Cardiorenal Nexus: A Review With Focus On Combined Chronic Heart And Kidney Failure, And Insights From Recent Clinical Trials

PATHOPHYSIOLOGY 

The cardiorenal syndromes develop along an inter-linked pathophysiological trajectory (Figure).1–3 In the type 2 syndrome, the presence of long-term cardiac dysfunction and the associated chronic adaptations to reduced cardiac output and flow rate and raised venous pressure lead to chronic renal hypoperfusion. In response, there is a chronic compensatory activation of both the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system. Angiotensin promotes vasoconstriction and an increase in blood volume resulting from aldosterone-triggered sodium and water retention. Excess aldosterone can stimulate maladaptive interstitial fibrosis and contribute to the development and progression of CVD and CKD.35 Differences in rebound after acute decompensation in patients with chronic HF are likely due to the status of the renal parenchyma and the overall function of remnant intact or hyper filtering nephrons— there is a discrepancy between current GFR measurement or estimation and the effective GFR achievable (also called renal functional reserve), which is not routinely measured in patients.36 Chronic cardiorenal syndromes in individuals with HF with preserved ejection fraction involve the sequelae of systemic inflammation, elevated central venous pressure, and endothelial, diastolic, and right ventricular dysfunction.37

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Reduction in renal blood flow, if sufficiently severe, will result in a decreasing GFR. Renal function decline leads to cardiac function decreases driven by progressive cardiac sodium and water overload, calcium and potassium abnormalities, and CKD-related anemia. Development of chronicity can occur in the setting in which acute kidney injury, induced by acute HF, accelerates cardiovascular pathophysiology via inflammatory pathway activation. In a renal ultrasonography study in patients with chronic HF (n=68), individuals with a renal Doppler pulsatile index above the median had a worsening of CKD stage after 6 months as compared with those with a lower pulsatile index.38 Pulsatile index—an indicator of downstream renal artery resistance and stiffness—was an independent predictor of change in eGFR.38 The results suggest that renal pulse pressure rises in chronic HF because of increased arterial stiffness, resulting in an increase in renal vascular resistance and a decrease in renal blood flow and GFR.38

In the type 4 syndrome, CKD-related anemia, electrolyte imbalances, increases in uremic toxins, chronic inflammation, and oxidative stress lead to cardiac and vascular dysfunction.1–3 With progressively declining kidney function, phosphate retention increases, and phosphate homeostasis is disrupted despite elevated levels of FGF23 (fibroblast growth factor 23) and parathyroid hormone.39 The increase in FGF23 levels and hyperphosphatemia trigger pathways that promote hypertension, left ventricular hypertrophy, and vascular calcification, contributing to CVD progression.39 Progression of CKD is often due to underlying diabetes and/or hypertension. Chronic renal dysfunction is linked with disruption of erythropoietin signaling and red blood cell turnover, leading to anemia, which is an important comorbidity of CKD and HF.40 Cachexia is common in individuals with chronic cardiorenal syndromes and may augment the pathophysiological interaction between the heart and kidneys via immune, neuroendocrine, and proinflammatory pathways.41

Right HF and hemodynamic dysfunction from pulmonary hypertension may also lead to the development of chronic cardiorenal syndromes as well as contribute to the progression of CKD.42,43 In patients with end-stage CKD on hemodialysis, the arteriovenous fistula required for access can cause excessive pulmonary blood flow, leading to a preload increase on the right heart and pulmonary hypertension.43,44

Type 2 diabetes is a common underlying causal factor in HF and CKD. In addition to its link with endothelial dysfunction and atherosclerotic vascular disease, type 2 diabetes is also associated with glomerular hyperfiltration and volume expansion, and tubuloglomerular feedback disruptions.45 The vascular theory of type 2 diabetes describes dysregulation of vasoactive factors and inactivation of tubuloglomerular feedback in type 2 diabetes, which lead to dilation of the renal afferent arteriole and constriction of the efferent arterioles, thereby resulting in glomerular hypertension and hyperfiltration.46

