[New Treatment Strategies in Patients with Heart Failure with Reduced Ejection Fraction: Beyond Neurohormonal Inhibition].

Patients affected by heart failure (HF) with reduced ejection fraction (HFrEF) are prone to experience episodes of worsening symptoms and signs despite continued therapy, termed "worsening heart failure" (WHF). Although guideline-directed medical therapy is well established, worsening of chronic heart failure accounts for almost 50% of all hospital admissions for HF with consequent higher risk of death and hospitalization than patients with "stable" HF. New drugs are emerging as cornerstones to reduce residual risk of both cardiovascular mortality and readmission for heart failure. The following review will debate about emerging definition of WHF in light of the recent clinical consensus released by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) and the new therapeutic strategies in cardiorenal patients.

[Atrial fibrillation, oral anticoagulation and nephroprotection: caution or bravery?]

Atrial fibrillation (AF) and chronic kidney disease (CKD) are strictly related and share several risk factors (i.e. hypertension, diabetes mellitus, congestive heart failure). As consequence, AF is very common among CKD patients, especially in those with end stage renal disease (ESRD). Moreover, patients with AF and advanced kidney disease have a higher mortality rate than patients with preserved renal function due to an increased incidence of stroke and an unpredicted elevated hemorrhagic risk. The adequate long-term oral anticoagulation in this subgroup of patients represents a major challenging issue faced by physicians in clinical practice. Direct oral anticoagulants (DOACs) are currently contraindicated in patients with ESRD while vitamin K antagonists (VKAs) are characterized by a narrow therapeutic window, increased tissue calcification and an unfavorable risk/benefit ratio with low stroke prevention effect and augmented risk of major bleeding. The purpose of this review is to shed light on the applications of DOAC therapy in CKD patients, especially in ESRD patients.

Cardionephrology and cardiorenal disease in Italy: state of the art.

The interactions and feedback mechanisms involved in heart and renal failure are more complex than previously thought and are grouped under the term "cardio-renal axis". In the last decades, it has always been emphasized that renal dysfunction in patients with heart failure can be attributed exclusively to low renal plasma flow resulting from reduced cardiac output. In the last two decades cardiorenal syndrome has been established to set complex and close interactions between heart and kidney. Cardiologists and nephrologist should interact in their daily clinical practice to provide better patients' management. In this review, we will point out main features of cardiorenal axis and cardiorenal syndrome to shift into specific sets of management in Italy starting by Guyton's hypothesis till present days.

Thromboembolic and Bleeding Risk in Atrial Fibrillation Patients with Chronic Kidney Disease: Role of Anticoagulation Therapy.

Atrial fibrillation (AF) and chronic kidney disease (CKD) are strictly related; several independent risk factors of AF are often frequent in CKD patients. AF prevalence is very common among these patients, ranging between 15% and 20% in advanced stages of CKD. Moreover, the results of several studies showed that AF patients with end stage renal disease (ESRD) have a higher mortality rate than patients with preserved renal function due to an increased incidence of stroke and an unpredicted elevated hemorrhagic risk. Direct oral anticoagulants (DOACs) are currently contraindicated in patients with ESRD and vitamin K antagonists (VKAs), remaining the only drugs allowed, although they show numerous critical issues such as a narrow therapeutic window, increased tissue calcification and an unfavorable risk/benefit ratio with low stroke prevention effect and augmented risk of major bleeding. The purpose of this review is to shed light on the applications of DOAC therapy in CKD patients, especially in ESRD patients.

Adverse Drug Reactions during Real-Life Use of Direct Oral Anticoagulants in Italy: An Update Based on Data from the Italian National Pharmacovigilance Network.

