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1.  Immunity in arterial hypertension: associations or causalities? 
Nephrology Dialysis Transplantation  2015;30(12):1959-1964.
Numerous studies describe associations between markers of inflammation and arterial hypertension (aHT), but does that imply causality? Interventional studies that reduce blood pressure reduced also markers of inflammation, but does immunosuppression improve hypertension? Here, we review the available mechanistic data. Aberrant immunity can trigger endothelial dysfunction but is hardly ever the primary cause of aHT. Innate and adaptive immunity get involved once hypertension has caused vascular wall injury as immunity is a modifier of endothelial dysfunction and vascular wall remodelling. As vascular remodelling progresses, immunity-related mechanisms can become significant cofactors for cardiovascular (CV) disease progression; vice versa, suppressing immunity can improve hypertension and CV outcomes. Innate and adaptive immunity both contribute to vascular wall remodelling. Innate immunity is driven by danger signals that activate Toll-like receptors and other pattern-recognition receptors. Adaptive immunity is based on loss of tolerance against vascular autoantigens and includes autoreactive T-cell immunity as well as non-HLA angiotensin II type 1 receptor-activating autoantibodies. Such processes involve numerous other modulators such as regulatory T cells. Together, immunity is not causal for hypertension but rather an important secondary pathomechanism and a potential therapeutic target in hypertension.
PMCID: PMC4832987  PMID: 25762356
atherosclerosis; blood pressure; infection; inflammasome; stenosis
2.  Oxidative Stress as Estimated by Gamma-Glutamyl Transferase Levels Amplifies the Alkaline Phosphatase-Dependent Risk for Mortality in ESKD Patients on Dialysis 
Alkaline phosphatase (Alk-Phos) is a powerful predictor of death in patients with end-stage kidney disease (ESKD) and oxidative stress is a strong inducer of Alk-Phos in various tissues. We tested the hypothesis that oxidative stress, as estimated by a robust marker of systemic oxidative stress like γ-Glutamyl-Transpeptidase (GGT) levels, may interact with Alk-Phos in the high risk of death in a cohort of 993 ESKD patients maintained on chronic dialysis. In fully adjusted analyses the HR for mortality associated with Alk-Phos (50 IU/L increase) was progressively higher across GGT quintiles, being minimal in patients in the first quintile (HR: 0.89, 95% CI: 0.77–1.03) and highest in the GGT fifth quintile (HR: 1.13, 95% CI: 1.03–1.2) (P for the effect modification = 0.02). These findings were fully confirmed in sensitivity analyses excluding patients with preexisting liver disease, excessive alcohol intake, or altered liver disease biomarkers. GGT amplifies the risk of death associated with high Alk-Phos levels in ESKD patients. This observation is compatible with the hypothesis that oxidative stress is a strong modifier of the adverse biological effects of high Alk-Phos in this population.
PMCID: PMC4976170  PMID: 27525053
3.  Prevalence of Undiagnosed Diabetes in Rheumatoid Arthritis: an OGTT Study 
Medicine  2016;95(7):e2552.
Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by an excess of cardiovascular disease (CVD) risk, estimated to be at least 50% greater when compared to the general population. Although the widespread diffusion of type 2 diabetes mellitus (T2DM) awareness, there is still a significant proportion of patients with T2DM that remain undiagnosed. Aim of this cross-sectional study was to evaluate the prevalence of undiagnosed diabetes and prediabetes in RA patients.
For the present study, 100 consecutive nondiabetic RA patients were recruited. Age- and sex-matched subjects with noninflammatory diseases (osteoarthritis or fibromyalgia) were used as controls. After overnight fasting, blood samples were obtained for laboratory evaluation including serum glucose, total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides, uric acid, erythrocyte sedimentation rate (ESR), high sensitivity C-reactive protein (hs-CRP), rheumatoid factor (RF), and anti-Cyclic Citrullinated Peptide Antibodies (ACPA). A standard Oral Glucose Tolerance Test (OGTT) with 75 g of glucose was performed and blood samples were collected at time 0, 30, 60, 90, and 120 minutes, for measurement of plasma glucose concentrations.
