Increased rho kinase activity in mononuclear cells of dialysis and stage 3-4 chronic kidney disease patients with left ventricular hypertrophy: Cardiovascular risk implications.

AIMS: Cardiovascular disease (CVD) is the leading cause of excess mortality in chronic kidney disease (CKD) and dialysis patients (DP) who have higher prevalence of left ventricular hypertrophy (LVH), the strongest predictor of CV events. Rho kinase (ROCK) activation is linked in hypertensive patients to cardiac remodeling while ROCK inhibition suppresses cardiomyocyte hypertrophy and, in a human clinical condition opposite to hypertension, its downregulation associates with lack of CV remodeling. Information on ROCK activation-LVH link in CKD and DP is lacking. MATERIALS AND METHODS: Mononuclear cells (PBMCs) MYPT-1 phosphorylation, a marker of ROCK activity, and the effect of fasudil, a ROCK inhibitor, on MYPT-1 phosphorylation were assessed in 23 DPs, 13 stage 3-4 CKD and 36 healthy subjects (HS) by Western blot. LV mass was assessed by M-mode echocardiography. KEY FINDINGS: DP and CKD had higher MYPT-1 phosphorylation compared to HS (p<0.001 and p=0.003). Fasudil (500 and 1000µM) dose dependently reduced MYPT-1 phosphorylation in DP (p<0.01). DP had higher LV mass than CKD (p<0.001). MYPT-1 phosphorylation was higher in patients with LVH (p=0.009) and correlated with LV mass both in DP and CKD with LVH (p<0.001 and p=0.006). SIGNIFICANCE: In DP and CKD, ROCK activity tracks with LVH. This ROCK activation-LVH link provided in these CVD high-risk patients along with similar findings in hypertensive patients and added to opposite findings in a human model opposite to hypertension and in type 2 diabetic patients, identify ROCK activation as a potential LVH marker and provide further rationale for ROCK activation inhibition as target of therapy in CVD high-risk patients.

Increased RBP4 in a human model of activated anti-atherosclerotic and antiremodelling defences.

BACKGROUND: Both increased and decreased levels of the adipokine retinol-binding protein 4 (RBP4) have been reported in cardiovascular disease, and levels of RBP4 have been related to diabetes, metabolic syndrome and cardiovascular risk. Recently, clear in vitro and ex vivo vasodilatory and inhibitory of platelet activation effects of RBP4 has been shown and a reduced RBP4 level was found in high cardiovascular risk patients, suggesting a potential cardiovascular protective role for increased levels of RBP4. PATIENTS AND METHODS: Plasma level of RBP4 (ELISA) was determined in a cohort of Bartter's and Gitelman's syndrome (BS/GS) patients, a human model of endogenous Ang II signalling antagonism and activation of anti-atherosclerotic and antiremodelling defenses, the opposite of cardiovascular risk patients, and in healthy normotensive subjects. Haem Oxygenase (OH)-1 protein level (sandwich immunoassay) as a potential mediator of RBP4 stimulation of PI3K/Akt pathway and flow-mediated dilation (FMD) as a measure of endothelium (NO)-dependent response have also been measured. RESULTS: RBP4 in BS/GS patients (40·59 ± 15·32 µg/mL vs. 25·05 ± 5·56, P = 0·011) along with HO-1 protein levels (9·44 ± 3·09 ng/mL vs. 5·49 ± 1·04, P = 0·003) and FMD (10·52% ± 2·22 vs. 7·99 ± 1·13 P = 0·006) were significantly increased compared with healthy normotensive subjects. CONCLUSIONS: The increase of RBP4 in BS/GS, a human model of endogenous Ang II signalling antagonism and activation of anti-atherosclerotic and antiremodelling defenses, the opposite of cardiovascular risk patient, found in concert with an increased NO-mediated vasodilation and HO-1 levels supports a protective role for this adipokine in vascular protection/cardiovascular risk.

"Of coronary arteries and men": the fight of a dialysis patient against his coronary arteries.

Acute myocardial infarction (AMI) in dialysis patients is associated with high mortality rate. Large randomized controlled trials documenting the benefits of revascularization in the general population have excluded chronic dialysis patients. Few observational data suggest that revascularization may provide a survival benefit compared with medical treatment alone also in these patients. We report a case of a dialysis patient who survived five documented AMIs, underwent five coronary angiographies in 11 years, had several episodes of angina pectoris and underwent percutaneous transluminal coronary angioplasty (PTCA) with stenting and heart surgery for coronary bypassing. It represents a highly unusual therapeutic approach and might contribute to support also in dialysis patients the use of revascularization to improve survival.

Molecular biology based assessment of green tea effects on oxidative stress and cardiac remodelling in dialysis patients.

