Ugo Vertolli

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.

Tissue factor pathway inhibitor (TFPI) activity in uremic patients during hemodialysis

We studied tissue factor pathway inhibitor (TFPI) activity during hemodialysis in 10 uremic patients who were not receiving anticoagulant for at least 120 minutes. TFPI activity before dialysis was normal (patients 107 +/- 5.8%, controls 104 +/- 4.5%). During extracorporeal circuit it rose progressively with a statistically significant difference, reaching a plateau between 60 and 120 minutes. Since thrombin induces a marked redistribution and release of TFPI from stimulated endothelial cells and platelets contain about 10% of TFPI activity that is secreted following activation it is possible that thrombin-induced release of TFPI by endothelium and platelets could account for the increased TFPI we found during hemodialysis. To investigate this possibility we measured during dialysis beta-thromboglobulin (beta-TG), thrombin-antithrombin complex (TAT) and prothrombin fragment 1.2 (F 1.2). The increased levels of beta-TG, TAT and F1.2 we noted during extracorporeal circuit are in keeping with this concept. One hundred eighty minutes after initiation of dialysis, by which time all patients were receiving heparin there was a further increase in TFPI (to more than 200% of baseline), due to the presence of the glycosaminoglycan. This was due the previously reported displacement by heparin of the major intravascular pool of TFPI, from endothelial cell surfaces.

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.

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.

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.

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

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.

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.

Hypoprothrombinemia and Cephalosporins in Uremics

Dr. Ugo Vertolli, Via Filiasi 394, I-35128 Padova (Italy) Dear Sir, The pathophysiology of coagulation in uremia is complex [1]. A special and probably underestimated problem is the interference of antibiotics with coagulative factors. Many authors observed bleeding episodes in patients with impaired renal function who had been given high doses of 3rd-generation cephalosporins, i.e., moxalactam, cefamandole and cefoperazone: the cause is hypoprothrombinemia and depression of other vitamin-K-dependent factors (factor VII, IX, X and protein C) [2]. Several lines of evidence point to an interaction between cephalosporins with an N-methyl-thiotetrazole side chain and hepatic vitamin K metabolism [3]. The reason why uremics are prone to this side effect is unknown, probably they are vitamin K depleted. Here we refer to 2 cases of interference of cephalosporins of the first and 3rd generation with vitamin K factors in 2 hemodialytic patients. The first patient, 55, was transferred to our unit from the surgical department after an endoscopic papillotomy for common bile duct stones. She had a prothrombin time of more than 3 times INR which rose to normal after withdrawal of cefamandole. The 2nd patient, 56, came from the cardio-surgery department after replacement of the mitral valve. His prothrombin time was more than 3 times INR after 10 days from withdrawal of dicumarol. Prothrombin time promptly rose after cephazoline was stopped. Cephalosporins only, which carry N-methyl-thiotetrazole, are claimed for hypoprothrombinemia; here we report a case of persistent low prothrombin time with the use of cephalosporin of the first generation with a thiodiazolyl side chain. Our statement is that probably the problem is underestimated and may be cleared by a more extensive prothrombin time testing in uremics treated with cephalosporins. References Remuzzi G: Bleeding disorders in uremia: Pathophysiology and treatment. Adv Nephrol 1989;18:171-186. Andrassy K, Ritz E: Uremia as a cause of bleeding. Am J Nephrol 1985;5:313-319. Lipsky J: Nmethyl-thiotetrazole inhibition of the gamma carboxilation of glutamic acid: Possible mechanism for antibiotics associated with hypoprothrombinemia. Lancet 1983 ;ii: 192-193.

Fractured catheter guide wire in the right ventricle of a dialysis patient.