BACKGROUND: The availability of direct oral anticoagulants (DOAC) in clinical practice has transformed the health care provided to patients for the prevention and treatment of thromboembolism. Safety and efficacy data guide clinicians in the choice of the drug used. To date, no evidence is available from head-to-head trials comparing different DOAC with regard to safety and efficacy; information is mainly derived from several meta-analyses and real-life studies. Conclusions from these studies are inconsistent and unsatisfactory. The evaluation of self-reported adverse drug reactions (ADR) available from databases of drug-regulatory agencies such as the Italian Medicines Agency (AIFA) pharmacovigilance database represents a novel aid to guide decision-making. OBJECTIVE: To analyze potential suspected ADR of DOAC using a previously described risk index (RI) in daily clinical practice in Italy. METHODS: The National Pharmacovigilance Network database (from the AIFA website) was searched in order to retrieve information on all ADR related to oral anticoagulants occurring from 2013 to 2018. The ADR RI for each drug was calculated, where an RI = 1 indicates a balance between the percentage of ADR share and the percentage of market share for each DOAC; and an RI <1 indicates a rate of ADR lower than the rate of market share (safer DOAC). The following DOAC molecules were considered: dabigatran, rivaroxaban, apixaban, and edoxaban. RESULTS: The results showed that rivaroxaban is the DOAC with the lowest RI among the 4 molecules available today in Italy. CONCLUSIONS: Based on the RI, we identified rivaroxaban as the DOAC having the best safety profile.

Cardiac valve calcification and use of anticoagulants: Preliminary observation of a potentially modifiable risk factor.

AIMS: Direct oral anticoagulant (DOAC) has been recently introduced in the clinical practice. Rather than interfering with vitamin K-dependent posttranscriptional modification of various proteins, DOACs selectively inhibit factors involved in the coagulation cascade. In particular, in contrast with Warfarin, Rivaroxabn does not interfere with activation of matrix Gla Protein (MGP), a potent vascular calcification Inhibitor. We herein sought to investigate the impact of Rivaroxaban and Warfarin on cardiac valve calcifications in a cohort of moderate-to advanced CKD patients. METHODS AND RESULTS: This is a multicenter, observational, retrospective, longitudinal study. Consecutive CKD stage 3b - 4 (according to KDIGO guidelines) patients from 8 cardiologic outpatient clinics were enrolled between May 2015 and October 2017. All patients received anticoagulation (100 Warfarin vs 247 Rivaroxaban) as part of their non-valvular atrial fibrillation management. Cardiac valve calcification was evaluated via standard trans-thoracic echocardiogram. 347 patients (mean age: 66 years; mean eGFR: 37 ml/min/1.73 m2) were studied. Over a mean follow-up period of 16 months, Rivaroxaban compared to Warfarin reduced both mitral and aortic valve calcifications (p < 0.001) independently of the degree of calcifications at baseline and potential confounders. Notably, Rivaroxaban use was also associated with a significant reduction in C reactive protein (CRP) (p < 0.001) during follow-up. CONCLUSION: This study generates the hypothesis that the use of Rivaroxaban associates with a reduction of cardiac valve calcification deposition and progression as compared to Warfarin, in a cohort of CKD stage 3b-4 patients. Future endeavors are needed to confirm and to establish the mechanisms responsible for these findings.

Chronic Hyperkalemia in Cardiorenal Patients: Risk Factors, Diagnosis, and New Treatment Options.

Chronic hyperkalemia (HK) is a serious medical condition that often manifests in patients with chronic kidney disease (CKD) and heart failure (HF) leading to poor outcomes and necessitating careful management by cardionephrologists. CKD, HF, diabetes, and renin-angiotensin-aldosterone system inhibitors use is known to induce HK. Current therapeutic options are not optimal, as pointed out by a large number of CKD and HF patients with HK. The following review will focus on the main risk factors for developing HK and also aims to provide a guide for a correct diagnosis and present new approaches to therapy.

Safety and effectiveness of rivaroxaban and warfarin in moderate-to-advanced CKD: real world data.

