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In heart failure, the heart and the kidneys share a rocky relationship. Cardiac dysfunction can heighten renal dysfunction and vice versa—appropriately dubbed “cardiorenal syndrome.”
Although classically defined by a reduction in the glomerular filtration rate (GFR),1 cardiorenal syndrome also encompasses complex neurohormonal, pharmacologic, and metabolic interactions affecting or affected by both glomerular and tubular function. Unfortunately, all of these maladaptive processes occur in heart failure and perpetuate a vicious circle of continued dual-organ dysfunction.
The central insult here is hemodynamic disarray from acute or chronic cardiac dysfunction, which can directly influence glomerular function. However, to understand the hemodynamic ramifications for glomerular function, we focus on the determinants of glomerular filtration.
DETERMINANTS OF GFR
The GFR is the rate of fluid flow between the glomerular capillaries and the Bowman capsule and is classically represented by the following equations2:
GFR = Kf × (PG – PB – πG + πB)
Kf = N × Lp × S
Kf is the filtration constant, N the number of functional nephrons, Lp the hydraulic conductivity of the glomerular capillary, S the filtration area, PG the hydrostatic pressure in the glomerular capillaries, PB the hydrostatic pressure in the Bowman capsule, and πG and πB the colloid osmotic pressures within the glomerular capillaries and Bowman space, respectively.
Based on this relationship, the GFR is reduced when PG is reduced in the setting of hypovolemia, hypotension, or renin-angiotensin system antagonist use or when PB is increased in the setting of elevated central venous pressure or elevated abdominal pressure—all common in heart failure. With this understanding, one would assume that strategies to increase PG (improve perfusion) and reduce PB (reduce congestion) might ameliorate ongoing renal dysfunction and improve the GFR in heart failure.
In this issue, Thind et al3 highlight the impact of hemodynamic derangements in heart failure with acute cardiorenal syndrome and provide an overview of its treatment. They review the complex relationship between progressive cardiac failure translating into accelerated neurohormonal responses (increases in sympathetic nervous system and renin-angiotensin-aldosterone system activation) and the impact of increased central venous pressure on progressive renal dysfunction. They also provide an overview of efforts to mitigate cardiorenal syndrome, after careful appraisal of volume status, through diuretic-mediated decongestion with aggressive use of loop diuretics (either in isolation or in the form of sequential nephron blockade with a thiazide or acetazolamide), and they highlight the lingering uncertainty regarding inotrope use.
VENOUS CONGESTION VS DECREASED CARDIAC OUTPUT
Returning to the GFR equation, it is clear that an imbalance in PG and PB can worsen glomerular function. Because cardiac dysfunction can lead to both venous congestion and decreased cardiac output, this leads to the question, “Of these, which is the more important driver of this imbalance and its effects on renal function?”
A compelling argument can be made for each side. On one hand, experiments over a half-century old in human models of venous congestion highlighted the profound impact of elevated venous pressure, which decreases electrolyte excretion (sodium included) and diminishes urine flow.4,5 This has been replicated in more-contemporary decompensated heart failure cohorts in which worsening renal function was more closely associated with elevated central venous pressure rather than cardiac output.6,7 On the other hand, early landmark experiments and more recent cohorts with heart failure have also shown that reductions in effective arterial blood volume, renal blood flow, and cardiac output are also associated with reductions in GFR.5,8,9
How then shall we reconcile whether cardiorenal syndrome is a “backward failure” (from central venous pressure) or a “forward failure” (from decreased perfusion) phenomenon?