BACKGROUND & AIMS: Cardiovascular disease, the most common cause for morbidity and mortality in end-stage renal disease (ESRD), has prompted the exploration of multiple approaches to improve outcomes. Cardiovascular risk factors such as oxidative stress (OxSt) and cardiac remodelling are common in ESRD and dialysis patients. Green tea (GT) is well recognized as reducing OxSt. This 6 months study evaluated in 20 ESRD patients under chronic dialysis, the effect of GT treatment (1 g/day as commercially available capsule) on cellular and plasma OxSt and proliferation related markers using a molecular biology approach. METHODS: Mononuclear cell p22(phox), Haeme Oxygenase (HO)-1 protein expression, and phosphorylated ERK1/2 status were evaluated in dialysis patients at baseline, after 3 and 6 months of GT treatment by Western blot analysis and plasma oxLDL by ELISA. Cardiac remodelling was assessed by echocardiographic left ventricular (LV) mass determination at baseline and at the end of the study. RESULTS: GT treatment reduced p22(phox) and pERK1/2 from baseline while HO-1 increased. At baseline, LV mass correlated with both p22(phox) and oxLDL. GT treatment decreased LV mass from baseline, which correlated with oxLDL. 9 patients had LV hypertrophy at baseline, which, at 6 months, was normalized in 5 and reduced in 3, showing a parallel decrease of p22(phox), pERK1/2, oxLDL and increase of HO-1. CONCLUSIONS: Treatment with GT decreased the expression of OxSt-related proteins tightly associated with cardiovascular disease and decreased LV mass. It appears highly likely that the addition of GT can provide a benefit in terms of cardiovascular protection in dialysis patients.

A very unusual case of hypokalaemia.

Cystic fibrosis (CF) is diagnosed in the first years of life. There are only two reports in the literature of adult patients with unusual presentation of newly diagnosed CF. We report here an adult patient apparently in a good health, who presented with serious hypokalaemia and metabolic alkalosis as the only abnormalities, who, through a fortuitous event, was tested by additional means for seemingly unrelated conditions that led to evidence of signs typical of CF, which was then confirmed by genetic analyses. This is the first adult patient in Italy with newly diagnosed CF. As unexplained hypokalaemia in an apparently healthy adult is very rare and has now been shown to represent an uncommon presentation of CF, physicians must take these facts into account when determining an appropriate imaging, biochemical work-up and genetic analyses to arrive at a diagnosis.

L carnitine in hemodialysis patients.

Carnitine, 3-hydroxy-4-trimethylaminobutyrate, a small, water soluble molecule that is essential for mitochondrial fatty acid oxidation, is significantly reduced in hemodialysis patients. Uremia-induced carnitine deficiency, which is magnified by dialysis, is associated with symptoms or clinical problems such as anemia hyporesponsive to erythropoietin, cardiovascular diseases, and muscle weakness. This review examines studies dealing with the different clinical aspects of chronic renal failure patients in which carnitine deficiency may play a role and has also examined the studies, which have evaluated the effect of carnitine deficiency treatment. The reports reviewed in this study, including those more recent from our laboratory, have provided data suggesting that chronic renal failure and particularly hemodialysis patients can benefit from carnitine treatment in particular for renal anemia, insulin sensitivity, and protein catabolism. On the other hand, the heterogeneous clinical response to carnitine therapy in dialysis patients, reported by other studies, and the lack of large-scale randomized trials are the rationale for the reluctance regarding a widespread use of carnitine supplements in dialysis patients. Well-designed randomized clinical trials are therefore required to fully address the potentially important carnitine treatment in dialysis patients.

Renal dysfunction is a confounder for plasma natriuretic peptides in detecting heart dysfunction in uremic and idiopathic dilated cardiomyopathies.

BACKGROUND: The diagnostic value of natriuretic peptides in uremic cardiomyopathy has not been defined, nor has the effect of a hemodialysis (HD) session on peptides. METHODS: We performed an observational study of 100 white adult outpatients in New York Heart Association class I-II, with neither diabetes nor ischemic heart disease, 50 of whom had idiopathic dilated cardiomyopathy (DCM) and 50 of whom had uremic cardiomyopathy and were undergoing HD. We measured plasma N-terminal proB-type natriuretic peptide (NT-proBNP), BNP, and atrial natriuretic peptide (ANP) both before and after a dialysis session. Doppler echocardiograms were evaluated. We performed multiple regression analysis on the logarithm of peptide concentrations using clinical, laboratory, and echocardio-Doppler data as explanatory variables. RESULTS: Mean peptide concentrations were higher in the HD group, with an HD:DCM ratio of 25 for NT-proBNP and 5 for BNP and ANP. Peptides were correlated with each other (r > 0.85). After HD, NT-proBNP significantly increased by 14%, BNP decreased by 17%, and ANP decreased by 56%. Predialysis concentrations correlated with postdialysis values (r > 0.85). A multiple regression equation significantly fitted the observed peptide concentrations, both pre- and postdialysis, using the same set of 4 variables: disease group (DCM or HD), diastolic pattern, left atrial volume, and body mass index. CONCLUSIONS: Renal dysfunction was a confounder for natriuretic peptides, which were present in higher concentrations in the uremic patients with milder cardiac dysfunction than in those with idiopathic DCM without renal dysfunction. Left diastolic function pattern and atrial volume were cardiac determinants of peptide concentrations in DCM and HD.

