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Sex steroids have direct effect on bone via their action on the estrogen and androgen receptors of bone cells. However, there is emerging evidence that their indirect actions on bone can play also important role in the pathogenesis of osteoporosis and bone loss in inflammatory diseases. The tissues that are involved in the extraskeletal actions of sex hormones and are better studied in the past few decades are adipose tissue, muscle tissue and the immune system. Key regulators on those complex pathways are molecules such as cytokines, adipokines and reactive oxygen species.

BACKGROUND AND AIMS A small percentage of patients with autosomal dominant polycystic kidney disease (ADPKD) have no clear family history. The clinical course and prognosis of the disease in this subgroup of patients may be different. The present study investigates the progression and prognostication of end-stage renal disease (ESRD) in a large cohort of patients with and without a family history of ADPKD. METHOD This study enrolled 291 patients who were being followed in a specialized outpatient ADPKD clinic. Patients having a total of more than 10 kidney cysts in a recent magnetic resonance imaging (MRI) scan were included in the study even if they had no clear family history or confirmatory genetic test. At enrollment, total kidney volume was calculated by MRI, and the Mayo Clinic Imagining Category (MCIC) was determined. The prediction of ESRD (future estimated-glomerular filtration rate [e-GFR RESULTS Of the 291 patients included in the study, 34 (11.68%) had no clear family history of ADPKD, and 257 (88.32%) had a clear family history. Age, gender, presence or not, and age at diagnosis of hypertension as well as BMI were similar in the two groups (P = 0.369, 0.398, 0.170, 0.295, 0.597, respectively). The age at diagnosis of ADPKD was similar between patients with and without a clear family history (P = 0.125) as well as, the e-GFR, the stage of chronic kidney disease and albuminuria (P = NS). The TKV tended to be higher in patients without a clear family history (median, [range]), 2210.3 (440.7–9137.5) mL versus 1649.9 (215.7–10 425.9) mL in those with a family history of ADPKD (P = 0.09), and the same was valid for the height-adjusted TKV (P = 0.08). In MCIC 1C, 1D and 1E, more patients without a known family history of ADPKD were classified than patients with a family history of ADPKD (88.89% versus 70.14%), and vice versa in MCIC 1A and 1B (11.11% versus 29.86%; P = 0.04). Finally, the ESRD prediction was (median, [range]) 15.66 (1–42) years for the patients without a clear family history and 34.1 (1–346) years for those with a clear family history of ADPKD (P = 0.025). CONCLUSION Patients with ADPKD without a clear family history tend to have a more rapid progression and a worse renal prognosis than those with a clear family history of the same disease.

BACKGROUND AND AIMS The identification of possible risk factors for the progression of autosomal dominant polycystic kidney disease (ADPKD) is an emerging field, especially after the introduction of tolvaptan as the first disease-specific treatment. The present study aims to explore the associations between epidemiological, clinical and imaging data in a large cohort of ADPKD patients. METHOD This study was from a single outpatient clinic, following patients with ADPKD. Patients were included in the study if they had recently undergone a magnetic resonance imaging for the measurement of total kidney volume (TKV). For all patients, the Mayo Clinic Imagining Category (MCIC) and the prediction of end-stage renal disease (ESRD) (future estimated-glomerular filtration rate [e-GFR] RESULTS A total of 250 patients were included. Based on measurements of height-adjusted TKV (ht-TKV) and age, 8.4% of the patients were classified as 1A, 19.6% as 1B, 34% as 1C, 24.8% as 1D and 13.2% as 1E, MCIC. In multivariable analysis, patient's age (P < 0.001), male sex (P < 0.001), parent's age at ESRD (adjusted for patient age) (P < 0.001) and hypertension (P = 0.009) were associated with log (ht-TKV). Parent's age at ESRD differed significantly between the MCICs of the offspring (mean±SD), 65.63 (12.13) in 1A, 61.9 (11.3) in 1B, 55.6 (9.6) in 1C, 51.64 (9.2) in 1D and 49.7 (8.3) in 1E, (P CONCLUSION As a heritability estimator, the age at which an affected parent had reached ESRD was significantly associated with a worse phenotype, prognosis and tolvaptan indication. Hypertension was associated with poor prognosis and an aggravated phenotype, whereas age at diagnosis of the disease and hypertension onset were associated with tolvaptan indication in ADPKD.

BACKGROUND AND AIMS Recent advances in the treatment of autosomal dominant polycystic kidney disease (ADPKD) highlight the interplay between the clinical and laboratory profile of the disease. This study aims to present the baseline characteristics of patients followed in a large ADPKD cohort from a single center and explore possible associations between demographic, clinical and laboratory parameters. METHOD This study enrolled patients who were being followed in a specialized outpatient ADPKD clinic from December 2018 to December 2021. At enrollment, demographics, medical and family history, and laboratory data were recorded using a standardized form. Estimated glomerular filtration rate (eGFR) was calculated and magnetic resonance imaging for total kidney volume (TKV) measurement was performed. RESULTS Three hundred (162 women and 138 men) ADPKD patients at a mean age ± SD of 40.87 ± 12.9 years were enrolled in the study. Overall, 67.3% of them were classified as chronic kidney disease, stage 1 and stage 2. The ADPKD was diagnosed at a mean age ± SD of 27.2 ± 11.65 years. Twenty-six % of 300 patients were diagnosed before the age of 20. A positive family history was present in 89.75% of patients. In this subgroup, the median age of the affected parent who reached end-stage renal disease was 55 (range 28–87) years. Hypertension was diagnosed in 88% of the patients at a mean ± SD age of 35.89 ± 11 years. Hepatic cysts were present in 78% of them, urinary tract infections, nephrolithiasis, macroscopic hematuria and pain in 44.87%, 43%, 24.71% and 54.23%, respectively. In 31% of the cases, there was a family history of intracranial bleeding. In multivariable analysis, lower eGFR was associated with older age (P CONCLUSION In this study, patients with ADPKD were diagnosed at a young age and hypertension developed in the majority of them early in the course of the disease. Renal function was influenced by age, height-adjusted cyst renal volume, early diagnosis of ADPKD and BMI.

