Patients with heart failure (HF) and associated chronic kidney disease (CKD) are a population less represented in clinical trials; additionally, subjects with more severe estimated glomerular filtration rate reduction are often excluded from large studies. In this setting, most of the data come from post hoc analyses and retrospective studies. Accordingly, in patients with advanced CKD, there are no specific studies evaluating the long-term effects of the traditional drugs commonly administered in HF.
1. Introduction
The most recent HF guidelines propose a revised algorithm for the treatment of heart failure with reduced ejection fraction (HFrEF), with the “quadruple therapy” approach with the use of SGLT-2 inhibitors, angiotensin receptor blocker neprilysin inhibitors (ARNI) (as a replacement of angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) or in de novo HFrEF patients with class of recommendation IIb), on top on B-blockers, and mineralocorticoid receptor antagonists (MRAs), with a substantial improvement in clinical outcomes in terms of hospitalization and mortality
[1]. However, renin angiotensin system (RAAS) inhibitors, MRAs, angiotensin receptor blocker neprilysin inhibitors (ARNI), and sodium glucose linked transporters 2 (SGLT2) inhibitors significantly impact the renal function due to changes in renal physiology. These drugs reset the renal function curve, affecting the intraglomerular hydrostatic pressures–natriuresis relationship through the tubule-glomerular feedback mechanism and by contrasting the effects on the afferent and efferent glomerular arteriola induced by different agents. These effects modify the physiological filtration fraction, have different baroceptorial and chemotactic repercussion on the macula densa, and may impact the tubular function (
Figure 1). The concomitant use of RAAS inhibitors, MRAs, and novel drug such as SGLT2 inhibitors and ARNI may amplify the process of transitory renal impairment occurring after the early administration, resulting in the inertia of the start and up-titration of these lifesaving therapies. In most of cases, renal impairment is transitory, and the kidney function tends to return to its prior conditions or remain stable in the long term
[2]. However, the effect on the renal function induced by polytherapy is not being sufficiently analyzed. Therefore, HF patients with concomitant renal dysfunction are less likely to receive guideline-recommended therapies, even though this is not always justified.
Figure 1. The effects of heart failure drugs on renal physiology. AA: afferent arteriole; ACE In.: angiotensin converting enzyme inhibitors; ARBs: angiotensin receptor blockers; ARNI: angiotensin receptor neprilisin inhibitor; ATII: angiotensin II; BB: beta blockers; BP: blood pressure; cGMP: cyclic guanosine monophosphate; eGFR: estimated glomerular filtration rate; EA: efferent arteriole; HypT: hypertension; Kf: glomerular capillary ultrafiltration coefficient; MRA: mineralcorticoid receptor antagonist; NPs: natriuretic peptides; RAAS: renin angiotensin aldosterone system; RBF: renal blood flow; SGLT2 In.: sodium glucose transporter protein 2 inhibitors; SNS: sympathetic nervous system.
2. Clinical Characteristics of Patients with Chronic Kidney Disease and Heart Failure
Previous studies on outpatients with chronic HF showed that one of the highest prevalence among the non-cardiovascular comorbidities was related to a renal failure ranging from 30% to 50%
[3]. The heart and kidneys were strictly related; the dysfunction of either of those organs led to a functional deterioration of the other due to various mechanisms, such as inflammation, oxidative stress, impaired hydro-saline homeostasis, and diuretic resistance
[4][5]. In chronic HF, there was decreased cardiac output, predominantly due HFrEF results in decreased organ perfusion. In patients with HFpEF, elevated filling pressures were the main hemodynamic feature and decreased systolic filling resulted in inadequate stroke volume reserved, ultimately causing a decreased cardiac output. A reduction in cardiac output in patients with chronic HF has been shown to result in a decrease in renal blood flow. Additionally, in response to a diminished cardiac output, the kidney promotes mechanisms that result in water and sodium retention, ultimately causing subclinical congestion, which in turn causes further kidney dysfunction. Both in experimental settings and in patients with either chronic or acute HF, an increase in central venous pressures or abdominal pressure was associated with an increased risk of worsening renal function. In cardiorenal syndrome type 2, CKD has been observed in 45 to 63% of patients. Renal congestion, hypoperfusion, and increased right atrial pressure represent hallmarks of this clinical condition
[6]. HF and CKD patients shared a poor quality of life and showed a high burden of cardiovascular (CV) risk due to several common risk factors, such as diabetes, hypertension, and coronary artery disease (CAD)
[7]. Phenotyping patients with renal dysfunction remains a real challenge; the pathophysiological mechanisms and the prognostic role of renal dysfunction may differ across HFrEF, HFmrEF, and HFpEF. CKD is often associated with more severe HF conditions and stages, independently of left ventricular ejection fraction (LVEF). The relationships between CKD, older age, female sex, diabetes, and HF stage were similar in the three HF groups, but several studies demonstrated that CKD was more prevalent in heart failure with preserved ejection fraction (HFpEF) than in heart failure with mildly reduced ejection fraction (HFmrEF) and HFrEF
[8][9]. Other studies showed a higher prevalence of CKD in HFrEF patients
[10]. The association between HFpEF and the deterioration of the renal function was independent of the presence of CKD at baseline. Renal dysfunction in HFpEF may be considered a major comorbidity, with a general prognostic impact without any relation with a worse HF status: conversely, in HFrEF patients, kidney dysfunction may reflect the progression of HF, perhaps due to low cardiac output, hemodynamic hypoperfusion, and sympathetic and neurohormonal activation
[11].