The prevalence of impaired fasting glucose (IFG) (9/100 vs 12/100, P = 0.49), impaired glucose tolerance (IGT) (19/100 vs 12/100, P = 0.17), and concomitant IFG/IGT (5/100 vs 9/100, P = 0.27) was similar between groups, whereas the prevalence of diabetes was significantly higher in RA patients (10/100 vs 2/100, P = 0.02). In a logistic regression analysis, increasing age (OR = 1.13, 95% CI 1.028–1.245, P = 0.01) and disease duration (OR = 1.90, 95% CI 1.210–2.995, P = 0.005) were both associated with an increased likelihood of being classified as prediabetes (i.e. IFG and/or IGT) or T2DM. A ROC curve was built to evaluate the predictivity of disease duration on the likelihood of being diagnosed with T2DM. The area under the ROC curve was 0.67 (95% CI: 0.56–0.78, P = 0.004). We identified the best cut-off of 33 months that yielded a sensitivity of 61% and a specificity of 70% for classification of T2DM patients.
According to our data, RA seems to be characterized by an elevated prevalence of undiagnosed diabetes, especially in patients with longer disease duration.
PMCID: PMC4998599  PMID: 26886599
4.  Joint effect of insulin signaling genes on all-cause mortality 
Atherosclerosis  2014;237(2):639-644.
We have previously reported the combined effect of SNPs perturbing insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on insulin resistance (IR), type 2 diabetes (T2D) and cardiovascular events.
We here investigated whether such a combined effect affects also all-cause mortality in a sample of 1,851 Whites of European ancestry.
We investigated a first sample of 721 patients, 232 deaths, 3,389 person-years (py). Replication was assessed in two samples of patients with T2D: the Gargano Mortality Study (GMS) of 714 patients, 127 deaths, 5,426 py and the Joslin Kidney Study (JKS) comprising 416 patients, 214 deaths, 5,325 py.
In the first sample, individuals carrying 1 or ≥ 2 risk alleles had 33% (p=0.06) and 51% (p=0.02) increased risk of mortality, as compared with individuals with no risk alleles. A similar, though not significant, trend was obtained in the two replication samples only for subject carrying ≥ 2 risk alleles. In a pooled analysis, individuals carrying ≥ 2 risk alleles had higher mortality rate as compared to those carrying 0 risk alleles (HR=1.34, 95%CI=1.08–1.67; p=0.008), and as compared to those carrying only one risk allele (HR=1.41, 95%CI=1.13–1.75; p=0.002). This association was independent from several possible confounders including sex, age, BMI, hypertension and diabetes status.
Our data suggest that variants affecting insulin signaling exert a joint effect on all-cause mortality and is consistent with a role of abnormal insulin signaling on mortality risk.
PMCID: PMC4294190  PMID: 25463099
ENPP1; IRS1; TRIB3; prospective study
5.  Methodology used in studies reporting chronic kidney disease prevalence: a systematic literature review 
Nephrology Dialysis Transplantation  2015;30(Suppl 4):iv6-iv16.
Many publications report the prevalence of chronic kidney disease (CKD) in the general population. Comparisons across studies are hampered as CKD prevalence estimations are influenced by study population characteristics and laboratory methods.
For this systematic review, two researchers independently searched PubMed, MEDLINE and EMBASE to identify all original research articles that were published between 1 January 2003 and 1 November 2014 reporting the prevalence of CKD in the European adult general population. Data on study methodology and reporting of CKD prevalence results were independently extracted by two researchers.
We identified 82 eligible publications and included 48 publications of individual studies for the data extraction. There was considerable variation in population sample selection. The majority of studies did not report the sampling frame used, and the response ranged from 10 to 87%. With regard to the assessment of kidney function, 67% used a Jaffe assay, whereas 13% used the enzymatic assay for creatinine determination. Isotope dilution mass spectrometry calibration was used in 29%. The CKD-EPI (52%) and MDRD (75%) equations were most often used to estimate glomerular filtration rate (GFR). CKD was defined as estimated GFR (eGFR) <60 mL/min/1.73 m2 in 92% of studies. Urinary markers of CKD were assessed in 60% of the studies. CKD prevalence was reported by sex and age strata in 54 and 50% of the studies, respectively. In publications with a primary objective of reporting CKD prevalence, 39% reported a 95% confidence interval.
