Special Features

Renal Angina

Stuart L. Goldstein and Lakhmir S. Chawla
CJASN May 2010, 5 (5) 943-949; DOI: https://doi.org/10.2215/CJN.07201009

Abstract

Small elevations in serum creatinine may reflect significant kidney damage and be associated with poor patient outcomes, thus rendering creatinine to be a late marker of acute kidney injury (AKI). AKI researchers refer to the AKI biomarker quest as the “search for the renal troponin I,” implying that such putative earlier AKI biomarker use could allow for earlier intervention. We consider the analogy to troponin I and its acceptance to prompt evaluation and therapeutic intervention to treat myocardial ischemia and prevent myocardial infarction an informative and potentially applicable model to the AKI field. Because AKI does not hurt, there is no validated equivalent of chest pain or anginal equivalent to increase suspicion for AKI presence on the part of the clinician. So, although biomarkers may ultimately be validated to detect AKI early, unless nephrologists and intensivists can define “renal angina” to initiate “renal troponin I” assessments, AKI biomarkers may never realize their full potential to improve patient care and outcomes. The purpose of this article is to review both adult and pediatric AKI literature to devise a definition for a renal anginal syndrome equivalent.

Intensive basic and translational research has been expended in the past decade to discover and validate urinary biomarkers to diagnose acute kidney injury (AKI) before rises in serum creatinine. The impetus for this research resulted from the understanding that even a small elevation in serum creatinine may reflect significant kidney damage and be associated with poor patient outcomes, thus rendering creatinine a late marker of AKI. AKI researchers refer to the AKI biomarker quest as the “search for the renal troponin I,” implying that such putative earlier AKI biomarker use could allow for earlier intervention, resulting in mitigation or even prevention of AKI progression to severe acute renal failure and resultant morbidity and mortality.

We consider the analogy to troponin I and its acceptance to prompt evaluation and therapeutic intervention to treat myocardial ischemia and prevent myocardial infarction an informative and potentially applicable model to the AKI field; however one obvious but nevertheless important difference exists. Simply put, AKI does not hurt. Thus, there is no validated equivalent of chest pain or anginal equivalent to increase suspicion for AKI presence on the part of the clinician. So, although biomarkers may ultimately be validated to detect AKI early, unless nephrologists and intensivists can define “renal angina syndrome” to initiate “renal troponin I” assessments, AKI biomarkers may never realize their full potential to improve patient care and outcomes.

The troponin analogy is particularly instructive. When troponin is measured in patients without a clinical syndrome of coronary angina, the performance of this heralded biomarker drops dramatically (1). In addition, when cardiac troponin is measured in cohorts of critically ill patients without a coronary angina syndrome, elevations of troponin that are not indicative of myocardial infarction or atherosclerotic coronary disease are found (2). We believe that if AKI biomarkers are used in conjunction with a renal angina syndrome, then the performance of these biomarkers will be significantly improved.

The purpose of this article is to review both adult and pediatric AKI literature to devise a definition for a renal anginal syndrome equivalent. Although all hospitalized adults and children can experience AKI, we limit our discussion to patients who receive care in an intensive care unit (ICU), where mortality risk is greatest.

First Steps: Determination of Patients Who Are at Risk for AKI

Adult Patients

In critically ill patients, multiple risk factors for the development of AKI have been identified. Demographic and clinical risk factors that have been identified for the development of AKI include advanced age, diabetes, cirrhosis/hepatic failure, congestive heart failure, chronic kidney disease, volume depletion, sepsis, cardiopulmonary bypass time, and exposure to nephrotoxins (3–8). The biochemical risk factors that have been identified include increased levels of IL-6, plasminogen activator inhibitor 1, and soluble TNF-α receptors (Table 1) (9–11). Patients who are on mechanical ventilation and require vasoactive agents also represent a cohort at risk for the development of AKI; however, in all of the studies referenced thus far, certain subsets (e.g., sepsis) of patients have been assessed as opposed to all comers.

View this table:
Table 1.

Risk factors for developing AKI

As a continuum of the coronary artery disease analogy, the identified risk factors can be used in same way that the Framingham data risk factors (hypercholesterolemia, hypertension, diabetes, tobacco use, and family history) are used to identify patients who are high risk for coronary disease.

In addition to risk factors, clinical context must be assessed. For example, a single hour of oliguria in an appropriately resuscitated patient with sepsis is considered an organ failure (12). In addition, small changes in serum creatinine in patients with sepsis likely provide evidence of a profound drop in GFR as compared with a patient with normal creatinine production. Thus, the pretest assessment for ruling in/out AKI must take into account identifiable AKI risk factors and the patient's clinical context. For this assessment to occur for AKI, trainees must be taught to apply this type of screening in the same way they are taught to assess coronary artery disease. Similarly, clinicians who care for critically ill patients should adopt these concepts to screen patients who are at risk for AKI development.