Among non-CV comorbidities, CKD was the disease more frequently associated with hospitalization
[12]. Renal dysfunction, regardless of its definition and screening method, conferred a clinically significant risk for excess mortality in patients with HF
[13]. CKD was associated with worse outcomes in all HF phenotype; however, the literature on mortality in HFpEF and CKD shows conflicting results. In the larger meta-analyses, which included a cohort of HFpEF patients, CKD was a more powerful predictor of death
[14]. Conversely, a meta-analysis of the Global Group in Chronic Heart Failure (MAGGIC) showed a lower mortality rate and a lower association between CKD and death in patients with HFpEF than in those with HFrEF
[15]. This result was confirmed in the Swedish Heart Failure registry, in which the association between CKD and mortality risk was less pronounced in HFpEF patients
[16].
In patients with acute heart failure (AHF), researchers can discern between two distinct phenotypes: patients with baseline renal dysfunction, defined as CKD, and patients developing worsening renal function (WRF) during hospitalization
[17]. A new classification of WRF has been proposed, according to the time frame resolution or persistence. The first clinical scenario was a patient with good renal function and occurrence of a “pseudo” WRF during hospitalization for acute HF, that was considered secondary to the decongestion therapy. The increase of in-hospital creatinine did not usually persist after discharge, without consequences for the prognosis if the patient was well treated, with efficient decongestion at discharge. The second scenario was a patient with true WRF due to congestion (increased renal venous pressure) and hypoperfusion (reduced arterial perfusion), in which renal deterioration persisted, with an increase in creatinine also in the post-discharge period and with a higher burden of HF re-hospitalization
[18]. Finally, in the third scenario, WRF could occur in the presence of CKD related to reduced cortical blood flow and chronic glomerulosclerosis with reduced cortical wall. This subtype was common in older patients with several comorbidities, where WRF reflected the real deterioration of the renal function, with worse prognostic value. Current classification was uncompleted, because it did not account for serial kidney evaluation after discharge and the severity of an effective estimated glomerular filtration rate (eGFR) impairment (
Table 1).
Table 1. Clinical scenarios and RIFLE (risk of renal failure, injury to the kidney, failure of kidney function, loss of kidney function, end-stage renal failure) criteria and AKIN (acute kidney injury network) criteria for diagnosis of acute kidney injury.
