Abstract

Inflammation is an important predictor of increased cardiovascular morbidity and mortality in patients with chronic kidney disease (CKD), but the mechanisms behind the chronic activation of the immune system are not clearly understood. CKD patients develop fluid overload, which has been proposed to be a stimulus for inflammatory activation due to the translocation of macromolecules from the gut. We hypothesize that fluid overload is associated with signs of systemic inflammation and endotoxaemia in stages 1–5 CKD patients. The aim of this prospective study was to evaluate the associations between renal function, fluid status [evaluated by the inferior vena cava diameter (IVCD) and the collapsibility index (CI)], systemic inflammation [plasma levels of C-reactive protein (CRP), fibrinogen and albumin] and endotoxaemia (through the Limulus amebocyte lysate enzymatic assay) in a group of CKD patients in our out-patient clinic. The population consisted of 74 (mean of 57; range 23–83 years of age; 47% males) CKD patients with glomerular filtration rate (based on the mean of urea and creatinine clearances) of 34 ml/min. Both albumin (Rho = 0.25; P = 0.05) and fibrinogen (Rho= − 0.48; P < 0.0001) were significantly correlated to glomerular filtration rate (GFR). According to the IVCD, 84% of the patients were fluid overloaded, while 83% were considered overloaded by the CI. Signs of endotoxaemia were detected in all patients. Endotoxin levels were higher in patients with signs of fluid overload (0.85 ± 0.11ng/l) when compared with patients with normal values of IVCD (0.61 ± 0.05 ng/l; P < 0.05). Endotoxin levels correlated to both IVCD (Rho=0.33, P < 0.005) and CI (Rho = −0.25, P < 0.05). There was no correlation between endotoxin levels and GFR, CRP or fibrinogen. In summary, although most CKD patients presented signs of fluid overload that was associated with endotoxaemia, there was no association between endotoxaemia and systemic inflammation, suggesting the endotoxaemia may not be the main determinant of the inflammatory status in this group of patients.

Introduction

Although there have been significant recent advances in dialysis therapy and in the understanding of the pathophysiology of chronic kidney disease (CKD), the rates of cardiovascular (CV) morbidity and mortality are still unacceptably high. The annual mortality rate of patients with CKD on dialysis is extremely high, and even after stratification for comorbidities, represents 10–20 times the risk described in the general population [ 1 ]. Interestingly, the Framingham risk factors for CV disease, such as hypertension, hyperlipidaemia, diabetes mellitus and smoking are prevalent in CKD patients, but do not fully explain the CV burden in CKD [ 2–4 ]. Therefore, much recent research has focused on non-traditional risk factors, such as anaemia, malnutrition, mineral metabolism disturbances, oxidative stress and inflammation. Of those, signs of systemic inflammation have consistently proven to be associated with a high CV mortality rate in patients with normal renal function [ 5 ] and particularly in those with CKD [ 6 ].

CKD has been considered an inflammatory disease, since multiple inflammatory stimuli present in CKD patients can cause the cellular release of cytokines such as interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-α. These cytokines increase the synthesis and the release of positive-phase proteins such as C-reactive protein (CRP), serum amyloid A and fibrinogen and decrease the synthesis and the release of negative acute-phase proteins such as albumin and transferrin, in a process named acute-phase response. High plasma levels of pro-inflammatory cytokines or acute-phase reactants can be observed in the early stages of CKD [ 7 ], and increase with the progression of the disease [ 8 ], for reasons not yet clarified.

During the past few years, it has become increasingly evident that impaired renal function is also an important and independent predictor of poor outcome in patients with CKD, including patients on haemodialysis [ 9 ] and peritoneal dialysis [ 10 ]. However, the impact of renal dysfunction on CV disease most likely begins with minor renal dysfunction manifested by proteinuria (albuminuria) or a mildly reduced glomerular filtration rate (GFR) [ 11 ]. Indeed, a substantial amount of data have accumulated in recent years which suggest that even minor renal dysfunction is an important independent risk of CV disease [ 12 ]. In parallel to the fall in GFR, patients develop impairment in the renal capacity to handle water and salt, resulting in fluid overload and high blood pressure [ 13 ], which is highly prevalent in dialysis patients and associated with poor clinical outcome [ 14 ]. There is increasing evidence that patients with CKD develop signs of fluid overload right at the early phases of the disease, and this may be a stimulus for inflammatory activation, that may lead to both accelerated CV disease and rapid progression to renal failure [ 15 ].

