The Heart-Kidney, Kidney-Heart Connection and Our Improving Understanding of a Complex and Intimate Relationship

The AHA Scientific Statement on Cardiorenal Syndrome (CRS) provides the most comprehensive and up to date review of this complex set of disease states. There is no more difficult and frustrating disorder that cardiologists and nephrologists are routinely faced with both in the outpatient and inpatient setting then CRS. The authors should be proud that this publication which serves as a comprehensive statement on CRS with up to date terminology, nomenclature, and associated abbreviations clinicians to more effectively communicate with each other and speak the same language when treating affected patients and developing clinical trials. What is also clear from this paper and what the authors deliver as we address CRS is the understanding deficit among clinical cardiologists on the important nuances of renal physiology, pathophysiology, and perhaps a similar understanding deficit among nephrologists on the nuances of cardiac pathophysiology. Clearly, without this marriage of understanding, the patient will not be treated optimally and innovation will be handicapped. Both cardiology and nephrology fellowship training programs should focus as partners in mastering this disease state.

One of the important accomplishments of Writing Committee is to expand upon the cardiorenal disease state into two major groups based on the primum movens, cardio-renal and reno-cardiac syndromes then also taking into account the acute and chronic presentations and dividing them into five distinct “phenotypes”. These five phenotypes have distinct primary organ involvement, pathophysiologies, and treatment strategies.

What this Statement has succeeded in is in putting the many pieces of the CRS puzzle together based on the current state of knowledge. A plethora of potential valuable diagnostic tools including biomarkers that can assist in the diagnosis, prognosis and treatment are described in detail. There remains a gap in translating many of these proven markers into routine clinical use. Tailored studies investigating their clinical use and subsequent algorithms will need to be developed for each of these five CRS phenotypes to optimize their application.

Agreeing to terms to describe this complex disease state will enhance our ability as clinicians to communicate among ourselves and will be an important result of this statement. Development of consistent terminology to characterize progressive decline of the cardiac or renal system as a result of the other will create a platform to facilitate meaningful clinical discussion. This continuum of term evolution can be a problem in that it creates confusion among clinicians in terms of their confidence that they are discussing the same disease state.

Mechanistically, the conventional understanding of how acute HF can lead to acute kidney injury (CRS type 1) has previously been attributed to poor cardiac output causing diminished blood flow to the kidneys. However, other causes are at play; this includes pre-glomerular vasoconstriction in the setting of upregulation of the renal-angiotensin-aldosterone system. In addition, elevated central venous pressure imposes increased renal venous hypertension, decreasing blood flow across the circuit from the renal artery¹. Furthermore, beyond hemodynamics, pathways including inflammation, nitric oxide, and ischemia are likely involved in the interplay between the failing heart and kidneys².

Rangaswami et al. detail the use of biomarkers to understand CRS beyond simply measuring urine output and serum creatinine. In fact, the use of blood markers including cystatin C, neutrophil gelatinase associated lipocalin (NGAL), and other tubular biomarkers have been shown to be highly prognostic of adverse outcomes in patients with CRS³. Beyond renal biomarkers, commonly associated cardiac biomarkers of fibrosis and matrix deposition such as galectin-3 and suppressor of tumorigenicity 2 (ST2) are similarly associated with poor outcomes. However, the use of measuring concentrations of these novel markers primarily has a role in prognostication; future steps include their use to understand mechanisms at play and guide management.

Patient volume status is not always easily discerned and fluctuations are mechanistically contributory to the worsening of CRS. Non-invasive tools such as echocardiography and bio impedance vector analysis (BIVA) can complement our real-time assessment of volume status⁴. Invasive approaches using pulmonary artery catheterization or implantable pulmonary artery sensor monitors (CardioMEMS Heart Sensor) can provide accurate real-time and remote estimation of filling pressures⁵. The collection of these data is meaningful when they can guide therapy to improve outcomes. Importantly, congestion and hypervolemia are commonly seen in acute HF and diuretics are part of the mainstay in management. We have learned through the DOSE (Diuretic Optimization Strategies Evaluation in Acute Heart Failure) trial that intermittent versus continuous dosing of loop diuretics does not impact the incidence of CRS⁶. Importantly, we also learned from the ESCAPE (Evaluation Study of Congestive heArt failure and Pulmonary artery catheterization Effectiveness) trial that a poor response of urine output to a set diuretic dose (i.e. diuretic inefficiency) is associated with poor outcomes⁷. Investigators have tried to capture the use of ultrafiltration (UF) as a strategy for decongestion in patients with or at risk for CRS. There have been mixed results with the UNLOAD (Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure) trial demonstrating a reduction in long-term rehospitalization while the CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) trial demonstrating no clinical gain by utilizing UF in acute HF^{8, 9}. Admittedly, we continue to utilize diuretics as a primary approach for symptom-relief in patients with congestion; however, their effects on neurohormonal activation and renal and systemic hemodynamics are not completely understood.

Therapies targeted to reduce morbidity and mortality in patients with chronic HF have varying impact on renal function. Overall, therapies which promote Renin Angiotensin Aldosterone System (RAAS) inhibition such as ACE inhibitors are largely beneficial in clinical scenarios associated with worsening renal function, with the trade-off of slight elevations of serum creatinine concentration¹⁰. Similarly, the addition of neprilysin inhibition to RAAS inhibition through novel therapies such as angiotensin receptor neprilysin inhibitors (ARNI) are also largely renally-protective, as long as tolerated by the patient¹¹. There has been much excitement recently in the advancement of therapies for patients with diabetes mellitus given trial findings studying the use of sodium glucose co-transporter 2 inhibitors (SGLT-2i)¹². Post-hoc analyses of trials which were primarily designed to decrease composite cardiovascular outcomes have also shown reduction in progression of renal disease¹³. Similarly, glucagon like peptide-1 (GLP-1) agonists have also shown promise by reducing new-onset persistent macro-albuminuria and the development of end-stage kidney disease in patients with type 2 diabetes mellitus and elevated CV risk¹⁴.

The primary therapy for end stage heart or kidney disease remains organ transplantation. The use of mechanical circulatory support (MCS) as a bridge to transplant strategy continues to rise; however the direct impact on renal function of these tools has not been examined in large studies. The development of de novo HF after kidney transplantation remains high, with a near 15% incidence of HF within 3 years of kidney transplant¹⁵. Once HF develops after kidney transplant, standard HF therapies are often used. However, they are not as vigorously studied in this unique patient population.

Cardio-renal medicine as its own subspecialty remains in its infancy. We are still early in our ability to wholly explain, quantify, and phenotype CRS. The Scientific Statement provides a comprehensive review of the current literature on CRS and future steps to improving our understanding. Figure 1 demonstrates a framework for the clinician to approach CRS. Future steps to improve our understanding of CRS will include defining specific clinical trial endpoints that emphasize clinically relevant adverse renal events, such Major Adverse Renal Cardiovascular Events (MARCE) and Major Adverse Kidney Events (MAKE). Beyond this, dedicated clinical investigators (both cardiologists and nephrologists) with vested interests in improving our understanding of CRS remain critical to ultimately reduce the dual burden of cardiovascular and renal disease.

Figure 1: