Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat.

Large numbers of inbred laboratory rat strains have been developed for a range of complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection for these phenotypes, we sequenced the genomes of 27 rat strains, including 11 models of hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, we identified more than 13 million single-nucleotide variants, indels, and structural variants across these rat strains. Analysis of strain-specific selective sweeps and gene clusters implicated genes and pathways involved in cation transport, angiotensin production, and regulators of oxidative stress in the development of cardiovascular disease phenotypes in rats. Many of the rat loci that we identified overlap with previously mapped loci for related traits in humans, indicating the presence of shared pathways underlying these phenotypes in rats and humans. These data represent a step change in resources available for evolutionary analysis of complex traits in disease models.

Serum Irisin May Predict Cardiovascular Events in Elderly Patients With Chronic Kidney Disease Stage 3-5.

OBJECTIVE: Irisin is a circulating myokine released from skeletal muscles after physical exercise. Irisin production decreases during the course of chronic kidney disease (CKD) as a potential consequence of sarcopenia and physical inactivity. METHODS: This observational study explored the relationship of serum irisin with cardiovascular outcome in 79 patients with stage 3-5 CKD. RESULTS: Serum irisin was significantly higher in healthy subjects (n = 20) than that in CKD patients (7 ± 2 vs. 3.1 ± 0.9 µg/mL; P = .0001) and was higher in patients with CKD stage 3 (3.2 ± 1 µg/mL) than in patients at stage 4 and 5 taken together (n = 36, 2.8 ± 0.7 µg/mL, P = .05). Patients in the lowest serum irisin tertile had lower serum 1,25(OH)2D levels (21 ± 11 pg/mL) than patients in the middle (30 ± 13 pg/mL; P = .005) and the highest tertile (27 ± 14 pg/mL; P = .047). Patients in the highest tertile had lower Kauppila score (10.6 ± 6.9) than patients in the middle (11.8 ± 5.5; P = .007) and the lowest tertile (6.9 ± 6.8; P = .043). Twenty patients suffered from cardiovascular events during a 3-year follow-up. A Cox regression model using age, body weight, presence of diabetes mellitus, gender, Kauppila calcification score, serum values of FGF23 (as logarithm), phosphate, sclerostin, albumin and cholesterol, estimated glomerular filtration rate, and serum irisin tertiles as covariates showed that patients in the highest tertile of serum irisin had a lower cardiovascular risk than patients in the middle tertile (B, 2.38; odds ratio, 10.8; 95% confidence interval, 1.65-58.13; P = .013) or in the lowest tertile (B, 1.61; odds ratio, 5; 95% confidence interval, 1.09-22.83; P = .038). CONCLUSIONS: These findings suggest that serum irisin may be a marker of cardiovascular outcome in patients with CKD.

Antihypertensive treatment guided by genetics: PEARL-HT, the randomized proof-of-concept trial comparing rostafuroxin with losartan.

We compared a standard antihypertensive losartan treatment with a pharmacogenomics-guided rostafuroxin treatment in never-treated Caucasian and Chinese patients with primary hypertension. Rostafuroxin is a digitoxigenin derivative that selectively disrupts the binding to the cSrc-SH2 domain of mutant α-adducin and of the ouabain-activated Na-K pump at 10-11 M. Of 902 patients screened, 172 were enrolled in Italy and 107 in Taiwan. After stratification for country and genetic background, patients were randomized to rostafuroxin or losartan, being the difference in the fall in office systolic blood pressure (OSBP) after 2-month treatment the primary endpoint. Three pharmacogenomic profiles (P) were examined, considering: P1, adding to the gene variants included in the subsequent P2, the variants detected by post-hoc analysis of a previous trial; P2, variants of genes encoding enzymes for endogenous ouabain (EO) synthesis (LSS and HSD3B1), EO transport (MDR1/ABCB1), adducin (ADD1 and ADD3); P3, variants of the LSS gene only. In Caucasians, the group differences (rostafuroxin 50 µg minus losartan 50 mg in OSBP mmHg) were significant both in P2 adjusted for genetic heterogeneity (P2a) and P3 LSS rs2254524 AA [9.8 (0.6-19.0), P = 0.038 and 13.4 (25.4-2.5), P = 0.031, respectively]. In human H295R cells transfected with LSS A and LSS C variants, the EO production was greater in the former (P = 0.038); this difference was abolished by rostafuroxin at 10-11 M. Chinese patients had a similar drop in OSBP to Caucasians with losartan but no change in OSBP with rostafuroxin. These results show that genetics may guide drug treatment for primary hypertension in Caucasians.