PATIENT CARE

The interlinked pathophysiology between the heart and the kidneys in the cardiorenal syndromes requires a holistic, comprehensive approach to management. There is a need for both primary and secondary prevention of adverse outcomes in patients with CVD, CKD, type 2 diabetes, and HF. CKD and chronic HF deteriorate progressively and need to be managed proactively. In addition, the risk of evolution of an acute condition to chronicity requires prompt identification of at-risk patients and implementation of preventative measures. It is crucial that leading risk factors such as hypertension and diabetes, and important comorbidities such as anemia, are managed. Patient–physician communication is an important part of care. Care planning includes management decisions around the often high symptom burden, which includes fatigue, chronic pain, and depression.3

Figure 1. Flow diagram showing the interplay of cardiovascular and renal systems in chronic kidney disease and cardiovascular disease. RAAS indicates renin–angiotensin–aldosterone

Optimal management first requires screening and early disease recognition. Patients with HF, as well as those with earlier forms of CKD who have proteinuria but preserved GFR, need to be identified in routine clinical care. However, the rate of screening of at-risk populations by routine testing (eg, by annual UACR assessment) is low (35%–57%) in primary care,42,47 highlighting the need for increased awareness of the cardiorenal nexus in the primary care setting. The UACR is now positioned as an important trigger for lower systolic blood pressure targets of 120 mm Hg or below according to the 2021 Kidney Disease Improving Global Outcomes guideline.48 Once identified, the complexity of chronic cardiorenal syndromes requires a collaborative approach to management, involving a multidisciplinary team that includes a primary care physician, cardiologist, nephrologist, and endocrinologist. Guidance from a dietitian can aid patients with following a heart- and kidney-healthy diet. Continuity of care between hospital and out-of-hospital follow-up needs to be ensured. Transitions of care and adherence to medications are significant strategies in disease prevention and mitigation of the progression of the disease.

Historically, therapy to relieve HF symptoms in particular was limited by fear of detrimental impact on declining kidney function. Fear of adverse events such as hyperkalemia can be a barrier to therapy with aldosterone antagonists because many patients with advanced CKD—particularly those receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blocker therapy—are already at increased risk of hyperkalemia.49

There is now a compendium of treatment options, from RAAS inhibitors to, more recently, sodium–glucose cotransporter-2 (SGLT2) inhibitors—both of which have positive outcome data in dedicated HF and CKD trials—and glucagon-like peptide-1 receptor antagonists, which have positive data in type 2 diabetes.6,50 Early, hypothesis-generating results from cardiovascular outcome trials with glucagon-like peptide-1 receptor antagonists noted some degree of renal protection with these agents, in addition to their ability to reduce CVD outcomes in patients with type 2 diabetes.51 Evaluation of the effect of a glucagon-like peptide-1 receptor antagonist on renal outcomes in patients with type 2 diabetes is ongoing (NCT03819153). Recent results with aldosterone antagonism, from FIDELIODKD and FIGARO-DKD, show decreased CKD and CVD events in patients with CKD and type 2 diabetes.28,29 The SGLT2 inhibitor class offers a new option that can have meaningful effects on the cardiorenal nexus: SGLT2 inhibition decreased CKD progression and CVD events in patients with CKD in DAPA-CKD23 and reduced adverse CVD-related outcomes including worsening HF in DAPA-HF,24 EMPEROR-Reduced,25 and EMPEROR-Preserved,30 regardless of the presence or absence of type 2 diabetes.

SGLT2 inhibitors have a multifactorial role in ameliorating the insults of cardiorenal syndromes. In addition to improving glycemic control, SGLT2 inhibitors can increase red blood cell mass and hematocrit via renal erythropoietin production and potentially have a role in reducing oxidative stress and inflammation by inhibiting proinflammatory pathways, inducing autophagy, and activating nonclassic RAAS pathways.52,53 SGLT2 inhibition with canagliflozin reduced the risk of hyperkalemia in patients treated with RAAS inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) in CREDENCE, which may contribute to cardiorenal benefits.54 However, a secondary analysis of DAPACKD showed no statistically significant difference in hyperkalemia between the dapagliflozin and placebo arms (regardless of mineralocorticoid receptor antagonist use).55 The risk of hyperkalemia is lower with nonsteroidal than steroidal mineralocorticoid receptor antagonists.56 There are different mechanisms that can be hypothesized for how SGLT2 inhibitors might affect RAAS,57 including hemodynamic modification of glomerular blood flow and level of hyperfiltration in intact nephrons. Hyperfiltration induces activation of profibrotic pathways and thus modulation of hyperfiltration, and tubular activity may have an impact on long-term nephron function.