The findings from this systematic review showed considerable variation in methods for sampling the general population and assessment of kidney function across studies reporting CKD prevalence. These results are utilized to provide recommendations to help optimize both the design and the reporting of future CKD prevalence studies, which will enhance comparability of study results.
PMCID: PMC4514069  PMID: 26209739
CKD; CKD-EPI equation; epidemiology; MDRD; systematic review
6.  Asymmetric dimethylarginine predicts survival in the elderly 
Age  2013;35(6):2465-2475.
Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase implicated in several age-related biological mechanisms such as telomere shortening and cell senescence. We tested the hypothesis that ADMA blood level is an independent predictor of mortality in elderly. This is a longitudinal population-based cohort study. Participants are a representative cohort of 1,025 men and women (age range 65–102 years) living in Chianti area, Tuscany, Italy. The plasma ADMA was measured by liquid chromatography–tandem mass spectrometry. During the follow-up (95 ± 32 months), 384 individuals died, of whom 141 (37 %) died of cardiovascular (CV) causes. In adjusted analyses, the plasma ADMA was the strongest predictor of all-cause mortality (HR (0.1 μMol/L) 1.26, 95 % CI 1.10–1.44, P < 0.001) with a non-significant trend for CV mortality (HR 1.22, P = 0.07). The predictive effect of the ADMA level on mortality was statistically significant among participants with low to low-normal l-arginine levels (≤60 μMol/L), but not in those with l-arginine >60 μMol/L. Notwithstanding the association of ADMA with all-cause mortality was robust, this biomarker failed to add predictive power to a simple model based on the risk factors in the elderly (area under the ROC curve 0.85 ± 0.01 vs. 0.84 ± 0.01). ADMA is a strong independent predictor of mortality in the older population, and l-arginine modifies the effect of ADMA on survival. The mechanisms for this association should be targeted by future studies.
PMCID: PMC3824988  PMID: 23584888
ADMA; Elderly; Cardiovascular risk factor; Survival; Population study
8.  Joint effect of insulin signalling genes on cardiovascular events and on whole body and endothelial insulin resistance 
Atherosclerosis  2012;226(1):140-145.
Insulin resistance (IR) and cardiovascular disease (CVD) share a common soil. We investigated the combined role of single nucleotide polymorphisms (SNPs) affecting insulin signaling (ENPP1 K121Q, rs1044498; IRS1 G972R, rs1801278; TRIB3 Q84R, rs2295490) on CVD, age at myocardial infarction (MI), in vivo insulin sensitivity and in vitro insulin-stimulated nitric oxide synthase (NOS) activity.
Design and Setting
1. We first studied, incident cardiovascular events (a composite endpoint comprising myocardial infarction -MI-, stroke and cardiovascular death) in 733 patients (2,186 person-years, 175 events). 2. In a replication attempt, age at MI was tested in 331 individuals. 3. OGTT-derived insulin sensitivity index (ISI) was assessed in 829 individuals with fasting glucose < 126 mg/dl. 4. NOS activity was measured in 40 strains of human vein endothelial cells (HUVECs).
1. Risk variants jointly predicted cardiovascular events (HR=1.181; p=0.0009) and, when added to clinical risk factors, significantly improved survival C-statistics; they also allowed a significantly correct reclassification (by net reclassification index) in the whole sample (135/733 individuals) and, even more, in obese patients (116/204 individuals). 2. Risk variants were jointly associated with age at MI (p=0.006). 3. A significant association was also observed with ISI (p=0.02). 4. Finally, risk variants were jointly associated with insulin-stimulated NOS activity in HUVECs (p=0.009).
Insulin signaling genes variants jointly affect cardiovascular disease, very likely by promoting whole body and endothelium-specific insulin resistance. Further studies are needed to address whether their genotyping help identify very high-risk patients who need specific and/or more aggressive preventive strategies.