The answer is complicated and is likely “both,” with the major component being increased central venous pressure. To understand this construct, we must first exclude frank cardiogenic shock—when the hydraulic function of the heart fails to provide enough flow, leading to a catastrophic drop in mean arterial pressure that supersedes the kidney’s ability to autoregulate renal blood flow.10,11
In patients with chronic heart failure and congestion who are not in shock, historical observations suggest that both intra-abdominal pressure (which increases renal venous pressure) and central venous pressure lead to reduced renal blood flow and increased renal vasomotor resistance (increase in afferent, intrarenal, and efferent vascular tone).12–14 More recent observations from epidemiologic studies have largely replicated these findings. Central venous pressure remains essential to impacting renal function in heart failure,6,15 and the impact of cardiac output on renal function remains uncertain.16
The relationship of intracardiac hemodynamics may also play a role in modifying renal function. Several reports recently described the relationship between both right- and left-sided filling pressures as being associated with worse renal function in heart failure.17–19 Patients with a disproportionately higher right atrial pressure to pulmonary capillary wedge pressure have higher serum creatinine during and after decongestive therapies. Therefore, the concept of “right-sided heart failure” expands beyond the simple representation of “backward congestion” at the level of venous return. In fact, a higher ratio of right atrial pressure to pulmonary capillary wedge pressure may point to an inability of the venous and pulmonary circulations to provide adequate left ventricular preload. Therefore, a relatively underfilled left ventricle in the face of biventricular dysfunction may result in worsening renal function.
TREATMENT IS CHALLENGING
The treatment of cardiorenal syndrome is challenging. It is often accompanied by heightened azotemia, diuretic resistance, electrolyte abnormalities, and a spectrum of hemodynamic disarray. As Thind et al point out, there is, unfortunately, no firmly established treatment. While “sequential nephron blockade” (pharmacologically blocking multiple sites on the nephron simultaneously) is theoretically promising, there are no rigorously studied therapeutic strategies with proven efficacy.
On the other hand, mechanical removal of isotonic fluid with ultrafiltration showed early promise in decompensated heart failure, but enthusiasm diminished with results from the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial.20 Ultrafiltration was roughly equivalent to aggressive pharmacologic therapy for fluid loss, was associated with higher serum creatinine levels, and was more challenging to administer.
Equally uncertain is the benefit of inotropic or vasoactive therapy, which directly alters cardiac hemodynamics. Low-dose dopamine or low-dose nesiritide is of no benefit toward enhancement of decongestion or renal protection when added to standard diuretic therapy.21 Furthermore, routine use of inotropes is fraught with more arrhythmias and hypotension and is associated with dismal long-term outcomes.22,23
Alternative therapies that act directly on renal physiology—eg, rolofylline, a selective adenosine A1 receptor antagonist that may enhance renal blood flow, augment natriuresis, and break diuretic resistance—have been similarly disappointing.24
With so much uncertainty, more investigation into novel treatments for cardiorenal syndrome is clearly warranted.
However, because venous congestion is the hemodynamic hallmark of acute cardiorenal syndrome (increasing PB), reducing central venous pressure remains the cornerstone treatment for cardiorenal syndrome. Additionally, efforts to preserve renal perfusion and avoid hypotension are prudent to maintain glomerular capillary hydrostatic pressure (PG).
In light of these considerations, there is no “one size fits all” for the treatment of cardiorenal syndrome. Treatment should be based on thoughtful individualized strategies tailored to the underlying cardiorenal pathophysiology, and with the understanding that the kidney is at the heart of the matter.
- House AA, Anand I, Bellomo R, et al; Acute Dialysis Quality Initiative Consensus Group. Definition and classification of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant 2010; 25:1416–1420.
- Tucker BJ, Blantz RC. An analysis of the determinants of nephron filtration rate. Am J Physiol 1977; 232:F477–F483.
- Thind GS, Loehrke M, Wilt JL. Acute cardiorenal syndrome: mechanisms and clinical implications. Cleve Clin J Med 2018; 85:231–239.
- Wilkins RW, Tinsley CM, Culbertson JW, et al. The effects of venous congestion of the limbs upon renal clearances and the excretion of water and salt. I. Studies in normal subjects and in hypertensive patients before and after splanchnicectomy. J Clin Invest 1953; 32:1101–1116.
