Practical approaches to building up a cardiorenal clinic.

The population with concomitant heart and kidney disease (often termed 'cardiorenal' disease) is expected to grow, significantly impacting public health and healthcare utilization. Moreover, the cardiorenal nexus encompasses a bidirectional relationship that worsens prognosis and may complicate pharmacological management in often elderly and frail patients. Therefore, a more cohesive multidisciplinary team approach aiming to provide holistic, coordinated and specialized care would be a positive shift towards improving patient outcomes and optimizing healthcare resources. This article aims to define the organizational aspects and key elements for setting up a multidisciplinary cardiorenal clinical program as a potential healthcare model adapted to the particular characteristics of patients with cardiorenal disease.

The "FIFTY SHADOWS" of the RALES Trial: Lessons about the Potential Risk of Dietary Potassium Supplementation in Patients with Chronic Kidney Disease.

Hyperkalaemia (HK) is one of the most common electrolyte disorders and a frequent reason for nephrological consultations. High serum potassium (K+) levels are associated with elevated morbidity and mortality, mainly due to life-threatening arrhythmias. In the majority of cases, HK is associated with chronic kidney disease (CKD), or with the use of renin-angiotensin-aldosterone system inhibitors (RAASis) and/or mineral corticoid antagonists (MRAs). These drugs represent the mainstays of treatment in CKD, HF, diabetes, hypertension, and even glomerular diseases, in consideration of their beneficial effect on hard outcomes related to cardiovascular events and CKD progression. However, experiences in relation to the Randomised Aldactone Evaluation Study (RALES) cast a long shadow that extends to the present day, since the increased risk for HK remains a major concern. In this article, we summarise the physiology of K+ homeostasis, and we review the effects of dietary K+ on blood pressure and cardiovascular risk in the general population and in patients with early CKD, who are often not aware of this disease. We conclude with a note of caution regarding the recent publication of the SSaSS trial and the use of salt substitutes, particularly in patients with a limited capacity to increase K+ secretion in response to an exogenous load, particularly in the context of "occult" CKD, HF, and in patients taking RAASis and/or MRAs.

New evidence of direct oral anticoagulation therapy on cardiac valve calcifications, renal preservation and inflammatory modulation.

BACKGROUND: Rivaroxaban is a direct inhibitor of activated Factor X (FXa), an anti-inflammatory protein exerting a protective effect on the cardiac valve and vascular endothelium. We compare the effect of Warfarin and Rivaroxaban on inflammation biomarkers and their contribution to heart valve calcification progression and renal preservation in a population of atrial fibrillation (AF) patients with chronic kidney disease (CKD) stage 3b - 4. METHODS: This was an observational, multicenter, prospective study enrolling 347 consecutive CKD stage 3b - 4 patients newly diagnosed with AF: 247 were treated with Rivaroxaban and 100 with Warfarin. Every 12 months, we measured creatinine levels and cardiac valve calcification via standard trans-thoracic echocardiogram, while plasma levels of inflammatory mediators were quantified by ELISA at baseline and after 24 months. RESULTS: Over a follow-up of 24 months, long-term treatment with Rivaroxaban was associated with a significative reduction of cytokines. Patients treated with Rivaroxaban experienced a more frequent stabilization/regression of valve calcifications comparing with patients treated with Warfarin. Rivaroxaban use was related with an improvement in kidney function in 87.4% of patients, while in those treated with Warfarin was reported a worsening of renal clearance in 98% of cases. Patients taking Rivaroxaban experienced lower adverse events (3.2% vs 49%, p-value <0.001). CONCLUSIONS: Our findings suggest that Rivaroxaban compared to Warfarin is associated with lower levels of serum markers of inflammation. The inhibition of FXa may exert an anti-inflammatory effect contributing to reduce the risk of cardiac valve calcification progression and worsening of renal function.

Classification of Uremic Toxins and Their Role in Kidney Failure.

Advances in our understanding of uremic retention solutes, and improvements in hemodialysis membranes and other techniques designed to remove uremic retention solutes, offer opportunities to readdress the definition and classification of uremic toxins. A consensus conference was held to develop recommendations for an updated definition and classification scheme on the basis of a holistic approach that incorporates physicochemical characteristics and dialytic removal patterns of uremic retention solutes and their linkage to clinical symptoms and outcomes. The major focus is on the removal of uremic retention solutes by hemodialysis. The identification of representative biomarkers for different classes of uremic retention solutes and their correlation to clinical symptoms and outcomes may facilitate personalized and targeted dialysis prescriptions to improve quality of life, morbidity, and mortality. Recommendations for areas of future research were also formulated, aimed at improving understanding of uremic solutes and improving outcomes in patients with CKD.