Genome-Wide Meta-Analysis Identifies Three Novel Susceptibility Loci and Reveals Ethnic Heterogeneity of Genetic Susceptibility for IgA Nephropathy.

BACKGROUND: Eighteen known susceptibility loci for IgAN account for only a small proportion of IgAN risk. METHODS: Genome-wide meta-analysis was performed in 2628 patients and 11,563 controls of Chinese ancestry, and a replication analysis was conducted in 6879 patients and 9019 controls of Chinese descent and 1039 patients and 1289 controls of European ancestry. The data were used to assess the association of susceptibility loci with clinical phenotypes for IgAN, and to investigate genetic heterogeneity of IgAN susceptibility between the two populations. Imputation-based analysis of the MHC/HLA region extended the scrutiny. RESULTS: Identification of three novel loci (rs6427389 on 1q23.1 [P=8.18×10-9, OR=1.132], rs6942325 on 6p25.3 [P=1.62×10-11, OR=1.165], and rs2240335 on 1p36.13 [P=5.10×10-9, OR=1.114]), implicates FCRL3, DUSP22.IRF4, and PADI4 as susceptibility genes for IgAN. Rs2240335 is associated with the expression level of PADI4, and rs6427389 is in high linkage disequilibrium with rs11264799, which showed a strong expression quantitative trail loci effect on FCRL3. Of the 24 confirmed risk SNPs, six showed significant heterogeneity of genetic effects and DEFA showed clear evidence of allelic heterogeneity between the populations. Imputation-based analysis of the MHC region revealed significant associations at three HLA polymorphisms (HLA allele DPB1*02, AA_DRB1_140_32657458_T, and AA_DQA1_34_32717152) and two SNPs (rs9275464 and rs2295119). CONCLUSIONS: A meta-analysis of GWAS data revealed three novel genetic risk loci for IgAN, and three HLA polymorphisms and two SNPs within the MHC region, and demonstrated the genetic heterogeneity of seven loci out of 24 confirmed risk SNPs.  These variants may explain susceptibility differences between Chinese and European populations.

A pharmacogenetic study implicates NINJ2 in the response to Interferon-ß in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a disease in which biomarker identification is fundamental to predict response to treatments and to deliver the optimal drug to patients. We previously found an association between rs7298096, a polymorphism upstream to the NINJ2 gene, and the 4-year response to interferon-ß (IFNß) treatment in MS patients. OBJECTIVES: To analyse the association between rs7298096 and time to first relapse (TTFR) during IFNß therapy in MS patients and to better investigate its functional role. METHODS: Survival analysis was applied in three MS cohorts from different countries (n = 1004). We also studied the role of the polymorphism on gene expression using GTEx portal and a luciferase assay. We interrogated GEO datasets to explore the relationship between NINJ2 expression, IFNß and TTFR. RESULTS: Rs7298096AA patients show a shorter TTFR than rs7298096G-carriers (Pmeta-analysis = 3 × 10-4, hazard ratio = 1.41). Moreover, rs7298096AA is associated with a higher NINJ2 expression in blood (p = 7.0 × 10-6), which was confirmed in vitro (p = 0.009). Finally, NINJ2 expression is downregulated by IFNß treatment and related to TTFR. CONCLUSIONS: Rs7298096 could influence MS disease activity during IFNß treatment by modulating NINJ2 expression in blood. The gene encodes for an adhesion molecule involved in inflammation and endothelial cells activation, supporting its role in MS.

Lanosterol Synthase Genetic Variants, Endogenous Ouabain, and Both Acute and Chronic Kidney Injury.