BACKGROUND: In recent years, novel anticoagulant drugs have been introduced in the clinical armamentarium and have progressively gained momentum. Although their use is increasing among CKD patients, some skepticism about their risk-benefit ratio still persists. We sought to investigate the safety and effectiveness of rivaroxaban in a cohort of moderate-to-advanced CKD patients. METHODS: This observational, retrospective, longitudinal study involved 347 consecutive CKD stage 3b-4 (according to NKF-KDOQI guidelines) patients enrolled from 8 cardiac outpatient clinics between March 2015 and October 2017. All patients received anticoagulation (100 warfarin vs. 247 rivaroxaban) as part of their non-valvular atrial fibrillation management at the attending physician's discretion. Clinical effectiveness (defined as the occurrence of ischemic stroke, venous thromboembolism, or transient ischemic attack) and safety (intracranial hemorrhage, gastrointestinal or other bleeding) were assessed separately. RESULTS: Over a mean follow-up period of 16 ± 0.3 months, 25 stroke episodes (15 hemorrhagic, and 10 ischemic) occurred in 24 warfarin treated patients vs. none in the rivaroxaban arm. There were 5 vs. 0 episodes of deep venous thrombosis and 8 vs. 2 major episodes of bleeding in the warfarin and rivaroxaban groups, respectively. In contrast, the proportion of minor episodes of bleeding was similar between groups. CONCLUSION: Rivaroxaban seems a safe and effective therapeutic option in CKD stage 3b-4 patients. However, future randomized controlled trials are needed to definitively establish the role of rivaroxaban in CKD patients.

Nutritional therapy in autosomal dominant polycystic kidney disease.

CKD-related nutritional therapy (NT) is a crucial cornerstone of CKD patients' treatment, but the role of NT has not been clearly investigated in autosomal dominant polycystic kidney disease (ADPKD). Several clinical studies have focused on new pharmacological approaches to delay cystic disease progression, but there are no data on dietary interventions in ADPKD patients. The aim of this paper is to analyze the evidence from the literature on the impact of five nutritional aspects (water, sodium, phosphorus, protein intake, and net acid load) in CKD-related ADPKD extrapolating-where information is unavailable-from what occurs in CKD non-ADPKD patients Sodium intake restriction could be useful in decreasing the growth rate of cysts. Although further evidence is needed, restriction of phosphorus and protein intake restriction represent cornerstones of the dietary support of renal non-ADPKD patients and common sense can guide their use. It could be also helpful to limit animal protein, increasing fruit and vegetables intake together with a full correction of metabolic acidosis. Finally, fluid intake may be recommended in the early stages of the disease, although it is not to be prescribed in the presence of moderate to severe reduction of renal function.

[Neprilysin inhibition and chronic kidney disease]. / Gli inibitori della Neprilisina nei pazienti affetti da Malattia Renale Cronica e Sindrome Cardio:Renale.

Patients with chronic kidney disease (CKD) have a higher incidence of cardiovascular (acute and chronic) events, which in turn have an increased risk of progression to end-stage renal disease (ESRD) Inhibition of neprilysin, in addition to offering a new therapeutic target in patients with heart failure, could represent a potential improvement strategy in cardiovascular and renal outcome of patients with CKD. Inhibition of neprilysin by inhibiting the breakdown of natriuretic peptides, increases their bioavailability resulting in an increase in diuresis and sodium excretion and, in addition to exerting an inhibition of the renin-angiotensin-aldosterone (RAAS) system. Inhibition of RAAS, in turn, generates a series of counter-regulations that can balance the adverse effects present in CKD and heart failure (HF). The idea of blocking neprilysin is not very recent, but the first drugs used as inhibitors had an inadmissible incidence of angioedema. Among the latest generation molecules that can perform a specific inhibitory action on the neprilysin receptor and, at the same time, on the angiotensin II receptor thanks to the association with valsartan there is the LCZ696 (sacubitril / valsartan). This drug has shown promising benefits both in the treatment arterial hypertension and heart failure. It is hoped that equally positive effects may occur in CKD patients, particularly those with macroproteinuria.

[Non vitamin-K dependent oral anticoagulants (NOACs) in chronic kidney disease patients with non-valvular atrial fibrillation].

Atrial fibrillation (AF) represents the most common arrhythmia in patients with chronic kidney disease (CKD). As in the general population, AF is associated with an increased risk of thromboembolism and stroke, according to progressive decline of glomerular filtration rate (GFR). 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 <25 ml/min who were excluded from all pivotal phase 3 NOACs trials. This review focuses on the current pharmacokinetic, observational, and prospective data on NOACs in patients with advanced chronic kidney disease (creatinine clearance <25 ml/) and those on dialysis.

[Hepato-renal syndrome].

