So-called Cardiorenal Syndrome Research Articles

Acute kidney injury in acute decompensated heart failure related cardiogenic shock: data from the Alt-Shock2 registry

Abstract Funding Acknowledgements None. Background Acute kidney injury (AKI) is one of the most common complications in patients with cardiogenic shock (CS), proving the strict relationship between heart and kidney (the so-called cardio-renal syndrome). AKI is a marker of shock severity, but also independently associated with worse outcomes. Purpose Many data are available on the prevalence of AKI in acute heart failure, but very few studies assessed the role of AKI in CS and they were mainly focused on acute myocardial infarction (AMI)-related CS. Aim of our study was to analyze the impact of AKI on acute decompensated heart failure (ADHF)-CS. Methods Between March 2020 and August 2022, we prospectively enrolled 375 CS patients from a Cardiac Intensive Care Units Network of 12 centers. Among these patients 121 (33.9% of the whole cohort) with ADHF-CS were included for the present analysis. AKI was defined according to KDIGO 2012 criteria as serum creatinine increase ≥ 0.3 mg/dl or 1.5 times compared to admission value, or urinary output < 0.5 ml/kg/h. Results Table 1 shows the baseline characteristics of the cohort. Patients with AKI were older (70 years old [55.5; 76] vs 61 [54; 69], p<0.05), had more comorbidities and a worse CS profile on admission. On multivariable analysis, SCAI stage D-E on admission was independently associated with a higher risk of AKI 24 hours after admission (OR 5.54 and p = 0.01). Treatment with mechanical circulatory support did not prevent AKI (OR 0.84 and p = 0.8). Notably, patients with a greater reduction in central venous pressure (CVP) 24 hours after admission had a lower risk of AKI (deltaCVP in AKI group 0 [-3;0] versus deltaCVP in no-AKI group -3 [-6;0], p = 0.025). Kaplan-Meier curves showed significantly worse survival in patients with AKI (Figure 1A). Cox regression analysis confirmed an association between AKI and increased risk of death (HR 2.14, CI 95% 1.16-3.96, p = 0.01). Notably, this association was even more pronounced in patients with SCAI stages A-B-C (HR 2.81, CI 95% 1.30-6.09, p = 0.01). Finally, in patients treated with renal replacement therapy (RRT) there was no association with lower survival at 180-days follow up (Figure 1B). Conclusions Our study confirms that AKI is a predictor of adverse outcomes in patients with ADHF-CS. Effective decongestion 24 hours after admission was associated with a lower risk of AKI. Considering that AKI had a negative impact even at lower SCAI stages, our findings underscore the importance of early identification of renal injury to promptly target decongestion with pharmacologic therapy and, ultimately, early use of RRT.

Mitochondrial Dysfunction in the Cardio-Renal Axis.

Cardiovascular disease (CVD) frequently complicates chronic kidney disease (CKD). The risk of all-cause mortality increases from 20% to 500% in patients who suffer both conditions; this is referred to as the so-called cardio-renal syndrome (CRS). Preclinical studies have described the key role of mitochondrial dysfunction in cardiovascular and renal diseases, suggesting that maintaining mitochondrial homeostasis is a promising therapeutic strategy for CRS. In this review, we explore the malfunction of mitochondrial homeostasis (mitochondrial biogenesis, dynamics, oxidative stress, and mitophagy) and how it contributes to the development and progression of the main vascular pathologies that could be affected by kidney injury and vice versa, and how this knowledge may guide the development of novel therapeutic strategies in CRS.

Effect of COVID-19 on cardiorenal axis: known or unknown universe?

Recent findings have confirmed relationships between coronavirus disease (COVID-19) and multiple organ dysfunction. The prevalence of cardiac and renal involvement in COVID-19 has been increasingly reported and is a marker of severe disease that not only directly or indirectly affects the organs, but may also exacerbate the underlying comorbid illness. In addition, patients affected by the new coronavirus present a systemic inflammatory condition that results in damage to several tissues, especially the heart, kidneys, and vessels. It is well known that the heart and kidneys are closely related, so that any change in one of the organs can lead to damage to the other, establishing the so-called cardiorenal syndrome. Herein, we explore some case reports of patients with COVID-19 who had heart and kidney abnormalities, consequently resulting in worse prognosis of the disease. These results highlight the importance of understanding the cause and effect between the cardiac and renal systems and the course of early SARS-CoV-2 infection.