RATIONALE & OBJECTIVE: Studies of humans and animals have suggested that endogenous ouabain (EO) and related genes are mediators of acute (AKI) and chronic kidney injury. We sought to examine the relationship among EO levels, genetic variants in lanosterol synthase (LSS; an enzyme that catalyzes synthesis of cholesterol, a precursor of EO), and both AKI and chronic kidney injury. STUDY DESIGN: 2 prospective observational cohort studies and a cross-sectional study of kidney tissue. SETTING & PARTICIPANTS: (1) A prospective cohort study of patients undergoing cardiovascular surgery, (2) measurement of EO concentration in kidney tissue removed because of an adjacent tumor, and (3) a prospective cohort study of patients with newly diagnosed essential hypertension. EXPOSURE: Missense variant in LSS (A instead of C allele at rs2254524), which leads to a valine to leucine substitution at amino acid 642. OUTCOMES: Development of postoperative AKI in the cardiovascular surgery cohort, EO concentration in kidney tissue, and estimated glomerular filtration rate (eGFR) reductions in the essential hypertension cohort. ANALYTICAL APPROACH: Logistic regression for analysis of postoperative AKI, analysis of variance for EO concentration in kidney tissue, and generalized linear models for changes in eGFR over time. RESULTS: AKI incidence following cardiovascular surgery was greater among those with the LSS rs2254524 AA genotype (30.7%) than in those with the CC genotype (17.4%; P=0.001). LSS rs2254524 AA kidneys had higher EO concentrations than CC kidneys (2.14±0.29 vs 1.25±0.08ng/g; P<0.001). In the longitudinal study of patients with essential hypertension (median follow-up, 4 years; range, 1-15 years), eGFR decline was greater among the LSS rs2254524 AA genotype group (-4.39±1.18mL/min/1.73m2 per year) than in the AC or CC genotype groups (-1.07±0.55 and -2.00±0.45mL/min/1.73m2 per year respectively; P = 0.03). LIMITATIONS: These associations do not necessarily represent causal relationships; LSS rs2254524 variants may have effects on other steroid hormones. CONCLUSIONS: These findings support the potential value of LSS rs2254524 genotype-based risk stratification to identify patients at high risk for AKI before cardiovascular surgery, as well as predict accelerated eGFR in the setting of hypertension. These findings also suggest that LSS may in part drive EO-mediated kidney damage. EO may represent a new potential therapeutic target for the prevention of AKI and slowing of kidney damage in the setting of hypertension.

Reply: "Comment on: Endogenous Ouabain and Related Genes in the Translation from Hypertension to Renal Diseases".

In his recent letter, Dr [...].

The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population.

Background: Vitamin K (VK)-dependent γ-glutamate carboxylation and serine phosphorylation activate matrix Gla protein (MGP) to a potent locally acting inhibitor of calcification. Nephrolithiasis represents a process of unwanted calcification associated with substantial mortality and high recurrence rates. We hypothesized that the risk of nephrolithiasis increases with VK shortage, as exemplified by higher plasma levels of desphospho-uncarboxylated MGP (dp-ucMGP). Methods: In 1748 randomly recruited Flemish individuals (51.1% women; mean age 46.8 years), we determined dp-ucMGP and the prevalence of nephrolithiasis at baseline (April 1996-February 2015) and its incidence during follow-up until March 2016. We estimated the multivariable-adjusted relative risk associated with the doubling of dp-ucMGP, using logistic or Cox regression. We did a Mendelian randomization analysis using four MGP genotypes as instrumental variables. Results: With adjustments applied for sex, age and 24-h urinary volume and calcium excretion, the odds of having prevalent nephrolithiasis [n = 144 (8.2%)] associated with dp-ucMGP was 1.31 [95% confidence interval (CI) 1.04-1.64; P = 0.022]. dp-ucMGP levels were associated (P ≤ 0.001) with MGP variants rs2098435, rs4236 and rs2430692. In the Mendelian analysis, the causal odds ratio was 3.82 (95% CI 1.15-12.7; P = 0.029). The incidence of nephrolithiasis over 12.0 years (median) was 37 cases (0.2%). With similar adjustments as before, the hazard ratio in relation to dp-ucMGP was 2.48 (95% CI 1.71-3.61; P < 0.001). Additional adjustment for a nephrolithiasis propensity score produced consistent results. Conclusion: Higher levels of inactive dp-ucMGP may be causally associated with the risk of nephrolithiasis. Whether or not VK deficiency plays a role in these observations remains to be firmly established.