Hepatic and kidney failure are often closely linked (Hepato-Renal Sindrome - HRS). Acute kidney injury (AKI) represents a well-known complication of liver or biliary tract disease. Pathophysiology of HRS is still not completely clear. At this stage we know the biological pathways of several kidney abnormalities in end stage liver disease patients. At the same time patient's prognosis is poor with bad outcomes despite the reversible nature of the kidneys' involvement. Liver transplantation represents the ultimate treatment for HRS patients.

[NOACs and Chronic kidney disease].

Atrial fibrillation (AF) represents the most common arrhythmia in patients with chronic kidney disease (CKD). As in the general population, AF is associated with an increased risk of thromboembolism and stroke, according to progressive decline of glomerular filtration rate (GFR). 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 <25 ml/min who were excluded from all pivotal phase 3 NOACs trials. This review focuses on the current pharmacokinetic, observational, and prospective data on NOACs in patients with advanced chronic kidney disease (creatinine clearance <25 ml/min) and those on dialysis.

The treatment of type 2 diabetes mellitus in patients with chronic kidney disease: What to expect from new oral hypoglycemic agents.

Worldwide, an estimated 200 million people have chronic kidney disease (CKD), whose most common causes include hypertension, arteriosclerosis, and diabetes. About 40% of patients with diabetes develop CKD and intensive blood glucose control through pharmacological intervention can delay CKD progression. Standard therapies for the treatment of type 2 diabetes mellitus include metformin, sulfonylureas, meglitinides, thiazolidinediones, and insulin. While these drugs have an important role in the management of type 2 diabetes, only the thiazolidinedione pioglitazone can be used across the spectrum of CKD (stages 2-5) and without dose adjustment. Newer therapies, particularly dipeptidyl peptidase-IV inhibitors, glucagon-like peptide-1 receptor agonists, and sodium-glucose cotransporter-2 inhibitors, are increasingly being used in the treatment of type 2 diabetes; however, a major consideration is whether these newer therapies can also be used safely and effectively across the spectrum of renal impairment.

[Newer anti - diabetic therapies and chronic kidney disease]. / Il trattamento del diabete mellito di tipo 2 nei pazienti affetti da malattia renale cronica: cosa aspettarsi dai nuovi ipoglicemizzanti orali.

Worldwide, an estimated 200 million people have chronic kidney disease (CKD), whose most common causes include hypertension, arteriosclerosis, and diabetes. About 40% of patients with diabetes develop CKD. Intensive blood glucose control through pharmacological intervention can delay CKD progression. Standard therapies for the treatment of type 2 diabetes include metformin, sulfonylureas, meglitinides, thiazolidinediones and insulin. While these drugs have an important role in the management of type 2 diabetes, only the thiazolidinedione pioglitazone can be used across the spectrum of CKD (stages 25) and without dose adjustment. Newer therapies, particularly dipeptidyl peptidase-IV inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors are increasingly being used in the treatment of type 2 diabetes. However, a major consideration is whether these newer therapies can also be used safely and effectively across the spectrum of renal impairment.

[Acute Kidney Injury, Type - 3 cardiorenal syndrome, Biomarkers, Renal Replacement Therapy]. / Aki (Acute Kidney Injury) e patologia cardiovascolare: dai dati epidemiologici alle strategie terapeutiche.

Cardiovascular disease and major cardiovascular events represent main cause of death in both acute and chronic kidney disease patients. Kidney and heart failure are common and frequently co-exist This organ-organ interaction, also called organ cross-talk, leads to well-known definition of cardiorenal syndrome (CRS). Here we will describe cardiovascular involvement in patients with acute kidney injury (AKI). Also known as Type-3 CRS or acute reno-cardiac CRS, it occurs when AKI contributes and/or precipitates development of acute cardiac injury. AKI may directly or indirectly produces an acute cardiac event and it can be associated with volume overload, metabolic acidosis and electrolytes disorders such as hyperkalemia and hypocalcemia, coronary artery disease, left ventricular dysfunction and fibrosis which has been also described in patients with AKI with the consequence of direct negative effects on cardiac performance.

[Troponins and chronic kidney disease]. / Malattia renale cronica e sindrome coronarica acuta: il ruolo della troponina.

