Maintaining renal perfusion pressure: a potential target to improve diuretic response?

In patients admitted with acute heart failure (AHF) and volume overload, the main goal of in-hospital treatment is to get rid of the excessive sodium and fluid accumulation contributing to the clinical picture of congestion. When doing so successfully, it is hoped that such a resolution of congestion improves the post-discharge outcome.1 This either directly through abolishment of congestion and volume overload or indirectly as a state of resolved congestion might allow for better initiation and titration of life-saving guideline-directed medical therapy. Diuretic resistance has been recognized to be a major reason as to why the resolution of congestion and volume overload cannot be attained.1,2 Numerous pathophysiologic elements have been implicated in the development of diuretic resistance, including neurohormonal activation, diminished intestinal uptake of loop diuretics, haemodynamic alterations (e.g. elevated venous pressures, low arterial blood pressures), metabolic factors (hypoalbuminaemia, hypochloraemia, metabolic alkalosis), or mechanical factors (extrinsic kidney compression).2 Measuring diuretic response (the converse of diuretic resistance) has become very popular in the treatment of AHF, as it potentially allows us to identify patients with diuretic resistance, allowing for the timely intensification of background therapy.1–5 However, as illustrated in the stepped pharmacologic arm of the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial, only 9% of patients achieved complete decongestion at 96 h, despite having a well-specified protocol that measured diuretic response (total urine output) and mandated therapy adjustment (increasing loop diuretic dose, or adding a thiazide diuretic) in the setting of poor diuretic response.6 Hereby illustrating that simply up-titrating loop diuretic therapy and adding a thiazide diuretic is not always capable of overcoming diuretic resistance. More recently, the Acetazolamide in Decompensated Heart Failure with Volume Overload (ADVOR) trial showed that by using acetazolamide, the likelihood of successful decongestion after 3 days increases from 30.5% in the placebo arm to 42.2% in the acetazolamide arm [risk ratio for successful decongestion = 1.46 (1.17–1.82), P < 0.001].7 At the time of discharge, up to 78.8% in the acetazolamide arm had complete decongestion (vs. 62.5% in the placebo arm that were only treated with loop diuretics). This overwhelming success of acetazolamide is perhaps best explained by the key pharmacologic properties counteracting numerous elements that contributed to diuretic resistance, such as enhanced proximal nephron sodium reabsorption due to either haemodynamic (e.g. renal venous congestion) or neurohormonal alterations, or through the prevention of development of metabolic alkalosis.8–10 However, even in the acetazolamide arm, almost one in four patients had residual congestion at the time of discharge. Therefore, understanding other potential drivers of poor diuretic response might lead to further therapeutic optimizations. In that aspect, the paper of Dotare et al.11 assesses the potential role of systolic blood pressure (SBP) drops during the early treatment phase of AHF, in influencing diuretic response and clinical outcome. In this large prospective registry that included data from 1682 consecutive patients with AHF enrolled in 20 hospitals across Japan, the authors assessed the relationship between early SBP changes, diuretic response, and clinical outcome. Systolic blood pressure change was measured as the difference between the baseline SBP and the lowest SBP at either 1.5, 6, 24, or 48 h. Loop diuretic response was measured as a total of 48 h diuresis per 40 mg furosemide equivalents and clinical outcome as all-cause mortality. On average, the median SBP drop in the study was 38 mmHg. The analysis of Dotare et al. shows that a higher drop in SBP was associated with a lower diuretic response. Patients who had both an SBP drop above the median and loop diuretic response below the median had the worse clinical outcome. While this is an interesting analysis, several limitations should be recognized. First, from the analysis, it remains difficult to discern how the starting SBP influences the relation between SBP drop and diuretic response. For instance, is a similar drop in SBP worse if the initial SBP is already lower? Second, while all-cause mortality is easy to capture in a multicentre registry because it does not require specific adjudication, having information on cause-specific cardiovascular mortality and heart failure readmissions would have been informative. Third, although diuretic response measured by urine output per 40 mg furosemide equivalents is a valuable endpoint, growing insight from recent AHF trials indicates that natriuretic response (e.g. total natriuresis in millimole or total natriuresis per 40 mg furosemide equivalent) might offer incremental insights into the degree of intrinsic renal sodium avidity.3,5 Based on the analysis of Dotare et al., it might be tempting to speculate that prevention of an SBP drop early during decongestion could lead to improved diuretic response and possibly improved outcome, it is important to emphasize that such causal assumptions can only be inferred from randomized controlled trials. Indeed other covariates that are not adjusted for (or even measured) could still mediate some or most of the relation between an early SBP drop and diuretic response. For instance, patients with AHF provoked by an infection might have an early drop in SBP and this infection might lead to a diminished diuretic response. In such patients, we might find a significant relation between SBP and diuretic response, although much of the relationship could be explained by the intercurring infection. Clearly, only randomized controlled trials that are randomized towards a strategy to maintain pressures within a specific range vs. for instance standard of care could help resolve the questions if SBP changes are a pathophysiologic (causal) factor in diuretic response. The physiologic reason at least supports this concept to some extent. Normally, the kidney maintains renal blood flow (and also glomerular filtration rate) stable within a mean arterial pressure range from 80 to 170 mmHg.12 Clearly, more profound drops in SBP could lead to a reduced renal blood flow. This invokes a mechanism of increasing the filtration fraction (amount of renal blood flow being filtered) to maintain eGFR (see Figure 1). This increase in filtration fraction increases proximal nephron sodium retention and induces diuretic resistance.12 So maintaining adequate renal blood flow might be important, although it remains to be determined whether prevention of SBP drops can meaningfully affect diuretic response. Because an SBP drop partially works through reducing renal blood flow and subsequently increasing the filtration fraction and the proximal nephron sodium avidity, it needs to be determined as to whether an SBP drop still affects diuretic response in the new era where combinational diuretic therapy with acetazolamide (which counteract the proximal nephron sodium avidity) and loop diuretics still holds true. The authors should be congratulated with the data from this large prospective registry, but perhaps the next endeavour could be a randomized controlled trial to assess if maintaining renal perfusion pressures within a certain range or preventing an early SBP drops could improve diuretic response. More causal answers between blood pressure drops and diuretic response could also come from ongoing studies with specific cardiorenal devices such as the second heart, Procyrion Aortix and Reitan catheter.13 These devices are built to selectively augment renal perfusion pressure and are propagated to overcome diuretic resistance in that way. For instance, a pilot study with the Reitan catheter in 18 AHF patients illustrated that the devices improved eGFR (suggestive of better renal blood flow) and improved diuretic response.13 Clearly, more decisive studies on the role of avoiding SBP drops and maintaining renal perfusion pressure during decongestion are necessary before we would embrace it as a clinically meaningful target to improve the diuretic response. Clinical context of study findings. The upper panel illustrates the renal pathophysiology basis of reduced renal blood flow occurring in the setting of systemic blood pressure drops. Low renal blood flow induces several mechanism of diuretic resistance. While the current study might generate the hypothesis that maintaining renal perfusion pressure improves diuretic response, only randomized controlled trials or specific mechanistic causal interventions will help to further elucidate if prevention of drops in systolic blood pressure is the mechanism of reduced diuretic response. AHF, acute heart failure; AA, afferent arteriole; EA, efferent arteriole; RBF, renal blood flow; GFR, glomerular filtration rate; FF, filtration fraction. P.M. is supported by a grant from the Belgian American Educational Foundation (BAEF) and from the Frans Van de Werf Fund. This editorial does not contain specific data for data sharing.