Variations In C-reactive Protein Levels Research Articles

C-reactive protein, cardiovascular issues of an acute-phase protein: an update for theclinician

Inflammation is an important pathogenic factor for the development of atherosclerotic cardiovascular disease. Currently, the most frequently used biomarker reflecting systemic inflammation is C-reactive protein (CRP), an acute-phase protein produced primarily by hepatocytes under the influence of interleukin-6, interleukin-1 beta, and tumor necrosis factor. Growing evidence from epidemiological studies has shown a robust association between elevated serum or plasma CRP concentrations and the incidence of a first cardiovascular adverse event (including acute myocardial infarction, ischemic stroke, and sudden cardiac death) in the general population, as well as recurrence of major adverse cardiovascular events among patients with established disease. The additive value that CRP measurement gives to traditional risk factors is reflected in novel cardiovascular risk calculators and in current intervention regimens, which already consider CRP as a target therapeutic. However, the variations in CRP levels, that depend on sex, ethnicity, hormonal status, and some peculiarities of the measurement assays, must be taken into consideration when deciding to implement CRP as a useful biomarker in the study and treatment of atherosclerotic cardiovascular disease. This review aims to offer an updated vision of the importance of measuring CRP levels as a biomarker of cardiovascular risk beyond the traditional factors that estimate the risk of atherosclerotic disease.

Cross-trait genome-wide association analysis of C-reactive protein level and psychiatric disorders

C-reactive protein (CRP) tends to be elevated in individuals with psychiatric disorders. Recent findings have suggested a protective effect of the genetic liability to elevated CRP on schizophrenia risk and a causative effect on depression despite weak genetic correlations, while causal relationships with bipolar disorder were inconclusive. We investigated the shared genetic underpinnings of psychiatric disorders and variation in CRP levels. Genome-wide association studies for CRP (n = 575,531), bipolar disorder (n = 413,466), depression (n = 480,359), and schizophrenia (n = 130,644) were used in causal mixture models to compare CRP with psychiatric disorders based on polygenicity, discoverability, and genome-wide genetic overlap. The conjunctional false discovery rate method was used to identify specific shared genetic loci. Shared variants were mapped to putative causal genes, which were tested for overrepresentation among gene ontology gene-sets. CRP was six to ten times less polygenic (n = 1400 vs 8600–14,500 variants) and had a discoverability one to two orders of magnitude higher than psychiatric disorders. Most CRP-associated variants were overlapping with psychiatric disorders. We identified 401 genetic loci jointly associated with CRP and psychiatric disorders with mixed effect directions. Gene-set enrichment analyses identified predominantly CNS-related gene sets for CRP and each of depression and schizophrenia, and basic cellular processes for CRP and bipolar disorder. In conclusion, CRP has a markedly different genetic architecture to psychiatric disorders, but the majority of CRP associated variants are also implicated in psychiatric disorders. Shared genetic loci implicated CNS-related processes to a greater extent than immune processes, which may have implications for how we conceptualise causal relationships between CRP and psychiatric disorders.

Omega-3 fatty acids, inflammatory status and biochemical markers of patients with systemic lupus erythematosus: a pilot study

BackgroundStudies have shown that omega-3 fatty acids reduce the concentrations of eicosanoids, cytokines, chemokines, C-reactive protein (CRP) and other inflammatory mediators. ObjectiveTo investigate the effects of omega-3 fatty acids on circulating levels of inflammatory mediators and biochemical markers in women with systemic lupus erythematosus (SLE). MethodsExperimental clinical study (clinical trial: NCT02524795); 49 women with SLE (ACR1982/1997) were randomized: 22 to the omega-3 group (daily intake of 1080mg EPA+200mg DHA, for 12 weeks) and 27 to the control group. The inflammatory mediators and biochemical markers at T0 and T1 in omega-3 group were compared using Wilcoxon test. U-Mann–Whitney test was used to compare variations of measured variables [ΔV=pre-treatment (T0)−post-treatment (T1) concentrations] between groups. p<0.05 was considered significant. ResultsThe median (interquartile range – IQR) of age was 37 (29–48) years old, of disease duration was 7 (4–13) years, and of SLEDAI-2K was 1 (0–2). The median (IQR) of variation in CRP levels between the two groups showed a decrease in omega-3 group while there was an increase in control group (p=0.008). The serum concentrations of IL-6 and IL-10, leptin and adiponectin did not change after a 12 week treatment. ConclusionsSupplementation with omega-3 had no impact on serum concentrations of IL-6, IL-10, leptin and adiponectin in women with SLE and low disease activity. There was a significant decrease of CRP levels as well as evidence that omega-3 may impact total and LDL-cholesterol.