Clinical Scenarios |
(1) “Pseudo” WRF |
Good renal function at baseline and occurrence of WRF during hospitalization for acute HF, usually secondary to the decongestion therapy. |
(2) “True” WRF |
WRF due to congestion and hypoperfusion, in which renal deterioration persisted also in the post-discharge period with a higher burden of HF re-hospitalization. |
(3) WRF in CKD |
WRF could occur in the presence of CKD. This subtype was common in older patients with several comorbidities, where WRF reflected the real deterioration of the renal function, with worse prognostic value. |
Laboratory/urine Output Criteria |
|
eGFR Criteria |
Urine output criteria |
RIFLE (an acute rise in SCr over 7d) |
|
|
Risk |
Increased SCr ≥ ×1.5 or eGFR decrease > 25% |
UO < 0.5 mL/kg/h × 6 h |
Injury |
Increase in SCr ≥ ×2 or eGFR decrease > 50% |
UO < 0.5 mL/kg/h × 12 h |
Failure |
Increase in SCr ≥ ×3 or eGFR decrease > 75% or SCr ≥ 4.0 mg/dL |
UO < 0.5 mL/kg/h × 24 h or anuria × 12 h |
Loss |
Persistent ARF = Complete loss of kidney function > 4 wk |
|
ESKD |
End stage renal disease (>3 months) |
|
AKIN (an acute rise in SCr within 48 h) |
|
|
Stage 1 |
Same as RIFLE Risk or increase in SCr ≥ 0.3 mg/dL (≥26.4 μmol/L) |
Same as RIFLE Risk |
Stage 2 |
Same as RIFLE Injury |
Same as RIFLE Injury |
Stage 3 |
Increase in SCr ≥ ×3 or serum creatinine of ≥4.0 mg/dL with an acute increase of at least 0.5 mg/dL or RRT |
Same as RIFLE Failure |
WRF: worsening renal function; CKD: chronic kidney disease; HF: heart failure; AKIN: acute kidney injury network; ARF: acute renal failure; d: days; ESKD: end-stage kidney disease; eGFR: estimated glomerular filtration rate; h: hour; RIFLE: risk of renal failure, injury to the kidney, failure of kidney function, loss of kidney function, and end-stage renal failure; RRT: renal replacement therapy; SCr: serum creatinine; UO: urine output; and wk: weeks.
3. Therapeutic Target and Limitations in Patients with Heart Failure and Chronic Kidney Disease
All drugs used in HF patients have potentially detrimental effects on the renal function, and they expose HF patients with renal dysfunction to a greater risk of adverse renal complications, such as hyperkalemia and dialysis. Historically, data from randomized controlled trials on the effect of HF medications in HF patients and CKD were limited, due to the exclusion of patients with CKD.
The studies of left ventricular dysfunction (SOLVD) trial enrolled 36% of patients with CKD and eGFR < 60 mL/min/1.73 m
2; 33% of all patients presented a >0.5 mg/dL increase in serum creatinine; in the final analyses, the benefits on all-cause mortality were maintained across the entire CKD spectrum
[19]. This finding was confirmed by the survival and ventricular enlargement (SAVE) trial, which demonstrated the improvement in survival and reduced morbidity in patients with asymptomatic left ventricular dysfunction treated with captopril vs. placebo regardless of CKD (exclusion criteria Cr > 2.5 mg/dL, 33% of patients with CKD). After 42 months of follow-up, the risk for death associated with renal events was hazard ratio (HR) 1.63 (95% CI 1.05–2.52) in the placebo group, versus HR 1.33 (95% CI 0.81–2.21) in the captopril group (
p = 0.49 for interaction)
[20]. Similar findings were found in the trandolapril cardiac evaluation (TRACE) study group, in which 40% of patients with post-myocardial infarct LV dysfunction had CKD. In this group, trandolapril significantly reduced the risk of CV mortality and HF progression
[21]. More recently, in the NETWORK and ATLAS trials, patients with Cr > 2.3 mg/dL and Cr > 2.5 mg/dL were excluded, and no specific therapeutic data on advanced CKD could be extrapolated. The valsartan heart failure trial (Val-HeFT) included the higher percentage of patients with HF and CKD (58% of the entire cohort); valsartan significantly reduced the combined endpoint of mortality and morbidity and improved HF symptoms also in HF patients with CKD
[22]. Notably, candesartan in heart failure assessment of reduction in mortality and morbidity (CHARM)-added and CHARM-alternative trials, which included a significant proportion of CKD population, confirmed the previous data. However, patients with more severe CKD (creatinine > 3.0 mg/dL) were excluded. A significant percentage of patients (7.1%) discontinued the therapy due to an increase in creatinine, in the absence of sufficient data regarding the permanent effect on the renal outcome
[23].
The Cox proportional hazards regression models in the SOLVD trial showed that, compared to placebo, ACE-I did not reduce the decline in eGFR, that was similar in both groups. However, the study recommended to avoid the withdrawal of ACE-I in patients with low and moderate eGFR decline due to the beneficial effect on the overall CV outcome
[24]. Moreover, both ACE-I and ARBs showed to significantly slow the eGFR decline in diabetes and nephropathy due to their favorable physiological effect
[25] (
Table 2).
