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Patients with diabetes mellitus (DM) often present other chronic comorbidities including arterial hypertension (AH), chronic kidney disease (CKD), ischemic heart disease (IHD) and heart failure with preserved ejection fraction (HFpEF). The frequent association of the latter conditions is considered part of the spectrum of cardio-renal syndromes (CRS), a group of disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. Verapamil is a non-dihydropyridine calcium channel blocker (CCB) widely used in the treatment of hypertension, chronic stable angina, secondary prevention of reinfarction, paroxysmal supra-ventricular tachycardia and for rate control in atrial fibrillation/flutter. In addition to its antihypertensive and anti-ischemic actions verapamil exerts favorable effects also on glycemic control, proteinuric diabetic nephropathy, left ventricular diastolic dysfunction and sympathetic nervous system overactivity which may potentially benefit patients with DM and CRS. In this narrative review, we summarize the current evidence on the potential role of verapamil in the prevention and treatment of CRS in diabetic hypertensive patients.

Background Patients with atrial fibrillation (AF) and severe chronic kidney disease (CKD) are at higher risk of both bleeding and thromboembolic events. Non-vitamin K antagonist oral anticoagulants (NOACs) are licensed to be used in these patients, although they were excluded from phase III controlled randomized trials comparing NOACs vs warfarin in AF. Thus, current evidence on NOACs use in such setting of patients is not definitive. Purpose Aim of our multicenter study was to perform a real-world comparison of clinical outcome with NOACs vs vitamin K antagonist anticoagulants (VKAs) also in AF patients having an estimated glomerular filtration rate (eGFR) 15–29 mL/min. Methods We retrospectively included a total of 266 patients receiving NOACs (N=159) or VKAs (N=107). Primary outcome measure was the cumulative incidence of the net composite endpoint including ischemic stroke, systemic thromboembolism or any bleeding. Mean follow-up was 2.6 years. Results CHA2DS2-VASc and HAS-BLED scores at baseline were similar in the two groups (3.4±1.3 with NOACs vs 3.4±0.9 with VKAs and 3.1±1.0 vs 3.0±0.7, respectively); eGFR and hemoglobin values were also comparable (31.8±12.3 vs 32±11.9 mL/min and 10.2±2.1 vs 11.0±2.3 g/dL, respectively). NOACs were not inferior to VKAs for the primary net composite endpoint: incidence 20.7% vs 29.9%, p Conclusions Our real-world data indicate that in patients with AF and severe renal failure NOACs are not inferior to VKAs for both safety and efficacy. The use of NOACs was associated with a numerically lower incidence of minor bleeding. Funding Acknowledgement Type of funding source: None

According to the recent definition proposed by the Consensus conference on Acute Dialysis Quality Initiative Group, the term cardio-renal syndrome (CRS) has been used to define different clinical conditions in which heart and kidney dysfunction overlap. Type 1 CRS (acute cardio- renal syndrome) is characterized by acute worsening of cardiac function leading to AKI (5, 6) in the setting of active cardiac disease such as ADHF, while type - 2 CRS occurs in a setting of chronic heart disease. Type 3 CRS is closely link to acute kidney injury (AKI), while type 4 represent cardiovascular involvement in chronic kidney disese (CKD) patients. Type 5 CRS represent cardiac and renal involvement in several diseases such as sepsis, hepato - renal syndrome and immune - mediated diseases.

The clinical manifestations of ADPKD are related to the growth of renal cysts. Renal volume has been recognised as the biomarker that is able to identify those patients at risk of complications (hypertension and haematuria) and at risk of progression to End Stage Renal Disease (ESRD). Recently, several scores have been introduced to predict the evolution of ADPKD. The Mayo Clinic Group developed a classification based on renal volume as measured by CT or MRI and corrected for age and height (Ht-TKV); this allowed predicting the evolution of the disease, but it has not been fully validated so far. In addition, it is used to identify patients labelled as “fast progressors” and eligible for Tolvaptan therapy according to the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) recommendations. We studied 80 patients who underwent MRI and had been classified as ADPKD typical form (class 1A-1E). A significant correlation between renal volume, hypertension, and low GFR was found (p<0.005). A progressive increase in disease severity has been found across the different Mayo classes; 41.2% were eligible for Tolvaptan therapy. The results demonstrate that the Mayo method is easy to perform and provides valid information in order to identify with rapidly progressing disease.