Tyrosine and Tryptophan vibrational bands as markers of kidney injury: a renocardiac syndrome induced by renal ischemia and reperfusion study

Renal injury caused by renal ischemia and reperfusion strongly influences heart morphology, electrophysiology, and redox unbalance. The so-called cardiorenal syndrome is an important class of dysfunction since heart and kidneys are responsible for hemodynamic stability and organ perfusion through a complex network. In the present work we investigate the vibrational spectral features probed by Fourier-Transform Raman (FT-Raman) spectroscopy due to physiological alterations induced by renal ischemic reperfusion aiming to detect molecular markers related to progression of acute to chronic kidney injury and mortality predictors as well. C57BL/6J mice were subjected to unilateral occlusion of the renal pedicle for 60 min and reperfusion for 5, 8, and 15 days. Biopsies of heart and kidney tissues were analyzed. Our findings indicated that cysteine/cystine, fatty acids, methyl groups of Collagen, α-form of proteins, Tyrosine, and Tryptophan were modulated during renal ischemia and reperfusion process. These changes are consistent with fibroblast growth factors and Collagen III contents changes. Interestingly, Tyrosine and Tryptophan, precursor molecules for the formation of uremic toxins such as indoxyl sulfate and p-cresyl sulfate were also modulated. They are markers of kidney injury and their increase is strongly correlated to cardiovascular mortality. Regarding this aspect, we notice that monitoring the Tyrosine and Tryptophan bands at 1558, 1616, and 1625 cm−1 is a viable and and advantageous way to predict fatality in cardiovascular diseases both “in vivo” or “in vitro”, using the real-time, multiplexing, and minimally invasive advantages of FT-Raman spectroscopy.

The effect of the drug “Bendamin” on the biochemical parameters of the blood of dogs in heart failure

Experimental studies obtained in recent years indicate the urgency of developing drugs of complex action to prevent the development of cardiovascular disease in dogs. This requires a much deeper study of the pathogenesis of heart failure, including cardiomyopathy. The aim of the study was to investigate the effect of the drug “Bendamin” on the biochemical parameters of the blood of dogs in heart failure. Two groups of dogs were formed for research: control (healthy) and experimental (sick). The 30-day experiment included 10 dogs of the control group and 10 dogs of the experimental (sick) breed of spaniel and dog 10–12 years of age. Treatment regimen for sick dogs: furosemide was administered orally on an empty stomach at 2 mg/kg every 12 hours; enalapril was administered orally at 0.5 mg/kg every 12 hours; bendamine was administered orally on an empty stomach at 20 mg/kg every 24 hours. It is recommended to divide the dose into two doses. An increase in the activity of aminotransferases (ALT by 59.2 %, AST – by 51.9 %) was found in the serum of dogs at heart failure. An increase in alkaline phosphatase activity was also found, which in the complex is an additional confirmation of changes in the heart muscle. Lactate dehydrogenase activity increased in the blood of sick dogs by 23.5 %. Minor changes in the content of total bilirubin and urea in the serum of sick dogs indicate the initial stage of liver pathology with impaired liver function due to congestion in the small circulation. This is also indicated by a decrease in the level of total protein in the blood of sick dogs, which was respectively 57.2 ± 3.57 g/l against the control group of 63.5 ± 4.15 g/l. On the basis of cardiac dysfunction and on the background of congestion, the function of not only the liver but also the kidneys is impaired (the so-called cardiorenal syndrome in heart failure). This is indicated by an increase in urea and creatinine by 38.5 and 36.9 %, respectively, compared with animals in the control group. The use of the drug “Bendamin” alleviated the manifestations of functional failure of the heart, liver and kidneys, as indicated by biochemical studies. Studies confirm the feasibility of using the drug “Bendamin” in dogs with the development of heart failure. The use of the drug “Bendamine” in patients with heart failure in dogs had a positive effect on the restoration of hematopoiesis and the normalization of biochemical parameters of the blood.