- Judson WE, Hatcher JD, Hollander W, Halperin MH, Wilkins RW. The effects of venous congestion of the limbs and phlebotomy upon renal clearances and the excretion of water and salt. II. Studies in patients with congestive failure. J Clin Invest 1955; 34:1591–1599.
- Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009; 53:589–596.
- Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 2009; 53:582–588.
- Ljungman S, Laragh JH, Cody RJ. Role of the kidney in congestive heart failure. Relationship of cardiac index to kidney function. Drugs 1990; 39(suppl 4):10–21; discussion 22–24.
- Damman K, Navis G, Smilde TD, et al. Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction. Eur J Heart Fail 2007; 9:872–878.
- Fincke R, Hochman JS, Lowe AM, et al. Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol 2004; 44:340–348.
- Adams PL, Adams FF, Bell PD, Navar LG. Impaired renal blood flow autoregulation in ischemic acute renal failure. Kidney Int 1980; 18:68–76.
- Maxwell MH, Breed ES, Schwartz IL. Renal venous pressure in chronic congestive heart failure. J Clin Invest 1950; 29:342–348.
- Blake WD, Wégria R, Keating RP, Ward HP. Effect of increased renal venous pressure on renal function. Am J Physiol 1949; 157:1–13.
- Bradley SE, Bradley GP. The effect of increased intra-abdominal pressure on renal function in man. J Clin Invest 1947; 26:1010–1022.
- Mullens W, Abrahams Z, Skouri HN, et al. Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J Am Coll Cardiol 2008; 51:300–306.
- Hanberg JS, Sury K, Wilson FP, et al. Reduced cardiac index is not the dominant driver of renal dysfunction in heart failure. J Am Coll Cardiol 2016; 67:2199–2208.
- Drazner MH, Brown RN, Kaiser PA, et al. Relationship of right- and left-sided filling pressures in patients with advanced heart failure: a 14-year multi-institutional analysis. J Heart Lung Transplant 2012; 31:67–72.
- Drazner MH, Velez-Martinez M, Ayers CR, et al. Relationship of right- to left-sided ventricular filling pressures in advanced heart failure: insights from the ESCAPE trial. Circ Heart Fail 2013; 6:264–270.
- Grodin JL, Drazner MH, Dupont M, et al. A disproportionate elevation in right ventricular filling pressure, in relation to left ventricular filling pressure, is associated with renal impairment and increased mortality in advanced decompensated heart failure. Am Heart J 2015; 169:806–812.
- Bart BA, Goldsmith SR, Lee KL, et al, for the Heart Failure Clinical Research Network. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012; 367:2296–2304.
- Chen HH, Anstrom KJ, Givertz MM, et al; NHLBI Heart Failure Clinical Research Network. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 2013; 310:2533–2543.
- Gorodeski EZ, Chu EC, Reese JR, Shishehbor MH, Hsich E, Starling RC. Prognosis on chronic dobutamine or milrinone infusions for stage D heart failure. Circ Heart Fail 2009; 2:320–324.
- Cuffe MS, Califf RM, Adams KF Jr, et al, for the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 2002; 287:1541–1547.
- Massie BM, O’Connor CM, Metra M, et al, for the PROTECT Investigators and Committees. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010; 363:1419–1428.
In heart failure, the heart and the kidneys share a rocky relationship. Cardiac dysfunction can heighten renal dysfunction and vice versa—appropriately dubbed “cardiorenal syndrome.”
Although classically defined by a reduction in the glomerular filtration rate (GFR),1 cardiorenal syndrome also encompasses complex neurohormonal, pharmacologic, and metabolic interactions affecting or affected by both glomerular and tubular function. Unfortunately, all of these maladaptive processes occur in heart failure and perpetuate a vicious circle of continued dual-organ dysfunction.
The central insult here is hemodynamic disarray from acute or chronic cardiac dysfunction, which can directly influence glomerular function. However, to understand the hemodynamic ramifications for glomerular function, we focus on the determinants of glomerular filtration.