Central vein catheters are often used in hemodialysis patients to gain vascular access when the artero-venous or prosthetic fistula becomes unavailable. Catheter insertion and maintenance, while routine, can result in complications of varying severity that include pneumothorax, arterial puncture, arrhythmias, line fracture, malposition, infection, thrombosis, and fibrin sheath formation. Another type of rare complication associated with catheterization involves the fracture of the guide wire of the catheter. We report here not only the fracture of the catheter guide wire during its insertion in the jugular vein but the absence of clinical signs or complications despite its migration in the right ventricle. A 70-year-old women under chronic hemodialysis presented with thrombosis of her artero-venous fistula used for vascular access. A catheter was inserted uneventfully in her right jugular vein to regain the vascular access necessary for hemodialysis. An immediate postcatheterization chest X-ray revealed a wire against the heart shadow (Fig. 1). However the patient was discharged as the radiology report interpreted this as representing an ECG wire. The patient then returned to her regular, three times a week hemodialysis treatment with no symptoms complained or problems observed by the clinical staff taking care of the patient’s dialysis sessions. This lack of symptoms related to vascular complications could have been due to both the biocompatibility of the wire and likely to the daily antiplatelet treatment with acetyl salicylic acid, the patient was already taking as treatment for minor atherosclerotic lesions at carotid arteries (IMT and two not hemodynamically relevant plaques resulting in 20% stenosis of internal carotid artery bilaterally), since approximately one year, and to the regular heparin based anticoagulation during dialysis sessions. Six months later, the patient presented with bronchitis for which she underwent a chest X-ray. The radiogram revealed the same image of the wire against the heart shadow (Fig. 2). A subsequent echocardiogram confirmed the presence of a piece of the catheter guidewire in her right ventricle (Fig. 3). The case was discussed with interventional cardiologists who, in consideration of the total absence of problems, including normal ECG with no evidence of arrhythmia, opted for no immediate intervention. The piece of guidewire therefore remained in the patient’s right ventricle. The patient continued her regular hemodialysis treatment and died 12 months later for respiratory complications associated with pneumonia with no clinical issues related to the piece of guidewire in her right ventricle.

Transplant osteonecrosis: can it be due to uremic neuropathy?

Dott. Massimo Bertoli, Riviera S. Benedetto, 124, I-35100 Padova (Italy) Dear Sir, Aseptic osteonecrosis of the femur head, a disabling disease which strikes about 16% of renal transplant recipients, seems clearly related to steroid therapy as its incidence drops sharply with the use of new immunosuppres-sants such as cyclosporin [1]. Several etiological factors related to corticosteroid treatment have been implicated, such as fat embolism in the small subchondral arteries associated with hyperîipidemia, or steroid-induced osteoporosis due to reduced osteogenesis as well as reduced interstinal calcium absorption, which may aggravate secondary hyperparathyroidism. Hypercoagulabil-ity related to steroid therapy may also lead to thrombosis of the bone arterioles with consequent avascular osteonecrosis. However, a recent editorial concluded that ‘there are no suitable biochemical or hormonal markers for predicting which patients will develop aspetic osteonecrosis after transplant surgery’ [1]. In our opinion, uremic neuropathy may also facilitate the onset of transplant osteonecrosis, which, in fact, has been described in pathologic situations characterized by severe peripheral nervous system disease, such as alcoholism [2], diabetes [3], familial dysautonomia [4] and in the uremic patient undergoing periodic dialysis [5]. Sixteen patients, 12 males and 4 females, ranging in age from 24 to 57 years, underwent renal transplantation and were treated with conventional immunotherapy (prednisolone and azathioprine). In addition to routine periodic laboratory tests, an electromyogram of the external popliteal sciatic nerve (velocity of neuromotor conduction) was performed once annually before and at 6 months following transplantation. Five patients in this group (31.2%) developed osteonecrosis; in 4 cases onset occurred within 10 months of transplantation, and in 1 after 38 months. One patient also developed aseptic necrosis of a metacarpal epiphy-sis. No significant differences were observed between patients with and without osteonecrosis regarding the biochemical parameters examined (hematocrit, serum alkaline phosphatase, calcium, phosphorus, cholesterol and triglycerides) and total steroid dose. From a neurological point of view, however, motor conduction velocity of the sciatic-popliteal nerve was significantly slower (p < 0.05) in patients with osteonecrosis before and also 6 months after renal transplantation (41.05 ± 1.4 and 41.25 ± 0.96 m/s, respectively), while in patients without osteonecrosis, values were 45.5 ± 1.96 and 46.8 ± 5.59 m/s, respectively.