PMCID: PMC3529747  PMID: 23107043
genetic susceptibility; non synonymous polymorphism; insulin sensitivity; insulin dependent endothelial function
9.  Estimated Glomerular Filtration Rate, All-Cause Mortality and Cardiovascular Diseases Incidence in a Low Risk Population: The MATISS Study 
PLoS ONE  2013;8(10):e78475.
Chronic kidney disease (CKD) independently increases the risk of death and cardiovascular disease (CVD) in the general population. However, the relationship between estimated glomerular filtration rate (eGFR) and CVD/death risk in a general population at low risk of CVD has not been explored so far.
Baseline and longitudinal data of 1465 men and 1459 women aged 35-74 years participating to the MATISS study, an Italian general population cohort, were used to evaluate the role of eGFR in the prediction of all-cause mortality and incident CVD.
Bio-bank stored sera were used to evaluate eGFR at baseline. Serum creatinine was measured on thawed samples by means of an IDMS-calibrated enzymatic method. eGFR was calculated by the CKD-EPI formula.
At baseline, less than 2% of enrolled persons had eGFR < 60 mL/min/1.73m2 and more than 70% had a 10-year cardiovascular risk score < 10%. In people 60 or more years old, the first and the last eGFR quintiles (<90 and ≥109 mL/min/1.73m2, respectively) were associated to an increased risk for both all-cause mortality (hazard ratio 1.6, 95% confidence interval 1.2-2.1 and 4.3, 1.6-11.7, respectively) and incident CVD (1.6, 1.0-2.4 and 7.0, 2.2-22.9, respectively), even if adjusted for classical risk factors.
These findings strongly suggest that in an elderly, general population at low risk of CVD and low prevalence of reduced renal filtration, even a modest eGFR reduction is related to all-cause mortality and CVD incidence, underlying the potential benefit to this population of considering eGFR for their risk prediction.
PMCID: PMC3797762  PMID: 24147135
10.  Homoarginine and Mortality in Pre-Dialysis Chronic Kidney Disease (CKD) Patients 
PLoS ONE  2013;8(9):e72694.
Background and Aims
Homoarginine, a precursor of nitric oxide, is an inverse predictor of death in dialysis patients and in subjects with cardiovascular disease and normal kidney function but its relationship with clinical outcomes in chronic kidney disease (CKD) patients not yet on dialysis is unknown.
Design, setting, participants and measurements
We enrolled 168 consecutive predialysis CKD patients (Age: 70±11 yrs; 26% Diabetics; eGFR 34±18 ml/min/1.73 m2) referred to a tertiary care centre and measured laboratory data on kidney function and cardiovascular risk factors. We modeled progression to dialysis or death as a function of homoarginine, using Cox’s regression, accounting for clinical characteristics, baseline levels of kidney function, and markers of inflammation.
On crude and adjusted analyses homoarginine was directly associated with the eGFR and patients with more compromised renal function exhibited lower homoarginine levels. Furthermore homoarginine was also independently related to L-arginine, serum albumin and body mass index, and inversely related to proteinuria, C-reactive protein and age. During the study (follow up median time 4 years, inter-quartile range 1.7 to 7.0 years) 56 patients started dialysis and 103 died and homoarginine was a strong inverse predictor of the incidence rate of both outcomes (P = 0.002 and P = 0.017).
Homoarginine declines with advancing renal disease and is inversely related to progression to dialysis and mortality. The nature of the link between homoarginine and clinical outcomes is amenable to testing in clinical trials.
PMCID: PMC3762798  PMID: 24023762
11.  Early measurement of CD34+ cells in peripheral blood after cyclophosphamide and granulocyte colony-stimulating factor treatment predicts later CD34+ mobilisation failure and is a possible criterion for guiding “on demand” use of plerixafor 
Blood Transfusion  2013;11(1):94-101.
Early identification of predictive factors of failure to mobilise CD34+ cells could enable rational use of plerixafor during first mobilisation, avoiding the need for a second mobilisation course. However, “on demand” administration of plerixafor needs to be driven by established parameters to avoid inappropriate use.