DETERMINANTS OF GFR
The GFR is the rate of fluid flow between the glomerular capillaries and the Bowman capsule and is classically represented by the following equations2:
GFR = Kf × (PG – PB – πG + πB)
Kf = N × Lp × S
Kf is the filtration constant, N the number of functional nephrons, Lp the hydraulic conductivity of the glomerular capillary, S the filtration area, PG the hydrostatic pressure in the glomerular capillaries, PB the hydrostatic pressure in the Bowman capsule, and πG and πB the colloid osmotic pressures within the glomerular capillaries and Bowman space, respectively.
Based on this relationship, the GFR is reduced when PG is reduced in the setting of hypovolemia, hypotension, or renin-angiotensin system antagonist use or when PB is increased in the setting of elevated central venous pressure or elevated abdominal pressure—all common in heart failure. With this understanding, one would assume that strategies to increase PG (improve perfusion) and reduce PB (reduce congestion) might ameliorate ongoing renal dysfunction and improve the GFR in heart failure.
In this issue, Thind et al3 highlight the impact of hemodynamic derangements in heart failure with acute cardiorenal syndrome and provide an overview of its treatment. They review the complex relationship between progressive cardiac failure translating into accelerated neurohormonal responses (increases in sympathetic nervous system and renin-angiotensin-aldosterone system activation) and the impact of increased central venous pressure on progressive renal dysfunction. They also provide an overview of efforts to mitigate cardiorenal syndrome, after careful appraisal of volume status, through diuretic-mediated decongestion with aggressive use of loop diuretics (either in isolation or in the form of sequential nephron blockade with a thiazide or acetazolamide), and they highlight the lingering uncertainty regarding inotrope use.
VENOUS CONGESTION VS DECREASED CARDIAC OUTPUT
Returning to the GFR equation, it is clear that an imbalance in PG and PB can worsen glomerular function. Because cardiac dysfunction can lead to both venous congestion and decreased cardiac output, this leads to the question, “Of these, which is the more important driver of this imbalance and its effects on renal function?”
A compelling argument can be made for each side. On one hand, experiments over a half-century old in human models of venous congestion highlighted the profound impact of elevated venous pressure, which decreases electrolyte excretion (sodium included) and diminishes urine flow.4,5 This has been replicated in more-contemporary decompensated heart failure cohorts in which worsening renal function was more closely associated with elevated central venous pressure rather than cardiac output.6,7 On the other hand, early landmark experiments and more recent cohorts with heart failure have also shown that reductions in effective arterial blood volume, renal blood flow, and cardiac output are also associated with reductions in GFR.5,8,9
How then shall we reconcile whether cardiorenal syndrome is a “backward failure” (from central venous pressure) or a “forward failure” (from decreased perfusion) phenomenon?
The answer is complicated and is likely “both,” with the major component being increased central venous pressure. To understand this construct, we must first exclude frank cardiogenic shock—when the hydraulic function of the heart fails to provide enough flow, leading to a catastrophic drop in mean arterial pressure that supersedes the kidney’s ability to autoregulate renal blood flow.10,11
In patients with chronic heart failure and congestion who are not in shock, historical observations suggest that both intra-abdominal pressure (which increases renal venous pressure) and central venous pressure lead to reduced renal blood flow and increased renal vasomotor resistance (increase in afferent, intrarenal, and efferent vascular tone).12–14 More recent observations from epidemiologic studies have largely replicated these findings. Central venous pressure remains essential to impacting renal function in heart failure,6,15 and the impact of cardiac output on renal function remains uncertain.16
The relationship of intracardiac hemodynamics may also play a role in modifying renal function. Several reports recently described the relationship between both right- and left-sided filling pressures as being associated with worse renal function in heart failure.17–19 Patients with a disproportionately higher right atrial pressure to pulmonary capillary wedge pressure have higher serum creatinine during and after decongestive therapies. Therefore, the concept of “right-sided heart failure” expands beyond the simple representation of “backward congestion” at the level of venous return. In fact, a higher ratio of right atrial pressure to pulmonary capillary wedge pressure may point to an inability of the venous and pulmonary circulations to provide adequate left ventricular preload. Therefore, a relatively underfilled left ventricle in the face of biventricular dysfunction may result in worsening renal function.
