Alternative Markers of Renal Function in Heart Failure

Treatment Strategies When a Rise in Serum Creatinine Is Observed During Diuresis in Acute Heart Failure with a Focus on Renal Preservation

The pathogenesis of AHF centers around congestion, which ultimately leads to organ dysfunction via persistently elevated central venous pressures and hypoperfusion of the kidneys [47]. During severely decompensated AHF, markedly reduced renal blood flow and extremely elevated renal vascular resistance generates a drop in GFR without a compensatory activation of the RAAS that preserves perfusion to vital organs including the brain and heart via an increase in filtration fraction [48].

The current treatment of AHF with diuretics, which acts to reduce arterial volumes, predisposes patients with more severe heart failure exacerbations to elevations in Cr levels [48]. In order to address the issue of reduced intravascular volumes leading to elevations in Cr, several small studies have looked at the combination of hypertonic saline with high-dose loop diuretics to augment decongestion and its effects on mortality and readmissions rates. In a small, single-blinded study involving 107 patients with refractory congestive heart failure, the use of hypertonic saline along with high-dose loop diuretics was associated with lower mortality (45.3% versus 87% in conventional treatment), which was attributed to the instantaneous mobilization of fluids into the intravascular space via the increased oncotic pressure of hypertonic saline [49]. This combination of hypertonic saline with high-dose loop diuretics lead to an overall reduction in atrial natriuretic peptide, B-type natriuretic peptide, and immune-inflammatory markers and achieved more rapid weight reduction and reduced hospitalization duration and 30-day readmission rates [50–52].

Another potential adjunct may be the use of serelaxin in the prevention of WRF. By acting as a vasodilator, serelaxin reduces end-organ damage by improving renovascular blood flow during AHF exacerbations, which may work to prevent diuretic-induced WRF [53]. Additionally, there is a rationale for the supplementation of thiamine to a patient on prolonged diuretic use. Loop diuretics, specifically furosemide, lead to increased urinary excretion of thiamine [54]. Thiamine supplementation was associated with an improvement in left ventricular ejection fraction, which translated into improved cardiac function and urine output [55].

In patients with AHF and WRF, renal adjuvant therapy with the use of low-dose dopamine has been used to augment decongestion while preserving renal perfusion during diuresis, leading to more electrolyte homeostasis, reduced hospital lengths of stay and decreased rates of 30-day readmissions [56, 57]. However, in a large, multicenter, randomized study looking at a population with CKD, it was shown that the addition of low-dose dopamine to diuretic therapy did not lead to enhanced decongestion nor improvement in renal function when compared to isolated diuretic therapy [58].

Inappropriately elevated levels of arginine-vasopressin during AHF lead to increased water retention, contributing to both congestive symptoms and electrolyte abnormalities. Tolvaptan, a V2 receptor antagonist, blocks the antidiuretic effects of this hormone and leads to improved fluid excretion and improved renal function [59, 60]. Although useful in achieving additional diuresis, the use of tolvaptan was not associated improved long-term mortality benefits nor heart failure-related morbidity [60].

Diabetes is associated with a substantial risk for the development of renal disease [33, 61]. Inhibition of the sodium glucose transporter-2 (SGLT-2) promotes fluid excretion via blockage of glucose reabsorption in the proximal tubules and promoting glycosuria [62]. In addition to aiding with glucose control and body weight, treatment with SGLT-2 inhibitors was associated with a lower risk of hospitalization for heart failure, progression of albuminuria, and loss of kidney function compared to placebo groups as well as a significant reduction in death from cardiovascular causes, non-fatal myocardial infarctions, and non-fatal strokes (HR 0.86, 95%CI 0.75–0.97) [63].

An additional method for achieving diuresis in the setting of worsening Cr levels is to augment diuresis through the blockade of aldosterone via mineralocorticoid receptor antagonists. Via competitive binding of receptors at the aldosterone-dependent sodium-potassium exchange site in the distal convoluted tubules and collecting ducts, spironolactone increases sodium and free water excretion while retaining potassium. However when compared to placebo, upfront high-dose spironolactone (100 mg daily for 96 hours) for patients with acute HF was well tolerated but did not improve change in NT-proBNP levels, clinical congestion score, dyspnea assessment, net urine output, or net weight change [64].

Treatment Pearls for the Case Vignette

Loop diuretics remain the cornerstone of therapy for the management of AHF, with their appropriate use, as in the case vignette, leading to resolution of symptoms as well as achieving clinical and subclinical decongestion. Commonly, AHF patients develop elevations in Cr as a consequence of diuretic use, which has led to cautious use of this vital therapy. Numerous studies have shown however that the poor outcomes associated with WRF are actually attributable to baseline kidney dysfunction, with higher incidences and poor outcomes associated with more severe CKD. Given this fact, the use of Cr as a marker of prognosis in AHF may not be accurate without taking into account the overall clinical picture, specifically whether or not WRF is taking place in the setting of appropriate decongestion. Therefore, we are confident Mr. Y is ready for discharge.