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Does Inflammation Fuel the Fire in CKD?
  Am Jnl of Kidney Disease
Dena E. Rifkin, MD, MS, Mark J. Sarnak, MD, MS
Tufts Medical Center, Boston, Massachusetts
Address correspondence to Mark J. Sarnak, MD, MS, Division of Nephrology, Tufts Medical Center, Box 391, 800 Washington St, Boston, MA 02111
Since the landmark 1961 publication from the Framingham Study identifying smoking as a modifiable cardiac risk factor,1 the field of preventive cardiology has burgeoned and the science of risk-factor analysis2 has been applied to other chronic diseases. Of most interest is the identification of risk factors that are not only predictive of disease, but also both modifiable and causal. For the example of cardiovascular disease (CVD), gender is predictive, but nonmodifiable; homocysteine levels are predictive and modifiable, but not necessarily causal; and hypertension is predictive, modifiable, and causal in that treatment reliably reduces the risk of disease..
For chronic kidney disease (CKD), risk factors can be divided into risk of initiation of kidney damage and risk of progression of established kidney damage. Unlike CVD, for which identifiable "events" demarcate the transition from risk and subclinical disease to overt disease, CKD typically is asymptomatic, and markers of damage, such as albuminuria, are few. Thus, for most patients, CKD is first diagnosed as an estimated glomerular filtration rate (GFR) less than 60 mL/min/1.73 m2. This diagnosis is a point on a continuous spectrum; thus, passing the CKD threshold is more likely a sign of progression than initiation. Despite the continuous nature of kidney function loss, passing below an estimated GFR of 60 mL/min/1.73 m2, well before end-stage renal disease, has been associated with a myriad of complications, including CVD,3, 4 muscle weakness,5 cognitive abnormalities,6 hospitalizations,3 physical impairment,7 and high cost.8 Thus, finding new targets for the early treatment and prevention of CKD would be a major advance.
On a population basis, a number of predictive, modifiable, and causal risk factors have been identified for kidney disease progression. Of these, diabetes, hypertension, and vascular disease9, 10 are the most common illnesses, whereas smoking and nonsteroidal anti-inflammatory drug use11 are the most common exposures.12, 13 However, these factors do not entirely explain the population prevalence of CKD.10
A host of inflammatory peptides, including C-reactive protein (CRP), fibrinogen, D-dimer, and many others, have been proposed as risk factors for CVD.14, 15 Many of these are not modifiable or causal, although recent data suggest that treatment of inflammation in those with increased CRP levels may decrease cardiac risk.16 Given the many similarities between risk-factor profiles for patients with cardiac and kidney diseases, it is reasonable to ask whether inflammation promotes the progression of kidney disease. Similarities between atherosclerosis and glomerulosclerosis have been proposed by various investigators; both atherosclerosis and glomerulosclerosis lead to influx of monocytes, production of lipid-laden macrophages, increased presence of cholesterol and cholesterol esters, proliferation of contractile cells, and matrix expansion resulting in fibrosis.17, 18 Biological studies suggest that inflammation has a key role in both processes,19, 20 and subclinical measures of atherosclerosis have been associated with kidney function decrease.21 CKD and an inflammatory milieu are often found together,22 with a high prevalence of increased CRP and fibrinogen levels and white blood cell count and low albumin level noted in patients with stages 3 to 5 CKD.23, 24, 25, 26 However, the causal links between the 2 have not been established in epidemiological studies.
Several analyses of large cohort studies have attempted to address these issues by examining inflammation and subsequent kidney disease outcomes. In the National Health and Nutrition Examination Survey (NHANES), low albumin level and high white blood cell count were associated with future end-stage renal disease or death from kidney disease.27 In the Cardiovascular Health Study (CHS) cohort, older adults with high levels of CRP, factor VII, fibrinogen, white blood cell count, and hemoglobin or low levels of albumin had a greater risk of progressive loss of kidney function, assessed by a change of more than 3 mL/min/1.73 m2/y over 7 years.28 Post hoc analysis of the Cholesterol and Recurrent Events (CARE) Trial suggested that in patients with established CKD, high CRP and soluble tumor necrosis factor receptor II levels were associated with faster progression.29 However, these associations have not been explored previously in a younger population with normal kidney function at baseline and multiple measures of kidney function over time to define incident CKD.
