD is still largely dependent on the SCr and does not consider acute changes in GFR or depleted muscle mass, as detailed above. Nonetheless, it has become established as the “gold standard” of estimation of GFR in stable patients with CKD.

In 2002 the National Kidney Foundation (NKF) used the MDRD to categorize CKD into 5 stages of increasing severity (Table 1); the criteria must have been present for longer than 3 months.6,7 Stage 1 CKD includes patients who have a normal eGFR (>90 mL/min/1.73 M2) but are found to have kidney damage defined by the presence of abnormal markers such as albuminuria. Stage 2 CKD is defined as the presence of kidney damage with an eGFR between 60 and 89 mL/min/1.73 M2. (Again, from a practical standpoint it should be recognized that any MDRD eGFR >60 mL/min/1.73 M2 is referred to as a “normal” GFR.) Stages 3 and 4 are characterized by diminishing eGFR, to 30 to 59 and 15 to 29 mL/min/1.73 M2, respectively. Stage 5 patients have an eGFR <15 mL/min/1.73 M2 or have become dependent on dialysis.

Table 1
Table 1:
Stages of CKD (National Kidney Foundation Kidney Disease Outcomes Quality Initiative Classification)

Some notes on terminology are warranted. RRT encompasses the gamut of dialysis (hemodialysis, peritoneal dialysis, continuous venovenous hemodialysis) as well as renal transplantation. End-stage renal disease is a Medicare-defined term that refers to CKD treated with RRT; it is not applied to stage 4 or 5 CKD patients not receiving these treatments.

Using the above definitions, it has been estimated that almost 20 million individuals (about 7% of the population) in the United States suffer from CKD.8 Of these, about 7.5 million have stage 3 CKD, and about three-quarters of a million have stages 4 and 5 CKD.

What are the implications? There is substantial evidence that preexisting CKD increases perioperative risk.9 Most of the data have been obtained in patients undergoing major surgery, notably high-risk vascular surgery or cardiac surgery with cardiopulmonary bypass. For example, in a large study on 37,735 patients undergoing coronary artery bypass graft surgery, Yeo et al. found that operative mortality increased exponentially with increasing stages of CKD.10 In comparison with patients who had an eGFR >60 mL/min/1.73 M2, mortality was increased by 18%, 223%, and 439% in patients with stages 3, 4, and 5 CKD, respectively.

In this edition of Anesthesia & Analgesia, Ackland et al.11 have used the MDRD equation to calculate preoperative eGFR in 526 patients aged 50 years or older undergoing elective major joint replacement procedures. They observed postoperative morbidity prospectively using a validated survey, the Postoperative Morbidity Survey (POMS).12 In comparison with patients with preoperative eGFR ≥60 mL/min/1.73 M2, patients with eGFR <50 mL/min/ 1.73/M2, which comprised more than one quarter of their population, had significantly increased postoperative pain and morbidity, and longer recovery times and hospital length of stay. Significant postoperative morbidity involved the pulmonary, cardiovascular, renal, and nervous systems as well as postoperative sepsis.

Given the relatively large literature on the impact of CKD on postoperative morbidity and mortality that already exists,9 what new information does the Ackland et al. study provide us? First, it addresses an orthopedic surgical population in which the connection between preexisting CKD and postoperative morbidity has not previously been characterized. It does this prospectively using a validated tool (the POMS) that provides us with a means of evaluating the risk of CKD in a wide variety of other noncardiac surgical procedures. Second, it increases our awareness that as our surgical population ages, we should expect a higher incidence of CKD. It is noteworthy that in the Ackland et al. study, the mean age of patients with eGFR >60 mL/min/1.73 M2 was 66 years, in comparison with a mean age of 74 years in patients with eGFR <60 mL/min/1.73 M2.

The Ackland et al. study adds measurably to our understanding of the perioperative risk of CKD, but it does have one unfortunate limitation. Instead of using the NKF stages of CKD as outlined in Table 1 (an eGFR of 30 to 59, 15 to 29, and <15 mL/min/1.73 M2 for stages 3, 4, and 5 CKD), the authors chose to divide their population into subgroups on the basis of an eGFR of 50 to 59, 40 to 49, and 20 to 39 mL/min/1.73 M2, and excluded patients with eGFR <20 mL/min/1.73 M2 or those on dialysis. Thus, one cannot draw conclusions from their study that directly relate to the NKF stage of CKD. In fact, the authors found a “cut-off” eGFR of <50 mL/min/1.73 M2, below which morbidity and mortality increased considerably. Patients with an eGFR of 50 to 59 mL/min/1.73 M2 had morbidity and mortality that differed little from patients with “normal” eGFR >60 mL/min/1.73 M2. Although the study was likely underpowered to detect differences in outcome among stages 3, 4, and 5 CKD, this would be useful information. Nonetheless, it does alert us to the significantly increased risk represented by an eGFR <50 mL/min/1.73 M2 in this population.

Notably, this study cannot begin to address the question of why patients with CKD have such an increased morbidity or mortality. It is clear that CKD must be considered a multisystem disease and that no organ system emerges unscathed. What is the common factor? It is very unlikely that it is urea itself. We know that although RRT controls very well the acute manifestations of uremia (hyperkalemia, acidosis, fluid overload, encephalopathy, enteropathy, and serositis), many others—such as anemia, thrombocytopathy, osteodystrophy, delayed wound healing, and increased susceptibility to sepsis—are incompletely controlled, if at all. We are beginning to understand that there is a multiplicity of unmeasured toxins besides urea that accumulate in CKD and that may play a role in organ dysfunction. More than 90 such toxins have already been identified,13 and include compounds such as β2-microglobulin, advanced glycation end products, advanced oxidation protein products, granulocyte inhibitory proteins, and homocysteine, among others.14 It is understood that small molecules (<500 Da) that are not protein bound, and which include urea and creatinine, are very easily dialyzed by all forms of RRT.15 However, larger, so-called “middle molecules” (>500 Da), or those that are protein bound, are poorly cleared by dialysis. These include inflammatory cytokines such as interleukins, tumor necrosis factor, and complement. Could a low-grade chronic inflammatory state exist in CKD that predisposes patients to multiorgan morbidity after major surgery? In patients with CKD who are not dialysis dependent, it is likely that these toxins accumulate pari passu with diminishing GFR, which may account for the exponential relationship of postoperative morbidity to advancing stages of CKD. For example, a small molecule, asymmetric dimethylarginine (ADMA), accumulates in patients with CKD well before they require RRT. ADMA inhibits nitric oxide synthase and appears to contribute to arterial stiffness, which is characteristic of vascular comorbidity in patients with CKD.13,16 Clearly, this is an avenue that bears fruitful ongoing exploration.

Meanwhile, the Ackland et al. study provides a practical, take-home message that is pertinent to all anesthesiologists in clinical practice. We should assess postoperative risk in patients with elevated SCr or advanced age by utilizing the MDRD nomogram to define the CKD stage. This can be readily accessed on the Internet on the Website of the National Kidney Disease Education Program at All one has to do is insert the patient's age and SCr and the eGFR will be calculated, which allows CKD stage classification. Although some have cautioned against untargeted screening for CKD in the general population,17 and risk may vary with the nature of the surgical procedure, in this author's opinion this simple and rapid assessment of perioperative risk should be incorporated into routine preoperative anesthetic assessment. And we need more studies like those of Ackland et al. to further define outcomes in all realms of surgery.


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