La peritonite fungina rappresenta una grave complicanza infettiva che si manifesta nei pazienti con insufficienza renale cronica in trattamento con dialisi peritoneale. Presenta una mortalità superiore al 25% dei casi (1, 2) ed è responsabile di ‘drop out’ dalla metodica, rimozione del catetere di Tenckhoff ed ospedalizzazione. La diagnosi eziologica viene, spesso, posta tardivamente a causa della aspecificità dei sintomi e segni clinici della FP rispetto alle più frequenti forme batteriche nonché della lenta crescita colturale delle specie fungine. La rimozione del catetere è immediatamente indicata dopo la identificazione microscopica o colturale dei funghi (International Society for Peritoneal Dialysis Guidelines/Recommendation: 2010 update) (4). Per quanto riguarda, invece, la chemioterapia antimicotica, le linee guida internazionali non forniscono chiare indicazioni riguardo la scelta, le dosi e le varie associazioni terapeutiche né per ciò che si riferisce alla durata del trattamento, che talora è necessario proseguire per diverse settimane o mesi. In questo report descriviamo il caso di una signora di 70 anni, in trattamento con APD, che sviluppò una FP da Aspergillus niger. La pronta rimozione del catetere peritoneale e la somministrazione di voriconazolo per via endovenosa portarono a un rapido miglioramento della sintomatologia clinica ed alla completa risoluzione di tale complicanza.

La sindrome cardio-renale (SCR) è una sindrome clinica ben nota, che descrive tanto gli effetti negativi dell'insufficienza renale sull'equilibrio cardio-circolatorio quanto quelli dell'insufficienza cardiaca sulla funzione renale. Molti autori hanno studiato l'utilità di marcatori sierologici ai fini dell'identificazione e del monitoraggio ambulatoriale delle varie forme di questa sindrome. L'analisi dei livelli sierici dei peptidi natriuretici è, al momento, quella maggiormente utilizzata, in quanto essi stessi non sono solo direttamente associati alla gravità delhinsufficienza cardiaca, ma anche capaci di rilevare precocemente la disfunzione renale, certamente prima che sia possible osservare un incremento nei livelli sierici di creatinina. NGAL, cistatina C, NAG, KIM-1 e IL-18 rappresentano interessanti biomarcatori per la diagnosi precoce di danno renale acuto (AKI), e quindi per la diagnosi precoce delle forme renocardiache acute, mentre il loro utilizzo in altre forme di SCR non appare codificato. Al contrario, la valutazione di KIM-1 e IL-18 sembra più utile per cercare una diagnostica differenziale tra forme diverse di insufficienza renale acuta. (Cardionephrology)

Atrial fibrillation (AF) represents the most common arrhythmia in patients with chronic kidney disease (CKD). As in the general population, in CKD patients AF is associated with an increased risk of thromboembolism and stroke. However, CKD patients, especially those on renal replacement therapy (RRT), also exhibit an increased risk of bleeding, especially from the gastrointestinal tract. Oral anticoagulation is the most effective form of thromboprophylaxis in patients with AF presenting increased risk of stroke. Limited evidence on efficacy, the increased risk of bleeding as well as some concern regarding the use of warfarin in CKD, has often resulted in the underuse of anticoagulation CKD patients. A large body of evidence suggests that non-vitamin K-dependent oral anticoagulant agents (NOACs) significantly reduce the risk of stroke, intracranial hemorrhage, and mortality, with lower to similar major bleeding rates compared with vitamin K antagonist such as warfarin in normal renal function subjects. Hence, they are currently recommended for patients with atrial fibrillation at risk for stroke. However, NOACs metabolism is largely dependent on the kidneys for elimination and little is known in patients with creatinine clearance