Resistencia diurética e insuficiencia cardiaca: entre la congestión y la disfunción renal

La Insuficiencia Cardiaca (IC), uno de los principales contribuyentes de la mortalidad cardiovascular en la actualidad, nos enfrenta a grandes retos. La interacción riñón corazón tiene particular atención por el desarrollo del denominado síndrome cardiorenal (SCR) y con este, la resistencia a los diuréticos (RD), predictor de eventos adversos en IC aguda independiente de la tasa de filtrado glomerular (TFG). Su desarrollo es secundario a múltiples causas, por lo que se requiere una evaluación integral de todas ellos. En los últimos años ha tomado relevancia la congestión dentro del mecanismo fisiopatológico del SCR, por generar y perpetuar mutuamente el daño en estos dos órganos. Ante la importancia de la congestión, los diuréticos se mantienen como clave para el tratamiento, aunque su empleo ampliamente es empírico por la escasa evidencia disponible. El paradigma del tratamiento basado en evidencia, es esquivo en este escenario, por lo que una pregunta permanece sin respuesta ¿intervenciones para tratar la RD o para prevenirla modifican el pronóstico en IC aguda?

Cardiorenal syndrome type 2: from diagnosis to optimal management

The deterioration of renal function, which is linked to chronic heart failure by a chronological and causal relationship (ie, the so-called cardiorenal syndrome [CRS] type 2), has recently become a matter of growing debate. This debate has concerned the efficacy, safety, and cost effectiveness of the therapies that have been implemented thus far for this syndrome (for example, the intravenous [IV] loop diuretics, such as repeated IV boluses or slow IV infusions, as well as mechanical fluid removal, particularly by means of isolated ultrafiltration [IUF]). Further controversies have also emerged concerning the optimal dosage and timing of some evidence-based drugs, such as angiotensin-converting-enzyme inhibitors. The present review summarizes the currently used diagnostic tools for detecting renal damage in CRS type 2. Subsequently, the meaning of worsening renal function is outlined, as well as the sometimes inconsistent therapeutic schemes that have been implemented in order to prevent or counteract worsening renal function. The need to elaborate upon more detailed and comprehensive scientific recommendations for targeted prevention and/or therapy of CRS type 2 is also underlined. The measures usually adopted (such as the more accurate modulation of loop diuretic dose, combined with the exploitation of other diuretics that are able to achieve a sequential blockade of the nephron, as well as the use of IV administration for loop diuretics) are briefly presented. The concept of diuretic resistance is illustrated, along with the paramount operational principles of IUF in diuretic-resistant patients. Some controversies regarding the comparison of IUF with stepped diuretic therapy in patients with CRS type 2 are also addressed.

Quantifying the effect of cardiorenal syndrome on mortality after left ventricular assist device implant

Comorbidities complicate recovery and contribute to mortality after implant of a left ventricular assist device (LVAD). Coexistent cardiac and renal dysfunction (so-called cardiorenal syndrome) increases the risk of death, both with advanced heart failure and after LVAD implantation. We analyzed patients from the Interagency Registry for Mechanically Assist Circulatory Support to better estimate postimplant mortality according to the severity of renal dysfunction. Patients with a continuous-flow LVAD were grouped according to their pre-implant level of renal dysfunction: severe was defined as dialysis and/or estimated glomerular filtration rate (eGFR) < 30 ml/min; moderate if eGFR was 30 to 59 ml/min or blood urea nitrogen (BUN) was > 60 mg/dl; and mild or no renal dysfunction if eGFR was ≥ 60 ml/min and BUN was < 60 mg/dl. Of the 4,917 patients with a continuous-flow LVAD implanted between June 2006 and March 2012, 3,160 (64%) were identified with mild or no renal dysfunction, 1,475 (30%) with moderate dysfunction, and 282 (6%) with severe dysfunction. Worsening renal dysfunction correlated with decreased survival, with nearly a 20% reduction in the 2-year survival going from low to severe dysfunction. The major negative survival effect occurred during the first 3 months. Combination of severe renal dysfunction and cardiogenic shock predicted the highest early mortality. Pre-implant renal dysfunction predicts higher mortality after LVAD implant. The progressive reduction in survival with higher grades of renal dysfunction supports consideration of LVAD implant before cardiorenal syndrome is advanced. For patients with severe renal dysfunction and other major comorbidities, initial support with a temporary device while awaiting organ recovery before implanting a durable pump could be considered.