Materials and methods
To address this issue, we studied the value of the peripheral blood CD34+ count, measured early (on days +10, +11, +12 and +13), in predicting the mobilisation outcome in the ensuing days. We retrospectively collected data from three Italian centres on 233 patients affected by multiple myeloma or lymphoma who underwent a first or second attempt at mobilisation with cyclophosphamide 4 g/m2 and granulocyte colony-stimulating factor. To assess the diagnostic value of peripheral blood white blood cell and CD34+ cell counts with respect to “mobilisation failure”, we considered failed mobilisation as “disease” and the CD34+ cell count in peripheral blood, on a specific day, as a “diagnostic test”. For various thresholds, we measured sensitivity, false positive rate, specificity and positive predictive value (PPV) as well as the area under the receiver-operating characteristic curves (AUC).
A CD34+ cell count <10×106/L on day 13 had high sensitivity (1.00) and high specificity (1.00) for predicting subsequent mobilisation failure, with an AUC of 1.0. However, good prediction was also obtained using a lower threshold (CD34+ cell count: <6×106/L) at an earlier time (day 12). The PPV of the day 13 threshold was 1.00 while that of the day 12 one was 0.87.
We propose that patients with <6×106/L CD34+ cells in peripheral blood on day 12 and <10×106/L on day 13 following mobilisation with cyclophosphamide 4 g/m2 and granulocyte colony-stimulating factor are candidates for “on demand” use of plerixafor, making the administration of this expensive agent more efficient and avoiding its inappropriate use.
PMCID: PMC3557479  PMID: 23114516
CD34+ cells; cyclophosphamide; PBSC mobilisation
12.  Cultural adaptation and validation of the “Kidney Disease and Quality of Life - Short Form (KDQOL-SF™) version 1.3” questionnaire in Egypt 
BMC Nephrology  2012;13:170.
Health Related Quality of Life (HRQOL) instruments need disease and country specific validation. In Arab countries, there is no specific validated questionnaire for assessment of HRQOL in chronic kidney disease (CKD) patients. The aim of this study was to present an Arabic translation, adaptation, and the subsequent validation of the kidney disease quality of life-short form (KDQOL-SFTM) version 1.3 questionnaire in a representative series of Egyptian CKD patients.
KDQOL-SFTM version 1.3 was translated into Arabic by two independent translators, and then subsequently translated back into English. After translation disparities were reconciled, the final Arabic questionnaire was tested by interviewing 100 pre-dialysis CKD (stage 1-4) patients randomly selected from outpatients attending the Nephrology clinic at the Main Alexandria University Hospital. Test re-test reliability was performed, with a subsample of 50 consecutive CKD patients, by two interviews 7 days apart and internal consistency estimated by Cronbach’s α. Discriminant, concept, and construct validity were assessed.
All items of SF-36 met the criterion for internal consistency and were reproducible. Of the 10 kidney disease targeted scales, only three had Cronbach’s α <0.7: quality of social interaction (0.23), work status (0.28), and cognitive function (0.60). All disease specific scales were reproducible. Results from discriminant validity showed that the study questionnaire could discriminate between patients’ subgroups. As for concept validity, the correlation between all domains of the questionnaire with overall health ratewas significant for all domains except for the work status, sexual function, emotional wellbeing, and role emotional. Furthermore, the correlation between the disease specific domains and the two composite summaries of SF-36 (physical and mental composite summaries) was significant for all domains except for sexual function with mental composite summary. Construct validity was indicated by the observation that the majority of the domains of the kidney disease targeted scale of KDQOL-SFTM 1.3 were significantly inter-correlated. Finally, principal component analysis of the kidney disease targeted scale indicated that this part of the questionnaire could be summarized into 10 factors that together explained 70.9% of the variance.
The results suggest that this Arabic version of the KDQOL-SFTM 1.3 questionnaire is a valid and reliable tool for use in Egyptian patients with CKD.
PMCID: PMC3583144  PMID: 23237591
Chronic kidney disease; Egypt; Health-related quality of life; KDQOL-SFTM 1.3; Questionnaire validation
13.  Pro-inflammatory cytokines and bone fractures in CKD patients. An exploratory single centre study 
BMC Nephrology  2012;13:134.