Patients with fluid overload, such as patients with congestive heart failure, present signs of systemic inflammation that reduce when the disease is compensated [ 16 ]. This inflammatory state appears to be associated with an altered gut barrier permeability that occurs as a consequence of the oedema, allowing the translocation of macromolecules including endotoxins into the circulation. As a consequence of the presence of circulating endotoxins, the immune system may be activated, generating a chronic inflammatory status.

We hypothesize that fluid overload develops early in the course of CKD as a consequence of renal function impairment, and may be associated with altered gut permeability with bacterial translocation and endotoxaemia, which in turn may trigger immune activation leading to increased levels of inflammation markers. Thus, the aim of this study was to evaluate the associations between renal function, fluid status and endotoxin-mediated inflammation in patients with stages 1–5 CKD.

Patients and methods

This was a cross-sectional and observational study, performed in a group of pre-dialysis CKD patients, followed in the out-patient clinic of the Pro-Renal Foundation in the period between September 2002 and May 2004. To be eligible for the study, the patients willing to participate in the study had to have CKD diagnosed for at least three months and had to be older than 18 years. Exclusion criteria were the clinical signs of active infection, liver dysfunction, autoimmune disease, malignancy, right chamber heart failure, tricuspid valve insufficiency and the use of anti-inflammatory or immunosuppressant drugs three months prior to the recruitment. Patients willing to participate in the study were contacted by their nephrologists and were sent to the protocol clinic, where the research team, composed of a research nurse and a trained nephrologist, performed the initial evaluation. Data regarding anthropometry, age, gender, primary kidney disease, smoking habit, history of dyslipidaemia, diabetes mellitus, hypertension, oedema and clinically detected cardiovascular disease (coronary heart disease, cerebrovascular disease, peripheral vascular disease and heart failure) were recorded by a detailed analysis of medical records, patient interview and physical examination. Eligible patients followed a standardized study protocol: in the following morning, blood samples were collected after an overnight fast for the determination of albumin according to the clinical chemistry routine. Renal function was evaluated through the estimation of GFR using two distinct determinations of the mean between creatinine and urea clearances. The concentration of CRP was measured by high-sensitivity automated nephelometric immunoassay (Dade Behring-BN II, Marburg, Germany). The sensitivity of the assay was 0.8 mg/l. Fibrinogen assessment was performed with an automated coagulometer (DADE Behring Coagulation Timer, Marburg, Germany). The remaining samples were stored in appropriate (endotoxin free) vials at −80°C until the analysis of endotoxin, which was performed using a commercially available kit [ Limulus amebocyte lysate (LAL), Chromogenic Endpoint Assay, Hycult Biotechnology, Uden, Netherlands]. This is a sensitive and specific method designed to detect and measure bacterial endotoxin in biological fluids including plasma. To neutralize endotoxin inhibitors, plasma was heated at 70°C for 5 min before being processed. The basis of the test is that endotoxin causes an opacity and gelation in LAL, based on an enzymatic reaction. Briefly, 50 μl of the sample (diluted 1:4) is added to the assigned wells, followed by the addition of 50 μl of reconstituted LAL reagent. In the presence of a colourless substrate, the enzymatic reaction will cause a yellow colour to develop. The reaction is stopped by the addition of 50 μl of a solution of acetic acid, and the absorbance at 405 nm is measured with a spectrophotometer. The endotoxin concentration of samples with unknown concentrations, which are run concurrently with the standards, can be determined from a standard curve. The minimum detection limit of the method is 1.4 pg/ml, with a measurable concentration range of 1–1000 pg/ml.