TREATMENT IS CHALLENGING
The treatment of cardiorenal syndrome is challenging. It is often accompanied by heightened azotemia, diuretic resistance, electrolyte abnormalities, and a spectrum of hemodynamic disarray. As Thind et al point out, there is, unfortunately, no firmly established treatment. While “sequential nephron blockade” (pharmacologically blocking multiple sites on the nephron simultaneously) is theoretically promising, there are no rigorously studied therapeutic strategies with proven efficacy.
On the other hand, mechanical removal of isotonic fluid with ultrafiltration showed early promise in decompensated heart failure, but enthusiasm diminished with results from the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial.20 Ultrafiltration was roughly equivalent to aggressive pharmacologic therapy for fluid loss, was associated with higher serum creatinine levels, and was more challenging to administer.
Equally uncertain is the benefit of inotropic or vasoactive therapy, which directly alters cardiac hemodynamics. Low-dose dopamine or low-dose nesiritide is of no benefit toward enhancement of decongestion or renal protection when added to standard diuretic therapy.21 Furthermore, routine use of inotropes is fraught with more arrhythmias and hypotension and is associated with dismal long-term outcomes.22,23
Alternative therapies that act directly on renal physiology—eg, rolofylline, a selective adenosine A1 receptor antagonist that may enhance renal blood flow, augment natriuresis, and break diuretic resistance—have been similarly disappointing.24
With so much uncertainty, more investigation into novel treatments for cardiorenal syndrome is clearly warranted.
However, because venous congestion is the hemodynamic hallmark of acute cardiorenal syndrome (increasing PB), reducing central venous pressure remains the cornerstone treatment for cardiorenal syndrome. Additionally, efforts to preserve renal perfusion and avoid hypotension are prudent to maintain glomerular capillary hydrostatic pressure (PG).
In light of these considerations, there is no “one size fits all” for the treatment of cardiorenal syndrome. Treatment should be based on thoughtful individualized strategies tailored to the underlying cardiorenal pathophysiology, and with the understanding that the kidney is at the heart of the matter.
In heart failure, the heart and the kidneys share a rocky relationship. Cardiac dysfunction can heighten renal dysfunction and vice versa—appropriately dubbed “cardiorenal syndrome.”
Although classically defined by a reduction in the glomerular filtration rate (GFR),1 cardiorenal syndrome also encompasses complex neurohormonal, pharmacologic, and metabolic interactions affecting or affected by both glomerular and tubular function. Unfortunately, all of these maladaptive processes occur in heart failure and perpetuate a vicious circle of continued dual-organ dysfunction.
The central insult here is hemodynamic disarray from acute or chronic cardiac dysfunction, which can directly influence glomerular function. However, to understand the hemodynamic ramifications for glomerular function, we focus on the determinants of glomerular filtration.
DETERMINANTS OF GFR
The GFR is the rate of fluid flow between the glomerular capillaries and the Bowman capsule and is classically represented by the following equations2:
GFR = Kf × (PG – PB – πG + πB)
Kf = N × Lp × S
Kf is the filtration constant, N the number of functional nephrons, Lp the hydraulic conductivity of the glomerular capillary, S the filtration area, PG the hydrostatic pressure in the glomerular capillaries, PB the hydrostatic pressure in the Bowman capsule, and πG and πB the colloid osmotic pressures within the glomerular capillaries and Bowman space, respectively.
Based on this relationship, the GFR is reduced when PG is reduced in the setting of hypovolemia, hypotension, or renin-angiotensin system antagonist use or when PB is increased in the setting of elevated central venous pressure or elevated abdominal pressure—all common in heart failure. With this understanding, one would assume that strategies to increase PG (improve perfusion) and reduce PB (reduce congestion) might ameliorate ongoing renal dysfunction and improve the GFR in heart failure.