Nephrotoxicity and Chinese Herbal Medicine.

Chinese herbal medicine has been practiced for the prevention, treatment, and cure of diseases for thousands of years. Herbal medicine involves the use of natural compounds, which have relatively complex active ingredients with varying degrees of side effects. Some of these herbal medicines are known to cause nephrotoxicity, which can be overlooked by physicians and patients due to the belief that herbal medications are innocuous. Some of the nephrotoxic components from herbs are aristolochic acids and other plant alkaloids. In addition, anthraquinones, flavonoids, and glycosides from herbs also are known to cause kidney toxicity. The kidney manifestations of nephrotoxicity associated with herbal medicine include acute kidney injury, CKD, nephrolithiasis, rhabdomyolysis, Fanconi syndrome, and urothelial carcinoma. Several factors contribute to the nephrotoxicity of herbal medicines, including the intrinsic toxicity of herbs, incorrect processing or storage, adulteration, contamination by heavy metals, incorrect dosing, and interactions between herbal medicines and medications. The exact incidence of kidney injury due to nephrotoxic herbal medicine is not known. However, clinicians should consider herbal medicine use in patients with unexplained AKI or progressive CKD. In addition, exposure to herbal medicine containing aristolochic acid may increase risk for future uroepithelial cancers, and patients require appropriate postexposure screening.

A Call to Action to Develop Integrated Curricula in Cardiorenal Medicine.

With the adoption of the new definition and classification of cardiorenal syndrome (CRS) and its relevant subtypes, much attention has been placed on elucidating the mechanisms of heart and kidney interactions. The pathophysiologic pathways are of great interest by which acute heart failure may result in acute kidney injury (AKI; type 1), chronic heart failure accelerates the progression of chronic kidney disease (CKD; type 2), AKI provokes cardiac events (type 3), and CKD increases the risk and severity of cardiovascular disease (type 4). A remarkable interest has also been placed on the acute and chronic systemic conditions, such as sepsis and diabetes, that simultaneously affect heart and kidney function (type 5). Furthermore, the physiology of acute and chronic heart-kidney crosstalk is drawing attention to hemodynamics (fluids, pressures, flows, resistances, perfusion), physiochemical (electrolytes, pH, toxins) and biologic (inflammation, immune system activation, neurohormonal signals) processes. Common clinical scenarios call for recognition, knowledge, and skill in managing CRS. There is a clear need for medical and surgical specialists who are well versed in the pathophysiology and clinical manifestations that arise in the setting of CRS. With this editorial, we make a call to action to encourage universities, medical schools, and teaching hospitals to create a core curriculum for cardiorenal medicine to better equip the physicians of the future for these common, serious, and frequently fatal syndromes.

Folic Acid and Homocysteine in Chronic Kidney Disease and Cardiovascular Disease Progression: Which Comes First?

BACKGROUND: Hyperhomocysteinemia (Hhcy) occurs in about 85% of chronic kidney disease (CKD) patients because of impaired renal metabolism and reduced renal excretion. Folic acid (FA), the synthetic form of vitamin B9, is critical in the conversion of homocysteine (Hcy) to methionine. If there is not enough intake of FA, there is not enough conversion, and Hcy levels are raised. SUMMARY: Hhcy is regarded as an independent predictor of cardiovascular morbidity and mortality in end-stage renal disease. Hhcy exerts its pathogenic action on the main processes involved in the progression of vascular damage. Research has shown Hhcy suggests enhanced risks for inflammation and endothelial injury which lead to cardiovascular disease (CVD), stroke, and CKD. FA has also been shown to improve endothelial function without lowering Hcy, suggesting an alternative explanation for the effect of FA on endothelial function. Recently, the role of FA and Hhcy in CVD and in CKD progression was renewed in some randomized trials. KEY MESSAGES: In the general population and in CKD patients, it remains a topic of discussion whether any beneficial effects of FA therapy are to be referred to its direct effect or to a reduction of Hhcy. While waiting for the results of confirmatory trials, it is reasonable to consider FA with or without methylcobalamin supplementation as appropriate adjunctive therapy in patients with CKD.

Healthcare systems and chronic kidney disease: putting the patient in control.