The echocardiographic examination was performed in the afternoon of the same day on which the blood samples were collected, to avoid interference of daily fluctuations of inflammation markers or fluid status. The anteroposterior inferior vena cava diameter (IVCD) was measured using two-dimensional and Doppler recordings 1.5 cm below the diaphragm in the hepatic segment. All measurements were performed in a supine position after 5–10 min of rest during normal expiration and inspiration while trying to avoid Valsalva manoeuvers. The IVCD was expressed as IVCD in expiration, adjusted for body surface area (BSA). Patients with an IVCD >11.5 mm/m 2 were considered fluid overloaded [ 17 ]. In addition, the collapsibility index (CI) was determined as the percentage of decrease in IVCD in inspiration vs expiration. Patients with a CI lower than 40% were considered fluid overloaded. The study protocol was approved by the Ethics Committee of Pontifícia Universidade Católica do Paraná, and an informed consent was obtained from each patient.

The normality of data distribution was assessed using the Kolmogorov–Smirnov test and the values are presented as mean ± SD or as median (range), unless otherwise specified. Student's t -test or Wilcoxon signed-ranked test were used to compare the differences between numerical values in different groups. Correlations between numerical values were assessed by the Pearson or Spearman analysis, accordingly. Multiple linear regression analysis was performed to identify the factors associated with CRP using log CRP as a dependent variable and albumin, fibrinogen, endotoxins, GFR and IVCD as independent variables. Comparisons of the prevalence in different groups were assessed by the chi-square test. Calculations were performed using the JMP package for Windows (version 7.0, USA) and a P -value ≤0.05 was judged to be significant.

Results

The study population consisted of 74 patients with a median age of 57 years. We observed a significant correlation between urine volume and GFR ( R = 0.25; P < 0.05). Most patients were in stage 3 (46%) and stage 4 (24%) of CKD, and only one patient was in stage 1 CKD. Patients were taking angiotensin-II receptor blockers or angiotensin-converting enzyme inhibitors (ACE-I) in 75% of the cases, diuretics in 55%, aspirin in 28% and statins in 12% of the cases. Main clinical and laboratory characteristics of the population are described in Table 1 .

The median value of CRP was 2.8 mg/l (range of 0.3–39.9 mg/l). According to the American Heart Association recommendations, a large proportion of patients (40%) were considered at an intermediate risk for CV disease (CRP > 1 mg/l), while 47% of patients were at high risk of CV disease (CRP > 3 mg/l). Only nine patients presented CRP levels lower than 1 mg/l. The median value of fibrinogen was 406 mg/dl (range 238–1003 mg/dl), and 51% of the patients presented fibrinogen levels above the normal range (400 mg/dl). Endotoxin was detected in all samples, in a median concentration of 0.84 ng/l (0.16–1.4 ng/l). Fibrinogen was significantly correlated to albumin (Rho = −0.34; P < 0.005) and to CRP (Rho = 0.38; P < 0.005). Endotoxin levels did not correlate to the levels of inflammation markers.

Both albumin (Rho = +0.25; P = 0.05) and fibrinogen (Rho = −0.48; P < 0.0001) were significantly correlated to GFR, while there was no association between CRP and renal function. Accordingly, patients with a GFR below the median presented lower levels of albumin and higher levels of fibrinogen when compared with the patients with a GFR higher than the median (3.76 ± 0.07 vs 3.98 ± 0.07; P < 0.05 and 467 ± 19 vs 377 mg/dl; P < 0.005, respectively) ( Figure 1 ). Endotoxin concentration was not correlated to GFR and was not different in patients with high or low GFR. To further explore these observations, we log-transformed the not normally distributed data and performed a multiple regression analysis with CRP as the dependent variable and albumin, fibrinogen, endotoxins, GFR and IVCD as independent variables (adjusted for use of statins, aspirin and ACE-I). In this model, only fibrinogen was associated with CRP levels.

Regarding fluid status, 24% of the patients presented clinically detected oedema and 58% of the patients were hypertensive despite the use of hypotensive medications. The mean IVCD was 16 ± 4 mm/m 2 , and 84% of the patients were considered fluid overloaded. In addition, the CI was 29 ± 13, and 83% of the patients were fluid overloaded according to this index. Left ventricle hypertrophy was observed in 48% of the patients. As expected, there was a negative correlation between IVCD and CI ( R = −0.39; P < 0.001). No significant associations were observed when clinical and echocardiographic evaluations of fluid status were compared. Patients with a GFR below the median presented significantly lower CI (25 ± 2) when compared with patients with higher GFR (33 ± 2; P < 0.05) ( Figure 2 ).