Ácidos graxos ômega‐3, estado inflamatório e marcadores bioquímicos de pacientes com lúpus eritematoso sistêmico: estudo piloto

BackgroundStudies have shown that omega‐3 fatty acids reduce the concentrations of eicosanoids, cytokines, chemokines, C‐reactive protein (CRP) and other inflammatory mediators. ObjectiveTo investigate the effects of omega‐3 fatty acids on circulating levels of inflammatory mediators and biochemical markers in women with systemic lupus erythematosus (SLE). MethodsExperimental clinical study (clinical trial: NCT02524795); 49 women with SLE (ACR1982/1997) were randomized: 22 to the omega‐3 group (daily intake of 1080mg EPA+200mg DHA, for 12 weeks) and 27 to the control group. The inflammatory mediators and biochemical markers at T0 and T1 in omega‐3 group were compared using Wilcoxon test. U‐Mann‐Whitney test was used to compare variations of measured variables [ΔV=pre‐treatment (T0) minus post‐treatment (T1) concentrations] between groups. p<0.05 was considered significant. ResultsThe median (interquartile range ‐ IQR) of age was 37 (29‐48) years old, of disease duration was 7 (4‐13) years, and of SLEDAI‐2K was 1 (0‐2). The median (IQR) of variation in CRP levels between the two groups showed a decrease in omega‐3 group while there was an increase in control group (p=0.008). The serum concentrations of IL‐6 and IL‐10, leptin and adiponectin did not change after a 12 week treatment. ConclusionsSupplementation with omega‐3 had no impact on serum concentrations of IL‐6, IL‐10, leptin and adiponectin in women with SLE and low disease activity. There was a significant decrease of CRP levels as well as evidence that omega‐3 may impact total and LDL‐cholesterol

Evolution of C-reactive protein values in the first month after anterior cruciate ligament reconstruction: reference values

C-reactive protein (CRP) is often used as an infection marker in orthopaedic patients and in particular after anterior cruciate ligament (ACL) reconstruction surgery. The aim of this study is to obtain the reference values of CRP during the first month after an ACL reconstruction and to analyse the epidemiological and surgical parameters that affect these values. One hundred and twenty ACL reconstructions were included. A CRP determination was performed preoperatively and 1, 7, 14, 21 and 28 days after surgery. CRP values under 5 mg/l were considered to be normal. One patient developed a septic arthritis in the second week postoperatively and was excluded. One hundred and seventeen patients [93 males and 24 females; mean age (standard deviation) 31.6 years (7.6)] underwent 119 ACL reconstructions with different techniques and grafts. Preoperative CRP (n = 119) was 1.80 mg/ml (2.6). Mean values at 1, 7, 14, 21 and 28 days were, respectively, 8.5 mg/ml (11.6), 10.5 mg/ml (17.0), 4.5 mg/ml (3.43), 4.4 mg/ml (7.59) and 3.4 mg/ml (3.03). Multivariate analysis showed that males had postoperative CRP levels 1.7 higher than females (p < 0.0001; 95 % CI 1.8-2.5); the patients operated by less experienced surgeons had levels 2.5 times higher than those operated by a highly experienced surgeons (p = 0.007; 95 % CI 1.2-3.4) and that if microfracture of a chondral lesion was associated, the levels increased 1.9 times (p = 0.021; 95 % CI 1.1-3.4). There are significant variations in CRP levels after ACL reconstruction in half of patients without infectious complications. Males, patients operated by less experienced surgeons and those with chondral lesions treated with microfracture had increased postoperative CRP levels. CRP values up to five times the normal limit are common in the month after an ACL reconstruction and are not necessarily associated with infection, especially in these groups.

