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Inflammation & Kidney Disease
 
 
  "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."
 
"Cardiovascular disease and CKD share several common antecedents, including increased blood pressure, dyslipidemia, and diabetes.1, 3, 4.......These results add to a growing body of evidence suggesting that inflammation and hemostasis are important pathways in the progression of kidney disease that are independent of major traditional risk factors. Although a specific mechanism that can be targeted for intervention has not been identified, these findings may help focus investigations into pathological mechanisms for CKD and have implications for the development of prevention and treatment strategies designed to reduce the impact of kidney disease in the population
......Our results suggest that markers of inflammation and hemostasis also are associated with risk of kidney function decrease in middle-aged persons. In this study, increased WBC, fibrinogen, factor VIIIc, and VWF levels and decreased serum albumin levels were associated with greater occurrences of CKD.We found that associations were stronger in individuals with diabetes than in those without diabetes for albumin, WBC, fibrinogen, VWF, and factor VIIIc values." from the study authors
 
"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." from the Editorial
 



 
Does Inflammation Fuel the Fire in CKD? Editorial

 
American Journal of Kidney Diseases
Volume 53, Issue 4 , Pages 572-575, April 2009
 
Dena E. Rifkin, MD, MS, Mark J. Sarnak, MD, MS
Division of Nephrology, Tufts Medical Center, Box 391, 800 Washington St, Boston, MA 02111
 
Related Article, p. 596
 
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.
 



 
Inflammation, Hemostasis, and the Risk of Kidney Function Decline in the Atherosclerosis Risk in Communities (ARIC) Study
 
American Journal of Kidney Diseases
Volume 53, Issue 4 , Pages 596-605, April 2009
 
Editorial, p. 572
 
Several risk factors for atherosclerotic cardiovascular disease, including hypertension and diabetes, also have a role in the development of chronic kidney disease (CKD).1, 2, 3, 4 Findings from recent studies suggest that markers of inflammation and hemostasis, many of which predict cardiovascular disease, may also predict kidney function decrease5, 6 and damage.7 The significant overlap between hemostatic and inflammatory processes suggests that these factors should be examined together.
 
Increased white blood cell (WBC) count and low serum albumin level predicted progression of kidney disease in a nationally representative sample of adults and in the elderly.5, 6, 8, 9 However, data for other inflammatory markers and markers of hemostasis are conflicting and sparse. C-Reactive protein level was not associated with progression of CKD in the Modification of Diet in Renal Disease (MDRD) Study, but was associated with decreasing kidney function in the elderly.6, 10 Plasma fibrinogen and factor VII levels were found to predict kidney function decrease in the elderly in 1 study, but these findings have not been observed in other populations.6
 
In the present study, we explore the association between circulating levels of several markers of inflammation and hemostasis and decreasing kidney function in a middle-aged population-based cohort, the Atherosclerosis Risk in Communities (ARIC) Study. We hypothesized that increased levels of markers of inflammation and hemostasis are associated with increased risk of kidney function decrease after adjusting for potential confounders and baseline kidney function.
 
Discussion
 
Cardiovascular disease and CKD share several common antecedents, including increased blood pressure, dyslipidemia, and diabetes.1, 3, 4
 
Our results suggest that markers of inflammation and hemostasis also are associated with risk of kidney function decrease in middle-aged persons. In this study, increased WBC, fibrinogen, factor VIIIc, and VWF levels and decreased serum albumin levels were associated with greater occurrences of CKD.
 
Among the strengths of the present study are the large population-based sample and the relatively long follow-up (mean follow-up, >14 years). In addition, the ARIC cohort is very well characterized and has a large number of African Americans, a group at particularly high risk of CKD. This study assessed multiple inflammatory and hemostatic markers and included extensive data for potential confounders.
 
Because measures for albuminuria were available at only visit 4, we could exclude only prevalent cases of CKD stage 3 or higher; therefore, our sample may include individuals with prevalent CKD stage 1 or 2 at baseline. Also among the limitations of the present study is the lack of a direct measure of kidney function. Direct measurement of kidney function is impractical in large cohorts, and this limitation is common in such studies. However, we found associations to be robust to case definitions because they persisted when defining cases based solely on coded hospitalizations and deaths. The stronger association observed when limiting the case definition to hospitalizations and deaths likely is caused by the greater specificity of this definition and limiting to more severe cases (cases in individuals admitted to the hospital).
 