In this issue of the American Journal of Kidney Diseases, Bash et al30 use 14-year follow-up from the Atherosclerosis Risk in Communities (ARIC) Study to provide insight into the links between inflammation and incident CKD, defined as estimated GFR (using the 4-variable Modification of Diet in Renal Disease [MDRD] Study equation) less than 60 mL/min/1.73 m2 or an International Classification of Diseases, Ninth Revision code reflective of CKD. Albuminuria was not measured in this study and therefore was not used as part of the definition of CKD. The ARIC cohort included a middle-aged (45 to 64 years old) group of white and African-American men and women drawn from 4 US cities. Those with baseline CKD were excluded, leaving a sample of 14,854 individuals. Six different markers of inflammation and hemostasis (white blood cell count, fibrinogen, von Willebrand factor, factor VIIc, factor VIIIc, and serum albumin) were assessed. The findings were striking: even after adjustment for known risk factors and baseline estimated GFR, 5 of the 6 analytes tested had significant associations with incident CKD. Factor VIIc (which was associated with incident CKD in the CHS) was not found to have a significant association in ARIC. For the other analytes, the highest quartile of each marker (except for albumin, for which it was the lowest quartile) was associated with a 20% to 40% increase in the adjusted risk of incident CKD in comparison to the lowest quartile. Graded associations were seen with incident CKD risk across the full measured range.
The large multiracial cohort, long follow-up, and robust results across different definitions of CKD and the various inflammatory markers are major strengths of this work. Most studies of incident CKD have had either estimates of GFR6, 9 or diagnostic codes for CKD-related hospitalizations,27 but not both; this limits the specificity or sensitivity of study findings, respectively. Results of this study were similar using either definition, but were stronger using diagnostic codes, as expected from others' findings that diagnostic codes are more specific and tend to detect more advanced CKD.31
A few limitations deserve mention. Although the investigators studied multiple different inflammatory markers, they did not include CRP, which currently is the most commonly measured inflammatory marker in clinical practice.32 It is not clear outside of the research setting whether measurement of multiple markers is required to define inflammation or whether 1 marker would suffice. In this study, for example, the correlation between factor VIIIc (factor VIII coagulant activity) and von Willebrand factor is 0.7, suggesting that only 1 of these would need to be measured in practice. Correlations between the other analytes are weaker, and it is not clear which combination of these would be of most value. We would infer that serum albumin would be the best single analyte to measure because the associations with increased risk of CKD were significant even with minimally decreased levels of albumin and given that these risks were minimally attenuated by multivariate adjustment. However, albumin level is less specific for inflammation or thrombosis than some of the other markers and may be confounded by other illnesses.
An additional question that is not specifically addressed in this report is the fraction of CKD risk attributable to this constellation of inflammatory markers versus other traditional markers of CVD. This would be important in directing potential therapeutic interventions. For example, if traditional factors account on a population basis for 95% of the risk of incident CKD or inflammation proves to be a relatively minor mediator of traditional risk factors,33 inflammation may be of only academic significance in promoting incident CKD. To move from a study like this, which assesses the relative risk associated with inflammation, to predictive use of inflammatory markers to identify individuals at risk of CKD, studies of the test characteristics of the markers are needed, including receiver-operator characteristic curves, discrimination, and test calibration, and a substantial addition to known risk factors would be required.34
Risk associations such as found in this work may be confounded by residual disease (eg, more severe diabetes not adequately characterized by a binary variable might be associated with inflammation and incident CKD) or such unmeasured disease as subclinical CVD and, in particular, albuminuria (as acknowledged by the investigators). The non-CKD cohort in this study is defined by an estimated GFR greater than 60 mL/min/1.73 m2. This cohort includes a subgroup of individuals with albuminuria who are more likely to progress than those with estimated GFR over 60 mL/min/1.73 m2 and no albuminuria; in fact, this subgroup may even be more likely to progress than those with estimated GFR less than 60 mL/min/1.73 m2 and no albuminuria.35, 36 Furthermore, albuminuria is independently associated with such inflammatory markers as fibrinogen level.37 Thus, the association of inflammatory markers with incident CKD may be confounded by unmeasured albuminuria at baseline.
The important findings of this study should be replicated in a population with data for albuminuria, and the comparative importance of inflammation versus other risk factors should be assessed. If a strong and independent association with a high attributable risk caused by inflammation is shown, the value of inflammatory markers in predicting CKD should be assessed, and trials using anti-inflammatory therapies to prevent the progression or initiation of CKD should be considered. Given what we know about the morbidity and mortality associated with CKD, identification of inflammation as a predictive, modifiable, and treatable risk factor would be welcome news indeed.
Acknowledgements Support: Dr Sarnak is supported by National Institutes of Health grant K24 DK078204.
Financial Disclosure: None.
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