Background and Aims Recent advances in the treatment of Autosomal Dominant Polycystic Kidney Disease (ADPKD) highlight the interplay between the clinical and the laboratory profile of the disease. This study aims to present the baseline characteristics of patients followed in a large ADPKD cohort from a single center in Greece, and explore possible associations between demographic, clinical and laboratory parameters. Method Patients followed in a specialized outpatient PKD clinic from December 2018 up to December 2019 were recruited in this study. At enrollment, demographics, medical and family history and laboratory data were recorded using a standardized form. Estimated glomerular filtration rate (eGFR) was calculated and Magnetic Resonance Imagining for total kidney volume (TKV) measurement was performed. Results One-hundred three females and 83 males with a mean age±SD of 41.4 ± 13 years (18.8 % < 30 years) were enrolled. Overall, 60.8% of them were classified as Chronic Kidney Disease, (CKD) stage 1 and 2. The ADPKD was diagnosed at a mean age±SD of 26.5±12.5 years. Thirty four percent out of 186 patients were diagnosed before the age of 20 and 9% of them before the age of 10. A positive family history was present in 89% of patients. In this subgroup, the median age of the affected parent that reached end stage renal disease (ESRD) was 55 (range 28-87) years. Hypertension was diagnosed in 89% at a mean± SD age of 37.2 ± 10.5 years. Hepatic cysts were present in 79.3% of patients, urinary tract infections, nephrolithiasis, macroscopic hematuria and pain in 44.3%, 42.5%, 24.8% and 54.4% respectively. A history of intracranial bleeding in family was positive in 21.5%. In multivariable analysis, lower eGFR was associated with younger age at the time of APKD diagnosis (p < 0.002), younger age at hypertension diagnosis (p < 0.08) and greater values of TKV (p < 0.001), height adjusted TKV (p < 0.001) and Body Mass Index (BMI) (p = 0.02). Conclusion In this study, patients with ADPKD were diagnosed at a young age and hypertension developed early on the course of the disease. Both these factors together with higher values of BMI and TKV were independently associated with low eGFR.

Background and Aims The identification of possible risk factors for the progression of Autosomal Dominant Polycystic Kidney Disease (ADPKD) is an emerging field especially after the introduction of the first disease-specific treatment. The present study aims to explore the associations between epidemiological, clinical and imagining data in a large cohort of ADPKD patients. Method This study was from a single outpatient clinic following patients with ADPKD. Patients were included in the study if they had a recent Magnetic Resonance Imaging (MRI) for measurement of Total Kidney Volume (TKV), a validated biomarker for disease progression. For all patients, the Mayo Clinic Imagining Category (MCIC) and the respective prediction for End Stage Renal Disease (ESRD) were calculated. Patients eligible for tolvaptan treatment (MCIC 1C, 1D, 1E, age < 55 years old and estimated-glomerular filtration rate (e-GFR) ≥ 25 ml/min) were identified. Characteristics including individual medical history, clinical and laboratory data were examined for possible associations with renal and imagining parameters using linear regression models. Results A total of 158 patients were included. Based on measurements of height-adjusted TKV (ht-TKV) and age, 5% of the patients were classified as 1A, 20% as 1B, 34% as 1C, 25% as 1D and 16% as 1E, MCIC. In multivariable analysis, patient’s age (p = 0.01), male sex (p < 0.001), parent’s age at which ESRD was reached (adjusted for patient age) (p < 0.001) and proteinuria (p = 0.04) were associated with ht-TKV. Parent’s age at ESRD differed significantly between the MCICs of the offspring (mean±(SD)), 70.83 (12.90) in 1A, 63.79 (11.39) in 1B, 57.32 (10.42) in 1C, 51.42 (9.18) in 1D and 47.94 (5.73) years old in 1E, (p < 0.001). Similarly, there were significant differences in the presence and the age of hypertension onset (p =0.004 and p = 0.003, respectively). In 104 patients (50 females, 54 males) who were eligible for tolvaptan treatment age at ADPKD diagnosis, age at hypertension onset and parent’s age reaching at ESRD were all significantly lower (p < 0.001 for all) when compared to non-eligible patients. Finally, factors associated with the prediction score of ESRD (e-GFR 10/ml/min) were hypertension, uric acid and the age at ESRD of the affected parent (p = 0.001, 0.02 and 0.01, respectively). Conclusion The age at which an affected parent had reached ESRD, as heritability estimator, was significantly associated with a worst phenotype, prognosis and tolvaptan indication. Early diagnosis of the disease, hypertension and its early onset, proteinuria and male sex are also possible risk factors for the progression of ADPKD.