Pulmonary hypertension is defined as an increased systolic pulmonary pressure of >30 mm Hg, and it shows a 40% prevalence in hemodialysis patients due to vascular access (both central venous catheter and arteriovenous fistula). Secondary pulmonary hypertension in chronic kidney disease patients is strictly related to pulmonary circulation impairment together with chronic volume overload and increased levels of cytokines and growth factors, such as FGF, PDGF, and TGF-β, leading to fibrosis. Endothelial dysfunction, together with lower activation of NOS, increased levels of serum endothelin and fibrin storages, involves an extensive growth of endothelial cells leading to complete obliteration of pulmonary vessels. Pulmonary hypertension has no pathognomonic and distinctive symptoms and signs; standard transthoracic echocardiography allows easy assessment of compliance of the right heart chambers. The therapeutic approach is based on traditional drugs such as digitalis-derived drugs, vasodilatory agents (calcium channel blockers), and oral anticoagulants. New pharmacological agents are under investigation, such as prostaglandin analogues, endothelin receptor blockers, and phosphodiesterase-5 inhibitors.

Chronic kidney disease (CKD) patients demonstrate higher rates of cardiovascular mortality and morbidity; and increased incidence of sudden cardiac death (SCD) with declining kidney failure. Coronary artery disease (CAD) associated risk factors are the major determinants of SCD in the general population. However, current evidence suggests that in CKD patients, traditional cardiovascular risk factors may play a lesser role. Complex relationships between CKD-specific risk factors, structural heart disease, and ventricular arrhythmias (VA) contribute to the high risk of SCD. In dialysis patients, the occurrence of VA and SCD could be exacerbated by electrolyte shifts, divalent ion abnormalities, sympathetic overactivity, inflammation and iron toxicity. As outcomes in CKD patients after cardiac arrest are poor, primary and secondary prevention of SCD and cardiac arrest could reduce cardiovascular mortality in patients with CKD.

Fungal peritonitis represents an infectious life-threatening complication in chronic kidney disease patients on peritoneal dialysis (PD). It causes more than 25% mortality rates (1, 2) often leading to patients' drop out from PD, Tenckhoff catheter removal and hospitalization. Causative diagnosis is often delayed because of non-specific clinical signs and symptoms in respect of bacterial infections and slow mycotic spores growth in coltures. Catheter removal is quickly recommended after microbiological or cultural mycotic identification based on International Society for Peritoneal Dialysis Guidelines/Recommendation 2010 update (3). Furthermore, international guidelines provide only few specific hints about drug choice, dosage, combination and length of antimycotic therapy; we must treat our patients for weeks or months most often.Our clinical report refers to a 70 years old woman, on APD (Automated Peritoneal Dialysis), who developed a fungal peritonitis by Aspergillus niger. Tenckhoff catheter was immed...

Nephroangiosclerotic chronic kidney disease's primary and secondary prevention is actually based on blood pressure control and reduction of proteinuria. In proteinuric patients, blood pressure cont...

non disponibile (Cardionephrology)

This multicentre phase II study was aimed at investigating the activity and safety of pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) as front-line therapy in a large series of chemotherapy-naïve recurrent/metastatic breast cancer patients. From June 2003 to December 2006, a total of 71 recurrent/metastatic breast cancer patients were enrolled. Median age was 63 years (range=37-79), and 31 patients (43.7%) wereor =65 years old. Patients received PLD, 25 mg m(-2), day 1, followed by GEM, 800 mg m(-2), days 1 and 8, q21. Response was evaluable in 64 cases. Eight complete (12.5%) and 17 partial responses (26.6%) were registered, with an overall response rate of 39.1%. Thirty patients (46.9%) experienced stable disease, with an overall clinical benefit of 85.9%. Median time to progression (TTP) was 11 months, whereas median overall survival (OS) was not reached. The rate of 1- and 2-year OS was 79 and 61%, respectively. A total of 443 courses were evaluable for toxicity: grade 3 and 4 neutropaenia affected 14 patients (20.3%) and 3 patients (4.3%), respectively. Grade 3 and 4 palmar-plantar erythrodysesthesia syndrome was documented in five cases (7.2%) and one case (1.4%), whereas grade 3 and 4 mucositis occurred in six cases (8.7%) and two cases (2.9%), respectively. Grade 2 cardiac toxicity was observed in only one case. Interestingly enough, there was no difference in the percentage and severity of either haematological or non-haematological toxicity according to the age of the patients (65 vsor =65 years). We confirmed in a large, very homogenous study sample of chemotherapy-naïve recurrent/metastatic breast cancer patients the efficacy and safety of PLD/GEM combination, providing response rates, median TTP and OS values comparable with those achieved with more toxic combinations.