C-Reactive Protein Is Elevated in Heart Failure Patients with Central Sleep Apnea and Cheyne-Stokes Respiration

Background: Manifestation of central sleep apnea (CSA) with Cheyne-Stokes respiration is of major prognostic impact in chronic heart failure (CHF). Inflammatory processes have been linked to a progression of cardiovascular diseases, including heart failure. While an association of C-reactive protein (CRP) levels to obstructive sleep apnea has been documented before, there is a lack of information regarding variation of CRP levels in patients with CSA. Objectives: The objective of this study was to investigate a potential association of CRP levels to CSA severity in CHF patients. Methods: High sensitivity CRP levels were analyzed in 966 patients with CHF (BMI 26.3 ± 4.6, New York Heart Association class 2.6 ± 0.5, left ventricular ejection fraction 29.4 ± 7.9%, N-terminal pro-brain natriuretic peptide, NT-proBNP, level 2,209 ± 3,315 pg/ml) without sleep-disordered breathing (SDB; Apnea-Hypopnea Index, AHI, <5/h) or various degrees of CSA, documented by in-hospital cardiorespiratory polygraphy or polysomnography. Results: The CRP concentration in CHF patients was 0.550 ± 0.794 mg/dl in patients without SDB (AHI 0-4/h, n = 403) versus 0.488 ± 0.708 mg/dl in patients with mild CSA (AHI 5-14/h, n = 123, p = n.s.) and 0.660 ± 0.963 mg/dl in patients with moderate CSA (AHI 15-29/h, n = 160, p = n.s.). In patients with severe CSA (AHI ≥30/h, n = 280), significantly higher CRP concentrations were documented (0.893 ± 1.384 mg/dl, p < 0.05). Stepwise regression analysis revealed AHI, NT-proBNP and heart rate to be independently associated with elevated CRP levels. Conclusion: Severe CSA in CHF patients is associated with elevated levels of CRP, a systemic marker of inflammation and cardiovascular risk. This might explain in part the negative prognostic impact of CSA in these patients.

A variant in theLRRFIP1gene is associated with adiposity and inflammation

Inflammation is an important factor linking abdominal obesity with insulin resistance and related cardiometabolic risk. A genome-wide association study of adiposity-related traits performed in the Quebec Family Study (QFS) revealed that a single-nucleotide polymorphism (SNP) in the LRRFIP1 gene (rs11680012) was associated with abdominal adiposity (P = 4.6 × 10(-6)). The objective of this study was to assess the relationship between polymorphisms in LRRFIP1 gene and adiposity (BMI, fat mass (FM), waist circumference (WC), and computed tomography-derived areas of total, subcutaneous and visceral abdominal adipose tissue) and markers of inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6)). Using Sequenom, 16 tag SNPs in the LRRFIP1 gene, capturing 78% of the genetic variation, were genotyped in 926 participants of the QFS. Eight SNPs (rs7575941, rs3769053, rs11689421, rs3820808, rs11680012, rs3806505, rs6739130, and rs11686141) showed evidence of association with at least two adiposity phenotypes and plasma levels of one marker of inflammation. The strongest evidence of association was observed with rs11680012, which explained 1.8-3.4% of the variance in areas of abdominal adiposity and 2.0% of the variation in CRP levels. Carriers of the rare allele of rs11680012 had ≈ 30% more abdominal adiposity (P values between 2.7 × 10(-4) and 3.8 × 10(-6)) and 75% higher CRP levels (P = 1.6 × 10(-4)) than the common allele in age and sex adjusted data. Rs11680012 is a G/C SNP converting an arginine into a threonine and this amino acid substitution may potentially alter exonic splicing. This gene may therefore represent a potential interesting target to investigate in further functional studies on adiposity and inflammation.

CRP identifies homeostatic immune oscillations in cancer patients: a potential treatment targeting tool?

The search for a suitable biomarker which indicates immune system responses in cancer patients has been long and arduous, but a widely known biomarker has emerged as a potential candidate for this purpose. C-Reactive Protein (CRP) is an acute-phase plasma protein that can be used as a marker for activation of the immune system. The short plasma half-life and relatively robust and reliable response to inflammation, make CRP an ideal candidate marker for inflammation. The high- sensitivity test for CRP, termed Low-Reactive Protein (LRP, L-CRP or hs-CRP), measures very low levels of CRP more accurately, and is even more reliable than standard CRP for this purpose. Usually, static sampling of CRP has been used for clinical studies and these can predict disease presence or recurrence, notably for a number of cancers. We have used frequent serial L-CRP measurements across three clinical laboratories in two countries and for different advanced cancers, and have demonstrated similar, repeatable observations of a cyclical variation in CRP levels in these patients. We hypothesise that these L-CRP oscillations are part of a homeostatic immune response to advanced malignancy and have some preliminary data linking the timing of therapy to treatment success. This article reviews CRP, shows some of our data and advances the reasoning for the hypothesis that explains the CRP cycles in terms of homeostatic immune regulatory cycles. This knowledge might also open the way for improved timing of treatment(s) for improved clinical efficacy.