Background Patients on long-term maintenance hemodialysis (HD) are at high risk of developing cardiovascular disease and suffering various cardiovascular complications during HD. Hypothesis The purpose of this study was to evaluate the influence of changing loading conditions on the myocardial performance index (MPI) in patients on long-term HD and to specify an optimal level of fluid loss during HD that would maintain stable global cardiac function. Methods The study consisted of 52 patients with end-stage renal failure (ESRF), mean age 56±11.7 y, range: 25–80 y, on regular HD. For each patient a complete echocardiographic-Doppler examination was performed before and after HD. Systolic and diastolic parameters of left ventricular function were measured, and the myocardial performance index (MPI) was calculated. Results The MPI was significantly prolonged after HD (0.47±0.15 before HD versus 0.59±0.16 after HD, p < 0.001). Mean change in body weight during HD was 2.1±0.86 kg. The MPI did not change significantly in patients with intradialytic weight loss up to 1.75 kg. Conclusions The MPI value seems to be independent of acute preload changes only when fluid loss is less than 1.75 kg. A 1.75-kg fluid loss during HD seems to be the optimal goal. In ESRF patients on HD, the MPI seems to be a good indicator of global left ventricular function and potentially a valuable aid in the effort to maintain optimal fluid balance. The authors have no funding, financial relationships, or conflicts of interest to disclose.

Atherosclerosis and vascular calcification often co-exist in chronic kidney disease (CKD) patients. Although the former has been recently recognized as an active inflammatory process, atherosclerosis-related calcification of the intima is still viewed as a passive epiphenomenon. Recent experimental data showed that ossification of the internal vascular wall might also be an active inflammatory process interrelated to atherosclerosis. Factors like RANKL (receptor activator of nuclear factor ĸB ligand), RANK and osteoprotegerin modulate vascular calcification and at the same time are involved in the process of atherosclerosis. Moreover, basic calcium phosphate crystals could interact with and activate monocytes-macrophages that produce proinflammatory cytokines capable of initiating – via endothelial activation and leukocyte adhesion – the atherosclerotic process. Thus, vascular calcification might be an active player and not simply an epiphenomenon in atherosclerosis. Should the above-mentioned data be confirmed in future studies, calcification of the internal vascular wall and atherosclerosis might be viewed and treated as tightly interconnected and linked by inflammation processes in CKD patients.

Telomerase is involved in the elongation of telomeres. It remains active in very few types of cell in mature organisms. One such cell type is the lymphocytes. In this study, we investigated the activity and expression of telomerase in lymphocytes from renal failure patients and compared it to that for normal controls. Inflammation status was determined at the same time. The enzyme activity was measured using PCR-ELISA with peripheral blood mononuclear cells (PBMCs) from three groups: 53 healthy individuals, 50 patients with chronic kidney disease (CKD) and 50 dialysis patients. In the same cell populations, the expression of the reverse transcriptase of the human telomerase gene (hTERT) was measured via real-time PCR. The inflammationstatus of these individuals was determined by calculating the interleukin 6 (IL-6), IL-10, C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-a) serum concentrations via ELISA. The lowest levels of telomerase activity were detected in CKD, and this group had the highest IL-6 and CRP values and the lowest hTERT expression. The dialysis group showed significant differences in comparison to the normal subjects and to the CKD patients. Further studies are warranted in order to explore the way inflammation influences telomerase activity and hTERT expression.

SUMMARY: Background: Telomerase preserves telomeres’ function and structure preventing cellular senescence. Its activity is reduced in peripheral blood mononuclear cells (PBMC) of haemodialysis (HD) patients. The purpose of this study is to investigate the potential correlation between increased oxidative stress/inflammation and telomerase activity in PBMC of HD patients. Methods: Telomerase activity was measured by PCR-ELISA in PBMC isolated from a group of 42 HD patients and 39 subjects with estimated glomerular filtration rate ≥80 mL/min (control group). Serum oxidized low-density lipoprotein (ox-LDL), tumour necrosis factor-α (TNF-α) and interleukin-10 (IL-10) were also measured in both groups by ELISA. Results: Ox-LDL was negatively correlated to percentage telomerase activity in PBMC (r = −0.506, P = 0.000 in the whole group of 81 HD and normal subjects and r = −0.559, P

Background: Telomerase preserves telomere length and structure, preventing cellular senescence, which is associated with alteration of the chromosomal ends. We hypothesized that telomerase activity is altered in peripheral blood mononuclear cells (PBMCs) of hemodialysis (HD) patients. To investigate this hypothesis as well as the relationship between telomerase and inflammation, we measured the activity of this reverse transcriptase as well as the level of several inflammatory markers in PBMCs and serum of an end-stage renal failure (ESRF) population and a non-renal-failure group of subjects. Methods: In PBMCs isolated from 42 HD and 39 non-renal-failure subjects of the same age (51.0 ± 12.4 and 51.4 ± 12.1 years, respectively) telomerase activity was measured using PCR-ELISA; the method was based on the telomeric repeat amplification protocol. Results: Telomerase activity in PBMCs was detected in 18 (42.9%) HD and 28 (71.8%) non-renal-failure subjects (p = 0.013). Among positive subjects, percent telomerase activity in PBMCs was significantly higher in non-renal- failure (117 ± 112 %) than in HD (47.6 ± 57.1 %) subjects (p = 0.008). Detectable telomerase activity was lower in long-term than in short-term HD patients (13.3 ± 8.9 vs. 75.0 ± 64.8%, respectively, p = 0.015). Although higher in HD group, inflammatory indexes (C-reactive protein, interleukin-6, IL-6, soluble IL-6 and soluble gp130) were not correlated to telomerase activity in PBMCs. Conclusion: Telomerase activity in PBMCs is reduced in HD patients. It seems that, at least in this type of cell in this population, defense from senescence, as assessed by telomerase activity, is altered and associated with the chronicity of uremia/HD procedure.