The purpose of this trial was to evaluate the effects of fluvastatin on the lipid pro-file and on renal function, as measured by creatinine clearance, in dyslipidemic patients with chronic renal failure. In this 8-month prospective, open-label, randomized, parallel-group trial, 130 patients (70 men and 60 women), after a 2-month washout period following previous lipid-lowering treatments, were randomly assigned to fluvastatin XL 80 mg given once daily (80 patients) or to standard treatment (50 patients). Mean total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride values after 3 and 6 months of treatment with fluvastatin showed statistically significant improvement compared with standard treatment. Improved renal function, as measured by creatinine clearance, was observed at the end of the 6-month treatment period in approximately 65% of patients treated with fluvastatin. The increase in creatinine clearance consistently reached 10% to 15% of baseline values. A statistically significant reduction in C-reactive protein (CRP) over baseline values was observed in approximately 75% of patients treated with fluvastatin. Furthermore, mean values of CRP for the fluvastatin standard treatment groups, respectively, were 6.78 and 10.19 at 3 months and 4.47 and 11 at 6 months. Both treatments were well tolerated. No major adverse events were noted. Results of this study suggest that fluvastatin treatment in patients with chronic renal failure is effective in improving the lipid profile, and it demonstrates good safety and tolerability. Furthermore, fluvastatin may contribute to improved nephroprotection in this patient population.

This multicentre phase II study was designed to evaluate the antitumour activity and toxicity of bifractionated camptothecin (CPT-11) and 5-fluorouracil/ leucovorin (5-FU/LV) in the treatment of patients with metastatic colorectal cancer (MCC) who had been pretreated with 5-FU/LV-oxaliplatin (FOLFOX regimen). In all, 35 patients were enrolled in a two-stage trial. Treatment consisted of two daily doses of CPT-11, 90 mg m2 administered over 90 min, followed by LV, 200 mg m2 administered over 2 h plus 5-FU 400 mg m2 as a bolus and 600 mg m2 as a 22-h continuous infusion administered with disposable pumps as outpatient therapy. Toxicity was closely monitored. Response was evaluated by computed tomography scans every 8 weeks. All 35 patients were assessable for toxicity and response to treatment. Seven patients had a partial response, giving an overall response rate of 20%; 11 patients had stable disease (31.4%) and 17 progressed (48.5%). The median progression-free survival was 7.1 months and median survival was 14 months. A total of 10 patients (30%) experienced grade 3-4 toxicity, including nausea (15%), diarrhoea (12%) and neutropenia (15%), while seven patients (21%) had grade 2 alopecia. The bifractionated bimonthly schedule of CPT-11 plus 5-FU/LV showed substantial antitumour activity and was well tolerated in this group of patients with a poor prognosis, pretreated with the FOLFOX regimen.

