Immune Cell Therapy: Promising Approach to Reduce Chronic Kidney Disease Risk in Heart Failure

Progression of cardiac disease and kidney disease is inexorably linked. This linkage is common due to similar risk factors including hypertension, diabetes, and obesity. The association of chronic kidney disease (CKD) and development of chronic heart failure is well established and appears to be due to the influence of the injured kidney on microvascular dysfunction, neurohormonal derangements, abnormal mineral metabolism, and systemic inflammation. ¹ , ² , ³ Prior data have demonstrated an association between CKD and prevalent HF from both reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). Cardiovascular disease processes have been understudied in women, especially postmenopausal women. Insights into risk factors and natural history of HF in this group of patients are important because they may result in potential therapeutic interventions to treat HF.

In this issue of the Journal of the American Heart Association (JAHA), the article by Cheng et al. presents observational data from 23 309 postmenopausal women followed on average for 18 years. ⁴ The data were abstracted from the WHI (Women's Health Initiative). The WHI was a landmark randomized placebo controlled trial to evaluate the risks and benefits of menopausal hormone therapy in 161 808 healthy postmenopausal women from 1993 to 1998 with extended postintervention follow‐up until the present. The investigators evaluated subjects with CKD defined by baseline estimated glomerular filtration rate during the enrollment period and the development of incident HF defined as first hospitalization for acute decompensated HF. The results demonstrated a stepwise increase in risk for incident HF with lower estimated glomerular filtration rate. The association between HF and declining GFR was observed in both subsets with HFrEF and HFpEF; the relationship was much stronger for HFpEF compared with HFrEF. This stratification has not been reported previously. Of importance, this association was attenuated with a history of current versus no or past hormone use. ⁴ , ⁵

These findings are important in further delineating the relationship between CKD and progression of both HFrEF and HFpEF and the suggestion that current hormonal therapy may slow this progression in postmenopausal women. This association was greater in HFpEF than HFrEF and is an important finding because in most large population studies, the majority of patients with HFpEF are women. ⁶ These observations raise the question as to the mechanism by which CKD is a risk factor for HF, especially HFpEF. In this regard, systemic inflammation is evolving into a target opportunity for treatment of HF.

Systemic inflammation has been identified as a key driver in the progression of HF across the spectrum of ejection fractions but especially HFpEF. ³ A proinflammatory state develops in the early stages of CKD. ⁷ Systemic inflammation accentuates the injurious processes on the cardiovascular system related to CKD with the hyperactivation of the renin‐angiotensin‐aldosterone system, erythropoietin resistance, and disordered mineral metabolism (calcium, phosphate, parathyroid hormone, and FGF‐23 [fibroblast growth factor‐23]). ³ In HFrEf, acute myocardial injury initiates a surge in proinflammatory cytokine and chemokines with infiltration of neutrophils and monocytes in the injured cardiac tissue. ⁸ , ⁹ After this initial inflammatory process, chronic inflammation persists with sustained proinflammatory processes involving renin‐angiotensin‐aldosterone system hyperactivation and persistent infiltration of circulating monocytes into the damaged myocardium with transformation into proinflammatory macrophages promoting continued tissue injury. ¹⁰ , ¹¹ In HFpEF the presence of concomitant comorbidities of CKD, diabetes, and obesity may trigger the inflammatory cascade resulting in similar chronic inflammatory processes similar to HFrEF.

Targeted anti‐inflammatory strategies to address systemic inflammation in chronic heart failure have been evaluated clinically with less than optimal and conflicting results. Evidence for a central role for IL‐1/IL‐1b (interleukin‐1/1b) has been suggested in the inflammatory process in HF. The clinical evaluation of IL‐1 receptor blockage with anakinra or direct inhibition of IL‐1b with cankinumab in the REDHART (Recently Decompensated Heart Failure Anakinra Response Trial) and CANTOS (Cardiovascular Risk Reduction Study [Reduction in Recurrent Major Cardiovascular Disease Events]) trials were inconclusive. ¹² , ¹³ Continuing clinical studies are ongoing to target singular inflammatory mediators but may not be successful due to the incredible redundancy of the immune system to overcome a singular inhibitory pathway. The use of systemic immunosuppression with glucocorticoids in acute HF has also not yielded clear results. ¹⁴ , ¹⁵

A new alternative immumomodulation strategy is being developed to treat both acute and chronic inflammatory conditions. This approach is based upon autologous immune cell directed therapy in situ. This treatment uses a combination device, called the selective cytopheretic device (SCD), composed of biocompatible, biomimetic membranes within a cartridge placed in an extracorporeal blood circuit. ¹⁶ , ¹⁷ During continuous extracorporeal blood perfusion, the SCD membranes selectively bind only activated circulating neutrophils and monocytes (not lymphocytes) and sequesters them for several hours in a low ionized calcium environment. This process results in a phenotypic change in the bound cells to a less proinflammatory state whereby they are released back into the systemic circulation resulting in systemic immunomodulation without immunosuppression. ¹⁸ SCD therapy has been used in clinical intensive care unit trials with an excellent safety profile with strong efficacy signals in patients with acute kidney injury, adult respiratory distress syndrome, and hepatorenal syndrome. ¹⁹ The SCD has been recently approved for use in children with acute kidney injury and multiorgan failure due to sepsis/septic condition requiring renal replacement therapy in the hospital intensive care unit. ¹⁷ The first in human use of the SCD in severe chronic heart failure with cardiorenal syndrome has been reported and demonstrated a significant improvement in cardiac performance. ²⁰ This approach is now being evaluated in a multicenter trial using SCD treatment as a bridge to left ventricular assist device implantation in patients ineligible for this procedure due to worsening renal function or right ventricular dysfunction (NCT03836482). Further studies are required in adequately powered randomized trials to carefully evaluate this innovative approach using immune cell directed therapy in chronic heart failure.

Observational studies such as that reported by Cheng et al. in this issue of JAHA are important to assist in the identification of important targets to treat HF, which is a growing health burden in postmenopausal women.

Disclosures

Dr Humes reports financial interests in Innovative Biotherapies, Inc.; Seastar Medical, Inc.