Background Systemic microinflammation is correlated with atherosclerosis. It needs a reliable assessment. This study explores the temporal variations of three inflammatory indexes [C-reactive protein (CRP), serum amyloid A (SAA) and interleukin-6 (IL-6)] in a period free of clinical events and tests the reliability of their multiple measurements for the assessment of microinflammation in haemodialysis (HD) patients, a population at high risk of atherosclerotic cardiovascular disease. Methods For 4 months, serum CRP, SAA and IL-6 were measured in 29 HD patients during the weeks they were free of inflammatory clinical events (> or =12 measurements for each index in every patient). The components of the variance as well as the reliability of two to five measurements for each index, aimed at assessing microinflammation precisely, were computed. Results The median (interquartile range) of CRP was 2.3 (0.9-4.9) mg/l, of SAA 3.7 (2.1-9.3) mg/l and of IL-6 4.4 (2.2-7.7) pg/ml. Patients were approximately equally distributed between three groups of low, intermediate and high variability for each index. The contribution of intraindividual (biological) variation to the total of variance was 71.3%, 69.3% and 86.7% for CRP, SAA and IL-6, respectively (higher than in all other similar studies in healthy populations). Using two measurements, the estimated reliability was 57-68% for CRP in two-thirds of the patients (comparable with that found in healthy subjects) and 57% for SAA and IL-6 in only one-third of the patients. Increasing the number of measurements up to five did not change the reliability. Conclusions Individual factors significantly influence the levels of inflammatory indexes in HD patients in periods free of inflammatory clinical events. The mean of two weekly CRP measurements, but not of SAA or IL-6, seems to assess microinflammation in most patients with a sufficient reliability.

Recently, Chlamydia pneumoniae is the microorganism frequently implicated in the infection-based inflammatory atherogenous hypothesis. Although in vitro experimental data and initial sero-epidemiologic, pathology-based studies and antibiotic trials supported this interesting hypothesis, later data are conflicting. Some confounding factors are the causes of uncertainty; lacking of standard methods for C. pneumoniae detection, co-existence of other atherosclerotic risk factors and anti-inflammatory effects of antibiotics used in clinical trials seem to be the principal ones. Standardization of methodology used, antibiotic trials with a different orientation-design and a vaccine preparation that eventually will be tested in clinical trials with a long follow-up, should provide a definite answer regarding the probability C. pneumoniae to be a main, a secondary or an irrelevant factor to atherosclerosis. Studies linking C. pneumoniae to inflammation and accelerated atherosclerosis in renal failure patients are accumulated but limitations are similar to the above mentioned.

Background: Inflammation is frequently elevated, and seems to be episodic in hemodialysis (HD) patients. Whether, its episodic character is due to the temporal variability, in periods free of clinical events, of the inflammatory indices or due, to the acute phase response induced by common inflammatory stimuli, has not been investigated yet in a longitudinal study. This study explores inflammation forms, characteristics and causes which are probably related to the high cardiovascular disease (CVD) morbidity in HD patients. Methods: In 37 HD patients, high-sensitivity C-reactive protein (hs-CRP), serum amyloid A (SAA) and interleukin-6 (IL-6) were weekly measured for 16 consecutive weeks. Inflammatory clinical events, in the week before every measurement, were recorded. Repeated measures ANOVA were applied for statistical analysis. Results: Fifty-one of 533 patient-weeks were positive for a clinical event. Mean ± SD (range) hs-CRP was 7.01 ± 16.06 (0.2–169) mg/l for all the weeks of the study, 38.25 ± 39.35 (2.1–169) mg/l for the weeks with clinical events and 3.70 ± 3.86 (0.2–26.1) mg/l for the weeks free of events. Variations for SAA and IL-6 were similar. ‘Clinical events’ strongly influenced acute-phase proteins and IL-6 levels. The effect of the factor ‘time’ (as assessed by inflammatory indices variation in weekly repeated measurements) was significant for all the 3 indices measured, independently of the factor ‘clinical events’. Conclusions: In periods free of clinical events, microinflammation characterizes HD patients and fluctuates in time. Inflammation due to common clinical events is added, periodically, to this microinflammation. The high level persistent microinflammation as well as the superimposed – due to clinical events – inflammation could be related to the CVD in these patients.

Although cellular senescence and inflammation have been indirectly associated, a direct connection was absent until recently, when two studies proved that senescence at a cellular level is directly linked to an interleukin (IL)-dependent inflammatory network. IL-6 and IL-8, two well-known proinflammatory cytokines, seem to play a central role in premature cellular senescence induction. Activation of the above-mentioned molecules and their receptors is necessary for the initiation of senescence while their deactivation ceases the process. Taking in consideration that atherosclerosis is an inflammatory process and cellular senescence is an emerging cardiovascular risk factor, these new data may be of great importance, especially for chronic kidney disease patients who suffer from increased cardiovascular disease morbidity.