Our finding of an inverse relationship between serum albumin level and risk of decreasing kidney function could reflect inadequate nutrition and not inflammation. As evidence against this hypothesis, the ARIC cohort comprised middle-aged free-living individuals in whom significant malnutrition is unlikely. Findings with respect to serum albumin level as a predictor of kidney function decrease are consistent with findings from 2 other large cohorts and consistent with levels of serum albumin shown to predict coronary heart disease.5, 6, 24
 
This study also lacks measurement of urinary albumin, requiring CKD to be defined solely on hospitalizations and estimated GFR (there was no estimate of the latter after 1999). Last, as in any observational study, there is potential for reverse causation. However, we also observed the relative risk of CKD to be stronger with increasing follow-up in several markers (results not shown), which helps rule out these concerns.
 
Our findings are consistent with those of the Cardiovascular Health Study (CHS), which found several markers of inflammation and hemostasis, including increased C-reactive protein, WBC, fibrinogen, and factor VIIc levels and decreased albumin and hemoglobin levels to be associated with increased risk of reduced kidney function.6, 8
 
They are also consistent with findings from follow-up of the Second National Health and Nutrition Survey (NHANES II), in which greater WBC and lower serum albumin values were associated with increased risk of kidney failure or death related to kidney disease.5 In addition, increased WBC count has been associated with more rapid kidney disease progression in patients with type 1 diabetes.9
 
Fibrinogen was inversely associated with estimated GFR in patients with CKD in the Heart and Soul Study, but was not associated in those with normal kidney function.25
 
These discrepancies could be explained by significant differences in the populations studied, with more polycystic kidney disease or primary glomerular disease and no person with diabetic kidney disease in the MDRD Study. Our study population is similar to the CHS study population, although younger, which may explain why our findings generally are consistent with those of the CHS. However, there are important differences between findings in the CHS and those presented here. Factor VIIc level was associated with decreased risk of GFR decrease in the CHS, but factor VIIc level was not associated with decreased estimated GFR in our study. These results suggest that factor VIIc is not an important hemostatic predictor of decreasing kidney function. Conversely, strong associations were seen for factor VIIIc and VWF levels with decreasing kidney function in this study. These factors were not measured in the CHS. Unlike the CHS, we found similar associations for all markers in both African Americans and whites.
 
We found that associations were stronger in individuals with diabetes than in those without diabetes for albumin, WBC, fibrinogen, VWF, and factor VIIIc values. The reasons for these findings are speculative. Advanced glycation end products (AGEs; glycated proteins) are driven forward by hyperglycemia, and increased AGE levels are observed even in persons with uncomplicated diabetes.26 AGEs, which stimulate inflammatory cytokine production, also have been implicated in the progression to diabetic nephropathy27, 28 and involved in inflammatory disorders.27 It is possible that increased inflammatory factor levels in individuals with diabetes represent increased AGE levels, in addition to a measure of inflammation from other causes.29 Because individuals with diabetes more often are overweight and obese, it also is possible that adipose tissue serves as a source of inflammation.30 Additional adjustment for body mass index or waist circumference did not meaningfully change the results. These findings could have important implications for the progression of diabetes-related nephropathy. Despite stronger associations in diabetic individuals for several risk factors studied, increased levels of inflammatory and hemostatic factors were also associated with incident CKD in persons without diabetes.
 
The analytes studied also may be markers or mediators of underlying disease, such as endothelial damage. Albuminuria, a potent predictor of kidney disease progression,31 is believed to represent systemic endothelial cell dysfunction.32 Unfortunately, we did not have measures of urinary albumin excretion available with which to test this hypothesis.
 
Increased levels of these analytes also are indicative of a prothrombotic state, which may directly or indirectly impact on progression of kidney disease. For example, hypertensive patients have been shown to experience changes in platelet physiological characteristics; specific changes differed by the presence or absence of target-organ damage and may be implicative of underlying cardiovascular disease pathological states, such as that related to abnormal platelet activation and a procoagulant state.33 There also has been other evidence of an activated coagulation system in hypertensive patients with mild to moderate kidney dysfunction.34
 
These results add to a growing body of evidence suggesting that inflammation and hemostasis are important pathways in the progression of kidney disease that are independent of major traditional risk factors. Although a specific mechanism that can be targeted for intervention has not been identified, these findings may help focus investigations into pathological mechanisms for CKD and have implications for the development of prevention and treatment strategies designed to reduce the impact of kidney disease in the population.
 
 
 
 
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