Coronary thrombosis was recognized since 19th century as clinical entity with bad outcomes; only in 1912 it was reported that acute myocardial infarction had to been distinguished from angina pectoris. First diagnostic test was electrocardiogram, while white blood cells count and erythrocytes sedimentation rate were the only available laboratory tests. Late in the 60s and 70s glutammic oxaloacetic and glutamic pyravate transaminase, lactate dehydrogenase and creatine kinase were added to biomarkers pool to provide a diagnosis of myocardial infarction related to myocardial cells injury. Only in 1987 assays for cardiac troponin were developed to assess structural damage of myocardial cells and in 2010 high sensibility troponins first dosage kits became available. It is well known that the population with chronic kidney disease (CKD) is at greater risk for cardiovascular disease and death than the general population. The use and interpretation of high sensitivity cardiac troponin (hs-cTn) assays have been particularly challenging in these patients with the majority having elevated levels at baseline. Aim of this review is to evaluate hs-cTn in patients with CKD for the diagnosis of AMI and for the prognostic significance of elevated levels in CKD patients without AMI.

[Chronic kidney disease and sudden death]. / Malattia renale cronica e morte cardiaca improvvisa: dati epidemiologici, fisiopatologia e strategie d'intervento.

Cardiovascular disease represents the major cause of death in chronic kidney disease patients accounting for about 43% of all mortality causes among hemodialysis patients. Sudden cardiac death (SCD) is one of the most frequent and dangerous clinical syndrome occurring in end stage renal disease (ESRD) patients. Hemodialysis patients present a great number of non traditional risk factors for cardiovascular disease such as left ventricular hypertrophy, coronary artery disease, rapid electrolyte shifts, QT dispersion, sympathetic hyperactivity and hyperphosphatemia. The aim of the following review is to summarize epidemiological aspects and pathophysiological pathways of SCD in CKD patients, defining prevention and treatment guidelines.

Penile calciphylaxis in end stage renal disease.

Calciphylaxis, better described as "Calcific uremic arteriolopathy" (CUA), involves about 1-4% of hemodialysis patients all around the world with high mortality rates. We describe a rare clinical case of CUA in peritoneal dialysis patient associated with urological disease. Penile calciphylaxis represents rare clinical complication, and an early diagnosis and multidisciplinary approach are requested. Pathogenesis is still unclear, and therapeutic approaches need more long-term clinical trials to test their efficacy and safety.

Progression of cardiac valve calcification and decline of renal function in CKD patients.

BACKGROUND: No study has evaluated the efficacy of non-calcium-containing phosphate binders in slowing progression of cardiac valve calcification or deterioration of kidney function in patients with chronic kidney disease not on dialysis. This study addressed these issues. METHODS: Outpatients (n = 170) with stage 3-4 chronic kidney disease and either mitral or aortic valve calcification were evaluated in this single-center, single-arm, prospective observational study. Patients received sevelamer hydrochloride (1,600 mg/day) for 1 year. Cardiac valve calcification progression was assessed by echocardiography, and decline of renal function by estimated glomerular filtration rate. Parathyroid hormone, FGF-23 and C-reactive protein (CRP) serum concentration and urinary phosphorus excretion were assayed. RESULTS: At the end of treatment with sevelamer (12th month), mitral valve calcification had decreased by 79.3% from baseline. At baseline, 69 patients had grade 1, 97 patients grade 2 and 4 patients grade 3 calcification scores; at the end of the study, 60 patients showed grade 1, and no mitral valve calcification was registered in the remaining patients. An aortic valve score of 1 was found in 32%, score of 2 in 58%, score of 3 in 9% and score of 4 in 1% of patients at baseline; at the end of the study, a score of 1 was found in 95% and a score of 2 in 5% of patients. Significant slowing down of renal function decline (p<0.001), reduction of FGF-23 and CRP concentration (p<0.0001) and phosphorus excretion (p<0.0001) were observed. CONCLUSIONS: One-year treatment with a non-calcium-containing phosphate binder may hamper the progression of cardiac valve calcification and slow the decline of renal function, as well as reduce serum concentration of FGF-23 and CRP and urinary phosphorus excretion.