Endogenous Ouabain and Related Genes in the Translation from Hypertension to Renal Diseases.

The endogenous ouabain (EO) is a steroid hormone secreted by the adrenal gland with cardio-tonic effects. In this article, we have reviewed and summarized the most recent reports about EO, particularly with regard to how it may interact with specific genetic backgrounds. We have focused our attention on the EO's potential pathogenic role in several diseases, including renal failure, essential hypertension and heart failure. Notably, these reports have demonstrated that EO acts as a pro-hypertrophic and growth-promoting hormone, which might lead to a cardiac remodeling affecting cardiovascular functions and structures. In addition, a possible role of EO in the development of acute kidney injury has been hypothesized. During the last decays, many important improvements permitted a deeper understanding of EO's metabolisms and functions, including the characteristics of its receptor and the effects of its activation. Such progresses indicated that EO has significant implications in the pathogenesis of many common diseases. The patho-physiological role of EO in the development of hypertension and other cardiac and renal complications have laid the basis for the development of a new selective compound that could selectively modulate the genetic and molecular mechanisms involved in EO’s action. It is evident that the knowledge of EO has incredibly increased; however, many important areas remain to be further investigated.

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population.

BACKGROUND: Platelet Endothelial Aggregation Receptor 1 (PEAR1), a membrane protein highly expressed in platelets and endothelial cells, plays a role in platelet contact-induced activation, sustained platelet aggregation and endothelial function. Previous reports implicate PEAR1 rs12041331 as a variant influencing risk in patients with coronary heart disease. We investigated whether genetic variation in PEAR1 predicts cardiovascular outcome in a white population. METHODS: In 1938 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (51.3% women; mean age 43.6 years), we genotyped 9 tagging SNPs in PEAR1, measured baseline cardiovascular risk factors, and recorded Cardiovascular disease incidence. For SNPs, we contrasted cardiovascular disease incidence of minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers vs. non-carriers. In adjusted analyses, we accounted for family clusters and baseline covariables, including sex, age, body mass index, mean arterial pressure, the total-to-HDL cholesterol ratio, smoking and drinking, antihypertensive drug treatment, and history of cardiovascular disease and diabetes mellitus. RESULTS: Over a median follow-up of 15.3 years, 238 died and 181 experienced a major cardiovascular endpoint. The multivariable-adjusted hazard ratios of eight PEAR1 SNPs, including rs12566888, ranged from 0.87 to 1.07 (P ≥0.35) and from 0.78 to 1.30 (P ≥0.15), respectively. The hazard ratios of three haplotypes with frequency ≥10% ranged from 0.93 to 1.11 (P ≥0.49) for mortality and from 0.84 to 1.03 (P ≥0.29) for a cardiovascular complications. These results were not influenced by intake of antiplatelet drugs, nonsteroidal anti-inflammatory drugs, or both (P-values for interaction ≥ 0.056). CONCLUSIONS: In a White population, we could not replicate previous reports from experimental studies or obtained in patients suggesting that PEAR1 might be a susceptibility gene for cardiovascular complications.

Genetics of ion homeostasis in Ménière's Disease.

Aim of this work was to assess the role of polymorphisms belonging to genes involved in the regulation of ionic homeostasis in Caucasian patients with Ménière Disease (MD). We recruited 155 patients with definite Ménière Disease and 186 controls (Control Group 1) without a lifetime history of vertigo, overlapping with patients for age and rate of hypertension. We validated the positive results on 413 Caucasian subjects selected from a European general population (Control Group 2). The clinical history for migraine and hypertension was collected; genomic DNA was characterized for a panel of 33 SNPs encoding proteins involved in ionic transport. We found a higher rate of migraineurs in MD subjects compared to Group 1 (46.8 vs 15.5%, p = 0.00005). Four SNPs displayed differences in MD patients compared to Group 1 controls: rs3746951 and rs2838301 in SIK1 gene, rs434082 and rs487119 in SLC8A1; the p values of Chi-squared test for genotype frequencies are 0.009, 0.023, 0.009 and 0.048, respectively. SLC8A1 gene encodes for Na+-Ca++ exchanger, while SIK1 gene encodes for Salt Inducible Kinase 1, an enzyme associated with Na+-K+ ATPase function. The validation with Control Group 2 displayed that only rs3746951 and rs487119 are strongly associated to MD (p = 0.001 and p = 0.0004, respectively). These data support the hypothesis that a genetically induced dysfunction of ionic transport may act as a predisposing factors to develop MD.

MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma.

BACKGROUND: A significant proportion of patients undergoing radical nephrectomy (RN) for clear-cell renal cell carcinoma (RCC) develop chronic kidney disease (CKD) within a few years following surgery. Chronic kidney disease has important health, social and economic impact and no predictive biomarkers are currently available. MicroRNAs (miRs) are small non-coding RNAs implicated in several pathological processes. METHODS: Primary objective of our study was to define miRs whose deregulation is predictive of CKD in patients treated with RN. Ribonucleic acid from formalin-fixed paraffin embedded renal parenchyma (cortex and medulla isolated separately) situated >3 cm from the matching RCC was tested for miR expression using nCounter NanoString technology in 71 consecutive patients treated with RN for RCC. Validation was performed by RT-PCR and in situ hybridisation. End point was post-RN CKD measured 12 months post-operatively. Multivariable logistic regression and decision curve analysis were used to test the statistical and clinical impact of predictors of CKD. RESULTS: The overexpression of miR-193b-3p was associated with high risk of developing CKD in patients undergoing RN for RCC and emerged as an independent predictor of CKD. The addition of miR-193b-3p to a predictive model based on clinical variables (including sex and estimated glomerular filtration rate) increased the sensitivity of the predictive model from 81 to 88%. In situ hybridisation showed that miR-193b-3p overexpression was associated with tubule-interstitial inflammation and fibrosis in patients with no clinical or biochemical evidence of pre-RN nephropathy. CONCLUSIONS: miR-193b-3p might represent a useful biomarker to tailor and implement surveillance strategies for patients at high risk of developing CKD following RN.

Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population.

BACKGROUND: In mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD). RESULTS: In 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardial infarction, coronary revascularisation and ischaemic cardiomyopathy occurred in 106, 53, 78 and 22 participants. For SNPs, we contrasted CHD risk in minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers (variant) vs. non-carriers. In multivariable-adjusted analyses with correction for multiple testing, CHD risk was associated with MEOX2 SNPs (P ≤ 0.049), but not with TCF15 SNPs (P ≥ 0.29). The MEOX2 GTCCGC haplotype (frequency 16.5 %) was associated with the sex- and age-standardised CHD incidence (5.26 vs. 3.03 events per 1000 person-years; P = 0.036); the multivariable-adjusted hazard ratio [HR] of CHD was 1.78 (95 % confidence interval, 1.25-2.56; P = 0.0054). For myocardial infarction, coronary revascularisation, and ischaemic cardiomyopathy, the corresponding HRs were 1.96 (1.16-3.31), 1.87 (1.20-2.91) and 3.16 (1.41-7.09), respectively. The MEOX2 GTCCGC haplotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7 % vs. 16.2 %). CONCLUSIONS: Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms.

Beta-adducin and sodium-calcium exchanger 1 gene variants are associated with systemic lupus erythematosus and lupus nephritis.

Genetic research in systemic lupus erythematosus (SLE) is rapidly developing, and numerous sets of genes are being associated with specific clinical subphenotypes in the setting of SLE. On the other hand, basic science studies are revealing strong connections between salt-water balance and inflammation. The aim of this study was to evaluate whether variants of genes known to influence the individual susceptibility to hypertension also influence the renal function in a cohort of SLE patients with and without lupus nephritis (LN). This study is a case-control study with candidate gene approach. A total of 111 patients with SLE (50 with SLE without nephritis, 55 with LN and 6 with simple urinary sediment abnormalities) and 62 healthy controls (HC) were genotyped for NCX1 rs11893826 (NCX1a) and rs434082 (NCX1b) and ADD2 rs4984 SNPs. Patients with ADD2 CT genotype were protected from LN and skin involvement; ADD2 CC | NCX1a AA/AG genotypes were associated with the presence of anti-cardiolipin antibodies; NCX1a AA genotype was slightly more frequent in lupus patients than in HC and associated with relapse risk and higher creatinine in patients with LN. NCX1b GG patients with LN had increased chances to reach complete remission. NCX1b GG | NCX1a GG genotype is associated with joint involvement. ADD2 and NCX1 variants influence the risk and the clinical features of SLE and LN, highlighting their potential role in regulating systemic inflammation and/or the local response to immune-mediated injury.