The cardiorenal syndrome in heart failure: cardiac? renal? syndrome?

There has been increasing interest on the so-called cardiorenal syndrome (CRS), defined as a complex pathophysiological disorder of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction in the other. In this review, we contend that there is lack of evidence warranting the adoption of a specific clinical construct such as the CRS within the heart failure (HF) syndrome by demonstrating that: (a) the approaches and tools regarding the definition of kidney involvement in HF are suboptimal; (b) development of renal failure in HF is often confounded by age, hypertension, and diabetes; (c) worsening of renal function (WRF) in HF may be largely independent of alterations in cardiac function; (d) the bidirectional association between HF and renal failure is not unique and represents one of the several such associations encountered in HF; and (e) inflammation is a common denominator for HF and associated noncardiac morbidities. Based on these arguments, we believe that dissecting one of the multiple bidirectional associations in HF and constructing the so-called cardiorenal syndrome is not justified pathophysiologically. Fully understanding of all morbid associations and not only the cardiorenal is of great significance for the clinician who is caring for the patient with HF.

Cardiorenal Syndrome in Acute Decompensated Heart Failure

Renal dysfunction is highly prevalent in patients with heart failure. Furthermore, worsening renal function in patients with acute decompensated heart failure (ADHF), the so-called cardiorenal syndrome, impacts short and long-term morbidity and mortality. In recent years, more evidence has surfaced from clinical trials and heart failure registries that a complex cross-talk between the kidney and heart in patients with ADHF exists. Meanwhile, management of patients presenting with ADHF and concomitant renal dysfunction continues to be challenging. Therefore, understanding the interaction of the heart and kidneys is pivotal in tailoring therapy of these patients. We have extensively reviewed the pathophysiology of ADHF, the role of neurohoromones as well as other biomarkers and predictors of mortality in these patients based on the current evidence. Moreover, we have discussed the current and future pharmacologic and non-pharmacologic therapies for treatment of this deadly disease. The strength of the evidence is limited, however, due to a paucity of randomized controlled trials in this patient population. What is evident from current national statistics; however, are the poor results in treating the congestion of ADHF. In this regard, the role of secondary hyperaldosteronism is discussed in the diuretic section as well as diuretic resistance in ADHF. In conclusion, since renal function is the single most important prognostic factor in the outcome of patients with ADHF, a better understanding of the pathophysiology of the cardiorenal syndrome is needed to target therapy and ultimately improve the mortality of patients with ADHF.

Abstract 5120: Cardiac Sympathetic Nerve Activity is Associated With the Progression of Cardiorenal Syndrome in Patients With Chronic Heart Failure: 10-Year Follow up Study

Background : Chronic heart failure (CHF) and renal dysfunction (RD) frequently coexist. Cardiac sympathetic nerve activity (CSNA) influences the clinical outcomes in CHF patients (pts), but there is no information available on the relation between CSNA and RD in CHF pts, so-called cardiorenal syndrome (CRS). Methods : We studied 101 CHF patients with left ventricular ejection fraction (LVEF) &lt; 40%. At the entry, I-123 MIBG imaging was performed, and washout rate (WR) was calculated from the chest anterior view images obtained at 20 and 200 min after isotope injection. Every year, estimated Glomerular Filtration Rate (GFR) by the MDRD equation was obtained in each patient. Results : GFR at the entry was significantly lower in pts with (n=49) than without abnormal WR (n=52) (more than 27%: the mean control WR +2SD) (59±18 vs 67±19 ml/min/1.73m 2 , p=0.029). With a mean follow-up of 7.3±3.5 yrs, GFR decreased from 64±19 to 50±21 ml/min/1.73m 2 , the median value of GFR depression rate (GFRdep) was 3.5%/year, and 31 of 101 pts died of cardiac death. GFRdep was also significantly greater in pts with than without abnormal WR (8.2 vs 2.5%/year, p&lt;0.01). There were no significant differences in gender, age, NYHA class, LVEF, or the content of anti-heart failure therapy between pts with and without WR≥27%. Cardiac death was significantly more frequently observed in pts with than without GFRdep≥3.5%/year (44 vs 16%, p&lt;0.01). The odds ratio of greater GFRdep for cardiac death was 3.8 (95%CI 1.7 to 8.5). Conclusion: In CHF pts, CSNA would be associated with the progression of RD. Furthermore, progression of RD had poor clinical outcome. Thus, CSNA might play an important role in the progression of CRS in CHF pts.

