American Journal of Kidney Diseases
Volume 56, Issue 4 , Pages 619-622, October 2010

Filtration Markers in Acute Kidney Injury

  • Andrew S. Levey, MD

      Affiliations

    • Tufts Medical Center, Boston, Massachussetts
    • Corresponding Author InformationAddress correspondence to Andrew S. Levey, MD, Division of Nephrology, Tufts Medical Center Box 391, 800 Washington St, Boston, MA 02111
    • ,
  • Aneet Deo, MD, MS

      Affiliations

    • Tufts Medical Center, Boston, Massachussetts
    • ,
  • Bertrand L. Jaber, MD, MS

      Affiliations

    • St Elizabeth's Medical Center, Boston, Massachusetts

published online 01 September 2010.

Article Outline

 

Commentary on Briguori C, Visconti G, Rivera NV, et al. Cystatin C and contrast-induced acute kidney injury. Circulation. 2010;121(19):2117-2122.

The recent resurgence of interest in acute kidney injury (AKI) is based in part on large epidemiologic studies showing adverse short-term and long-term prognosis.1 The widely used RIFLE (risk, injury, failure, loss, end-stage disease) and AKIN (Acute Kidney Injury Network) definitions and staging systems for AKI rely on changes in serum creatinine and urine output as surrogates for an acute decline in glomerular filtration rate (GFR).2, 3 There are 2 principal limitations of these definitions: reliance on GFR, a measure of kidney function, as a marker for structural damage, and dependence on creatinine as a filtration marker. These limitations have lead to a search for new biomarkers in AKI, including cystatin C, a filtration marker with better prognostic utility than creatinine in chronic kidney disease (CKD). A recent study by Briguori and colleagues,4 published in 2010 by Circulation, is one of several that evaluate cystatin C as a filtration marker for AKI.

As in other diagnostic test studies, reports of novel biomarkers in AKI must clearly indicate the reference standard for comparison. For studies of novel filtration markers, the ideal reference standard would be measured GFR (mGFR). For studies of novel markers of damage, the ideal reference standard would be kidney pathology, which would also allow ascertainment of the damage site and differential diagnosis. However, few studies include mGFR or kidney pathology; as a result, most studies compare markers to other markers and, therefore, cannot assess accuracy. Another approach is to study the clinical utility of novel biomarkers, in which the reference standard is prognosis or response to therapy assessed either using clinical outcomes, such as mortality or kidney failure, or accepted surrogates, such as time to reach AKI stages based on RIFLE or AKIN criteria. A recent systematic review categorizes studies of novel biomarkers for AKI according to their utility in differential diagnosis, early diagnosis, and prognosis.5

In clinical practice, GFR generally is estimated from the serum level of endogenous filtration markers, such as creatinine or cystatin C. In principle, the serum level of an endogenous filtration marker is determined not only by the level of GFR, but also by its “non-GFR determinants,” including the rates of generation, tubular reabsorption and secretion, and extrarenal elimination of the marker; the volume of fluid in which it is distributed; and the accuracy of its measurement.6 GFR estimating equations use the serum level of the marker and demographic and clinical surrogates for the non-GFR determinants to estimate mGFR. Age, sex, and race are surrogates of muscle creatinine generation. Factors affecting generation of cystatin C are less well known,7 although serum levels are affected by thyroid function8 and inflammation.9 Figure 1 shows changes in the serum level of an endogenous filtration marker and estimated GFR (eGFR) after an abrupt change in GFR.6 In the steady state, the serum level is inversely proportional to the level of GFR, and eGFR would be similar to mGFR. In the nonsteady state, the rate of rise in serum level is influenced by the generation rate, and the decline in eGFR would lag behind the decline in mGFR. As shown by Waikar and Bonventre, the time to reach thresholds for AKI stages would vary according to the baseline level and generation rate of a given marker.10 Differences among filtration markers in baseline levels and generation rates would affect the accuracy of changes in the serum level for detecting a decline in mGFR. In addition, the clinical settings associated with AKI may directly affect generation of filtration markers, leading to differences among the rates of rise in serum levels; this is seen in animal models of sepsis, in which the creatinine generation rate appears to be reduced.11

  • View full-size image.
  • Figure 1. 

    Effect of an acute glomerular filtration rate (GFR) decline on generation, filtration, excretion, balance, and serum level of endogenous filtration markers. After an acute GFR decline (first panel), generation of the marker is unchanged, but filtration and excretion are reduced, resulting in retention of the marker (the nonshaded area in the second panel), a rising positive balance (the shaded area in the third panel) and a rising plasma level until a new steady state is reached (bottom panel). During the non–steady state, estimated GFR (eGFR) would be lower than measured GFR. Although GFR remains reduced, the rise in plasma level leads to an increase in filtered load (the product of GFR times the plasma level) until filtration equals generation. At that time, cumulative balance and the plasma level plateau at a new steady state. In the new steady state, eGFR would approximate measured GFR. GFR is expressed in units of milliliter per minute per 1.73 m2. Tubular secretion and reabsorption and extrarenal elimination are assumed to be zero.