Today, health policy seems to be on the top of governments' agendas around the world. Healthcare systems are challenged by a number of phenomena happening on a global scale; these trends include demographic change in terms of an ageing population, an increase in chronic disease, patients having higher expectations on healthcare delivery and above all a major pressure on public finances to slow increasing healthcare expenditures. Such developments are forcing policy-makers to reform healthcare systems. First, there is a tendency towards decentralization of responsibilities. Second, governments are moving towards reimbursement schemes rewarding good outcomes and performance. Third, great importance is being attributed to transparency and accountability, and to introduce competition in healthcare. Fourth, attention is being shifted from simple treatment of a disease towards preventive initiatives, in a more holistic approach to health. Finally, healthcare policy-makers are recognizing the importance of empowering patients to give them control over decisions regarding their own health. These dynamics can be observed in chronic kidney disease, the management of which is a huge economic burden to healthcare systems globally, and which represents a good example of a field where important changes can be witnessed in therapy, technology, delivery and financing.

The role of therapeutic plasma exchange in poisonings and intoxications.

Poisonings, intoxications, and drug overdoses are common occurrences and rapid lowering of the toxin level is a cornerstone of all effective therapies. Therapeutic plasma exchange (TPE) has several unique characteristics that allow it to be a potentially effective therapy in rapidly achieving this goal. Specifically, TPE allows for the removal of large molecular weight, protein-bound molecules that have a small volume of distribution. Due to the nature of poisonings, intoxications, and drug overdoses, no randomized controlled trials studying the efficacy of TPE in these situations exist. Thus, careful interpretation and analysis of case reports and series are required to assess the potential efficacy of this therapy. Recent data suggest that TPE may also be effective in the therapy of patients receiving biologic treatments who develop life-threatening complications due to therapy.

Mineral metabolism abnormalities and vitamin D receptor activation in cardiorenal syndromes.

Over the last decade, it has become increasingly clear that the cardiovascular and renal systems are interdependent. Primary disorders of either system have been shown to disturb the other system. As a result, a class of cardiorenal syndromes (CRS) has been identified wherein a vicious cycle is established as an acute/chronic dysfunction of either the kidney or the heart exacerbates the loss of function in the other organ. Progressive loss of kidney function observed in patients with CRS (mostly types 2 and 4) leads to reduced production of calcitriol (active vitamin D) and an imbalance in calcium and phosphorus levels, which are correlated with increased rates of cardiovascular events and mortality. In addition, hypocalcemia can lead to prolonged and excessive secretion of parathyroid hormone (PTH), eventually leading to development of secondary hyperparathyroidism. Therefore, based on this important mechanism of organ damage, one of the major goals of therapy for patients with CRS is to restore regulatory control of PTH. Although administration of calcitriol increases serum calcium levels and reduces PTH levels, it is also associated with elevated serum levels of calcium-phosphorus product. Therefore, compounds that selectively activate vitamin D receptors, potentially reducing calcium × phosphate toxicity, are likely to enhance cardiorenal protection and provide significant clinical benefit.

The impact of paricalcitol on left ventricular hypertrophy.

Cardiovascular (CV) morbidity and mortality are significantly higher in patients with chronic kidney disease (CKD). Mineral metabolism disorders, such as hyperphosphatemia, hypocalcemia, and vitamin D deficiency, have been deeply associated not only with bone disease, but also with vascular calcification and CV disease. In addition, the decrease in vitamin D production stimulates the renin-angiotensin-aldosterone system, resulting in vasoconstriction and salt and water retention, which further promotes arterial stiffening. Several studies have shown that supplementation with vitamin D ameliorates some of these issues and is associated with improved survival. However, vitamin D also elevates serum levels of calcium and phosphorus. Selective vitamin D receptor (VDR) activators, such as paricalcitol, provide similar efficacy but are not associated with elevated serum concentrations of calcium and phosphorus. By selectively activating VDR, paricalcitol should enhance cardiorenal protection and provide significant clinical benefit. Therefore, paricalcitol may offer a novel and interesting approach to supplement and potentially enhance the standard of care in CKD patients.

Metabolic and toxicological considerations for diuretic therapy in patients with acute heart failure.

INTRODUCTION: Diuretics are widely recommended in patients with acute heart failure (AHF). However, loop diuretics predispose patients to electrolyte imbalance and hypovolemia, which in turn leads to neurohormonal activation and worsening renal function (WRF). Unfortunately, despite their widespread use, limited data from randomized clinical trials are available to guide clinicians with the appropriate management of this diuretic therapy. AREAS COVERED: This review focuses on the current management of diuretic therapy and discusses data supporting the efficacy and safety of loop diuretics in patients with AHF. The authors consider the challenges in performing clinical trials of diuretics in AHF, and describe ongoing clinical trials designed to rigorously evaluate optimal diuretic use in this syndrome. The authors review the current evidence for diuretics and suggest hypothetical bases for their efficacy relying on the complex relationship among diuretics, neurohormonal activation, renal function, fluid and sodium management, and heart failure syndrome. EXPERT OPINION: Data from several large registries that evaluated diuretic therapy in hospitalized patients with AHF suggest that its efficacy is far from being universal. Further studies are warranted to determine whether high-dose diuretics are responsible for WRF and a higher rate of coexisting renal disease are instead markers of more severe heart failure. The authors believe that monitoring congestion during diuretic therapy in AHF would refine the current approach to AHF treatment. This would allow clinicians to identify high-risk patients and possibly reduce the incidence of complications secondary to fluid management strategies.