Pro-inflammatory cytokines play a key role in bone remodeling. Inflammation is highly prevalent in CKD-5D patients, but the relationship between pro-inflammatory cytokines and fractures in CKD-5D patients is unclear. We studied the relationship between inflammatory cytokines and incident bone fractures in a cohort of CKD-5D patients.
In 100 CKD-5D patients (66 on HD, 34 on CAPD; males:63, females:37; mean age: 61 ± 15; median dialysis vintage: 43 months) belonging to a single renal Unit, we measured at enrolment bone metabolic parameters (intact PTH, bone and total alkaline phosphatase, calcium, phosphate) and inflammatory cytokines (TNF-α, IL-6, CRP). Patients were followed-up until the first non traumatic fracture.
During follow-up (median: 74 months; range 0.5 -84.0) 18 patients experienced fractures. On categorical analysis these patients compared to those without fractures had significantly higher intact PTH (median: 319 pg/ml IQ range: 95–741 vs 135 pg/ml IQ: 53–346; p = 0.04) and TNF-α levels (median: 12 pg/ml IQ: 6.4-13.4 vs 7.8 pg/ml IQ: 4.6-11; p = 0.02). Both TNF-α (HR for 5 pg/ml increase in TNF-α: 1.62 95% CI: 1.05-2.50; p = 0.03) and intact PTH (HR for 100 pg/ml increase in PTH: 1.15 95% CI: 1.04-1.27; p = 0.005) predicted bone fractures on univariate Cox’s regression analysis. In restricted (bivariate) models adjusting for previous fractures, age, sex and other risk factors both PTH and TNF-α maintained an independent association with incident fractures.
In our bivariate analyses TNF-α was significantly associated with incident fractures. Analyses in larger cohorts and with adequate number of events are needed to firmly establish the TNF α -fracture link emerged in the present study.
PMCID: PMC3472278  PMID: 23043229
Bone fractures; CKD; Dialysis; Hyperparathyroidism; TNF-alpha; Inflammation
14.  The ENPP1 Q121 Variant Predicts Major Cardiovascular Events in High-Risk Individuals 
Diabetes  2011;60(3):1000-1007.
Insulin resistance (IR) and cardiovascular disease may share a common genetic background. We investigated the role of IR-associated ENPP1 K121Q polymorphism (rs1044498) on cardiovascular disease in high-risk individuals.
A prospective study (average follow-up, 37 months) was conducted for major cardiovascular events (myocardial infarction [MI], stroke, cardiovascular death) from the Gargano Heart Study (GHS; n = 330 with type 2 diabetes and coronary artery disease), the Tor Vergata Atherosclerosis Study (TVAS; n = 141 who had MI), and the Cardiovascular Risk Extended Evaluation in Dialysis (CREED) database (n = 266 with end-stage renal disease). Age at MI was investigated in cross-sectional studies of 339 type 2 diabetic patients (n = 169 from Italy, n = 170 from the U.S.).
Incidence of cardiovascular events per 100 person--years was 4.2 in GHS, 10.8 in TVAS, and 11.7 in CREED. Hazard ratios (HRs) for KQ+QQ versus individuals carrying the K121/K121 genotype (KK) individuals were 1.47 (95% CI 0.80–2.70) in GHS, 2.31 (95% CI 1.22–4.34) in TVAS, and 1.36 (95% CI 0.88–2.10) in CREED, and 1.56 (95% CI 1.15–2.12) in the three cohorts combined. In the 395 diabetic patients, the Q121 variant predicted cardiovascular events among obese but not among nonobese individuals (HR 5.94 vs. 0.62, P = 0.003 for interaction). A similar synergism was observed in cross-sectional studies, with age at MI being 3 years younger in Q121 carriers than in KK homozygotes among obese but not among nonobese patients (P = 0.035 for interaction).
The ENPP1 K121Q polymorphism is an independent predictor of major cardiovascular events in high-risk individuals. In type 2 diabetes, this effect is exacerbated by obesity. Future larger studies are needed to confirm our finding.
PMCID: PMC3046818  PMID: 21282363

Results 1-14 (14)