PEAR1 is not a human hypertension-susceptibility gene.

OBJECTIVE: Platelet endothelial aggregation receptor 1 (PEAR1) is a membrane protein involved in platelet contact-induced activation and sustained platelet aggregation. Experimental studies identified PEAR1, as a candidate gene that may be linked to the blood-pressure driven kidney injury in salt-sensitive Dahl rats. AIM: In a family-based European population study (mean age 39.7 years; 52.2% women), we searched for association of changes in blood pressure or incidence of hypertension with genetic variation in PEAR1. METHODS: Among 1973 randomly recruited people, genotyped for PEAR1, we measured blood pressure at baseline and follow-up. RESULTS: Median follow-up was 10.0 years. While accounting for family clusters and blood pressure at baseline and with adjustments applied for sex, age, body mass index, smoking and drinking, total cholesterol, and antihypertensive drug treatment, all associations of systolic and diastolic blood pressure changes with nine single nucleotide polymorphisms (SNPs) in PEAR1 were all non-significant (p ≥ 0.059). With similar adjustments, the incidence of hypertension (397 cases among 1532 participants were normotensive at baseline [25.9%]) was not related to the SNPs in PEAR1 (hazard ratios ≤ 1.09; p ≥ 0.09). CONCLUSION: Our study suggests that PEAR1 is not a hypertension susceptibility gene in humans.

Histone-Specific CD4+ T Cell Plasticity in Active and Quiescent Systemic Lupus Erythematosus.

OBJECTIVE: The aim of this study was to assess whether circulating histone-specific T cells represent tools for precision medicine in systemic lupus erythematosus (SLE). METHODS: Seroprevalence of autoantibodies and HLA-DR beta (DRB) 1 profile were assessed among 185 patients with SLE and combined with bioinformatics and literature evidence to identify HLA-peptide autoepitope couples for ex vivo detection of antigen-specific T cells through flow cytometry. T cell differentiation and polarization was investigated in patients with SLE, patients with Takayasu arteritis, and healthy controls carrying HLA-DRB1*03:01 and/or HLA-DRB1*11:01. SLE Disease Activity Index 2000 and Lupus Low Disease Activity State were used to estimate disease activity and remission. RESULTS: Histone-specific CD4+ T cells were selectively detected in patients with SLE. Among patients with a history of anti-DNA antibodies, 77% had detectable histone-specific T cells, whereas 50% had lymphocytes releasing cytokines or upregulating activation markers after in vitro challenge with histone peptide antigens. Histone-specific regulatory and effector T helper (Th) 1-, Th2-, and atypical Th1/Th17 (Th1*)-polarized cells were significantly more abundant in patients with SLE with quiescent disease. In contrast, total Th1-, Th2-, and Th1*-polarized and regulatory T cells were similarly represented between patients and controls or patients with SLE with active versus quiescent disease. Histone-specific effector memory T cells accumulated in the blood of patients with quiescent SLE, whereas total effector memory T cell counts did not change. Immunosuppressants were associated with expanded CD4+ histone-specific naive T (TN) and terminally differentiated T cells. CONCLUSION: Histone-specific T cells are selectively detected in patients with SLE, and their concentration in the blood varies with disease activity, suggesting that they represent innovative tools for patient stratification and therapy.

Profiling Covid-19 patients with respect to level of severity: an integrated statistical approach.