Prevention of acute kidney injury and protection of renal function in the intensive care unit. Expert opinion of the Working Group for Nephrology, ESICM.

BACKGROUND: Acute renal failure on the intensive care unit is associated with significant mortality and morbidity. OBJECTIVES: To determine recommendations for the prevention of acute kidney injury (AKI), focusing on the role of potential preventative maneuvers including volume expansion, diuretics, use of inotropes, vasopressors/vasodilators, hormonal interventions, nutrition, and extracorporeal techniques. METHOD: A systematic search of the literature was performed for studies using these potential protective agents in adult patients at risk for acute renal failure/kidney injury between 1966 and 2009. The following clinical conditions were considered: major surgery, critical illness, sepsis, shock, and use of potentially nephrotoxic drugs and radiocontrast media. Where possible the following endpoints were extracted: creatinine clearance, glomerular filtration rate, increase in serum creatinine, urine output, and markers of tubular injury. Clinical endpoints included the need for renal replacement therapy, length of stay, and mortality. Studies are graded according to the international Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) group system. CONCLUSIONS AND RECOMMENDATIONS: Several measures are recommended, though none carries grade 1A. We recommend prompt resuscitation of the circulation with special attention to providing adequate hydration whilst avoiding high-molecular-weight hydroxy-ethyl starch (HES) preparations, maintaining adequate blood pressure using vasopressors in vasodilatory shock. We suggest specific vasodilators [corrected] under strict hemodynamic control, sodium bicarbonate for emergency procedures administering contrast media, and periprocedural hemofiltration in severe chronic renal insufficiency undergoing coronary intervention. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00134-009-1678-y) contains supplementary material, which is available to authorized users.

Oxidative stress and anemia in chronic hemodialysis: the promise of bioreactive membranes.

Patients with advanced chronic kidney disease are characterized by an imbalance between pro- and antioxidant factors, and increased oxidative stress has been associated with complications of end-stage renal disease such as atherosclerosis, Beta2-microglobulin amyloidosis and anemia. Antioxidants such as vitamin E work by inhibiting LDL oxidation by oxidants and by limiting cellular response to oxidized LDL, and are potentially useful adjuncts to the usual medical therapy provided to such patients. In chronic hemodialysis (HD) patients, vitamin E therapy may be administered in the form of dietary supplementation, or as an integral part of the HD procedure in the form of bioreactive dialysis membranes, in which the blood surface has been modified with alpha-tocopherol. Since blood membrane interaction plays a key role in generating oxidative stress, direct free radical scavenging at the membrane site is a logical approach. Dialysis with vitamin E-coated membranes (VECM) is associated with an improvement in circulating biomarkers of lipid peroxidation. Other than antioxidant activity, the modified surface appears to render these dialyzers more biocompatible, in that cellulose-based membranes behave similar to synthetic dialyzers in terms of cytokine induction. In small studies in chromic HD patients, both dietary vitamin E supplementation as well as use of VECM have been associated with reduced RBC fragility, prolonged RBC lifespan, and improvements in hemoglobin and rHuEpo requirements. Newer VECM based on polysulfone bring us further down the road towards complete biocompatibility, and represent a promising therapy against oxidative stress in chronic HD patients.

Phosphate kinetics during different dialysis modalities.