Antiphospholipid syndrome (APS) is an autoimmune disease. Less than 1% of patients with APS present with life-threatening catastrophic APS (CAPS). We report here a case of CAPS in a young girl with cardiac, gastrointestinal and renal involvement. Although the management was complicated, the outcome was better than expected. We suggest that CAPS be included in the differential diagnosis of acute renal failure in children with multi-organ involvement and prolonged phospholipid-dependent coagulation time and promptly treated with immunomodulating agents and anticoagulants.

Hepcidin has emerged as a peptide with a key role in the regulation of iron homeostasis in patients with chronic kidney disease (CKD), having a strong dependence on inflammation. Recent studies reveal that hepcidin may be also associated with the progression of atherosclerosis. This study was performed to analyze the relation of hepcidin to markers of atherosclerosis and inflammation in patients on dialysis. A total of 90 individuals were enrolled. Sixty patients with end-stage renal disease, who were on hemodialysis (HD) (N = 30) and peritoneal dialysis (N = 30) were compared with 30 normal controls (NC). Age, body mass index, time on dialysis, serum lipids, C-reactive protein (CRP) and interleukin-6 (IL-6) were measured and analyzed in correlation with hepcidin concentration. It was found that patients on HD and peritoneal dialysis have significantly higher (P 0.0001) levels of hepcidin, CRP and IL-6 than NC. Hepcidin in dialysis patients is significantly related to age (r = 0.373, P = 0.012), serum triglycerides (r = 0.401, P = 0.005), HDL-C (r = -0.268, P = 0.048), CRP (r = 0.436, P = 0.0007) and IL-6 (r = 0.569, P 0.0001). In multiple regression analysis, hepcidin correlated independently with triglycerides (β = 0.402, P = 0.041) and IL-6 (β = 0.559, P = 0.006). Moreover, patients with high triglycerides in combination with high IL-6 levels have significantly increased concentrations of hepcidin than those with low triglycerides and low IL-6 levels (P 0.0001). Elevated levels of hepcidin in patients with CKD on dialysis may be related to the occurrence of high triglycerides and high IL-6 serum concentrations. This probably suggests that hepcidin may play a role to the progression of atherosclerosis and inflammation, but this hypothesis should be further evaluated.

Hepcidin has emerged as a peptide with a key role in the regulation of iron homeostasis in patients with chronic kidney disease (CKD), having a strong dependence on inflammation. Recent studies reveal that hepcidin may be also associated with the progression of atherosclerosis. This study was performed to analyze the relation of hepcidin to markers of atherosclerosis and inflammation in patients on dialysis. A total of 90 individuals were enrolled. Sixty patients with end-stage renal disease, who were on hemodialysis (HD) (N = 30) and peritoneal dialysis (N = 30) were compared with 30 normal controls (NC). Age, body mass index, time on dialysis, serum lipids, C-reactive protein (CRP) and interleukin-6 (IL-6) were measured and analyzed in correlation with hepcidin concentration. It was found that patients on HD and peritoneal dialysis have significantly higher (P

Patients suffering from renal failure exhibit an impaired immune system function. We wanted to investigate the transcription of the tumor suppressor genesp53andRBto record, if these cells could be stimulatedin vitroin order to divide, after the addition of antigenic and inflammatory factors. This expression was measured by real-time PCR in peripheral blood mononuclear cells (PBMCs) from three different groups: ten healthy individuals, ten patients with chronic kidney disease (CKD), and ten dialysis patients with end stage renal disease (ESRD). The transcription rate of these genes was also measured after the cultivation of PBMCs under four different conditions: just with the culture medium, with lipopolysaccharide (LPS), with C-reactive protein (CRP), and with lipoxin A4(LXA4)-LPS. Our results show that in most cases after the cultivation with additives, the transcription levels were higher in dialysis patients compared to those of the other two groups. Our findings serve as indications of cellular senescence on a molecular level, while it seems that these cells are less easily stimulatedin vitroin order to duplicate.

Low and not high cholesterol seems to predict high mortality in hemodialysis (HD) patients. The confirmation of this reverse epidemiology as well as its possible interconnection with the increased inflammatory activity observed in this population is being explored in the present study. A group of 136 HD patients was prospectively studied for 2 years, and cardiovascular disease (CVD) as well as all-cause mortality and morbidity were recorded. Baseline lipid profile, inflammatory status, and patients' characteristics were studied as potential survival and hospitalization predictors. During the 24-month follow-up, 21 deaths (52.4% due to CVD) and 38 hospitalizations (55.3% due to CVD) were recorded. In multivariate Cox regression analysis, decreased interleukin-10 (IL-10) and decreased total serum cholesterol (TChol) were the only independent predictors of CVD mortality while C-reactive protein and decreased TChol predicted all-cause mortality. Interleukin-10 at baseline was 11.29 +/- 21.49 vs. 5.51 +/- 4.57 pg/mL (P0.018) and TChol 167.37 +/- 47.84 vs.122.04 +/- 26.48 mg/dL (P0.000) in survivors vs. nonsurvivors from CVD, while C-reactive protein at baseline was 9.37 +/- 11.54 vs. 23.15 +/- 18.76 mg/L (P0.000) and TChol 169.26 +/- 46.42 vs. 133.26 +/- 46.33 mg/dL (P0.003) in survivors vs. nonsurvivors from any cause of death. Using the same method of statistical analysis, IL-6 and decreased soluble gp130 (sgp130)--an antagonist of IL-6 action--were found to be the only independent prognostic factors for hospitalization due to CVD while decreased soluble gp130 remained the sole predictor of hospitalization due to any cause. In conclusion, reverse epidemiology regarding cholesterol is confirmed in the present study. Furthermore, inflammatory activity also predicts, independently of or in conjunction with low-cholesterol, CVD and all-cause morbidity and mortality in HD patients.