A full understanding of the characteristics of Covid-19 patients with a better chance of experiencing poor vital outcomes is critical for implementing accurate and precise treatments. In this paper, two different advanced data-driven statistical approaches along with standard statistical methods have been implemented to identify groups of patients most at-risk for death or severity of respiratory distress. First, the tree-based analysis allowed to identify profiles of patients with different risk of in-hospital death (by Survival Tree-ST analysis) and severity of respiratory distress (by Classification and Regression Tree-CART analysis), and to unravel the role on risk stratification of highly dependent covariates (i.e., demographic characteristics, admission values and comorbidities). The ST analysis identified as the most at-risk group for in-hospital death the patients with age > 65 years, creatinine [Formula: see text] 1.2 mg/dL, CRP [Formula: see text] 25 mg/L and anti-hypertensive treatment. Based on the CART analysis, the subgroups most at-risk of severity of respiratory distress were defined by patients with creatinine level [Formula: see text] 1.2 mg/dL. Furthermore, to investigate the multivariate dependence structure among the demographic characteristics, the admission values, the comorbidities and the severity of respiratory distress, the Bayesian Network analysis was applied. This analysis confirmed the influence of creatinine and CRP on the severity of respiratory distress.

[The Management of Patients with Adult Autosomal Dominant Polycystic Kidney Disease (ADPKD) Requires a Multidisciplinary Approach].

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disease. Its main feature is the progressive enlargement of both kidneys with progressive loss of kidney function. ADPKD is the fourth leading cause of terminal renal failure in the world. Even today there are still uncertainties and poor information. Patients too often have a renunciatory and passive attitude toward the disease. However, there are currently no internationally accepted clinical practice guidelines, and there are significant regional variations in approaches to the diagnosis, clinical evaluation, prevention, and treatment of ADPKD. Therefore, we believe it is important to point out the conduct of our specialist outpatient clinic for ADPKD, which from the beginning has developed a multidisciplinary approach (nephrologists, geneticists, psychologists, radiologists, nutritionists) to face the disease at 360° and therefore not only from a purely nephrological point of view. Such a strategy not only enables patients to receive a timely and accurate diagnosis of the disease, but also ensures that they will receive a thorough and focused follow-up over time, that can prevent or at least slow down the disease in its evolution providing patients with a serene awareness of their condition as much as possible.

Inverse salt sensitivity: an independent risk factor for cardiovascular damage in essential hypertension.

OBJECTIVE: Salt sensitivity is a powerful risk factor for cardiovascular (CV) disease and mortality in both normotensive and hypertensive patients. We investigated the predictive value of the salt sensitivity phenotype in the development of CV events and hypertensive target organ damage (TOD) among essential hypertensive patients. METHODS: Eight hundred forty-four naive hypertensive patients were recruited and underwent an acute saline test during which blood pressure (BP) displayed either no substantial variation (salt-resistant, SR individuals), an increase (salt-sensitive, SS), or a paradoxical decrease (inverse salt-sensitive, ISS). Sixty-one patients with the longest monitored follow-up (median 16 years) for blood pressure and organ damage were selected for the present study. A clinical score for TOD development based on the severity and the age of onset was set up by considering hypertensive heart disease, cerebrovascular damage, microalbuminuria, and vascular events. RESULTS: CV events were significantly higher among SS and ISS than in SR patients. The relative risk of developing CV events was 12.67 times higher in SS than SR and 5.94 times higher in ISS than SR patients. The development of moderate to severe TOD was 10-fold higher in SS and over 15-fold higher in ISS than in SR patients. Among the three phenotypes, changes in plasma endogenous ouabain were linked with the blood pressure effects of saline. CONCLUSIONS: Salt sensitivity and inverse salt sensitivity appear to be equivalent risk factors for CV events. The response to an acute saline test is predictive of CV damage for newly identified ISS individuals.

[New year, new variant: drawing lessons from frail elderly people].

A recent study called FRASNET enrolled on a voluntary basis a cohort on 1240 elderly people. They were either patients of the Nephrology and Dialysis unit at San Raffaele hospital in Milan, guests of care homes, or members of cultural, social and recreational centers for the elderly in the wider Milan area. Demographic, anthropometric and biochemical data were collected, together with information on comorbidities and pharmacological therapies, psychophysical test results and biological samples. After the first wave of the SARS-Cov-2 pandemic, we have interviewed the members of this same cohort to gather information on possible coronavirus infections and evaluate the impact of the pandemic on frail patients. It emerged that the prevalence of SARS-Cov-2 infections was 0.7% within this cohort. This encouraging result seems to confirm the effectiveness of the measures taken at the start of the pandemic, especially social distancing and personal protective equipment.