TAPSE measurement during echocardiography is a well known measure of right heart systo-diastolic function. Low TAPSE means reduced cranio-caudal excursion of tricuspidal annulus, sign of both reduced ejection fraction and reduced distensibility of right ventricle. It is a good prognostic index for cardiac mortality risk in CHF patients, adding significant prognostic information to NYHA stadiation. Nephrologists do not always fully aware of right ventricular function in their patients affected by chronic renal failure (CRF), even if this datum is probably crucial in vascular access policy. Our study was designed to study right ventricle function and TAPSE on 202 patients affected by moderate chronic renal failure, free from overt pulmonary hypertension. TAPSE, PAPs, right chambers diameters, classical Framingham factors, estimated glomerular filtration rate were recorded. TAPSE was reduced (23 mm) in 43% of patients enrolled, while dilated right chambers were present in 24%. PAPs exceeded 30 mmHg in 29% of patients. Echocardiographic signs of left ventricular hypertrophy were found in 36% of patients. The ejection fraction was normal in all patients. Statistical analysis showed a significant indirect correlation between TAPSE and PAPs and between TAPSE and tele-diastolic diameters and volumes of the right ventricle, while a direct correlation was observed between TAPSE and Framingham score. TAPSE showed a bimodal distribution, with a subpopulation "low TAPSE - high PAPs", next to a population characterized by normal values ??for both parameters. A reduction in compliance and systolic function of the right heart chambers is quite early and frequent in course of CKD, a fact that the nephrologist should take in due consideration, managing blood volume or planning vascular access for hemodialysis.La misurazione dell'indice TAPSE nel corso di un esame ecocardiografico rappresenta un parametro ben codificato per la studio della funzione sisto – diastolica del cuore destro.Bassi valori di TAPSE indicano una ridotta escursione cranio – caudale dell'anulus tricuspidale, a sua volta indice di ridotta frazione d’eiezione e distensibilità del ventricolo destro.Al tempo stesso rappresenta un buon indice prognostico per il rischio di mortalità cardiovascolare in pazienti affetti da malattia renale cronica e conferisce ulteriore valore prognostico alla sola stadiazione NYHA.I nefrologi non sono ancora del tutto consapevoli dell’importanza dello studio della funzione ventricolare destra nei pazienti affetti da malattia renale cronica (CKD) anche se il dato sembra essere cruciale soprattutto in vista di una buona politica riguardante il confezionamento dell’accesso vascolare per emodialisi.Il nostro studio è stato progettato per valutare la funzione ventricolare destra e la TAPSE in 202 pazienti affetti da Malattia Renale Cronica di grado moderato senza segni clinici evidenti di ipertensione polmonare.Sono stati presi in considerazione i seguenti parametri: TAPSE, PAPs, diametri delle sezioni cardiache di destra, fattori di rischio di Framingham e stima della frazione di filtrazione glomerulare.I valori di TAPSE erano ridotti (23 mm) nel 43% dei pazienti arruolati, mentre il 24% dei pazienti esaminati presentava dilatazione delle camere cardiache di destra con PAPs superiori ai 30 mmHg nel 29% dei pazienti. Segni ecocardiografici di ipertrofia ventricolare sinistra sono stati riscontrati nel 36% dei pazienti. La frazione di eiezione era normale in tutti i pazienti studiati.L’analisi statistica dei dati ha evidenziato una significativa correlazione indiretta tra TAPSE e PAPs e tra TAPSE e diametri/volumi del ventricolo destro, mentre una correlazione diretta è stata trovata tra TAPSE e punteggio di Framingham.I valori di TAPSE si sono distribuiti in maniera bimodale con una sottopopolazione “a bassi valori di TAPSE ed alti valori di PAPs” vicina ad un’altra caratterizzata dalla presenza di valori normali per entrambi i parametri.Una riduzione della compliance e della funzione sistolica delle sezioni cardiache destre rappresenta un elemento precoce e frequente in corso di CKD, elemento che va tenuto in considerazione dai nefrologi allo scopo di controllare in maniera ottimale lo stato d’idratazione dei pazienti e pianificare una buona politica di allestimento di un accesso vascolare per emodialisi.

Dyspnea is an extremely common symptom among patients on dialysis [1–3]. At first instance nephrologists generally considers it as a symptom of volume overload in patients with uremia and manages it by gradually reducing the patient’s dry weight. Here we describe two clinical cases in which echocardiography proved to be a very useful tool in the differential diagnosis of dyspnea in patients on hemodialysis.

A series of experiments were conducted to investigate the role of presynaptic dopamine (DA) and noradrenaline (NA) neurotransmission in stimulant-unconditioned and conditioned locomotion and defecation. (+)-Amphetamine (AMP, 1.5 mg/kg, s.c.) increased both locomotion and defecation in rats, and both of these effects were conditioned to environmental stimuli. Some groups of rats were treated with DSP4 (50 mg/kg, i.p.), a selective, long-lasting NA neurotoxin, given 7 days prior to conditioning with AMP. This treatment depleted forebrain NA to between 1% and 54% of control levels, depending on the brain region, but did not attenuate either AMP-unconditioned or conditioned locomotion. These results indicate that NA does not mediate either AMP unconditioned or conditioned locomotion. alpha-Methyl-para-tyrosine methyl ester (alpha MPT, 25-50 mg/kg, s.c.), a selective inhibitor of catecholamine synthesis given during conditioning with AMP, attenuated unconditioned AMP-induced locomotion and defecation but did not influence AMP-conditioned locomotion and defecation. Thus, alpha MPT blocked AMP-induced unconditioned locomotion, supporting the hypothesis that the locomotor and defecation stimulant effects of AMP are mediated by DA release. In spite of the attenuation of the direct effects of AMP, alpha MPT did not attenuate AMP-conditioned locomotion or defecation. It is concluded that AMP-induced release of dopamine is responsible for the unconditioned behavioral effects of amphetamine but not for the conditioning of amphetamine-induced locomotion and defecation.