Modified and reproduced from Kassirer30 with permission of the Massachusetts Medical Society.

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What Does This Important Study Show? 

Briguori and colleagues conducted a diagnostic test study in 410 consecutive patients with eGFR <60 mL/min/1.73 m2 undergoing diagnostic angiography using iodinated contrast media. The study population had a mean age of 70 ± 9 years and eGFR of 41 ± 10 mL/min/1.73 m2. All patients were treated with isotonic sodium bicarbonate plus N-acetylcysteine before and after contrast media administration. GFR was not measured. The reference test for the diagnosis of AKI was a 0.3-mg/dL increase in serum creatinine within 48 hours. The index test was a 10% increase in cystatin C within 24 hours. Of the 410 patients, 34 (8.2%) had an increase in both serum creatinine and cystatin C, and 53 (13.0%) had an increase in serum cystatin C only. Among 377 patients with 12-month follow-up, 26 (6.9%) died and 8 (2.1%) developed kidney failure. For the composite outcome, the adjusted odds ratios (and 95% confidence intervals) were 2.52 (1.17-5.41) for an increase in serum cystatin C only and 4.45 (1.72-11.54) for an increase in both serum creatinine and cystatin C. The authors concluded that a 10% increase in cystatin C might be a reliable marker for the early diagnosis and prognosis of contrast-induced AKI. It might also identify declines in GFR that are less than the threshold defined by a 0.3-mg/dL rise in serum creatinine, which nonetheless have prognostic importance. Limitations of the study include inability to determine the accuracy of changes in creatinine or cystatin C for detection of changes in mGFR. Additionally, administration of contrast media, bicarbonate-containing fluid, and N-acetylcysteine may affect the non-GFR determinants of these markers; thus, it is not possible to discern whether changes in GFR or changes in non-GFR determinants of the markers are associated with mortality and kidney failure. Another limitation is the absence of separate development and validation cohorts. In particular, the threshold value of 10% for an increase in serum cystatin C was derived from results in the same study population, and may not perform as well in other study populations.

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How Does This Study Compare With Prior Studies? 

Cystatin C is a 13.3 kDa peptide that is freely filtered at the glomerulus, reabsorbed, catabolised by the proximal tubules, and not excreted in the urine; thus, steady-state levels should be highly correlated with serum creatinine and mGFR. Cystatin C may have a shorter half-life and smaller volume of distribution than creatinine; thus, it would be predicted that serum levels of cystatin C would rise proportionately faster than creatinine after a decline in GFR.12, 13 Several studies report a strong relationship between serum creatinine and cystatin C levels in a variety of settings associated with AKI, including cardiac surgery, liver transplant, and cisplatin therapy.14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27 A number of studies show improved detection of decreased mGFR with cystatin C, and some but not all have shown that increases in serum levels in cystatin C can predict the development of AKI, kidney failure, and death. It is likely that some of the differences in findings in these studies are due to the use of different definitions for the index and reference tests and differences in assay performance. (Of note, the detection of cystatin C in the urine has also been used as a marker of kidney damage, reflecting impaired proximal tubular protein absorption.)

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What Should Clinicians and Researchers Do? 

Clinicians should appreciate that changes in serum levels of both creatinine and cystatin C are surrogates for an acute decline in GFR. Differences in accuracy of changes in these markers compared to a decline in mGFR can reflect differences in the non-GFR determinants of the filtration markers (especially their generation and volume of distribution), in the effect of clinical conditions causing AKI on the non-GFR determinants, or in assay performance. At the present time, the changes in serum creatinine included in the RIFLE and AKIN definitions of AKI have been extensively validated and can be applied in clinical practice. A KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline on AKI that is under development will address detection, evaluation, and management.

Further study is necessary to determine the usefulness of serum cystatin C to enable earlier detection of AKI, including validation of the threshold used by Brigouri and colleagues, as well as validation in other causes of AKI. Other filtration markers are under evaluation for CKD, which could be applied in AKI as well.28 Whether earlier diagnosis of AKI will translate into improved patient outcomes must also be tested.

Another question is the utility of eGFR in AKI. GFR estimates in the non–steady state are less accurate than in the steady state; nonetheless, the change in eGFR may be as useful as the change in the serum level of the filtration marker alone in detecting and staging AKI. Potentially, GFR estimates may be more useful than the level of the filtration marker alone when an estimate of the level of kidney function is required, including assessing the severity of AKI, dosing drugs, and gauging recovery. Some have already attempted to develop better estimating equations for non–steady state.29 Ultimately, investigating the accuracy of filtration markers will be facilitated by developing simpler methods for GFR measurements in clinical settings associated with AKI.6

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Acknowledgements 

Financial Disclosure: The authors declare that they have no relevant financial interests.

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References 

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 Originally published online as doi:10.1053/j.ajkd.2010.08.001 on September 1, 2010.

PII: S0272-6386(10)01148-0

doi:10.1053/j.ajkd.2010.08.001

American Journal of Kidney Diseases
Volume 56, Issue 4 , Pages 619-622, October 2010

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