Although we could not identify correlations between inflammation markers and signs of fluid-overload, there was a significant association between endotoxin concentrations and both IVCD (Rho = 0.33; P < 0.005) and CI (Rho = −0.23; P < 0.05). Accordingly, fluid-overloaded patients presented higher endotoxin levels (defined by IVCD: 0.85 ± 0.11 ng/l or by CI: 0.89 ± 0.05 ng/l) when compared with patients with normal fluid status (defined by ICVD: 0.61 ± 0.05; P < 0.05 or by CI:0.0.47 ± 0.05 ng/l; P < 0.0001) ( Figure 3 ).

Discussion

Inflammation is an important predictor of increased CV morbidity and mortality in patients with CKD, but the mechanisms behind the chronic activation of the immune system are not clearly understood. CKD patients are frequently fluid overloaded, as a consequence of the impairment in the renal capacity to handle sodium and water, and this altered fluid status has been proposed to be a stimulus for inflammatory activation due to the translocation of macromolecules from the hyper-permeable oedematous gut. In this study, we looked at the associations between renal function, fluid status and systemic inflammation, and found that although most CKD patients presented signs of fluid overload that was associated with endotoxaemia, there were no clear links between circulating endotoxin levels and markers of systemic inflammation.

In physiological conditions, inflammation is the body's local and finely tuned reaction to the invasion by an infectious agent, antigen challenge or even just physical, chemical or traumatic damage, which must be precisely regulated since both deficiencies and excesses in an inflammatory response may cause morbidity and mortality [ 18 ]. About 30–50% of patients in advanced (stage 5) CKD have serological evidence of an activated inflammatory response [ 6 ], and the introduction of dialysis treatment may have an enhancer effect. Interestingly, recent data suggest that signs of a chronic and low-grade inflammation are already present at early stages of CKD [ 19 ], and the reduction of renal function per se may be associated with an increase in inflammatory response, since increasing concentrations of plasma pro-inflammatory cytokines and other inflammatory biomarkers are observed both in mild [ 20 ] and advanced [ 21 ] renal failure. When serum levels of IL-1 and TNF-α were compared in patients prior to the initiation of dialysis and in those on long-term therapy, no differences were found [ 8 ]. Moreover, the deterioration of renal function has been associated with a significant increase in serum cytokine levels in CKD patients, and creatinine clearance correlates with the circulating levels of various cytokines and their soluble receptors in patients with varying degrees of renal failure [ 6 , 22 ]. The present study confirmed these observations, showing that there was a close relationship between GFR and both fibrinogen and albumin in a representative population, presenting a wide variation in GFR and a high degree of co-morbidity, such as diabetes, hypertension, CV disease and obesity. Regardless of the marker utilized, the prevalence of inflammation was always high, and related to the degree of renal dysfunction in the case of albumin and fibrinogen. Although there was a positive correlation between CRP and fibrinogen, we could not demonstrate the same relationship between CRP levels and renal function, as observed with albumin and fibrinogen. This unexpected observation may be justified by the fact that levels of CRP have a shorter half-life in comparison to fibrinogen and albumin, and are more likely to fluctuate in response to clinical events, such as hidden infections, physical activity and even momentary changes in fluid status. The unexpected lack of correlation between albumin and CRP could be further explained by the dual role of albumin as a marker of nutritional status and inflammation. It is also possible that the lack of correlation between GFR and CRP and between CRP and albumin was due to an insufficient number of observations. Although there was no difference in the levels of inflammation markers in patients using and not using drugs that are known to affect the inflammatory status (data not shown), it is possible that this confounding factor had an influence on the results of our study. In the multivariate analysis performed in this study to analyse factors associated with CRP levels, fibrinogen, but not albumin, GFR, fluid overload and circulating endotoxin, were associated with CRP. These results confirm the univariate analysis and may again be due to the small sample size of the study.