In this issue, Thind et al3 highlight the impact of hemodynamic derangements in heart failure with acute cardiorenal syndrome and provide an overview of its treatment. They review the complex relationship between progressive cardiac failure translating into accelerated neurohormonal responses (increases in sympathetic nervous system and renin-angiotensin-aldosterone system activation) and the impact of increased central venous pressure on progressive renal dysfunction. They also provide an overview of efforts to mitigate cardiorenal syndrome, after careful appraisal of volume status, through diuretic-mediated decongestion with aggressive use of loop diuretics (either in isolation or in the form of sequential nephron blockade with a thiazide or acetazolamide), and they highlight the lingering uncertainty regarding inotrope use.
VENOUS CONGESTION VS DECREASED CARDIAC OUTPUT
Returning to the GFR equation, it is clear that an imbalance in PG and PB can worsen glomerular function. Because cardiac dysfunction can lead to both venous congestion and decreased cardiac output, this leads to the question, “Of these, which is the more important driver of this imbalance and its effects on renal function?”
A compelling argument can be made for each side. On one hand, experiments over a half-century old in human models of venous congestion highlighted the profound impact of elevated venous pressure, which decreases electrolyte excretion (sodium included) and diminishes urine flow.4,5 This has been replicated in more-contemporary decompensated heart failure cohorts in which worsening renal function was more closely associated with elevated central venous pressure rather than cardiac output.6,7 On the other hand, early landmark experiments and more recent cohorts with heart failure have also shown that reductions in effective arterial blood volume, renal blood flow, and cardiac output are also associated with reductions in GFR.5,8,9
How then shall we reconcile whether cardiorenal syndrome is a “backward failure” (from central venous pressure) or a “forward failure” (from decreased perfusion) phenomenon?
The answer is complicated and is likely “both,” with the major component being increased central venous pressure. To understand this construct, we must first exclude frank cardiogenic shock—when the hydraulic function of the heart fails to provide enough flow, leading to a catastrophic drop in mean arterial pressure that supersedes the kidney’s ability to autoregulate renal blood flow.10,11
In patients with chronic heart failure and congestion who are not in shock, historical observations suggest that both intra-abdominal pressure (which increases renal venous pressure) and central venous pressure lead to reduced renal blood flow and increased renal vasomotor resistance (increase in afferent, intrarenal, and efferent vascular tone).12–14 More recent observations from epidemiologic studies have largely replicated these findings. Central venous pressure remains essential to impacting renal function in heart failure,6,15 and the impact of cardiac output on renal function remains uncertain.16
The relationship of intracardiac hemodynamics may also play a role in modifying renal function. Several reports recently described the relationship between both right- and left-sided filling pressures as being associated with worse renal function in heart failure.17–19 Patients with a disproportionately higher right atrial pressure to pulmonary capillary wedge pressure have higher serum creatinine during and after decongestive therapies. Therefore, the concept of “right-sided heart failure” expands beyond the simple representation of “backward congestion” at the level of venous return. In fact, a higher ratio of right atrial pressure to pulmonary capillary wedge pressure may point to an inability of the venous and pulmonary circulations to provide adequate left ventricular preload. Therefore, a relatively underfilled left ventricle in the face of biventricular dysfunction may result in worsening renal function.
TREATMENT IS CHALLENGING
The treatment of cardiorenal syndrome is challenging. It is often accompanied by heightened azotemia, diuretic resistance, electrolyte abnormalities, and a spectrum of hemodynamic disarray. As Thind et al point out, there is, unfortunately, no firmly established treatment. While “sequential nephron blockade” (pharmacologically blocking multiple sites on the nephron simultaneously) is theoretically promising, there are no rigorously studied therapeutic strategies with proven efficacy.
On the other hand, mechanical removal of isotonic fluid with ultrafiltration showed early promise in decompensated heart failure, but enthusiasm diminished with results from the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial.20 Ultrafiltration was roughly equivalent to aggressive pharmacologic therapy for fluid loss, was associated with higher serum creatinine levels, and was more challenging to administer.
Equally uncertain is the benefit of inotropic or vasoactive therapy, which directly alters cardiac hemodynamics. Low-dose dopamine or low-dose nesiritide is of no benefit toward enhancement of decongestion or renal protection when added to standard diuretic therapy.21 Furthermore, routine use of inotropes is fraught with more arrhythmias and hypotension and is associated with dismal long-term outcomes.22,23
Alternative therapies that act directly on renal physiology—eg, rolofylline, a selective adenosine A1 receptor antagonist that may enhance renal blood flow, augment natriuresis, and break diuretic resistance—have been similarly disappointing.24
With so much uncertainty, more investigation into novel treatments for cardiorenal syndrome is clearly warranted.
However, because venous congestion is the hemodynamic hallmark of acute cardiorenal syndrome (increasing PB), reducing central venous pressure remains the cornerstone treatment for cardiorenal syndrome. Additionally, efforts to preserve renal perfusion and avoid hypotension are prudent to maintain glomerular capillary hydrostatic pressure (PG).
In light of these considerations, there is no “one size fits all” for the treatment of cardiorenal syndrome. Treatment should be based on thoughtful individualized strategies tailored to the underlying cardiorenal pathophysiology, and with the understanding that the kidney is at the heart of the matter.
- House AA, Anand I, Bellomo R, et al; Acute Dialysis Quality Initiative Consensus Group. Definition and classification of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant 2010; 25:1416–1420.
- Tucker BJ, Blantz RC. An analysis of the determinants of nephron filtration rate. Am J Physiol 1977; 232:F477–F483.
- Thind GS, Loehrke M, Wilt JL. Acute cardiorenal syndrome: mechanisms and clinical implications. Cleve Clin J Med 2018; 85:231–239.
- Wilkins RW, Tinsley CM, Culbertson JW, et al. The effects of venous congestion of the limbs upon renal clearances and the excretion of water and salt. I. Studies in normal subjects and in hypertensive patients before and after splanchnicectomy. J Clin Invest 1953; 32:1101–1116.
- Judson WE, Hatcher JD, Hollander W, Halperin MH, Wilkins RW. The effects of venous congestion of the limbs and phlebotomy upon renal clearances and the excretion of water and salt. II. Studies in patients with congestive failure. J Clin Invest 1955; 34:1591–1599.
- Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009; 53:589–596.
- Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 2009; 53:582–588.
- Ljungman S, Laragh JH, Cody RJ. Role of the kidney in congestive heart failure. Relationship of cardiac index to kidney function. Drugs 1990; 39(suppl 4):10–21; discussion 22–24.
- Damman K, Navis G, Smilde TD, et al. Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction. Eur J Heart Fail 2007; 9:872–878.
- Fincke R, Hochman JS, Lowe AM, et al. Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: a report from the SHOCK trial registry. J Am Coll Cardiol 2004; 44:340–348.
- Adams PL, Adams FF, Bell PD, Navar LG. Impaired renal blood flow autoregulation in ischemic acute renal failure. Kidney Int 1980; 18:68–76.
- Maxwell MH, Breed ES, Schwartz IL. Renal venous pressure in chronic congestive heart failure. J Clin Invest 1950; 29:342–348.
- Blake WD, Wégria R, Keating RP, Ward HP. Effect of increased renal venous pressure on renal function. Am J Physiol 1949; 157:1–13.
- Bradley SE, Bradley GP. The effect of increased intra-abdominal pressure on renal function in man. J Clin Invest 1947; 26:1010–1022.
- Mullens W, Abrahams Z, Skouri HN, et al. Elevated intra-abdominal pressure in acute decompensated heart failure: a potential contributor to worsening renal function? J Am Coll Cardiol 2008; 51:300–306.