BACKGROUND: An abnormal serum phosphate concentration is common in acute renal failure patients, with a reported incidence of 65-80%. Phosphate removal and kinetics during intermittent hemodialysis (IHD) have been investigated, but there is no information on its kinetics during slow low-efficiency dialysis (SLED) and continuous renal replacement therapy (CRRT). METHODS: Eight IHD, 8 SLED, and 10 continuous venovenous hemofiltration (CVVH) patients with a residual renal clearance of <4.0 ml/min were studied during a single treatment to evaluate phosphate removal and kinetics. CVVH was studied the first 24 h after initiation. Dialysis/replacement fluid contained no phosphate. Kt/V, clearance of urea (Ku), inorganic phosphate (Kp) and solute removal was determined by direct dialysate quantification (DDQ). RESULTS: Kp recorded with the three techniques were: IHD, 126.9 +/- 18.4 ml/min; SLED, 58.0 +/- 15.8 ml/min, and CVVH, 31.5 +/- 6.0 ml/min. However, in shorter dialysis treatment the total removal of phosphate was significantly lower than in longer dialysis (IHD, 29.9 +/- 7.7 mmol; SLED, 37.6 +/- 9.6 mmol; CVVH, 66.7 +/- 18.9 mmol, p = 0.001). The duration of treatment is the only factor determining phosphate removal (r = 0.7, p < 0.0001 by linear correlation model). Like IHD, phosphate kinetics during SLED could not be explained by the two-pool kinetic model, and the rebound of phosphate extended beyond 1 h after dialysis. Rebound, however, is less marked than in short dialysis. CONCLUSION: These results are reliable evidence about amount of phosphate removal and behavior of intradialytic phosphate kinetics in renal failure patients undergoing different dialysis modalities. These data will help clinicians plan phosphate supplementation and treatment intensity.

Mononuclear leukocyte apoptosis in haemodialysis patients: the role of cell thiols and vitamin E.

BACKGROUND: An increased apoptotic rate of peripheral blood mononuclear leukocytes (PBMLs) in haemodialysis (HD) patients has been reported in several studies, but its underlying mechanisms remain poorly understood. Oxidant stress is a well known cause of cell damage, and several lines of evidence suggest that it might influence the induction and signalling steps of mononuclear cell apoptosis through different mechanisms so as to provoke disturbances of the intracellular pool of thiols (SHi). In this study, we investigated the in vitro apoptotic rate and SHi of PBMLs in end-stage renal disease (ESRD) patients on HD or peritoneal dialysis (PD). METHODS: Apoptosis and SHi were evaluated in vitro in PBMLs obtained from 40 ESRD patients (HD, n = 30 and PD, n = 10) and 10 healthy controls. A subgroup of HD patients was also studied before and after 1 month of treatment with a vitamin E-coated dialyser (CL-E). Cell thiols and viability were also assessed in the monocyte-like cell line U937 and PBMLs after incubation in the presence of uraemic plasma with or without supplementation of the antioxidants vitamin E (70 micro M) or N-acetyl-cysteine (NAC) (0.5 mM). RESULTS: After 24 h in culture, the PBMLs of HD patients, but not those of CAPD patients, showed an apoptotic rate twice that of healthy controls and a 40% decrease of SHi levels (P < 0.01 in both). A negative correlation between the apoptotic rate and SHi was observed in both patients and controls (r = 0.648, P < 0.001). Plasma and ultrafiltrate samples from HD patients contained solutes (mainly in the low-middle molecular weight range) able to trigger apoptosis and oxidative stress in U937 cells. The treatment of HD patients with CL-E, as well as the in vitro supplementation of U937 cells with vitamin E or NAC during the exposure to uraemic plasma, decreased the rate of apoptosis and partially restored SHi. CONCLUSIONS: This study showed an association between an increased apoptotic rate and decreased SHi in PBML of HD patients, but not of CAPD patients. These changes are partially due to different pro-apoptogens that accumulate in the plasma and are at least partially prevented by exogenous antioxidants able to restore SHi, such as vitamin E or thiol suppliers.

How to feed patients with renal dysfunction.

Renal dysfunction is common in critically ill patients and its presence has, in the past, posed serious challenges to nutritional support. Such challenges were due to the increased azotemia induced by protein or amino acid administration, the fluid overload caused by the administration of nutrients, and the difficulties associated with the control of these complications by means of conventional dialytic techniques.The development and increasing application of continuous renal replacement therapy has removed such concerns, because control of azotemia and fluid balance can be predictably and reliably achieved in all patients. Accordingly, the presence of renal failure should in no way influence the amount or type of nutritional support administered to a critically ill patient. We recommend that approximately 30-35 kCal/kg/d be administered enterally and begun within the first few hours of admission to the intensive care unit, and that protein intake be kept in the 1.5-2 g/kg/d range.Accumulating evidence also suggest that immune-enhancing enteral preparations decrease the duration of hospital stay, the number of infections, and perhaps mortality. Such preparations should be used in these patients. Finally, adequate vitamin and trace element supplementation is recommended to counterbalance the decrease in antioxidants and the loss of some vitamins during continuous renal replacement therapy. Available evidence suggests that if these steps are applied as part of a protocol-based approach to the nutritional support of patients with renal failure, morbidity and perhaps mortality can be significantly decreased.