Markers of a chronically activated immune system are closely linked to several complications of CKD, such as accelerated atherosclerosis, vascular calcification, insulin resistance, increased muscle catabolism, loss of appetite, bone remodelling and increased peritoneal membrane permeability [ 23 ]. Interestingly, all the aforementioned pathological states are strongly associated with increased morbidity and mortality in CKD. Additionally, inflammation may be a predictor of accelerated loss of renal function [ 24 ], although this is not a consistent finding [ 3 ]. In recent studies, it has been repeatedly demonstrated that various inflammation biomarkers such as CRP, IL-6, fibrinogen, albumin, white blood cell count and hyaluronan are powerful predictors for mortality in dialysis patients, whereas indices of dialysis adequacy and nutrition are much weaker predictors of risk factors [ 25 ]. On the basis of available evidence, the systemic inflammatory response in CKD is critical to several pathological processes, and by implication, reduction of the systemic inflammatory response in CKD could be effective in reducing the risk of mortality in CKD. Since both albumin and fibrinogen are important risk factors for poor clinical outcome in CKD patients, it is important to clarify in future studies if preserving the renal function will have an impact on these risk factors and, ultimately, will provide a reduction in morbidity and mortality in CKD patients.

In CKD patients in advanced stages treated with haemodialysis or peritoneal dialysis, it is obvious that a number of both dialysis-related (such as dialyser or dialysate bio-incompatibility and quality of dialysis water) and dialysis-unrelated factors (such as fluid overload, uraemic toxicity, comorbidities and chronic infections) have been proposed as contributors to a state of chronic inflammation [ 25 ]. One important and still unexplored potential cause of inflammation in CKD patients is fluid overload [ 26 ], which appears to be exacerbated with the progression of renal disease [ 27 ]. In our study, we analyzed the presence of fluid overload using the measurement of IVCD and the calculation of the CI, which are non-invasive, simple and fast methods that correlate well with right atrial pressure [ 17 ] and circulating blood volume [ 28 ]. We observed in our study population an extremely high prevalence of signs of fluid overload. In addition, the echocardiographic evaluation significantly increased the sensitivity of the diagnostic of fluid overload, when compared with the physical examination. Interestingly, we observed that the patients with lower GFR presented more striking signs of fluid overload when compared with the patients with more preserved renal function, suggesting that the impaired capacity of the kidneys to remove water and salt from the organism may play a role in the development of fluid accumulation in pre-dialysis CKD.

Potentially, fluid overload may be in itself associated with immune activation [ 26 ]. This activation has been proposed to occur because of bacterial or endotoxin translocation in patients with severe gut edema as a result of severe volume overload [ 29 ]. Endotoxin circulation potentially leads to an increased production of pro-inflammatory cytokines [ 30 ]. This hypothesis is in keeping with a study showing that dialysis patients with a history of heart failure had higher CRP levels [ 27 ]. Patients with fluid overload, such as patients with congestive heart failure and normal renal function, present increased concentration of endotoxin and cytokines during acute oedematous exacerbation [ 26 ]. After the treatment with diuretics and clinical compensation, a significant reduction in the concentration of inflammatory mediators and endotoxin levels was observed. No studies focusing on the relationship between fluid status, endotoxaemia and inflammation were performed in the CKD population until the present. Endotoxins are macromolecules (lipopolysaccharides, LPS) present in the wall of Gram-negative bacteria. The LPS can bind to lipoprotein or to the LPS-binding protein (LBP) in the circulation, but only the LPS–LPB complex can activate the membrane receptors (toll-like receptors; Tlr) in the cells of the immune system, cardiomyocites and endothelial cells. This cell response is mediated by the CD14 and leads to the activation of nuclear factor-κB, which in turn plays a main role in the activation and transcription of genes from innate immune response. In this study, we hypothesized that the circulating endotoxin generated as a consequence of reduced tissue perfusion and altered gut permeability and congestion, may play an important role in the activation of a pro-inflammatory response as renal failure progresses. Our data do not confirm the hypothesis, since no correlation was observed between circulating endotoxin levels and markers of systemic inflammation. There are several reasons to justify this lack of association between endotoxaemia and systemic inflammation. First, levels of circulating endotoxin may be too low in this group of patients to clinically justify detectable differences in the levels of markers of inflammation, as opposed to the higher levels observed in patients with severely decompensated congestive heart failure [ 26 ]. Also, circulating endotoxin in patients with CKD could be biologically inactive, similar to the IL-1β in dialysis patients, in whom the IL-1β converting enzyme is impaired [ 31 ]. Finally, the stimuli to produce acute-phase reactants are clearly multifactorial in CKD patients, including diabetes, ischaemic CV disease, chronic infections, uraemic toxicity and many other factors. Therefore, it may be difficult to demonstrate the association of a single factor among many others in studies with a relatively small sample size such as the present.