„Cross-talk“ zwischen Herz und Niere – das Kardiorenale Syndrom und seine Therapie aus der Sicht des Nephrologen

Renal dysfunction represents a frequent comorbidity in patients with in chronic heart failure and is not only a strong predictor of mortality, but also causally linked to the development and progression of CHF. Mechanisms involved in the cross-talk between the kidney and the heart include the up-regulated sympathetic nerve system, activation of the renin-angiotensin-aldosterone system, vasopressin release and decreased activity of arterial baroreceptors and natriuretic peptides resulting in abnormal salt and water retention. The main therapeutic goals for patients with the so-called cardiorenal syndrome is the normalization of volume status while avoiding overdiuresis and renal dysfunction as well as the implementation of an evidence-based pharmacologic treatment to improve patient outcome. If these two goals are not achieved with conventional therapy, renal replacement therapy should be discussed in an interdisciplinary approach. All current renal replacement techniques have proved to be useful in controlling hypervolemia and ameliorating functional cardiac parameters and quality of life in patients with heart failure. Nevertheless, the influence of renal replacement therapy on long-term survival of affected patients has not been addressed in large controlled studies.

Cardiorenal syndrome in heart failure: A cardiologist's perspective

One of the most important comorbidities in heart failure is renal dysfunction. Diminished estimated glomerular filtration rate is a potent predictor of cardiovascular mortality and complications. On the other hand, worsening heart failure or acute decompensated heart failure can accelerate worsening of renal function--the so-called cardiorenal syndrome. Risk factors include hypertension, diabetes, elderly age, and prior history of heart or renal failure. The pathophysiology of the cardiorenal syndrome involves intrarenal hemodynamics, transrenal perfusion pressure and systemic neurohormonal factors. Clinical management of the patient with cardiorenal syndrome includes the challenge of diuretic resistance, which may involve correcting the underlying cause, combination diuretics or diuretic infusions. The key to improved outcome is the optimization of proven heart failure therapies. The use of vasodilator therapy is the current mainstay of treatment. Nesiritide, or recombinant B-type natriuretic peptide, has courted controversy regarding its role in cardiorenal syndrome. However, data are emerging that low doses appear to be renal-protective. Other more recent strategies include ultrafiltration, vasopressin antagonists and adenosine antagonists. All of these newer modalities promise more rapid volume removal, but their ultimate impact on survival or preservation of renal function is unknown at the present time. Because of the complex nature of these patients, and the compromised outcome, it is important that cardiologists, nephrologists and internists all work together toward the common goal of protecting the patient with cardiorenal syndrome, and use the best available evidence for management.

Recognition and treatment of anemia in the setting of heart failure due to systolic left ventricular dysfunction

Anemia is increasingly recognized as a common, important and treatable condition in patients with congestive heart failure. Despite increasing knowledge of anemia, as well as its coassociation with chronic renal disease, advanced New York Heart Association class and worse prognosis, there are very few evidence-based recommendations for treatment. The use of supplemental iron, especially intravenous forms, for the treatment of iron-deficiency anemia in heart failure patients is associated with improved symptoms, cardiac size and function, and possibly improved outcomes. However, many patients with heart failure suffer from anemia due to other causes, including renal failure (so-called cardiorenal syndrome), erythropoietin resistance, possible ACE inhibitor use and extracellular fluid expansion. The association between anemia and adequate iron stores has led to interest in the use of erythrocyte-stimulating agents, such as erythropoietin and darbepoetin. While early data are promising, recent evidence in non-heart failure trials has led to caution in their use and given way to anticipation of results of ongoing definitive randomized trials of this therapy, such as the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) and Reduction of Events with Darbepoetin-α in Heart Failure (RED-HF) studies.