Cystatin C in heart failure is nothing more than a bystander of glomerular filtration.

BACKGROUND: Cystatin is an ubiquitous protease inhibitor involved in degradation of cellular proteins and has recently been associated with increased risk of cardiovascular disease and heart failure independent of renal function. We tested whether cystatin in heart failure is only associated with renal function or also with echocardio-Doppler parameters and factors of myocardial remodeling (C-reactive protein, endothelin, and natriuretic peptides). METHODS: This was an observational study conducted in 100 adult Caucasian outpatients with NYHA class I-II heart function without diabetes and ischemic heart, 50 with idiopathic dilated cardiomyopathy (DCM) and 50 with uremic cardiomyopathy undergoing hemodialysis (HD). Multiple linear regression analysis was performed on cystatin concentration using clinical, laboratory (creatinine, high sensitivity C-reactive protein, endothelin, B-type natriuretic peptide [BNP]) and echocardio-Doppler data as explanatory variables. RESULTS: The heart was more severely involved in DCM patients (worse ejection fraction, diastolic volume index, index of myocardial performance, left ventricular mass index). Mean values of cystatin, creatinine, BNP and C-reactive protein in HD compared with DCM patients were 6, 9, 5 and 3 times higher, respectively. Mean values of endothelin were comparable in both groups. Cystatin significantly correlated with creatinine in both groups (r=0.50 in DCM and r=0.37 in HD, and r=0.95 in pooled groups). In the multiple regression analysis, only disease group and creatinine within groups were significant independent factors that accounted for 94% of the variability of cystatin. CONCLUSION: Renal function was the determinant of cystatin in a concentration range of 6 times regardless of severity of heart involvement.

Evidence for decreased circulating apelin beyond heart involvement in uremic cardiomyopathy.

BACKGROUND: Plasma apelin concentration in heart failure has been described in small studies reporting conflicting results. In hemodialysis (HD) patients, apelin decreased more in those with more severe heart involvement. It is unclear if uremia is connected to this reduction irrespective of heart failure. We compared apelin in two cardiomyopathies with different renal function. METHODS: Observational study conducted in 30 adult Caucasian outpatients in class I NYHA not affected by diabetes or ischemic heart, 15 with idiopathic dilated cardiomyopathy (DCM) and 15 with uremic dilated cardiomyopathy undergoing HD. Plasma apelin, creatinine, high-sensitivity C-reactive protein, endothelin, NT proB-type natriuretic peptide (NT-proBNP), and Doppler echocardiogram were evaluated. RESULTS: Heart involvement was more severe in the DCM patients (lower ejection fraction, greater diastolic volume index, and worse index of myocardial performance). Median value of apelin in HD patients (19.1 pg/ml) was one third of that in DCM patients (58.2 pg/ml) whereas creatinine, NT-proBNP, and C-reactive protein were 11, 80, and 9 times higher respectively in HD than in DCM patients. Median values of endothelin were comparable in both groups. Apelin was not significantly correlated with any variable. CONCLUSION: Uremic status was the determinant for decreased plasma apelin in HD patients regardless of the severity of heart involvement.

Dent's disease and prevalence of renal stones in dialysis patients in Northeastern Italy.

Dent's disease (DD) involves nephrocalcinosis, urolithiasis, hypercalciuria, LMW proteinuria, and renal failure in various combinations. Males are affected. It is caused by mutations in the chloride channel CLCN5 gene. It has been suggested that DD is underdiagnosed, occurring in less overt forms, apparently without family history. A possible approach to this problem is to search for CLCN5 mutations in patients who may have a high prevalence of mutations: end-stage renal disease (ESRD) patients with previous calcium, struvite, or radio-opaque (CSR) stones. We looked for CLCN5 mutations in 25 males with ESRD-CSR stones selected from all of the patients (1,901 individuals, of which 1,179 were males) of 15 dialysis units in the Veneto region. One DD patient had a new DD mutation (1070 G > T) in exon 7. The new polymorphism IVS11-67 C > T was detected in intron 11 in one patient and one control. We also found 28 females with ESRD and stone history, and seven more males with ESRD and non-CSR stones. The prevalence of stone formers among dialysis patients in our region was 3.2%, much lower than the prevalence observed in older studies. Struvite stones continue to play a major role in causing stone-associated ESRD .