Cellular senescence is associated with shortened or damaged telomeres and is characterized by permanent exit from the cell cycle, morphological changes, and altered function. It develops after repeated cell divisions and also can be induced prematurely by stress conditions. The senescent phenotype, depending on cell type and atherosclerosis phase, seems to be a proatherosclerotic one: it promotes endothelial dysfunction and appears to be implicated in plaque destabilization, as well as in endothelial progenitor cell alteration. Many traditional and nontraditional cardiovascular disease risk factors induce senescence in a variety of vascular cells. Several of these factors, such as diabetes, hypertension, oxidative stress, and inflammation, are clustered in patients with chronic kidney disease. In a limited number of recent studies, stress-induced premature cellular senescence in this biologically aged population also was described. The hypothesis that premature cellular senescence might be considered an additional atherosclerosis-inducing factor in patients with chronic kidney disease is proposed.

In the last few years atherosclerosis has been recognized as an inflammatory process. Assessment of low-grade inflammation with indexes like C-reactive protein (CRP) is considered indicative and potentially predictive for this disease. On the other hand, in a large number of clinical studies, a grade of microinflammation has been found to be associated with numerous other processes that may be directly, indirectly or not related to atherosclerosis. The most interesting finding these studies have yielded is that innate immunity is activated in various, previously unexpected, conditions. This phenomenon is better explained by the application of a recently proposed immune activation mechanism, namely, the ‘danger model’. It seems that many conditions related to metabolic or homeostatic stress or to pro-atherosclerotic and pre-diabetic dysfunctions, established atherosclerosis or diabetes, but also other early tissue injury – like renal, pulmonary or connective tissue – and several exogenous stimuli, constitute ‘danger signals’ that induce inflammation which interacts with and complicates the above-mentioned processes. On this basis the complex relationships between CVD risk factors, atherosclerotic process, other tissue injury and inflammation is examined. The practical application of this hypothesis, namely the new clinical use of CRP as a sensitive – although not specific for atherosclerosis – index of low-grade inflammatory activity as well as to the atherosclerosis treatment are also discussed.

SUMMARY: Background: Infectious agents may be implicated in the inflammatory atherosclerotic process. Not only specific microorganisms but also the infectious burden, defined as the number of pathogens to which a patient is exposed, has been associated with atherosclerosis. In the present study, the infectious burden, determined directly (by identification of viable pathogens in peripheral blood mononuclear cells (PBMC)) and indirectly (by serum antibodies detection) is correlated to the inflammatory and atherosclerotic status in haemodialysis (HD) patients, a population at high risk for cardiovascular disease. Methods: The viable forms of four microorganisms ( Chlamydia pneumoniae , herpes virus 1 and 2 and cytomegalovirus) were identified in patients PBMC by cell cultures and subsequent polymerase chain reaction. Serum IgG against the above pathogens and Helicobacter pylori were also determined. Inflammation was assessed by measurement of C-reactive protein (CRP), serum amyloid A (SAA), three pro- and one anti-inflammatory cytokines and four adhesion molecules. Atherosclerosis was defined by a scoring system using medical history data. Results: The number of viable pathogens identified in PBMC in the 122 HD patients included in the study were zero in 22.1% of them, one in 33.6%, two in 43.4% and three in one patient. The number of IgG antibodies determined was one in 6.6% of patients, two in 32%, three in 48.4% and four in 13.1%. Seropositivity was not significantly different between patients with or without the respective viable pathogen identified in PBMC. Atherosclerosis was present in 40.2% of patients, and CRP, SAA and interleukin-6 were all increased in these patients. Neither inflammatory indexes nor atherosclerosis were significantly different in patients with a higher number of viable pathogens detected in PBMC or in those with a higher antibodies number. Conclusions: The direct infectious burden determination (the number of viable pathogens in PBMC) does not coincide with the serum (by IgG detection) infectious burden. Although inflammation correlates to atherosclerosis, neither PBMC nor the serum infectious burden is associated with these two entities in the inflamed and atherosclerotic HD patients.

Background: A reverse association between cholesterol level and cardiovascular disease mortality is observed in hemodialysis (HD) patients; this paradoxical relationship may be explained by the coexistence of inflammation. Interleukin-6 (IL-6) is a central regulator of inflammation; its action is augmented by the soluble IL-6 receptor (sIL-6R) and inhibited by the soluble gp130 (sgp130). In order to investigate the potential association of inflammation with cholesterol levels in the HD population, release of soluble IL-6 components by peripheral blood mononuclear cells (PBMCs) was measured in two groups of HD patients with distinctly different lipid profile and in a control group. Methods: Twenty-two HD patients with low serum cholesterol (range 85–171 mg/dl), 23 HD patients with high cholesterol (189–342 mg/dl) and 21 normolipidemic non-renal failure subjects were enrolled in the study. IL-6, sIL-6R and sgp130 were measured by ELISA in the serum and in the supernatant collected from cell cultures of activated or resting PBMCs isolated from all three groups. Results: Serum IL-6 and sgp130 level was higher while sIL-6R was lower in both groups of HD patients compared to the control group. The ex-vivo release of the IL-6 and sgp130 by unstimulated PBMCs did not differ significantly between the three groups but that of the sIL-6R was higher in non-renal failure than in hypercholesterolemic HD subjects. Production of sIL-6R by stimulated PBMCs was higher in low-cholesterol HD patients (p < 0.001) and the same was valid for the sgp130 release (p = 0.034). Release of IL-6 by activated PBMCs was higher in the low-cholesterol compared to the high-cholesterol HD patients group (p = 0.011 for post hoc test). Major serum lipid fractions were inversely correlated to IL-6 and sIL-6R production from stimulated PBMCs in HD but not in non-renal failure subjects. Finally, release of the sgp130 by PBMCs was significantly reduced in 13 hypertriglyceridemic – and hypercholesterolemic – HD patients. Conclusion: Production of soluble components of a crucial pro-inflammatory and potentially atherogenic cytokine, namely the IL-6, by stimulated PBMCs appears to be inversely correlated with the serum cholesterol levels in HD patients.