FUTURE DIRECTIONS

With the beneficial potential of new medications comes a renewed focus on the cardiorenal nexus. The underlying pathophysiology of the cardiorenal nexus remains to be further elucidated. Capturing the underlying pathophysiology will enable physicians to choose the appropriate treatment earlier. Broader recognition of the cardiorenal nexus will emphasize the need to evaluate and manage CKD in patients who are primarily being treated for CVD issues and vice versa. Paying attention to underlying cardiorenal syndromes will enable primary care physicians and endocrinologists to take a comprehensive approach to the care of their patients with hypertension, type 2 diabetes, and obesity. Development of a combined heatmap system that visually presents cardiorenal syndrome risk in the electronic medical record based on CVD and CKD severity, and how this risk is affected by type 2 diabetes, would aid earlier identification and treatment of high-risk patients. Further research into the mechanisms of action of potentially disease-modifying medications, and the role that these medications may have when used in combination, will improve treatment algorithms. Further research on health economics and outcomes will drive improvements in long-term continuity of care.

REFERENCES 

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2. Ronco C, McCullough P, Anker SD, Anand I, Aspromonte N, Bagshaw SM, Bellomo R, Berl T, Bobek I, Cruz DN, et al. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J. 2010;31:703–711. doi: 10.1093/eurheartj/ehp507 

3. Rangaswami J, Bhalla V, Blair JEA, Chang TI, Costa S, Lentine KL, Lerma EV, Mezue K, Molitch M, Mullens W, et al. Cardiorenal syndrome: classification, pathophysiology, diagnosis, and treatment strategies: a scientific statement from the American Heart Association. Circulation. 2019;139:e840–e878. doi: 10.1161/CIR.0000000000000664 

4. Ronco C, Cicoira M, McCullough PA. Cardiorenal syndrome type 1: pathophysiological crosstalk leading to combined heart and kidney dysfunction in the setting of acutely decompensated heart failure. J Am Coll Cardiol. 2012;60:1031–1042. doi: 10.1016/j.jacc.2012.01.077 5. Baethge C, Goldbeck-Wood S, Mertens S. SANRA—a scale for the quality assessment of narrative review articles. Res Integr Peer Rev. 2019;4:

5. doi: 10.1186/s41073-019-0064-8 6. Rangaswami J, Bhalla V, de Boer IH, Staruschenko A, Sharp JA, Singh RR, Lo KB, Tuttle K, Vaduganathan M, Ventura H, et al. Cardiorenal protection with the newer antidiabetic agents in patients with diabetes and chronic kidney disease: a scientific statement from the American Heart Association. Circulation. 2020;142:e265–e286. doi: 10.1161/CIR.00000 00000000920

7. , Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, Chamberlain AM, Chang AR, Cheng S, Delling FN, et al. Heart disease and stroke statistics—2020 update: a report from the American Heart Association. Circulation. 2020;141:e139–e596. doi: 10.1161/CIR.00000 00000000757 

8. Conrad N, Judge A, Tran J, Mohseni H, Hedgecott D, Crespillo AP, Allison M, Hemingway H, Cleland JG, McMurray JJV, et al. Temporal trends and patterns in heart failure incidence: a population-based study of 4 million individuals. Lancet. 2018;391:572–580. doi: 10.1016/S0140 -6736(17)32520-5

9. Schrauben SJ, Chen H-Y, Lin E, Jepson C, Yang W, Scialla JJ, Fischer MJ, Lash JP, Fink JC, Hamm LL, et al. Hospitalizations among adults with chronic kidney disease in the United States: a cohort study. PLoS Med. 2020;17:e1003470. doi: 10.1371/journal.pmed.1003470

10. Centers for Disease Control and Prevention. Chronic kidney disease surveillance system—United States. Available at: https://nccd.cdc.gov/ ckd. Accessed April 7, 2021.

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