- Hanberg JS, Sury K, Wilson FP, et al. Reduced cardiac index is not the dominant driver of renal dysfunction in heart failure. J Am Coll Cardiol 2016; 67:2199–2208.
- Drazner MH, Brown RN, Kaiser PA, et al. Relationship of right- and left-sided filling pressures in patients with advanced heart failure: a 14-year multi-institutional analysis. J Heart Lung Transplant 2012; 31:67–72.
- Drazner MH, Velez-Martinez M, Ayers CR, et al. Relationship of right- to left-sided ventricular filling pressures in advanced heart failure: insights from the ESCAPE trial. Circ Heart Fail 2013; 6:264–270.
- Grodin JL, Drazner MH, Dupont M, et al. A disproportionate elevation in right ventricular filling pressure, in relation to left ventricular filling pressure, is associated with renal impairment and increased mortality in advanced decompensated heart failure. Am Heart J 2015; 169:806–812.
- Bart BA, Goldsmith SR, Lee KL, et al, for the Heart Failure Clinical Research Network. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med 2012; 367:2296–2304.
- Chen HH, Anstrom KJ, Givertz MM, et al; NHLBI Heart Failure Clinical Research Network. Low-dose dopamine or low-dose nesiritide in acute heart failure with renal dysfunction: the ROSE acute heart failure randomized trial. JAMA 2013; 310:2533–2543.
- Gorodeski EZ, Chu EC, Reese JR, Shishehbor MH, Hsich E, Starling RC. Prognosis on chronic dobutamine or milrinone infusions for stage D heart failure. Circ Heart Fail 2009; 2:320–324.
- Cuffe MS, Califf RM, Adams KF Jr, et al, for the Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) Investigators. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 2002; 287:1541–1547.
- Massie BM, O’Connor CM, Metra M, et al, for the PROTECT Investigators and Committees. Rolofylline, an adenosine A1-receptor antagonist, in acute heart failure. N Engl J Med 2010; 363:1419–1428.
- House AA, Anand I, Bellomo R, et al; Acute Dialysis Quality Initiative Consensus Group. Definition and classification of cardio-renal syndromes: workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant 2010; 25:1416–1420.
- Tucker BJ, Blantz RC. An analysis of the determinants of nephron filtration rate. Am J Physiol 1977; 232:F477–F483.
- Thind GS, Loehrke M, Wilt JL. Acute cardiorenal syndrome: mechanisms and clinical implications. Cleve Clin J Med 2018; 85:231–239.
- Wilkins RW, Tinsley CM, Culbertson JW, et al. The effects of venous congestion of the limbs upon renal clearances and the excretion of water and salt. I. Studies in normal subjects and in hypertensive patients before and after splanchnicectomy. J Clin Invest 1953; 32:1101–1116.
- Judson WE, Hatcher JD, Hollander W, Halperin MH, Wilkins RW. The effects of venous congestion of the limbs and phlebotomy upon renal clearances and the excretion of water and salt. II. Studies in patients with congestive failure. J Clin Invest 1955; 34:1591–1599.
- Mullens W, Abrahams Z, Francis GS, et al. Importance of venous congestion for worsening of renal function in advanced decompensated heart failure. J Am Coll Cardiol 2009; 53:589–596.
- Damman K, van Deursen VM, Navis G, Voors AA, van Veldhuisen DJ, Hillege HL. Increased central venous pressure is associated with impaired renal function and mortality in a broad spectrum of patients with cardiovascular disease. J Am Coll Cardiol 2009; 53:582–588.
- Ljungman S, Laragh JH, Cody RJ. Role of the kidney in congestive heart failure. Relationship of cardiac index to kidney function. Drugs 1990; 39(suppl 4):10–21; discussion 22–24.
- Damman K, Navis G, Smilde TD, et al. Decreased cardiac output, venous congestion and the association with renal impairment in patients with cardiac dysfunction. Eur J Heart Fail 2007; 9:872–878.
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