Background: Hemodialysis (HD) patients are frequently in an elevated inflammatory state which is correlated to the atherosclerosis-related and overall morbidity and mortality in this population. Statins, beyond their antilipidemic effects, are also considered to have anti-inflammatory, immunomodulating and antioxidant properties. The individual response of HD patients to a short course of fluvastatin, the mechanisms involved in the immunomodulating and anti-inflammatory effects of this drug and the time interval to the appearance of these effects are investigated in this longitudinal study. Methods: In a group of 51 HD patients, fluvastatin 40 mg/day was administered for 4 weeks. Serial measurements of the lipid profile, C-reactive protein (CRP), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), interleukin-10 (IL-10), and serum oxidized LDL (ox-LDL), were performed before, during, and after the treatment period. Results: Total cholesterol was significantly reduced after 14 days of treatment with fluvastatin (from mean ± SD 216.7 ± 34.3 to 179.2 ± 42.3 mg/dl, p < 0.001). IL-6 and ox-LDL were reduced on day 28 (p < 0.001 and p < 0.01, respectively) and IL-10 was increased on day 14 (p = 0.05); CRP did not change significantly during the treatment period while sIL-6R was increased on day 28 of fluvastatin administration (p < 0.05). In a subgroup of patients with CRP, IL-6, sIL-6R, and ox-LDL baseline serum values ≧ the median and IL-10 ≤ the median, CRP was reduced on day 28 of fluvastatin treatment (p < 0.01), IL-6 and ox-LDL were reduced earlier, on day 14 (p = 0.05 and p < 0.05, respectively) while sIL-6R did not change significantly during the treatment period. Conclusions: Treatment with fluvastatin rapidly modulates inflammation in HD patients. Enhancement of anti-inflammatory mechanisms and attenuation of the inflammatory and oxidative state contribute to this modulation. Patients in an elevated baseline inflammatory state respond more rapidly and effectively to the treatment. This immediate and multi-potent action of the statins could be clinically useful in acute atherosclerosis complications or in the treatment of chronic inflammation in HD patients.

Inflammatory indexes are frequently elevated in end-stage renal failure (ESRF) patients. It seems that the pattern of inflammation is particular in this population. In the presence of a higher than normal microinflammatory background (CRP, C-reactive protein, values between 0.1 and 10–15 mg/l) that varies with time, waves of ‘true’ inflammation (CRP > 10–15 mg/l), mainly due to infections, are added periodically. To accurately assess the average microinflammation in these patients, multiple CRP measurements are required. As recent experimental studies showed that inflammation and particularly elevated CRP levels may be risk factors and not just a risk index for atherosclerosis, in this case, the characteristic inflammation pattern might be of importance in the evolution of this disease in ESRF patients. The causes of the inflammatory state in ESRF patients are multiple: renal insufficiency per se and its complications, coexisting diseases, established atherosclerosis, the consequences of renal replacement treatment, and frequent infections are potentially the main ones. The fluctuating inflammatory pattern is probably due to destabilization or changes in time of the above-mentioned parameters. Thus, the clinical meaning of the average microinflammation in these patients, as assessed by CRP measurements, seems to be that of an index indicative of the grade of their health aggravation by the multiple factors implicated in the inflammation formation. CRP is a sensitive, but not specific, risk index of the overall morbidity and mortality in these patients. The manipulation of the inflammation in ESRF patients should include follow-up and treatment of all the factors that contribute to this state and probably medications such as the statins. If inflammation and CRP in particular definitely prove to be risk factors for atherosclerosis, intensification of this treatment will be necessary.

Inflammation is frequently elevated, and seems to be episodic in hemodialysis (HD) patients. Whether, its episodic character is due to the temporal variability, in periods free of clinical events, of the inflammatory indices or due, to the acute phase response induced by common inflammatory stimuli, has not been investigated yet in a longitudinal study. This study explores inflammation forms, characteristics and causes which are probably related to the high cardiovascular disease (CVD) morbidity in HD patients.In 37 HD patients, high-sensitivity C-reactive protein (hs-CRP), serum amyloid A (SAA) and interleukin-6 (IL-6) were weekly measured for 16 consecutive weeks. Inflammatory clinical events, in the week before every measurement, were recorded. Repeated measures ANOVA were applied for statistical analysis.Fifty-one of 533 patient-weeks were positive for a clinical event. Mean +/- SD (range) hs-CRP was 7.01 +/- 16.06 (0.2-169) mg/l for all the weeks of the study, 38.25 +/- 39.35 (2.1-169) mg/l for the weeks with clinical events and 3.70 +/- 3.86 (0.2-26.1) mg/l for the weeks free of events. Variations for SAA and IL-6 were similar. 'Clinical events' strongly influenced acute-phase proteins and IL-6 levels. The effect of the factor 'time' (as assessed by inflammatory indices variation in weekly repeated measurements) was significant for all the 3 indices measured, independently of the factor 'clinical events'.In periods free of clinical events, microinflammation characterizes HD patients and fluctuates in time. Inflammation due to common clinical events is added, periodically, to this microinflammation. The high level persistent microinflammation as well as the superimposed--due to clinical events--inflammation could be related to the CVD in these patients.

