Advances in the area of cardiorenal medicine: clinical research highlights from selected papers published in NDT

The coronavirus disease 2019 (COVID-19) pandemic has exerted a substantial impact on clinical research. In its initial phase, the redistribution of resources and inability to schedule in-person visits retarded progress in non-COVID-19 medical research [1]. Hopefully, response to the pandemic with proactive measures has introduced innovations that facilitated the maintenance of interest, participation and high-quality scientific standards in the conduct of clinical research [1]. In this editorial, we discuss advances in non-COVID-19 clinical research in the field of cardiorenal medicine provided by selected studies that were published in Nephrology Dialysis and Transplantation during 2021.

RENIN–ANGIOTENSIN–ALDOSTERONE SYSTEM (RAAS)-INHIBITOR THERAPY ENABLEMENT IN ADVANCED CHRONIC KIDNEY DISEASE (CKD)

According to guidelines, angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are recommended as first-line antihypertensive therapies for patients with high blood pressure and CKD, particularly in those with severely increased albuminuria [2]. In such patients, RAAS blockade is effective in improving kidney failure and cardiovascular outcomes, but ACEIs/ARBs are often underused in daily clinical practice for a variety of reasons.

In a retrospective cohort study enrolling 141 252 veterans with stage 3–4 CKD who were incident ACEI/ARB users, Walther et al. [3] explored whether the interruption of these cardio and renoprotective therapies is associated with excess risk for adverse clinical outcomes. Discontinuation events were defined as a gap in ACEI/ARB use of at least 14 days and were further classified in severity according to the duration of the off-treatment period (14–30, 31–60, 61–90, 91–180 and >180 days) [3]. Over a mean follow-up of 4.87 years, exposure even to short periods of RAAS inhibitor discontinuation was associated with an increased risk of all-cause mortality. The hazard ratio (HR) for all-cause death ranged from a low of 1.74 for discontinuation of >180 days to a high of 2.30 for patients who experienced a short discontinuation of 14–30 days [3]. A similar pattern of association was observed between discontinuation of ACEI/ARB therapy and the risk for incident end-stage kidney disease (ESKD), with an HR ranging from 1.47 to 1.65 for different durations of discontinuation [3]. The observational design of this study precludes the opportunity to derive direct cause-and-effect risk associations. However, if a causal risk association truly exists, the identification and amelioration of factors associated with the underuse of ACEIs/ARBs may be a therapeutic opportunity to prolong life expectancy and delay the progression of kidney injury in high-risk patients with stage 3–4 CKD.

In a subsequent retrospective analysis of 434 027 RAAS-inhibitor users enrolled in the linked UK Clinical Practice Research Datalink and Hospital Episodes Statistics database during 2009–14, Wetmore et al. [4] aimed to describe the patterns of treatment and identify factors associated with interruption and/or cessation of ACEIs/ARBs. Over a median follow-up period of 5.11 years, 73.7% of all RAAS-inhibitor users had exposure to off-treatment periods, 66.1% experienced at least one interruption and 16.1% had a cessation. In half of the patients who experienced at least one interruption, the duration of the off-treatment period was <40 days. The median time to reinitiation was also short (13 days). Among patients who experienced permanent discontinuation, the median time to cessation was 0.40 years over a mean follow-up of 3.47 years [4]. This analysis did not evaluate the proportion of discontinuation events that were directly attributable to hyperkalemia. However, as compared with the referent category of no hyperkalemia, patients with moderate–severe hyperkalemia (defined as serum potassium >5.5 mmol/L) during follow-up had a 1.10-fold higher risk for a first interruption and 3.37-fold higher risk for cessation of RAAS-inhibitor therapy [4]. Compared with no CKD, the HR for permanent treatment discontinuation was 2.20 in stage 4 CKD and 2.87 in stage 5 CKD [4]. Accordingly, moderate–severe hyperkalemia appeared to be an important barrier that limited persistent RAAS-inhibitor use, particularly in patients with stage 4–5 CKD.

Can we enable the adequate blockade of the RAAS in patients with advanced CKD if we mitigate the risk of hyperkalemia with the administration of newer agents that bind potassium in the gut? Preliminary evidence to support the efficacy of this therapeutic strategy was provided by the Patiromer versus Placebo to Enable Spironolactone Use in Patients with Resistant Hypertension and Chronic Kidney Disease (AMBER) trial [5]. In this phase 2b trial, 295 patients with uncontrolled resistant hypertension and an estimated glomerular filtration rate (eGFR) of 25–≤45 mL/min/1.73 m² received spironolactone in addition to double-blind treatment either with the potassium binder patiromer or with placebo. Over 12 weeks of follow-up, compared with placebo, patiromer enabled more patients to tolerate and continue spironolactone treatment with less severe hyperkalemia {between-group difference 19.5% [95% confidence interval (CI) 10.0–29.0]} [5]. Whether the enablement of adequate RAAS blockade with newer potassium-binding agents is translated into an improvement in “hard” clinical outcomes remains unknown. The Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure (DIAMOND) trial (NCT03888066) [6], which was designed to explore this crucial research question in patients with heart failure with reduced ejection fraction, was prematurely terminated and is unlikely to provide a clear answer.