Table 2. Comparison in renal function outcome between trials evaluating therapy with ACE-I, ARBs, and MRAs in HF patients.
Trial; Author; Year |
Pts (n) |
Design |
Main Eligibility Criteria |
Primary Outcome |
Mean Follow up (years) |
Renal Function Exclusion |
CKD Groups (eGFR, mL/min/ 1.73 m2) |
Main Findings |
Angiotensin Converting Enzyme inhibitors |
CONSENSUS; 1987; The CONSENSUS Trial Study Group |
253 |
Enalapril vs. Pl. |
Congested HF, NYHA IV, cardiomegaly on chest X-ray |
ACM |
0.5 |
Serum creatinine concentration > 3.4 mg/dL |
NA |
Enalapril significantly reduced ACM in patients with sCr > 1.39 mg/dL compared to pl. (30% vs. 55%) but did not have a significant effect in those with sCr < 1.39 mg/dL. |
SOLVD treatment; 1991; The SOLVD Investigators [19] |
2569 |
Enalapril vs. Pl. |
LVEF ≤ 35%, NYHA I–IV (90% NYHA II, III) |
ACM |
3.4 |
Creatinine > 2 mg/dL |
≥60 (n = 1466) (59, 7%) <60 (n = 1036) (40, 3%) |
Enalapril reduced mortality and hospitalization in SHF patients without significant heterogeneity between those with and without CKD. |
SOLVD prevention; 1992; The SOLVD Investigators |
4228 |
Enalapril vs. Pl. |
Receiving digitalis, diuretics, or vasodilators (remainder same as SOLVD treatment trial) |
ACM |
3.08 |
Creatinine > 2 mg/dL |
<45 (n = 450) 10.6% ≥45 <60 (n = 669) 15.8% ≥60 <75 (n = 640) 15.1% >75 (n = 863) 20.4 |
No significant interaction between CKD and treatment |
SAVE; 1992; Tokmakova et al. [20] |
2331 |
Captopril vs. Pl. |
Acute myocardial infarction (age 21–80 years) LVEF < 40% |
ACM |
3.5 |
Creatinine > 2.5 mg/dL |
≥60 (n = 1562) 67% <60 (n = 769) 33% |
Captopril reduced CV events irrespective of baseline kidney function. CKD was associated with a heightened risk for all major CV events after MI, particularly among subjects with an eGFR < 45 mL/min/1.73 m2. |
AIRE; 1997; Hall et al. |
2006 |
Ramipril vs. Pl. |
Acute myocardial infarction (ECG and enzymes) and transient or persistent congestive heart failure after index infarct. Clinical CHF by physical examination or radiography. |
ACM |
1.25 |
NA |
NA |
ACM significantly lower for Ramipril (17%) than pl. (23%). |
TRACE; 1995; Køber et al. [21] |
1749 |
Trandolapril vs. Pl. |
Able to tolerate a test dose of 0.5 mg trandolapril adults with acute myocardial infarction 2–6 days prior to trial entry. Echocardiographic ejection fraction < 35% |
ACM |
3 |
Creatinine > 2.5 mg/dL |
NA |
Trandalopril reduced relative risk of death. Trandolapril also reduces the risk of death from CV causes. |
NETWORK; 1998; The NETWORK investigators |
1532 |
Enalapril 2.5 vs. 5 vs. 10 mg BID |
Age 18 to 85 years, NYHA II–IV, abnormality of the heart and current treatment for heart failure |
ACM, HFH, WHF |
0.5 |
Creatinine > 2.3 mg/dL |
|
No relationship between dose of enalapril and clinical outcome in patients with HF. |
ATLAS; 1999; Packer et al. |
3174 |
Lisinopril high vs. low dose |
LVEF ≤ 30 NYHA II–IV |
ACM |
3.8 |
Creatinine > 2.5 mg/dL |
Creatinine > 1.5 mg/dL 2176 (68.5%) Creatinine < 1.5 mg/dL 998 (31.5%) |
ACM was non-significantly reduced both in patients with and without CKD. |
Angiotensin Receptor Blockers |
Val-HeFT; 2003; Carson et al. [22] |
5010 |
Valsartan vs. Pl. |
LVEF < 40%; clinically stable CHF NYHA II–IV; treatment with ACE inhibitors; LVDD > 2.9 cm/bsa |