Plasma CRP Levels in Premenopausal Women with Major Depression: A 12-Month Controlled Study

C-reactive protein (CRP), an inflammatory marker of cardiovascular risk, is often elevated in major depressive disorder (MDD). The magnitude and consistency of this elevation have not been previously characterized in premenopausal women with MDD. The aim of the study was to prospectively assess plasma CRP levels, body composition, endocrine and metabolic parameters, and depressive status in premenopausal women with MDD (n=77) and controls (n=41), aged 21 to 45. Women were enrolled in a 12-month, controlled study of bone turnover, the P.O.W.E.R. ( Premenopausal, Osteoporosis, Women, Al Endronate, Dep Ression) Study. Blood samples were taken at Baseline, Month 6, and Month 12. Most subjects with MDD were in clinical remission. These women tended to have consistently higher CRP levels than controls over 12 months (p=0.077). BMI was positively related to log[CRP] in women with MDD only. Nine women with MDD had CRP levels greater than 10 mg/l, a value associated with a very high cardiovascular risk. This subset was obese and had significantly higher triglycerides, total cholesterol, LDL-cholesterol, fasting insulin, and HOMA-IR than the rest of women with MDD. The variations in CRP levels over time were high (intra- and inter-individual coefficients of variations of approximately 30-50% and approximately 70-140%, respectively). No control had CRP levels greater than 10 mg/l. Depression was associated with increased plasma CRP in women with MDD. The clinical significance of abnormal plasma CRP for cardiovascular risk needs to be assessed in large prospective studies of women with depression.

The role of C-reactive protein polymorphisms in inflammation and cardiovascular risk

Interest in C-reactive protein (CRP) and the association of its serum level in apparently healthy individuals to their cardiovascular disease risk has soared over the past decade. Recent studies have shown that the interindividual variations in CRP levels not only reflect environmental cues but are also a consequence of the genetic variation in the CRP gene itself. The importance of the relationship of CRP gene variants to CRP serum level and cardiovascular disease risk is important to establish CRP gene profiling as a clinical risk prediction tool and also to help test the cause-effect relationship between CRP and vascular disease. This article reviews recent studies that address the relationship of CRP gene polymorphisms to inflammation and cardiovascular risk.

Polymorphisms in the NQO1, GSTT and GSTM genes are associated with coronary heart disease and biomarkers of oxidative stress

It was hypothesized that the presence of genetic polymorphisms that decrease activity of the detoxification enzymes glutathione-S-transferase (GST) and quinone oxido-reductase (NQO1) may contribute to heart disease and affect biomarkers of coronary health and oxidative stress. Sixty-seven patients with angiographically confirmed coronary heart disease (CHD) and 63 healthy controls were genotyped for polymorphisms in the GST isoforms Mu and Theta (GSTM and GSTT respectively) and NQO1. Participants’ blood levels of homocysteine (Hcy), C-reactive protein (CRP), oxidized low density lipoprotein (LDL) and total antioxidant capacity (TAOX) were measured. TAOX levels were significantly lower in women than men ( P ≤ 0.001) and this finding was more marked in the control group ( P ≤ 0.001). Hcy levels were higher in CHD patients ( P = 0.003 vs. control) which was mostly attributed to female patients ( P = 0.034 case vs. control). GSTM polymorphisms were present with greater frequencies in CHD cases with the odds ratio (OR) for GSTM equal to 3.77 vs. control. CHD patients also have an increased incidence of both GSTM and GSTT null polymorphisms (OR = 5.13). In contrast, NQO1 polymorphisms were protective in CHD patients (OR = 0.18 vs. control), which when stratified for genotype was due to heterozygous individuals. Significantly higher C-reactive protein levels occurred in CHD patients with lower NQO1 activity ( P = 0.001), however, due to the large variations in CRP levels seen in CHD patients; the clinical importance of this difference is unclear. Smokers with the GSTM null polymorphism were more likely to have CHD than non-smokers expressing the GSTM null polymorphism (OR = 3.54, P = 0.079). We conclude that a lack of activity in the detoxification enzymes NQO1 and GSTM, and biomarker levels are strongly associated with coronary heart disease with sex as a mitigating factor.