INVESTIGATIONAL THERAPIES IN DIABETIC KIDNEY DISEASE

Optimized RAAS blockade and sodium-glucose co-transporter type 2 (SGLT2) inhibition are the two guideline-based therapies for improving kidney failure and cardiovascular outcomes in patients with CKD and type 2 diabetes mellitus (T2DM) [7]. However, the residual cardiorenal risk of these patients remains substantial, despite standard-of-care treatment. Therefore the development of novel therapies proven to be safe and effective in retarding the progression of diabetic kidney disease remains a high-priority goal of future research.

Preclinical studies showed that the expression of the protease chymase is markedly elevated in the diabetic kidney and suggested that chymase inhibition may exert kidney-protective effects through antiproliferative and antifibrotic actions. These positive preclinical data provided the rationale for the design of the Double-Blind Study to Investigate Efficacy, Safety and Tolerability of BAY1142524 in Patients with Type II Diabetes and a Clinical Diagnosis of Diabetic Kidney Disease (CADA DIA) trial, in which Rossing et al. [8] investigated the safety and efficacy of the chymase inhibitor fulacimstat in 148 patients with T2DM and a clinical diagnosis of diabetic kidney disease. In this phase 2a trial, patients were randomly assigned in a 2:1 ratio to receive fulacimstat (25 mg/day) or a placebo for 24 weeks. Fulacimstat was well tolerated and was not associated with excess risk for serious adverse events [8]. Despite the fact that fulacimstat achieved mean total trough concentrations that were 9-fold higher than those expected to be mandatory for minimal therapeutic activity, this investigational agent failed to improve albuminuria. After 24 weeks of follow-up, the urinary albumin:creatinine ratio (UACR) was increased by 27.4% with placebo and by 3% with active treatment. In the analysis of covariance, fulacimstat provoked a statistically nonsignificant placebo-subtracted reduction of 19.6% in UACR [8]. This modest effect, which was primarily driven by an unexpected deterioration of albuminuria in placebo-treated participants, precluded the further clinical investigation of chymase inhibition in diabetic kidney disease.

A SIMPLIFIED LUNG ULTRASOUND (US) B-LINE SCORE FOR THE ASSESSMENT OF LUNG CONGESTION IN HEMODIALYSIS PATIENTS

Since clinical assessment of dry weight in patients on hemodialysis is challenging, lung US is currently under investigation as a novel assistive technique that promises a more “objective” estimation of subclinical lung congestion. This examination is based on a semiquantitative score incorporating the sum of US B-lines recorded at 28 sites in the intercostal spaces. Torino et al. [9] explored whether lung US could be simplified with the use of an abbreviated eight-sites US B-line score in a prospective cohort study of 303 hemodialysis patients. In correlation analysis, a strong positive interrelation between the 8- and 28-sites US B-line scores was observed (Spearman's coefficient 0.93, P < 0.001). The agreement between these two scores in the classification of the severity of lung congestion was also fairly good [Cohen's k coefficient 0.79 (95% CI 0.74–0.84)] [9]. Over 3 years of follow-up, every five US B-lines increase in the 28-sites score was associated with a significantly higher risk for cardiovascular events and all-cause death. Similarly, the eight-sites US B-line score was also prognostically associated with the risk for adverse cardiovascular outcomes and all-cause mortality [9]. While the median duration of the examination was 3.05 minutes with the 28-sites score, the required time to complete the simplified examination was only 1.35 minutes.

Taken together, these observations suggest that among patients on hemodialysis, the 8-sites US B-line score retains a strong prognostic power that is comparable with that of the reference standard 28-sites US B-line score. The examination using the abbreviated score saves <2 minutes in time. The question that arises is whether lung US is a useful tool to guide therapeutic decisions and improve the management of dry weight. In the recently completed Lung Water by Ultrasound Guided Treatment in Hemodialysis Patients (LUST) trial [10], as compared with usual care, a lung US-guided treatment strategy appeared to be more effective in improving lung congestion over a mean follow-up of 1.49 years. However, this improvement in volume status was not accompanied by a significant benefit of lung US-guided management of dry weight on the prespecified primary composite outcome of all-cause death, nonfatal myocardial infarction or hospitalization for decompensated heart failure [HR 0.88 (95% CI 0.63–1.24)] [10]. Until firm clinical trial evidence demonstrating the benefit of lung US and other assistive technologies become available, careful evaluation of clinical signs and symptoms remains the standard of care in the management of dry weight.

FUNDING

R.A. is supported by the National Heart Lung and Blood Institute (grant R01 HL126903).

CONFLICT OF INTEREST STATEMENT

R.A. reports personal fees and nonfinancial support from Bayer Healthcare Pharmaceuticals, Akebia Therapeutics, Boehringer Ingelheim, Eli Lilly, Relypsa, Vifor Pharma, Lexicon and Reata; is a member of data safety monitoring committees for Vertex and Chinook and a member of steering committees of randomized trials for Akebia Therapeutics, Bayer and Reata; has served as an associate editor of the American Journal of Nephrology and Nephrology Dialysis and Transplantation and has been an author for UpToDate and has received research grants from the National Institutes of Health and the US Veterans Administration. P.I.G. has nothing to disclose.