ACM |
1.9 |
Creatinine > 2.5 mg/dL |
<60 2114 (47%) ≥60 2196 (53%) |
Patients with WRF demonstrated the same benefits with valsartan treatment compared with pl. in the overall population. |
CHARM added, 2001; McMurray et al. [23] |
2548 |
Candesartan vs. Pl. |
LVEF ≤ 40%; NYHA II–IV; treatment with ACE inhibitor |
CV death or HFH |
3.4 |
Creatinine >3 mg/dL |
≥60 67% <60 33% |
The risk for CV death or hospitalization for worsening CHF as well as the risk for ACM increased significantly below an eGFR of 60 mL/min per 1.73 m2. |
CHARM alternative, 2003; Granger et al. |
2028 |
Candesartan vs. Pl. |
CHF NYHA II–IV, LVEF ≤ 40%, ACE inhibitors intolerance |
CV death or HFH |
2.8 |
Creatinine > 3 mg/dL |
≥60 57.4% <60 42.6% |
See above |
HEEAL; 2009; Konstam et al. |
3846 |
High dose vs. Low dose Losartan |
LVEF ≤ 40%; NYHA II–IV; ACE inhibitors intolerance |
ACM or HFH |
4.7 |
Creatinine > 2.5 mg/dL |
NA |
Losartan 150 mg vs. 50 mg maintained its net clinical benefit and was associated with reduced risk of death or HFH, despite higher rates of WRF and greater rates of eGFR decline. |
Mineralcorticoid Receptor Antagonist |
RALES; 1999; Kulbertus et al. |
1663 |
Spironolactone vs. Pl. |
LVEF < 35%; NYHA III–IV; creatinine ≤ 2.5 mmol/L |
ACM |
2 |
creatinine ≥ 2.5 mg/dL |
<60 (n = 792) 47.62% ≥60 (n = 866) 52.07% |
Individuals with reduced baseline eGFR exhibited similar relative risk reductions in all-cause death and the combined. Endpoint of death or hospital stayed for HF as those with normal renal function and greater absolute risk reduction compared with those with a higher baseline eGFR. |
EMPHASIS-HF, 2001; Zannad et al. [26] |
2737 |
Eplerenone vs. Pl. |
LVEF ≤ 35%; NYHA II; eGFR ≥ 30 mL/min/1.73 m |
CV death or HFH |
1.75 |
eGFR < 30 mL/min/1.73 m |
<60 (n = 912) 33.32% ≥60 (n = 1821) 66.53% |
Eplerenone, as compared with placebo, reduced both the risk of death and the risk of hospitalization in HFrEF patients with CKD. |
TOPCAT; 2021; Khumbanj, et al. |
3445 |
Spironolactone vs. placebo (n = 3445) |
LVEF ≥ 45%; HF hospitalization or elevated NP level; eGFR ≥ 30 mL/min/1.73 m2 or creatinine ≤ 2.5 |
CV death or aborted cardiac arrest or hospitalization for HF |
3.3 |
eGFR < 30 mL/min/1.73 m or serum creatinine >2.5 mg/dL |
<45 (n = 411) 11.9% 45–60 (n = 533) 15.47% ≥60 (n = 823) 23.88% |
The primary endpoint was similar between the spironolactone and placebo arms. The risk of adverse events was amplified in the lower eGFR categories. These data supported use of spironolactone to treat HFpEF patients with advanced CKD only when close laboratory surveillance was possible. |
ACE: angiotensin-converting enzyme inhibitor; ACM: all-cause mortality; CHF: congestive heart failure; CKD: chronic kidney disease; CV: cardiovascular; ECG: electrocardiogram; eGFR: estimated glomerular filtration rate; HF: heart failure; HFH: hospitalization for heart failure; HR: hazard ratio; LVEF: left ventricular ejection fraction; LVDD: left ventricular diastolic diameter; MI: myocardial infarction; NYHA: New York Heart Association; Pts: patients; NA: not available; Pl.: placebo; sCr: serum creatinine; SHF: sever heart failure; WHF: worsening heart failure; and WRF: worsening renal function.