Compensatory post-diuretic renal sodium reabsorption is not a dominant mechanism of diuretic resistance in acute heart failure

Abstract

Aims In healthy volunteers, the kidney deploys compensatory post-diuretic sodium reabsorption (CPDSR) following loop diuretic-induced natriuresis, minimizing sodium excretion and producing a neutral sodium balance. CPDSR is extrapolated to non-euvolemic populations as a diuretic resistance mechanism; however, its importance in acute decompensated heart failure (ADHF) is unknown. Methods and results Patients with ADHF in the Mechanisms of Diuretic Resistance cohort receiving intravenous loop diuretics (462 administrations in 285 patients) underwent supervised urine collections entailing an immediate pre-diuretic spot urine sample, then 6-h (diuretic-induced natriuresis period) and 18-h (post-diuretic period) urine collections. The average spot urine sodium concentration immediately prior to diuretic administration [median 15 h (13–17) after last diuretic] was 64 ± 33 mmol/L with only 4% of patients having low (<20 mmol/L) urine sodium consistent with CPDSR. Paradoxically, greater 6-h diuretic-induced natriuresis was associated with larger 18-h post-diuretic spontaneous natriuresis (r = 0.7, P < 0.001). Higher pre-diuretic urine sodium to creatinine ratio (r = 0.37, P < 0.001) was the strongest predictor of post-diuretic spontaneous natriuresis. In a subgroup of patients (n = 43) randomized to protocol-driven intensified diuretic therapies, the mean diuretic-induced natriuresis increased three-fold. In contrast to the substantial decrease in spontaneous natriuresis predicted by CPDSR, no change in post-diuretic spontaneous natriuresis was observed (P = 0.47). Conclusion On a population level, CPDSR was not an important driver of diuretic resistance in hypervolemic ADHF. Contrary to CPDSR, a greater diuretic-induced natriuresis predicted a larger post-diuretic spontaneous natriuresis. Basal sodium avidity, rather than diuretic-induced CPDSR, appears to be the predominant determinate of both diuretic-induced and post-diuretic natriuresis in hypervolemic ADHF.

Assessing intrinsic renal sodium avidity in acute heart failure: implications in predicting and guiding decongestion

“…However, some challenges to a global implementation exist as (i) not all cardiology/medicine inpatient wards are equipped with the personnel to perform well timed urine samples, (ii) inconsistencies outside of trial settings occur with regard to the timing of diuretic administration and UNa sampling, sometimes occurring simultaneously (with the sample reflecting a random sample), (iii) incontinence and other patient features such as delirium might interfere with appropriate sample collection, (iv) not all in‐hospital settings have access to 24 h laboratory analysis making UNa analysis after diuretics less actionable as they will be analysed in batch with the day‐shift, and (v) even if laboratory analysis would be available in the middle of the night on a hospitalization ward, physicians to take action on the results might not always be available. Because the peak natriuretic response after a loop diuretic heavily relies on the intrinsic renal sodium avidity, a random UNa sample at the time of ED admission could be an alternative option 18,19 . Identifying a low UNa in a random sample is useful even if patients have received diuretic administration in the hours before, as a low value would still imply poor diuretic response, which is intrinsically linked to the renal sodium avidity state.…”

“…Recently, a simple UNa sample (random sample outside the post‐diuretic phase) has been shown to convey information about the state of intrinsic renal sodium avidity in heart failure and has been shown to be strongly correlated with the post‐diuretic UNa concentration 17–19 . Yet, no studies have investigated the role of assessing the intrinsic renal sodium avidity through a random UNa sample in predicting decongestive response.…”

Multimodal Strategies for the Diagnosis and Management of Refractory Congestion. An Integrated Cardiorenal Approach

“…Several mechanisms have been classically described as causes of an impaired diuretic response. Among these, we have: 1) a reduced delivery of diuretic to the kidney's proximal tubule due to reduced cardiac output, which constitutes the cause of the increasingly high diuretic doses required in HF; 2) compensatory sodium reabsorption either after the diuretic effect wears off or at other nephron segments, something that has been described in healthy adults but seems not to occur in patients with AHF (Cox et al, 2021); and 3) congestive nephropathy, where the increased sympathetic tone causes a chronic redistribution of blood into the central circulation, FIGURE 1 | Cardiorenal pathophysiology. Interrelation between heart and kidney in the development of the different types of cardiorenal syndrome (CRS).…”

“…CPSR was described in healthy individuals as a decrease in renal sodium secretion after the loop diuretic level drops to concentrations lower than its threshold (Kelly et al, 1983). This phenomenon was not only recently disproven to participate in the development of diuretic resistance in AHF, but that those patients who have a greater diuretic and natriuretic response to furosemide present a larger post-diuretic spontaneous diuresis (Cox et al, 2021).…”

Classic and Novel Mechanisms of Diuretic Resistance in Cardiorenal Syndrome

“…Multiple studies, old and new, have illustrated that the underlying level of renal sodium avidity is of primary importance in determining diuretic response. (10,29) Some of the seminal work in diuretic response research demonstrated that healthy volunteers provided a very low salt diet had dramatically reduced response to even the first dose of loop diuretic. (10) This prediuretic or basal sodium avidity describes the proclivity of the kidney to excessively retain sodium in the absence of diuretics.…”