In vitro and in vivo studies have shown that oxaliplatin (L-OHP), 5-fluorouracil (5-FU) and leucovorin (L) have a synergistic activity on metastatic colorectal cancer (MCC). In order to better exploit the synergism of action between the three drugs, L-OHP was administered over 2 days, together with 5-FU-L, in a cohort of patients with MCC that had been pre-treated with chemotherapy. Forty-six patients were entered into the trial. All had been pre-treated with chemotherapy for metastatic disease: 14 with the 'de Gramont' regimen alone, and 32 with the same regimen combined with irinotecan (CPT-11). The outpatient treatment consisted of L-OHP 50 mg/m(2), followed immediately by the 'de Gramont' regimen. All drugs were administered on days 1 and 2, every 14 days. Median patient age was 65 years (range: 46-78), male/female ratio was 29/17. All 46 patients were evaluated for response and toxicity. We observed 1 complete response (2.2%) and 14 partial responses (30.4%), giving an overall response rate of 32.6% (95% CI: 19.5-48.06%); 22 patients had stable disease (47.8%) and 9 patients progressed (19.6%). After a median follow-up of 13 months, median time to progression was 6.4 months (range: 3.1-31.2+), while overall median survival was 12.2 months (range: 3.7-31.2+). Toxicity was manageable: grade 3 or 4 neutropenia was observed in 33% of patients, while only 6% of patients had grade 1-2 neurotoxicity. The fractionated bimonthly schedule of L-OHP plus 5-FU-L, showed activity, with an acceptable toxicity profile, both in patients with MCC pre-treated with the 'de Gramont' regimen alone, or with this regimen associated with CPT-11.

To define the maximum tolerated dose (MTD) of irinotecan (CPT-11) given on days 1 and 8 with mitomycin C (MMC) given on day 1 in a monthly cycle, and to assess the toxicity and activity of this regimen in patients with previously treated colorectal carcinoma.Fifty-two patients, all pretreated with adjuvant 5-fluorouracil (20 patients) and/or one (35 patients) or two (8 patients) lines of chemotherapy, were entered in this study. Escalating doses of CPT-11 (starting from 150 mg/m2) were administered on days 1 and 8, with escalating doses of MMC (starting from 8 mg/m2) given on day 1, recycling every 28 days. At least 3 patients were treated at each dose level. Escalation proceeded unless 2 out of 3 or 4 out of 6 patients experienced a dose-limiting toxicity (DLT) after the first cycle.Twelve patients were entered in the phase I study, and 4 consecutive dose levels were tested. At the last dose level (CPT-11 200 mg/m2 plus MMC 10 mg/m2) 4 of 6 patients experienced a DLT (i.e., grade 4 neutropenia in 2 patients and grade 3 diarrhea in 2 patients). Therefore, this dose level was considered as the MTD. Forty patients were treated at the previous dose level (CPT-11, 175 mg/m2 plus MMC 10 mg/m2). One complete, 4 partial, 3 minor responses and 11 cases of stable disease were registered, giving a response rate of 12% [95% confidence interval (CI), 4-27%] and an overall control of tumor growth in 47% (95% CI, 31-64%) of patients. The median time to treatment failure was 6 months (range 1-19+). The median survival time was 14.5 months, and the 1-year and 2-year probability of survival were 56 and 43%. Neutropenia and diarrhea affected 62 and 58% of patients, grade 3 or 4 being registered in 26 and 23% of them, respectively. One episode of neutropenic fever was reported. Other acute toxicities were usually mild and manageable.CPT-11 175 mg/m2 on days 1 and 8 associated with MMC 10 mg/m2 on day 1, every 4 weeks, is a safe and moderately active regimen in heavily pretreated patients with advanced colorectal carcinoma. The role of MMC in this combination is doubtful, and further attempts with other new agents should be made to improve the outcome in these patients.