Response to Drs. Ohayon and Guilleminault

DEAR EDITOR, WE THANK DRS. OHAYON AND GUILLEMINAULT FOR THEIR COMMENTS ON OUR ARTICLE ON THE ASSOCIATION BETWEEN SLEEP-DISORDERED BREATHING (SDB) and C-reactive protein (CRP).1 We share their concern that to discern the role of SDB in systemic inflammation, the effects of adiposity should be carefully considered. In fact, numerous studies have shown that both total body fat and the amount of visceral fat are strong correlates of CRP levels.2–5 Thus, inclusion of obesityrelated indices in the analysis of observational data relating SDB to CRP levels is absolutely essential. The scientific challenge is to determine which aspects of obesity should be accounted for in such analyses. Inclusion of several variables, especially correlated variables, in a statistical model can lead to overadjustment and multi-collinearity. Conversely, exclusion of variables that are biologically important can lead to concerns of residual confounding from factors that are omitted or inadequately controlled. Therefore, there is an obvious tension between the need to construct the most parsimonious statistical model and the need to adjust for scientifically relevant variables. Recognizing the influence of obesity on CRP levels, we opted to adjust for obesity using various measures simultaneously. Parameter estimates resulting from such models with collinear variables will have inflated standard errors. Large standard errors make it difficult to identify “statistically significant” associations and often require acceptance of null hypotheses. By including the apnea-hypopnea index (AHI), BMI, waist circumference, and percent of body fat in our models, we biased against finding an independent association between SDB severity and CRP levels. Furthermore, the decision to include the different indices of obesity was driven by the concern for the effects of body fat amount and distribution on CRP levels. To decrease multi-collinearity, we have repeated our analyses by including each of the obesity measures individually and in all possible pairwise combinations with AHI as predictors of CRP levels. Irrespective of the set of obesity variables used, our conclusion of an independent association between SDB severity and CRP levels remains materially unchanged. It is also argued that the BMI of the sample was high and hence adjustment for BMI does not circumvent the concern for confounding due to obesity. Indeed, the median BMI of the sample was 30.5 kg/m2 (interquartile range: 27.2–35.0 kg/m2). Although the sample was predominantly overweight or obese, this issue by itself does not invalidate our conclusions on SDB and CRP levels. Surely, the lack of variation in one predictor (i.e., BMI) does not completely dissolve the possibility that there is some level of unique variation in CRP levels that can be accounted for by another predictor (i.e., AHI). The fact that the sample was overweight and obese merely limits the generalizability and suggests that in this subgroup, CRP levels vary as a function of the AHI. Another concern raised is that there are other factors that were not adequately considered such as habitual sleep duration and cigarette smoking. Here again, we agree that there is an enlarging list of factors that have causal relevance with regards to increasing CRP levels. It was this very concern that led us to exclude a majority of health conditions that are prevalent in patients with SDB. The strict exclusion criteria greatly limited our capability to identify a large enough sample across the spectrum of SDB severity. Imposing additional constraints and/or assessing other measures (e.g., habitual sleep duration) are not insurmountable tasks. The enlarging list of variables that can influence CRP levels is actually welcomed by many as it provides a roadmap for future research for those entrenched in understanding the complex pathophysiology of SDB-related adverse outcomes. So did our study shed absolutely no new light on the topic of SDB and systemic inflammation? On the contrary, this collegial debate is telling evidence that our study has had an impact as it has highlighted the paucity of observational and experimental data on CRP levels in SDB. We admit that we are in equipoise on whether SDB is a causal correlate of higher CRP levels. It seems to us that by demonstrating an independent SDB-CRP association, albeit in a non-generalizable sample, we are making headway toward the kind of clarity required in future research efforts on the causal effects of SDB in systemic inflammation. Additional research is obviously necessary and it is a tricky task. Ohayon and Guilleminault remind us to pay more attention to the fundamental issues of observational research and indirectly highlight many ways that future studies can be better designed and analyzed. We thank our esteemed colleagues for their thoughtful comments and welcome continued discussion on these important topics.