The effect of viable Chlamydia pneumoniae on serum cytokines and adhesion molecules in hemodialysis patients. Background Chlamydia pneumoniae (Cp) induces the production of cytokines and adhesion molecules in infected host eukaryotic cells. The causes for pro-inflammatory cytokine and adhesion molecule increase in hemodialysis (HD) patients have not been fully elucidated. The possibility that, in this particularly atherosclerotic population, Cp, a microorganism implicated in the infectious-based inflammatory hypothesis of atherosclerosis' is also responsible for these molecules' increase is assessed in this study. Methods In 130 stable HD patients, serum interleukin-1β (IL-1), interleukin-6, tumor necrosis factor α, interleukin-10, L-selectin, E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 (VCAM-1) levels were determined. Cp presence was identified by inoculation of the patient's peripheral blood mononuclear cells (PBMCs) in Hep-2 cell lines and subsequent polymerase chain reaction (PCR) in DNA extracted from cell cultures, as well as by determination of serum IgG antibodies against Cp (IgGCp). Results Patients, positive or negative for IgGCp, had no statistically significant differences in all molecules measured. Patients with viable Cp in PBMCs had higher serum levels of IL-1 and soluble VCAM-1 than negative ones for IgGCp (IL-1 6.87 ± 7.35 vs. 2.34 ± 1.47 pg/mL; P = 0.0009 and VCAM-1 1647.16 ± 513.64 vs. 1162.14 ± 546.83 ng/mL; P = 0.0115, respectively). Viable Cp in PBMCs remained a significant predictor factor for IL-1 and VCAM-1 in statistical analysis, when patients' characteristics and dialysis conditions were also evaluated. Conclusions Our results showed that some serum cytokine and adhesion molecule increase in HD patients could be attributed to viable Cp presence in PBMCs. These findings support the Cp-based inflammatory atherogenous hypothesis and add a better understanding of these molecules' increase in HD patients.

Background. Chlamydia pneumoniae has been implicated as an inflammatory agent in atherosclerosis. Clinical studies in this field have yielded conflicting results, which may have resulted from a lack of standardization for C.pneumoniae detection. We attempted to accurately estimate C.pneumoniae prevalence and to examine whether C.pneumoniae is associated with atherosclerosis and inflammation in haemodialysis (HD) patients. To do this, we assessed C.pneumoniae presence by a combination of methods and correlated its levels with inflammatory and atherosclerotic indexes in these patients. Methods. Chlamydia pneumoniae was identified by polymerase chain reaction (PCR) in DNA extracted from cell cultures inoculated with patient buffy coats and by serum IgG antibodies against C.pneumoniae (IgGCp). Inflammation was assessed by C-reactive protein and serum amyloid A and atherosclerosis was evaluated from clinical and laboratory data. Results. Of the 130 patients, only nine had viable C.pneumoniae in peripheral blood mononuclear cells (PBMCs) while 64 had serum IgGCp. Although patients with viable C.pneumoniae had higher atherosclerotic scores, seropositive and negative patients showed similar scores. Patients with atherosclerosis exhibited higher inflammatory indexes. Neither patients with detectable C.pneumoniae in PBMCs nor seropositive subjects had higher inflammation than negative patients. Conclusions. We found that viable C.pneumoniae in PBMCs, assessed by cell culture and PCR, was present in a small percentage of HD patients and was correlated with atherosclerosis. Seropositivity was much higher in HD patients but was not associated with viable C.pneumoniae or with atherosclerosis. Further studies in HD patients using high sensitivity and specificity methods in larger populations will be necessary to clarify the relationship between C.pneumoniae and atherosclerosis.

To the Editor: In their study, Pupim et al1 show that patients with end-stage renal failure (ESRF) in the highest quartile of C-reactive protein (CRP) and interleukin-6 (IL-6) before hemodialysis (HD) initiation have a significant decrease in the serum level of both markers after 12 months of HD treatment. The baseline levels for IL-6 and CRP in these subgroups were about 58 pg/mL and 62 mg/L, respectively. As the authors note, no exclusion criteria were used for enrollment in the study. These CRP and IL-6 serum levels are probably indicative of an infection or other cause of "real inflammation" (trauma, malignancy, etc.). In the referred study microinflammation investigation is warranted. It is low-grade inflammation that is correlated to atherosclerosis or other threatening processes. Recently, a cut-off for CRP (10 mg/L) indicative for inflammation versus microinflammation was established for the general population2. We also found a similar cut-off for CRP and IL-6 (9.5 mg or pg/L) indicative for an inflammatory clinical event, in a group of HD patients3. Possibly this cut-off is higher in other HD patients, but, as the results in the majority of studies with ESRF patients show, it seems improbable to be higher than 15 mg/L for the CRP.