Children

Children typically do not have the comorbid conditions noted for adult patients; however, the epidemiology of AKI in children has changed in the past decade from primary kidney disease, such as hemolytic uremic syndrome, to diseases in which the kidneys are affected as a result of another systemic disease or its treatment (13–15). However, no prospective study has evaluated the rate of AKI development in matched control subjects who are exposed to the same multiple potential AKI causes to identify truly who is at risk. In response, we have had to reverse-engineer to be cognizant of those who are at greatest risk for death with AKI, to guide vigilance and low threshold for evaluation for AKI (not of AKI). Critically ill children who have multiorgan dysfunction or are exposed to nephrotoxic medications represent the most prevalent pediatric cohorts who develop AKI (13). The rates of AKI development in pediatric ICUs depend on the populations studied and the AKI definition used, ranging from 4.5% (16) (all admitted patients with AKI defined as a doubling of serum creatinine, whereby worse organ dysfunction, thrombocytopenia, neurologic dysfunction, nephrotoxic mediations, and hypoxemia were risk factors for AKI) to 82% (17,18) (only children who receive invasive mechanical ventilation and one or more vasoactive medications with AKI defined by a 25% decrease in estimated creatinine clearance). Thus, we suggest that all children with any of these risks factors be monitored closely for the development of AKI.

Next Step: Renal Angina Syndrome Equivalents of AKI

As noted already, patients with AKI do not display a characteristic syndrome that prompts concern and investigation. This lack of an AKI angina equivalent is problematic because we often determine that a patient has AKI well after the window for potentially successful intervention has passed. As a consequence, we offer some AKI angina syndrome equivalents to “chest tightness, shoulder pain, and shortness of breath” that can be symptoms of acute chest pain syndrome.

Adult Patients

On the basis of the available evidence, three objective criteria should prompt the concern of evolving AKI: (1) oliguria, (2) any increase in serum creatinine, and (3) fluid overload (19–21). More specifically, we recommend using oliguria and/or serum creatinine with clinical context and risk factors as a definition of renal angina (Figures 1 and 2). Once an AKI anginal syndrome equivalent is recognized, the process of ruling in/out AKI should begin in earnest. The essential nature of this process is to look for signs and symptoms of kidney injury and to consider whether renal blood flow is adequate. In clinical practice, the process of ruling out AKI is as important as ruling in AKI. Widely available investigations include assessment of urinalysis, urine electrolytes, urine sediment, and presence of urine eosinophils and calculating the fractional excretion of sodium or the fractional excretion of urea in patients who receive diuretics. More frequent sampling of serum creatinine should be initiated when the current routine is only every 24 hours. Cystatin C should be assessed as well in centers with access to its measurement. If any of these investigations are consistent with injury (e.g., urinary casts consistent with tubular necrosis), then AKI management should be instituted. In addition, if the patient progresses to RIFLE (Risk, Injury, Failure, Loss, ESRD) R (1.5× increase in serum creatinine or >6 hours of oliguria in an appropriately resuscitated patient [Table 2]) (20), then AKI is ruled in and AKI management should begin. Centers with available access and experience can use current AKI biomarkers (e.g., NGAL, KIM-1) to help identify patients with AKI. In the future and with larger clinical trials, biomarkers can serve the role of ruling in/out AKI as well as be tools for assessing severity, phenotyping, and prognosis (22,23).

Figure 1.
Figure 1.

Renal angina threshold as a function of predisposition to develop AKI in adults. §Patients with septic shock or patients receiving vasopressors and mechanical ventilation (12,36). Because a change of 0.1 mg/dl is within interassay range for serum creatinine in many laboratories, a repeat of a serum creatinine or more frequent measurement may be required to make sure that the trend is not a consequence of laboratory error. ¥After cardiac surgery: Thakar score ≥5 (7); after general surgery: Michigan classes III through V (6); general ICU: High-risk patients (37,38). ΦAfter cardiac surgery: Thakar score >3 (7); after general surgery: Michigan class II (6); general ICU: Low-risk patients (37,38).

Figure 2.
Figure 2.

Renal angina threshold as a function of predisposition to develop AKI in children. §Patients receiving mechanical ventilation and one or more vasoactive medications (17,18). ¥Patients with acute decompensated heart failure (24) or patients after stem cell transplantation (30,31). ΦPatients admitted to pediatric ICU (16).

View this table:
Table 2.