Etiology and Management of Anemia in Patients With Heart Failure: How Much Iron Is Missing?

Anemia is common among patients with heart failure (HF) and has been associated with worse prognosis. To date, it is not well known whether correction of anemia in these patients can improve outcome. Proposed modalities for correction of anemia have been either administration of erythropoiesis-stimulating proteins, which appears plausible in patients with concomitant renal failure (so-called cardiorenal syndrome), or iron supplementation, which is particularly attractive in patients with no overt renal failure and chronic disease anemia with some degree of iron deficiency. This article reviews the rationale for anemia correction and the latest randomized clinical trial assessing clinical utility of erythropoiesis-stimulating proteins and/or iron supplementation through oral or intravenous administration in anemic HF patients.

Anaemia as a contributor to morbidity and mortality in congestive heart failure

Anaemia is present in approximately 40% of cases of congestive heart failure (CHF) and is associated with a higher mortality, a lower left ventricular ejection fraction, a lower cardiac functional status, a higher rate of hospitalization, signs of malnutrition, a lower exercise capacity, a progressive fall in renal function, an increased need for high dose diuretics, hyponatraemia, an increased plasma volume, a reduced red cell volume and a lower quality of life. In both uncontrolled and controlled studies, correction of the anaemia with subcutaneous erythropoietin and, in some cases, with the addition of intravenous iron, has been shown to improve these parameters. A vicious circle is present between CHF, chronic kidney insufficiency (CKI) and anaemia, each capable of causing or being caused by the other, the so-called cardio renal syndrome. If larger randomized, controlled, double-blind studies confirm these observations, correction of the anaemia may prove to be a useful addition to the prevention and progression of both CHF and CKI. Cooperation between nephrologists, cardiologists and other internists to identify and treat these anaemic CHF patients early will help prevent progression of both the cardiac and renal disease.

Beware the rising creatinine level

In this issue of the Journal, Smith and colleagues report their findings that demonstrate increases in serum creatinine levels during heart failure hospitalization are associated with worsened outcomes after hospital discharge. The authors conducted a cohort study of 412 patients hospitalized at their institution over a 30-month period who survived to discharge. The change in serum creatinine level (Cr) was defined simply as the difference between the baseline and discharge levels, with “worsened renal function” defined as a Cr 0.1mg/dL. The outcomes examined in this study were survival, readmission, and change in functional status during the 6 months after hospitalization. A Cr 0.3mg/dL was associated with a 60% increased adjusted mortality risk, and surprisingly the Cr was a stronger mortality predictor than the baseline creatinine level. Furthermore, the higher mortality risk associated with Cr 0.3mg/dL was similar at all levels of baseline creatinine level. These findings build upon prior studies that have determined the importance of renal function in the prognosis and management of heart failure. Most previous analyses evaluating the effect of renal function on heart failure outcomes have used a baseline measure from the outpatient setting. 1 A prior study from this group of authors similarly found elevations of creatinine 0.3 mg/dL during heart failure hospitalization to be associated with greater inhospital length of stay and mortality risk. The current study extends these findings by demonstrating an association of increased Cr with worse outcomes for survivors of hospitalization up to 6 months after discharge, and showing a dose-dependent relationship of Cr and increased mortality risk. However, as with most interesting studies, this analysis provokes as many questions as it answers for clinicians managing heart failure patients. The primary questions that arise from this study are: (1) Can the Cr be interpreted as a “diagnostic test” for high mortality risk? (2) Is worsened renal function a causal mechanism leading to increased mortality risk or a marker of poor cardiac function and subsequent under-treatment? and (3) What are the clinical implications of these findings for inpatient and postdischarge heart failure management?