Seasonal variation of C-reactive protein in apparently healthy Koreans

Background C-reactive protein (CRP) is known as an emerging recognized marker of the potential risk of myocardial infarction and stroke, and several studies have reported higher incidences of cardiovascular events during the winter months. Here, we investigated seasonal CRP variations using a high-sensitivity immunoradiometric assay in apparently healthy Koreans. Methods This study included 18,445 apparently healthy Koreans (12,064 men and 6381 women, 47.2 (11.5) years of age). Anthropometric indices of adiposity, metabolic variables, blood pressure (BP), and several cardiovascular risk factors were measured. High sensitivity CRP testing was performed by immunonephelometry. Results The mean (SD) CRP level in the study population was 1.66 (2.15) mg/L, and mean (SD) CRP levels in the spring, summer, fall and winter were 1.76 (2.30) mg/L, 1.51 (1.94) mg/L, 1.61 (2.08) mg/L, and 1.76 (2.30) mg/L, respectively. After adjusting for age, sex, diabetes, hypertension, regular exercise, smoking, and body mass index, the odds ratios of an elevated CRP in the spring, fall and winter season were 1.196 (95% CI, 1.024–1.396 p = 0.024), 1.086 (95% CI, 0.943–1.250 p = 0.251) and 1.258 (95% CI, 1.088–1.456 p = 0.002), respectively, as compared with the summer season. Conclusions Our results indicate a highly significant seasonal variation in CRP levels, with higher values during winter and spring than in summer. Elevated plasma CRP levels can be related to an increased risk of cardiovascular events, which are more prominent during the winter months. To further elucidate this relationship additional studies are needed.

Variation of C-Reactive Protein Levels in Adolescents

There is increasing evidence that sleep-disordered breathing (SDB) is an independent risk factor for cardiovascular disease (CVD) in adults. C-reactive protein (CRP), a marker of systemic inflammation, is an important predictor of future cardiovascular events. The goal of this study was to quantify the associations of SDB, sleep duration, and CRP in adolescents to better understand the role of SDB in CVD risk. Adolescents (n=143; age, 13 to 18 years; 36% black; 50% female) with a wide range of SDB severity underwent polysomnography and measurement of high-sensitivity CRP. SDB was quantified with the apnea hypopnea index (AHI) and oxygen desaturation measures. Sleep duration was estimated from 7-day actigraphy. The independent and dose-response associations of SDB with CRP were addressed through linear mixed-effects models. Forty-eight percent were overweight or obese, and 12% had SDB (AHI > or =5). CRP levels varied with increasing body mass index and SDB. After adjustment for body mass index , age, sex, and race, mean CRP levels were 0.50, 0.43, 0.97, and 1.66 mg/L for SDB severity levels of AHI <1, 1 to 4.9, 5 to 14.9, and > or =15, respectively (P=0.0049, AHI > or =15 versus <1). Adjusted mean CRP levels demonstrated a dose response with SDB above a threshold AHI of 5. This association was partially explained by overnight hypoxemia and less so by sleep duration. In adolescents free of known CVD, an AHI > or =5 is associated with increasing levels of CRP, suggesting that pediatric SDB may confer additional CVD risk beyond that of obesity.

Cardiology Patient Page. C-reactive protein: a simple test to help predict risk of heart attack and stroke.

Cardiology Patient Page. C-reactive protein: a simple test to help predict risk of heart attack and stroke.

Acute-phase response, interleukin-6, and alteration of cyclosporine pharmacokinetics

Administration of interleukin-6 partially reproduces the inhibitory effects of the acute-phase response on cytochrome P450-dependent drug metabolism. The aim of the study was to determine whether endogenous cytokine has such an effect in patients treated by cyclosporine, which is metabolized by the cytochrome P4503A subfamily. Blood cyclosporine and serum interleukin-6 levels were determined in six patients undergoing bone marrow transplantation, as long as they received cyclosporine by continuous infusion. Two serum acute-phase proteins, C-reactive protein and alpha 1-acid glycoprotein, and two cyclosporine metabolites, AM1 and AM9, were also determined. At the time of marrow infusion, levels of specific markers of inflammation were low. A peak in interleukin-6 level was then observed a mean of 10.8 days after transplantation, closely associated with variations in C-reactive protein levels. A parallel twofold increase in AM1 concentrations was observed, followed by a three-fold increase in cyclosporine levels, which peaked 4.8 days after interleukin-6. The times of peak cyclosporine and AM1 levels correlated with the time of peak interleukin-6 levels. AM9 was detectable in three patients but concentrations fell when interleukin 6 became detectable. An inflammatory reaction could be an important source of intraindividual variability in cyclosporine pharmacokinetics, possibly through an inhibition of cytochrome P4503A-dependent enzyme activities by endogenous interleukin-6. Blood AM1 accumulation might be explained by a secondary metabolic step that is highly sensitive to the inhibitory effect of interleukin-6.