Moreover, we did not observe an association between signs of fluid overload and markers of systemic inflammation. On the other hand, signs of fluid overload correlated closely with the presence of endotoxin in the circulation of the patients in our study. Although this is an indirect observation, it is possible that endotoxinaemia may be related to a possible altered gut permeability observed in CKD patients.

In summary, a large proportion of CKD patients in stages 1–5 presented signs of systemic inflammation and fluid overload, which increase in advanced stages of CKD. Although endotoxin levels were clearly related to fluid overload, we did not observe an association between endotoxaemia and systemic inflammation, suggesting that endotoxaemia may not be the main determinant of the inflammatory status in this group of patients, reinforcing the idea that inflammation in CKD is multifactorial, with each causal component contributing only modestly. Further studies in a larger population group will be needed to explore the relationship between inflammation, fluid status and renal function.

Table 1.

Main clinical and laboratory characteristics of the study population

Number of patients 74 
Age (years) 57 ± 12.6 
Male gender 47% 
Caucasians 91% 
BMI (kg/m 3 )  28 ± 4 
Follow up [months (range)] 24 (2–372) 
Primary kidney disease  
 Nephrosclerosis 30% 
 Diabetic nephropathy 30% 
 Polycystic kidney disease 12% 
 Chronic glomerulonephritis 12% 
 Unknown 9% 
 Other 7% 
Comorbidity  
 Hypertension 89% 
 Diabetes mellitus 36% 
 Hyperlipidaemia 24% 
 CV disease 53% 
 Smokers 12% 
 Obesity 30% 
Albumin (mg/l) 3.8 ± 0.5 
Urinary volume (ml) 2081 ± 578.5 
GFR (ml/min) 34(6–107) 
Number of patients 74 
Age (years) 57 ± 12.6 
Male gender 47% 
Caucasians 91% 
BMI (kg/m 3 )  28 ± 4 
Follow up [months (range)] 24 (2–372) 
Primary kidney disease  
 Nephrosclerosis 30% 
 Diabetic nephropathy 30% 
 Polycystic kidney disease 12% 
 Chronic glomerulonephritis 12% 
 Unknown 9% 
 Other 7% 
Comorbidity  
 Hypertension 89% 
 Diabetes mellitus 36% 
 Hyperlipidaemia 24% 
 CV disease 53% 
 Smokers 12% 
 Obesity 30% 
Albumin (mg/l) 3.8 ± 0.5 
Urinary volume (ml) 2081 ± 578.5 
GFR (ml/min) 34(6–107) 

Fig. 1.

Albumin and fibrinogen plasma levels in groups divided according to the median GFR.

Fig. 1.

Albumin and fibrinogen plasma levels in groups divided according to the median GFR.

Fig. 2.

Collapsing index in patients with GFR below and above the median.

Fig. 2.

Collapsing index in patients with GFR below and above the median.

Fig. 3.

Correlation between endotoxin levels and parameters of fluid status.

Fig. 3.

Correlation between endotoxin levels and parameters of fluid status.

Acknowledgements

We thank Diego Valderrama, Margarete Mara da Silva, Luciana Soares Percegona, Alexandre Bignelli and Paulo Fortes for the collaboration recruiting patients for the study. This study was supported by a grant from the Renal, Diabetes and Hypertension Research Center of Pro-Renal Foundation, Brazil. During these studies, R.P.F. was a recipient of a scholarship from CNPq ( Conselho Nacional de Desenvolvimento Científico e Tecnológico ), Brazil.

Conflict of interest statement . None declared.

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:
S282
–S285.

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