RIFLE classification system (35)

Children

As noted previously, few data exist to identify children who may be truly at risk for developing AKI. Recent data do exist, however, to show that children with small changes in serum creatinine/estimated creatinine clearance or with increasing degrees of fluid overload are at risk for poor outcome. It is these characteristics that have provided a transformative conceptual framework for focusing on detecting AKI development and its effects earlier in its course. Two pediatric studies demonstrated that the pediatric modified RIFLE AKI classification system (pRIFLE) can be useful to determine AKI severity and potential associations with poor outcome, because critically ill intubated children who develop pRIFLE I or pRIFLE F (>50% decrease in estimated creatinine clearance) are at increased risk for persistent AKI of >48 hours and exhibit higher mortality rates (17,18). A previous study showed that a pRIFLE equivalent of serum creatinine doubling (pRIFLE I) was associated with a 27.4% mortality compared with 2.4% mortality in a cohort of all children were admitted to an ICU (16). Another study that assessed the association of AKI in children with acute decompensated heart failure revealed that in-hospital serum creatinine increase of >0.3 mg/dl was independently associated with patient mortality, need for mechanical ventricular assistance, or heart transplantation (24). Thus, we suggest that attention must be paid to critically children who have small increases in serum creatinine (>0.3 mg/dl) or decreases in estimated creatinine clearance (> 25%) and propose that children who meet either of these thresholds are demonstrating a renal angina equivalent. Furthermore, critically ill patients who develop pRIFLE I or F or doubling of serum creatinine are “ruled in” for AKI (Table 3). Although the urine output pRIFLE criteria did not add any precision in the association between pRIFLE strata and outcome, we still recommend assessing urine output pRIFLE criteria given the small cohorts of patients reported to date.

View this table:
Table 3.

pRIFLE AKI classification system

Critically ill children often require aggressive fluid and inotropic support to maintain adequate perfusion. Substantial single-center (25–28) and multicenter (29) pediatric studies in the past decade demonstrated that increasing degrees of relative fluid accumulation or percentage of fluid overload at the time of renal replacement therapy initiation in children with AKI is independently associated with mortality. Percentage of fluid overload is calculated by totaling fluid volumes from ICU admission to renal replacement therapy (RRT) initiation using the following equation:

[(fluid input in liters) − fluid output in liters)/patient ICU admission weight in kg]

Analysis of various percentage thresholds from these studies suggests that mortality increases from 40 to 60% in children with >10 to 20% fluid overload at RRT initiation, independent of patient severity of illness (Table 4). The pediatric stem cell transplant patient seems to be especially vulnerable to the ill effects of fluid accumulation; although these patients have multiple comorbidities, including the need for mechanical ventilation and sepsis, maintenance of <10% fluid overload is necessary, albeit insufficient alone, to ensure survival of children with pRIFLE I AKI (30,31). Thus, we suggest that critically ill children or children who receive stem cell transplants and develop AKI and >10% ICU fluid overload may be exhibiting a renal angina equivalent and should be monitored closely to determine the cause of AKI and assess the likelihood of prompt kidney function recovery. If such patients develop >15% fluid overload and optimal care requires administration of essential fluids (e.g., total parenteral nutrition, antibiotics, blood products), we suggest that the patient has been ruled in for severe AKI and RRT should be initiated to allow for essential fluid provision and to prevent further fluid overload.

View this table:
Table 4.

Fluid overload and outcome in children receiving continuous RRT

AKI Ruled in

If renal injury is confirmed and the patient is ruled in for AKI, then multiple interventions can be initiated. A full review of interventions in beyond the scope of this article and has been reviewed in detail in recent reviews (32,33). We offer an abbreviated list here:

  1. Evaluate treatable causes of AKI: (a) Rhabdomyolysis, (b) obstruction, (c) volume depletion, (d) glomerulonephritis, (e) sepsis, (f) acute interstitial nephritis, (g) vascular events (e.g., arterial dissection, atheroembolic disease, thrombotic thrombocytopenic purpura).

  2. Optimize hemodynamics and consider objectively assessing cardiac output (e.g., pulmonary artery catheter, echocardiography, noninvasive cardiac output monitoring via arterial line).

  3. Consider initiating goal-directed therapy with an emphasis on conservative late fluid management after the initial resuscitation (34).

  4. Minimize exposure (discontinue when possible) all nephrotoxic drugs (e.g., nonsteroidal anti-inflammatory drugs, aminoglycosides, amphotericin, radiocontrast material).

  5. If the patient is fluid overloaded and resistant to diuretics, then consider ultrafiltration.

Limitations of Recommendations

The renal angina equivalent thresholds recommended in this article are based on available epidemiologic literature and clinical practice. We suggest that the proposed thresholds are testable hypotheses, and the validity of these recommendations should be assessed. In developing this article, some of our colleagues suggested that Acute Kidney Injury Network (AKIN) stage 1/RIFLE R should be the definition of renal angina. As our understanding of early AKI develops, renal angina thresholds will need to be recalibrated; however, it is our strong belief that the combination of clinical risk factors and the patient's clinical context in conjunction with kidney function parameters will be more effective than either alone (Figure 3).

Figure 3.
Figure 3.

Framework of coronary and renal angina. £Cardiac output monitoring is currently the most precise form of intravascular volume status assessment; therefore, volume status is not listed separately.

It should also be noted that we did not address or recommend specific pharmacologic strategies to prevent or mitigate AKI, such as loop diuretics, adenosine antagonists, or fenoldopam. Although some of these agents have shown promise in animal studies or select human populations, large, well-designed studies have not demonstrated any benefit from a specific pharmacologic agent. The lack of positive study likely resulted from the late diagnosis of AKI in the study design, which relied on much greater changes in serum creatinine than suggested here, to herald a renal angina syndrome equivalent.

Although the associations between fluid overload at RRT initiation and mortality in the pediatric population have been consistent, no published have detailed the “fluid overload epidemiology” in pediatric patients who do not receive continuous RRT. Thus, these data have internal validity only in the continuous RRT subset cohort but may not generalize well to patients without AKI. Further study is needed to assess AKI incidence in children with fluid overload and without AKI (e.g., heart failure, liver failure, sepsis with capillary leak) to determine the sensitivity and specificity of fluid overload to predict poor patient outcome.

In addition, we have not recommended a dosage of dialysis small solute clearance or one RRT modality over another, because this was not the purpose of this article. We hope that we have provided evidence for a change in the conceptual approach to an earlier focus on changes in kidney function or, more appropriate, earlier recognition of kidney dysfunction with tools that are available today to prompt therapeutic maneuvers to prevent potentially unnecessary ill effects of AKI, once it is ruled in.

Disclosures

L.S.C. has received consulting fees/honoraria from Astute Medical, Quark Biotech, Sanofi-Aventis, and Nxstage Medical and has received research support from Astute Medical, Quark Biotech, Nephrion, Eli Lilly & Company, and Biosite Medical; S.L.G. has received research support from Gambro Renal Products and serves on the Medical Advisory Board for Gambro Renal Products and Baxter.

Acknowledgments

We thank John Kellum for reviewing the manuscript and his insights about the RIFLE classification system.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • See related editorial, “Acute Renal Syndrome/Renal Angina: A New Paradigm for Studies of Acute Kidney Injury?” on pages 753–755.

Appendix (reproduced from reference 37): Prediction of Acute Kidney Injury (AKI) by Risk Factors Classification

Rakesh Malhotra, Etienne Macedo, Josee Bouchard, Susan Wynn, Ravindra L. Mehta

Medicine, University of California, San Diego, San Diego, CA

Background

Identifying patients at risk for AKI is necessary to enable preventive and early therapeutic strategies. Chawla et al. (Kidney International; 2005) proposed combining individual risk factors to improve predictive value for AKI. We evaluated the performance of their criteria in critically ill patients.

Methods

Patients admitted to a surgical intensive care unit were screened for a prospective observational study on the incidence of AKI. Risk factors were classified as chronic major comorbidities (e.g., advanced age, diabetes mellitus, chronic kidney disease, chronic cardiovascular disease), chronic minor (e.g., hypertension, elevated bilirubin, morbid obesity, chronic lung disease), and acute (e.g., hypotension, sepsis, high-risk surgery, mechanical ventilation or nephrotoxin exposure). Patients were stratified as high risk (HR), low risk (LR), and no risk (NR) based on their risk factor profile at the time of intensive care unit admission. Outcomes included the incidence of AKI, need for RRT, and mortality. AKI was defined by an absolute increase of 0.3 mg/dl from the first measured sCr within 48 hours.

Results

The overall incidence of AKI was 19.5% (63 cases). The LR and NR groups had similar outcomes, whereas HR patients had a higher incidence of AKI (40.2 versus 6.4%; P < 0.001). HR patients also had a significantly higher mortality (12.9 versus 0.7%; P < 0.001) and need for RRT (10.3 versus 0.7%; P = 0.001) compared with LR.

View this table:

Characteristics and outcome of the patients based on risk factor group

Conclusion

A simple risk classification system based on chronic comorbidities and acute events can identify patients at high risk to develop AKI and adverse outcomes. Future studies on AKI should incorporate these factors to stratify patients for prevention and early therapeutic interventions.

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Renal Angina
Stuart L. Goldstein, Lakhmir S. Chawla
CJASN May 2010, 5 (5) 943-949; DOI: 10.2215/CJN.07201009
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